Insulin-loaded biodegradable PLGA microcapsules: initial burst release controlled by hydrophilic additives.

PubMed

Yamaguchi, Y; Takenaga, M; Kitagawa, A; Ogawa, Y; Mizushima, Y; Igarashi, R

2002-06-17

We investigated the controlled release of human insulin at an initial stage from poly(DL-lactic-co-glycolic acid) (PLGA, M(w) 6600) spherical matrices. PLGA microcapsules were prepared by the novel solvent evaporation multiple emulsion process. When the crystalline insulin was dispersed in dichloromethane as solid-in-oil (S/O) dispersion, it was found that most of insulin molecules were inlaid on the surface of PLGA microcapsules. Consequently, insulin-loaded PLGA microcapsules exhibited marked rapid release of insulin within several hours in both in vivo and in vitro experiments. On the other hand, the addition of glycerol or water in the primary dichloromethane dispersion results in drastically suppressed initial release. It was found by SEM observation that water- or glycerol-in-oil (W/O or G/O) type mini-emulsion droplets with a mean diameter of 300-500 nm were formed in this primary solution. This phenomenon can be theoretically presumed to occur because insulin and PLGA molecules, having amphiphilic properties, converge on the interface between the hydrophilic additive and dichloromethane. Hence, insulin molecules heterogeneously located in the inside of PLGA microcapsules, not on the surface, would be gradually released with PLGA hydrolytic decomposition. As an additional effect of glycerol, the initial burst was further suppressed due to the decrease of the glass transition temperature of PLGA from 42.5 to 36.7 degrees C. Since the annealing of PLGA molecules took place at around 37 degrees C, the porous structure of microspheres immediately disappeared after immersion in PBS or subcutaneous administration. The insulin diffusion through the water-filled pores would be effectively prevented. The strict controlled initial release of insulin from the PLGA microsphere suggested the possibility of utilization in insulin therapy for type I diabetic patients who need construction of a basal insulin profile.

[News and perspectives in insulin treatment].

PubMed

Haluzík, Martin

2014-09-01

Insulin therapy is a therapeutic cornerstone in patients with type 1 diabetes and also in numerous patients with type 2 diabetes especially with longer history of diabetes. The initiation of insulin therapy in type 2 diabetes patients is often delayed which is at least partially due to suboptimal pharmacokinetic characteristics of available insulins. The development of novel insulins with more favorable characteristics than those of current insulins is therefore still ongoing. The aim of this paper is to review current knowledge of novel insulins that have been recently introduced to the market or are getting close to routine clinical use. We will also focus on the perspectives of insulin therapy in the long-term run including the alternative routes of insulin administration beyond its classical subcutaneous injection treatment.Key words: alternative routes of insulin administration - diabetes mellitus - hypoglycemia - insulin - insulin analogues.

Diabetes management: optimizing roles for nurses in insulin initiation

PubMed Central

Levich, Bridget R

2011-01-01

Type 2 diabetes is a major public health concern. Screening and early diagnosis followed by prompt and aggressive treatment interventions can help control progression of diabetes and its complications. Nurses are often the first healthcare team members to interact with patients and are being called on to apply their specialized knowledge, training, and skills to educate and motivate patients with diabetes about insulin use and practical ways to achieve treatment goals. Clinical nurse specialists possess specific training and skills to provide this level of care, while staff or office-based nurses may be trained by physicians to fulfill a task-specific role. This manuscript reviews the benefits of intensive glycemic control in type 2 diabetes, therapeutic goals and guidelines, advances in insulin therapy, and contribution of nurses in overcoming barriers to insulin initiation and related aspects of diabetes care. Nurses are particularly well positioned to fill the gap and improve efficiency in diabetes-related healthcare by assisting patients with insulin initiation and other aspects of glycemic self-management. PMID:21468244

Utilization patterns of insulin therapy and healthcare services among Japanese insulin initiators during their first year: a descriptive analysis of administrative hospital data.

PubMed

Ikeda, Shunya; Crawford, Bruce; Sato, Masayo

2016-01-12

Type 2 diabetes poses an increasing healthcare burden in Japan. Although insulin treatment has diversified in recent years, the literature on the utilization of healthcare services among patients with type 2 diabetes undergoing different insulin therapy regimens is scarce. The current study aimed to characterize the real-world insulin treatment patterns and associated utilization of healthcare services among patients with type 2 diabetes who initiated insulin therapy during the study period. We examined data from a hospital-based database consisting of administrative and laboratory data from 121 acute-phase hospitals throughout Japan from April 2008 to August 2012. Patients diagnosed with type 2 diabetes and receiving continuous insulin therapy, defined by three insulin claims or more, were included in the analysis. Of the 2,145 insulin initiators, at initiation 46.5% received rapid-acting insulin alone, 36.6% received an intensive regimen, 11.4% received long-acting insulin alone, and 5.5% received pre-mixed insulin alone. Patients treated with rapid-acting insulin alone were older, experienced more comorbid conditions, had lower HbA1c, and more often had initiated their insulin treatment at inpatient admission, compared to patients treated with other types of insulin. Inpatient admission was more common and longer for patients taking rapid-acting insulin and an intensive regimen than those taking long-acting or pre-mixed insulin, and most were readmitted within 1 year. Utilization of outpatient clinics was approximately once per month, and emergency department visits were observed to be rare. This retrospective observational descriptive study found varied treatment and healthcare service utilization patterns, as well as disparities in patient characteristics across insulin regimens. Future research should assess the basis for these various utilization patterns associated with insulin to conduct robust analyses of clinical and economic outcomes.

Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial.

PubMed

Schmidt, H; Kern, W; Giese, R; Hallschmid, M; Enders, A

2009-04-01

The 22q13 deletion syndrome (Phelan-McDermid syndrome) is characterised by a global developmental delay, absent or delayed speech, generalised hypotonia, autistic behaviour and characteristic phenotypic features. Intranasal insulin has been shown to improve declarative memory in healthy adult subjects and in patients with Alzheimer disease. To assess if intranasal insulin is also able to improve the developmental delay in children with 22q13 deletion syndrome. We performed exploratory clinical trials in six children with 22q13 deletion syndrome who received intranasal insulin over a period of 1 year. Short-term (during the first 6 weeks) and long-term effects (after 12 months of treatment) on motor skills, cognitive functions, or autonomous functions, speech and communication, emotional state, social behaviour, behavioural disorders, independence in daily living and education were assessed. The children showed marked short-term improvements in gross and fine motor activities, cognitive functions and educational level. Positive long-term effects were found for fine and gross motor activities, nonverbal communication, cognitive functions and autonomy. Possible side effects were found in one patient who displayed changes in balance, extreme sensitivity to touch and general loss of interest. One patient complained of intermittent nose bleeding. We conclude that long-term administration of intranasal insulin may benefit motor development, cognitive functions and spontaneous activity in children with 22q13 deletion syndrome.

Time to and factors associated with insulin initiation in patients with type 2 diabetes mellitus.

PubMed

Machado-Alba, Jorge Enrique; Machado-Duque, Manuel Enrique; Moreno-Gutierrez, Paula Andrea

2015-03-01

Determine the time between the start of oral antidiabetic therapy (OAD) and the initiation of insulin therapy and to establish factors associated with insulin prescription among patients with type 2 diabetes mellitus (T2DM) in Colombia. Cohort, retrospective, population-based study. We identify patients with T2DM who started OAD therapy between 1 January 2007 and 31 December 2008, and a 5-year follow-up was performed. Kaplan-Meier survival analysis for time to start insulin therapy was generated and factors associated with insulin initiation were determined using logistic regression. A total of 1042 patients (52.4% women), mean age 63.4 years at the start of pharmacological treatment. After 5 years, 272 patients (26.1%) initiated insulin therapy. Using combination therapy of metformin and glibenclamide was associated with greater risk of insulin initiation (OR: 1.64, 95% CI: 1.12-2.40, p=0.010), while being a male over 45 years of age (OR: 0.59, 95% CI: 0.37-0.96, p=0.034) and initiating OAD therapy with metformin (OR: 0.30, 95% CI: 0.20-0.46, p<0.001) reduced the risk of insulin use. After 5 years of OAD treatment, 26.1% of people with T2DM started insulin therapy. Age, sex and type of initial OAD affected the probability of switching to insulin in these patients in Colombia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The evaluation of clinical and cost outcomes associated with earlier initiation of insulin in patients with type 2 diabetes mellitus.

PubMed

Smolen, Harry J; Murphy, Daniel R; Gahn, James C; Yu, Xueting; Curtis, Bradley H

2014-09-01

The treatment for patients with type 2 diabetes mellitus (T2DM) follows a stepwise progression. As a treatment loses its effectiveness, it is typically replaced with a more complex and frequently more costly treatment. Eventually this progression leads to the use of basal insulin typically with concomitant treatments (e.g., metformin, a GLP-1 RA [glucagon-like peptide-1 receptor agonist], a TZD [thiazolidinedione] or a DPP-4i [dipeptidyl peptidase 4 inhibitor]) and, ultimately, to basal-bolus insulin in some forms. As the cost of oral antidiabetics (OADs) and noninsulin injectables have approached, and in some cases exceeded, the cost of insulin, we reexamined the placement of insulin in T2DM treatment progression. Our hypothesis was that earlier use of insulin produces clinical and cost benefits due to its superior efficacy and treatment scalability at an acceptable cost when considered over a 5-year period. To (a) estimate clinical and payer cost outcomes of initiating insulin treatment for patients with T2DM earlier in their treatment progression and (b) estimate clinical and payer cost outcomes resulting from delays in escalating treatment for T2DM when indicated by patient hemoglobin A1c levels. We developed a Monte Carlo microsimulation model to estimate patients reaching target A1c, diabetes-related complications, mortality, and associated costs under various treatment strategies for newly diagnosed patients with T2DM. Treatment efficacies were modeled from results of randomized clinical trials, including the time and rate of A1c drift. A typical treatment progression was selected based on the American Diabetes Association and the European Association for the Study of Diabetes guidelines as the standard of care (SOC). Two treatment approaches were evaluated: two-stage insulin (basal plus antidiabetics followed by biphasic plus metformin) and single-stage insulin (biphasic plus metformin). For each approach, we analyzed multiple strategies. For each analysis

Adipocyte-specific deficiency of NADPH oxidase 4 delays the onset of insulin resistance and attenuates adipose tissue inflammation in obesity

PubMed Central

Den Hartigh, Laura J.; Omer, Mohamed; Goodspeed, Leela; Wang, Shari; Wietecha, Tomasz; O’Brien, Kevin D.; Han, Chang Yeop

2017-01-01

Objective Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown. Approach and Results In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high fat, high sucrose (HFHS) diet. During the development of obesity in control mice, adipocyte NOX4 and PPP activity were transiently increased. Primary adipocytes differentiated form mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged HFHS feeding. Conclusions These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions such as insulin resistance. PMID:28062496

Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity.

PubMed

Den Hartigh, Laura J; Omer, Mohamed; Goodspeed, Leela; Wang, Shari; Wietecha, Tomasz; O'Brien, Kevin D; Han, Chang Yeop

2017-03-01

Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown. In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high-fat, high-sucrose diet. During the development of obesity in control mice, adipocyte NOX4 and pentose phosphate pathway activity were transiently increased. Primary adipocytes differentiated from mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged high-fat, high-sucrose feeding. These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions, such as insulin resistance. © 2016 American Heart Association, Inc.

Clinical Evidence for the Earlier Initiation of Insulin Therapy in Type 2 Diabetes

PubMed Central

2013-01-01

Abstract The natural history of type 2 diabetes mellitus (T2DM) is a relentless progression of β-cell failure and dysregulation of β-cell function with increasing metabolic derangement. Insulin remains the only glucose-lowering therapy that is efficacious throughout this continuum. However, the timing of introduction and the choice of insulin therapy remain contentious because of the heterogeneity of T2DM and the well-recognized behavioral and therapeutic challenges associated with this mode of therapy. Nevertheless, the early initiation of basal insulin has been shown to improve glycemic control and affect long-term outcomes in people with T2DM and is a treatment strategy supported by international guidelines as part of an individualized approach to chronic disease management. The rationale for early initiation of insulin is based on evidence demonstrating multifaceted benefits, including overcoming the glucotoxic effects of hyperglycemia, thereby facilitating “β-cell rest,” and preserving β-cell mass and function, while also improving insulin sensitivity. Independent of its effects on glycemic control, insulin possesses anti-inflammatory and antioxidant properties that may help protect against endothelial dysfunction and damage resulting in vascular disease. Insulin therapy and the achievement of good glycemic control earlier in T2DM provide long-term protection to end organs via “metabolic memory” regardless of subsequent treatments and degree of glycemic control. This is evidenced from long-term observations continuing from trials such as the United Kingdom Prospective Diabetes Study. As such, early initiation of insulin therapy may not only help to avoid the effects of prolonged glycemic burden, but may also positively alter the course of disease progression. PMID:23786228

Changes in metformin use and other antihyperglycemic therapies after insulin initiation in patients with type 2 diabetes.

PubMed

Pilla, Scott J; Dotimas, James R; Maruthur, Nisa M; Clark, Jeanne M; Yeh, Hsin-Chieh

2018-05-01

When patients with type 2 diabetes initiate insulin, metformin should be continued while continuation of other antihyperglycemics has unclear benefit. We aimed to identify practice patterns in antihyperglycemic therapy during the insulin transition, and determine factors associated with metformin continuation. We performed a retrospective analysis of the Look AHEAD (Action for Health in Diabetes) trial which randomized overweight/obese adults under ambulatory care for type 2 diabetes to an intensive lifestyle intervention or diabetes support and education. Among the 931 participants who initiated insulin over ten years, we described longitudinal changes in antihyperglycemic medications during the insulin transition, and performed multivariable logistic regression to estimate the association between patient characteristics and metformin continuation. Before insulin initiation, 81.0% of patients used multiple antihyperglycemics, the most common being metformin, sulfonylureas, and thiazolidinediones. After insulin initiation, metformin was continued in 80.3% of patients; other antihyperglycemics were continued less often, yet 58.0% of patients were treated with multiple non-insulin antihyperglycemics. Metformin continuation was inversely associated with age (fully adjusted (a) OR 0.60 per 10 years [0.42-0.86]), serum creatinine above safety thresholds (aOR 0.09 [0.02-0.36]), lower income (P = 0.025 for trend), taking more medications (aOR 0.92 per medication [0.86-0.98]), and initiating rapid, short, or premixed insulin (aOR 0.59 [0.39-0.89]). The vast majority of patients with type 2 diabetes continue metformin after insulin initiation, consistent with guidelines. Other antihyperglycemics are frequently continued along with insulin, and further research is needed to determine which, if any, patients may benefit from this. Copyright © 2018 Elsevier B.V. All rights reserved.

A qualitative study on healthcare professionals' perceived barriers to insulin initiation in a multi-ethnic population.

PubMed

Lee, Yew Kong; Lee, Ping Yein; Ng, Chirk Jenn

2012-07-04

Nationwide surveys have shown that the prevalence of diabetes rates in Malaysia have almost doubled in the past ten years; yet diabetes control remains poor and insulin therapy is underutilized. This study aimed to explore healthcare professionals' views on barriers to starting insulin therapy in people with type 2 diabetes. Healthcare professionals consisting of general practitioners (n = 11), family medicine specialists (n = 10), medical officers (n = 8), government policy makers (n = 4), diabetes educators (n = 3) and endocrinologists (n = 2) were interviewed. A semi-structured topic guide was used to guide the interviews by trained facilitators. The interviews were transcribed verbatim and analysed using a thematic analysis approach. Insulin initiation was found to be affected by patient, healthcare professional and system factors. Patients' barriers include culture-specific barriers such as the religious purity of insulin, preferred use of complementary medication and perceived lethality of insulin therapy. Healthcare professionals' barriers include negative attitudes towards insulin therapy and the 'legacy effect' of old insulin guidelines; whilst system barriers highlight the lack of resources, language and communication challenges. Tackling the issue of insulin initiation should not only happen during clinical consultations. It requires health education to emphasise the progressive nature of diabetes and the eventuality of insulin therapy at early stage of the illness. Healthcare professionals should be trained how to initiate insulin and communicate effectively with patients from various cultural and religious backgrounds.

Insulin degludec/insulin aspart combination for the treatment of type 1 and type 2 diabetes

PubMed Central

Dardano, Angela; Bianchi, Cristina; Del Prato, Stefano; Miccoli, Roberto

2014-01-01

Glycemic control remains the major therapeutic objective to prevent or delay the onset and progression of complications related to diabetes mellitus. Insulin therapy represents a cornerstone in the treatment of diabetes and has been used widely for achieving glycemic goals. Nevertheless, a large portion of the population with diabetes does not meet the internationally agreed glycemic targets. Moreover, insulin treatment, especially if intensive, may be associated with emergency room visits and hospitalization due to hypoglycemic events. Therefore, fear of hypoglycemia or hypoglycemic events represents the main barriers to the attainment of glycemic targets. The burden associated with multiple daily injections also remains a significant obstacle to initiating and maintaining insulin therapy. The most attractive insulin treatment approach should meet the patients’ preference, rather than demanding patients to change or adapt their lifestyle. Insulin degludec/insulin aspart (IDegAsp) is a new combination, formulated with ultra-long-acting insulin degludec and rapid-acting insulin aspart, with peculiar pharmacological features, clinical efficacy, safety, and tolerability. IDegAsp provides similar, noninferior glycemic control to a standard basal–bolus regimen in patients with type 1 diabetes mellitus, with additional benefits of significantly lower episodes of hypoglycemia (particularly nocturnal) and fewer daily insulin injections. Moreover, although treatment strategy and patients’ viewpoint are different in type 1 and type 2 diabetes, trial results suggest that IDegAsp may be an appropriate and reasonable option for initiating insulin therapy in patients with type 2 diabetes inadequately controlled on maximal doses of conventional oral agents. This paper will discuss the role of IDegAsp combination as a novel treatment option in diabetic patients. PMID:25143741

Primary care physician perspectives on basal insulin initiation and maintenance in patients with type 2 diabetes mellitus.

PubMed

Kalirai, Samaneh; Stephenson, Judith; Perez-Nieves, Magaly; Grabner, Michael; Hadjiyianni, Irene; Geremakis, Caroline; Pollom, Roy Daniel; Reed, Beverly; Fisher, Lawrence

2018-04-01

To describe primary care physicians' (PCPs) perceptions of patient reactions and concerns about insulin initiation and identify opportunities for increased support. Cross-sectional, online survey of PCPs prescribing basal insulin to adults with type 2 diabetes mellitus (T2DM). PCPs were identified from administrative claims of a large commercial health plan and descriptive results of PCP responses were reported. PCPs (N=100) treated an average of 17 patients receiving insulin during a typical week. More than 85% of insulin initiation recommendations originated with PCPs. Most offered glucose monitoring instructions (96%) and advice on diet, exercise, and diabetes management (96%); 35% provided insulin titration algorithms; 93% reported that patients often or always took their insulin daily within 3 months of initiation; 31% of PCPs reported monthly office contacts with patients for the first 3 months; 16% reported no outreach efforts; fewer than 20% connected patients with support groups. When starting basal insulin, PCPs reported patients feeling personal failure regarding their diabetes treatment (33% often/always) and lacking confidence in their ability to manage insulin therapy (38% often/always). Study results identify additional opportunities for assisting patients in making the transition to insulin, including more frequent direct outreach to monitor insulin usage. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

A qualitative study on healthcare professionals’ perceived barriers to insulin initiation in a multi-ethnic population

PubMed Central

2012-01-01

Background Nationwide surveys have shown that the prevalence of diabetes rates in Malaysia have almost doubled in the past ten years; yet diabetes control remains poor and insulin therapy is underutilized. This study aimed to explore healthcare professionals’ views on barriers to starting insulin therapy in people with type 2 diabetes. Methods Healthcare professionals consisting of general practitioners (n = 11), family medicine specialists (n = 10), medical officers (n = 8), government policy makers (n = 4), diabetes educators (n = 3) and endocrinologists (n = 2) were interviewed. A semi-structured topic guide was used to guide the interviews by trained facilitators. The interviews were transcribed verbatim and analysed using a thematic analysis approach. Results Insulin initiation was found to be affected by patient, healthcare professional and system factors. Patients’ barriers include culture-specific barriers such as the religious purity of insulin, preferred use of complementary medication and perceived lethality of insulin therapy. Healthcare professionals’ barriers include negative attitudes towards insulin therapy and the ‘legacy effect’ of old insulin guidelines; whilst system barriers highlight the lack of resources, language and communication challenges. Conclusions Tackling the issue of insulin initiation should not only happen during clinical consultations. It requires health education to emphasise the progressive nature of diabetes and the eventuality of insulin therapy at early stage of the illness. Healthcare professionals should be trained how to initiate insulin and communicate effectively with patients from various cultural and religious backgrounds. PMID:22469132

Considerations for diabetes: treatment with insulin pen devices.

PubMed

Cuddihy, Robert M; Borgman, Sarah K

2013-01-01

Insulin is essential for the treatment of type 1 diabetes, and most patients with type 2 diabetes will eventually require insulin for glycemic control. Several barriers contribute to delays in initiating insulin therapy in type 2 diabetes. Furthermore, insulin-treated patients often miss doses or otherwise fail to self-administer their insulin as prescribed, placing themselves at the risk of developing complications. Insulin pens can help overcome barriers to initiating insulin therapy and can facilitate the self-management of diabetes. Compared with the vial and syringe, insulin pens are more accurate, associated with greater adherence, and preferred by patients because of their convenience and ease of use. Large database analyses suggest that insulin pens may reduce the rate of occurrence of hypoglycemic events in patients with type 2 diabetes. Despite higher costs of insulin pens vs vials and syringes, studies suggest little or no increase in total health care costs and decreases in diabetes-related costs associated with reduced health care utilization with pens. Interestingly, the use of insulin pens within the United States lags far behind the use of pens in Europe and Japan. Insulin pens may be disposable or refillable, and some pens have special features [eg, audible clicks, large-dose selector and dial, memory function, half-unit dosing, high dosing (ie, 80 U)] that offer the opportunity to individualize treatment by meeting patients' needs. This review compares available insulin pens, describes strategies to facilitate their usage, and discusses how insulin pens can improve self-management of diabetes while reducing cost.

Delays in initiation of acyclovir therapy in herpes simplex encephalitis.

PubMed

Hughes, Peter S; Jackson, Alan C

2012-09-01

Diagnosis of herpes simplex encephalitis (HSE) is based on clinical findings, MRI, and detection of herpes simplex virus (HSV) DNA in cerebrospinal fluid (CSF) using polymerase chain reaction amplification. Delays in starting treatment are associated with poorer clinical outcomes. We assessed the timing of initiation of acyclovir therapy in HSE. Inpatient databases from seven hospitals in Winnipeg, Manitoba were used to identify individuals diagnosed with encephalitis and HSE from 2004 to 2009. The time taken to initiate therapy with acyclovir and the reasons for delays were determined. Seventy-seven patients were identified; 69 (90%) received acyclovir; in the others a non-HSV infection was strongly suspected. Thirteen patients were subsequently confirmed to have HSE. Acyclovir was initiated a median of 21 hours (3-407) after presentation in encephalitis cases, and a median of 11 hours (3-118) in HSE. The most common reason for delay was a failure to consider HSE in the differential diagnosis, despite suggestive clinical features. Where therapy was delayed in HSE patients, the decision to begin acyclovir was prompted by transfer of the patient to a different service (55%), recommendations by consultants (18%), imaging results (18%), and CSF pleocytosis (9%). Delays in initiating acyclovir for HSE are common, and are most often due to a failure to consider HSE in a timely fashion on presentation. In order to improve patient outcomes, physicians should be more vigilant for HSE, and begin acyclovir therapy expeditiously on the basis of clinical suspicion rather than waiting for confirmatory tests.

Insulin initiation in primary care for patients with type 2 diabetes: 3-year follow-up study.

PubMed

Dale, Jeremy; Martin, Steven; Gadsby, Roger

2010-07-01

To evaluate the 3-year impact of initiating basal insulin on glycaemic control (HbA1c) and weight gain in patients with poorly controlled type 2 diabetes registered with UK general practices that volunteered to participate in an insulin initiation training programme. Audit utilising data collected from practice record systems, which included data at baseline, 3, 6 months and subsequent six-monthly intervals post-insulin initiation for up to 10 patients per participating practice. Of 115 eligible practices, 55 (47.8%) contributed data on a total of 516 patients. The mean improvement in HbA1c levels in the first 6 months was 1.4% (range -3.8% to 8.2%, median=1.40%). Thereafter, there was no overall change in HbA1c levels, although the change for individual patients ranged from -4.90% to +7.50%. At 36 months, 141 (41%) patients for whom data were provided had achieved the pre-2006/2007 UK Quality and Outcomes Framework (QOF) target of 7.4% or less, including 98 (29%) who had achieved an HbA1c of 7% or less. Patients who achieved target had a lower HbA1c at baseline (mean 9.1% compared to 9.7%; p<0.001); had a lower weight at 36 months (mean 88.0kg compared to 93.5kg; p=0.05); were more likely to be on basal insulin alone (88, 47.1% compared to 46, 34.6%; p<0.05); and were slightly older (mean 64.5 years compared to 61.7 years; p<0.05). Attending an insulin initiation training programme may successfully prepare primary healthcare professionals to initiate insulin therapy as part of everyday practice for patients with poorly controlled type 2 diabetes. The impact on glycaemic control is maintained over a 3-year period. Although intensification of treatment occurred during this period, the findings suggest scope for further intensification of insulin therapy in order to improve on the glycaemic control achieved during the first 6 months post-insulin initiation.

Investigation of stability in a two-delay model of the ultradian oscillations in glucose-insulin regulation

NASA Astrophysics Data System (ADS)

Huard, B.; Easton, J. F.; Angelova, M.

2015-09-01

In this paper, a two-delay model for the ultradian oscillatory behaviour of the glucose-insulin regulation system is studied. Hill functions are introduced to model nonlinear physiological interactions within this system and ranges on parameters reproducing biological oscillations are determined on the basis of analytical and numerical considerations. Local and global stability are investigated and delay-dependent conditions are obtained through the construction of Lyapunov-Krasovskii functionals. The effect of Hill parameters on these conditions, as well as the boundary of the stability region in the delay domain, are established for the first time. Numerical simulations demonstrate that the model with Hill functions represents well the oscillatory behaviour of the system with the advantage of incorporating new meaningful parameters. The influence of the time delays on the period of oscillations and the sensitivity of the latter to model parameters, in particular glucose infusion, are investigated. The model can contribute to the better understanding and treatment of diabetes.

Insulin Pump and Continuous Glucose Monitor Initiation in Hospitalized Patients with Type 2 Diabetes Mellitus.

PubMed

Levitt, David L; Spanakis, Elias K; Ryan, Kathleen A; Silver, Kristi D

2018-01-01

Insulin pumps and continuous glucose monitoring (CGM) are commonly used by patients with diabetes mellitus in the outpatient setting. The efficacy and safety of initiating inpatient insulin pumps and CGM in the nonintensive care unit setting is unknown. In a prospective pilot study, inpatients with type 2 diabetes were randomized to receive standard subcutaneous basal-bolus insulin and blinded CGM (group 1, n = 5), insulin pump and blinded CGM (group 2, n = 6), or insulin pump and nonblinded CGM (group 3, n = 5). Feasibility, glycemic control, and patient satisfaction were evaluated among groups. Group 1 had lower mean capillary glucose levels, 144.5 ± 19.5 mg/dL, compared with groups 2 and 3, 191.5 ± 52.3 and 182.7 ± 59.9 mg/dL (P 1 vs. 2+3  = 0.05). CGM detected 19 hypoglycemic episodes (glucose <70 mg/dL) among all treatment groups, compared with 12 episodes detected by capillary testing, although not statistically significant. No significant differences were found for the total daily dose of insulin or percentage of time spent below target glucose range (<90 mg/dL), in target glucose range (90-180 mg/dL), or above target glucose range (>180 mg/dL). On the Diabetes Treatment Satisfaction Questionnaire-Change, group 3 reported increased hyperglycemia and decreased hypoglycemia frequency compared with the other two groups, although the differences did not reach statistical significance. Insulin pump and CGM initiation are feasible during hospitalization, although they are labor intensive. Although insulin pump initiation may not lead to improved glycemic control, there is a trend toward CGM detecting a greater number of hypoglycemic episodes. Larger studies are needed to determine whether use of this technology can lower inpatient morbidity and mortality.

Glucose delays the insulin-induced increase in thyroid hormone-mediated signaling in adipose of prolong-fasted elephant seal pups

PubMed Central

Soñanez-Organis, José G.; Viscarra, Jose A.; Jaques, John T.; MacKenzie, Duncan S.; Crocker, Daniel E.; Ortiz, Rudy M.

2016-01-01

Prolonged food deprivation in mammals typically reduces glucose, insulin, and thyroid hormone (TH) concentrations, as well as tissue deiodinase (DI) content and activity, which, collectively, suppress metabolism. However, in elephant seal pups, prolonged fasting does not suppress TH levels; it is associated with upregulation of adipose TH-mediated cellular mechanisms and adipose-specific insulin resistance. The functional relevance of this apparent paradox and the effects of glucose and insulin on TH-mediated signaling in an insulin-resistant tissue are not well defined. To address our hypothesis that insulin increases adipose TH signaling in pups during extended fasting, we assessed the changes in TH-associated genes in response to an insulin infusion in early- and late-fasted pups. In late fasting, insulin increased DI1, DI2, and THrβ-1 mRNA expression by 566%, 44%, and 267% at 60 min postinfusion, respectively, with levels decreasing by 120 min. Additionally, we performed a glucose challenge in late-fasted pups to differentiate between insulin- and glucose-mediated effects on TH signaling. In contrast to the insulin-induced effects, glucose infusion did not increase the expressions of DI1, DI2, and THrβ-1 until 120 min, suggesting that glucose delays the onset of the insulin-induced effects. The data also suggest that fasting duration increases the sensitivity of adipose TH-mediated mechanisms to insulin, some of which may be mediated by increased glucose. These responses appear to be unique among mammals and to have evolved in elephant seals to facilitate their adaptation to tolerate an extreme physiological condition. PMID:26739649

Basal insulin initiation use and experience among people with type 2 diabetes mellitus with different patterns of persistence: results from a multi-national survey.

PubMed

Perez-Nieves, Magaly; Ivanova, Jasmina I; Hadjiyianni, Irene; Zhao, Chen; Cao, Dachuang; Schmerold, Luke; Kalirai, Samaneh; King, Sarah; DeLozier, Amy M; Birnbaum, Howard G; Peyrot, Mark

2017-10-01

People with type 2 diabetes mellitus (T2DM) often interrupt basal insulin treatment soon after initiation. This study aimed to describe the experiences during and after basal insulin initiation among people with T2DM with different persistence patterns. Adults with T2DM from France, Germany, Spain, UK, US, Brazil, and Japan were identified from consumer panels for an online survey. Respondents who initiated basal insulin 3-24 months prior to survey date were categorized as continuers (no gaps of ≥7 days in insulin treatment); interrupters (first gap ≥7 days within 6 months of initiation and restarted insulin); and discontinuers (stopped insulin for ≥7 days within 6 months of initiation without restarting). Among 942 participants, continuers were older than interrupters and discontinuers (46, 37, and 38 years, respectively, p < .01). Continuers reported having fewer concerns before and after insulin initiation than interrupters and discontinuers, while interrupters had the most concerns. Continuers also reported fewer challenges during the first week of insulin use. Continuers were more likely to respond that insulin use had a positive impact on specific aspects of life than interrupters and discontinuers, for example on glycemic control (73.0%, 63.0%, and 61.8%, respectively; p < .01 vs. continuers). Among people with T2DM with different persistence patterns after basal insulin initiation there were significant differences in patient characteristics and experience during and after insulin initiation. Interrupters and discontinuers more frequently reported having concerns and challenges during the initiation process, negative impacts after initiation, and less improvement in glycemic control than continuers.

Predictors of insulin initiation in metformin and sulfonylurea users in primary care practices: the role of kidney function.

PubMed

Kostev, Karel; Dippel, Franz-Werner; Rathmann, Wolfgang

2014-09-01

The aims were to investigate predictors of insulin initiation in new users of metformin or sulfonylureas in primary care practices, in particular, its association with decreased renal function. Data from 9103 new metformin and 1120 sulfonylurea users with normal baseline glomerular filtration rate (eGFR) >90 ml/min/1.73 m(2) from 1072 practices were retrospectively analyzed (Disease Analyzer Germany: 01/2003-06/2012). Cox regression models and propensity score matching was used to adjust for confounders (age, sex, practice characteristics, comorbidity). Insulin treatment was started in 394 (4.3%) metformin and in 162 (14.5%) sulfonylurea users within 6 years (P < .001). Kaplan-Meier curves (propensity score matched patients) showed that the metformin group was at a lower risk of insulin initiation compared to sulfonylurea users throughout the study period. A substantial eGFR decline (category: 15-<30 ml/min/1.73 m(2)) was significantly associated with a higher likelihood to have insulin initiated (adjusted hazard ratio [HR]: 2.39; 95% CI: 1.09-5.23) in metformin but not in sulfonylurea (HR: 0.45; 95% CI: 0.16-1.30) users. New users of sulfonylurea monotherapy in primary care practices in Germany were about 3-fold more likely to start insulin therapy than those with metformin. Kidney function decline was associated with earlier insulin initiation in metformin but not in sulfonylurea users. © 2014 Diabetes Technology Society.

Initiation of Basal Insulin Analog Treatment for Type 2 Diabetes and Reasons Behind Patients' Treatment Persistence Behavior: Real-World Data from Germany.

PubMed

Moennig, Elisabeth; Perez-Nieves, Magaly; Hadjiyianni, Irene; Cao, Dachuang; Ivanova, Jasmina; Klask, Ralf

2018-05-01

Poor treatment persistence can affect the real-world effectiveness of insulin therapy. A cross-sectional online survey in 942 patients with type 2 diabetes from 7 different countries evaluated patient experience when initiating basal insulin and the reasons behind insulin persistence patterns. Here, we report the quantitative results for the subset of patients from Germany. Adults with type 2 diabetes who had initiated basal insulin during the last 3-24 months, identified from market-research panels, participated in the survey. Patients were asked if they had ≥7-day gaps in basal insulin treatment, and were then classified as "continuers" (no gap since starting insulin), "interrupters" (≥1 gap within the first 6 months after starting insulin and subsequently restarted insulin), or "discontinuers" (stopped insulin within the first 6 months after starting and had not restarted at the time of the survey). For each country, 50 participants were planned per persistence category. Enrollment ended if the target quota was reached or enrollment plateaued. Data were analyzed overall and separately for each persistence cohort. The 131 participants from Germany included 55 (42.0%) continuers, 50 (38.2%) interrupters and 26 (19.9%) discontinuers. The most common motivations to initiate basal insulin therapy were encouragement by physician or other healthcare provider (HCP; 54.2%) and expectation to improve glycemic control (42.0%). More than 95% of participants received training before and during insulin initiation (considered as helpful by 81.7%); most (67.2%) preferred in-person training. Continuers more frequently felt that insulin would help to manage diabetes and that their own views were considered when initiating insulin, they reported less concerns and challenges before and during insulin initiation than interrupters or discontinuers. The most common motivations to continue basal insulin were improved glycemic control (72.7%), improved physical well-being (49

Comparison of three algorithms for initiation and titration of insulin glargine in insulin-naive patients with type 2 diabetes mellitus.

PubMed

Dailey, George; Aurand, Lisa; Stewart, John; Ameer, Barbara; Zhou, Rong

2014-03-01

Several titration algorithms can be used to adjust insulin dose and attain blood glucose targets. We compared clinical outcomes using three initiation and titration algorithms for insulin glargine in insulin-naive patients with type 2 diabetes mellitus (T2DM); focusing on those receiving both metformin and sulfonylurea (SU) at baseline. This was a pooled analysis of patient-level data from prospective, randomized, controlled 24-week trials. Patients received algorithm 1 (1 IU increase once daily, if fasting plasma glucose [FPG] > target), algorithm 2 (2 IU increase every 3 days, if FPG > target), or algorithm 3 (treat-to-target, generally 2-8 IU increase weekly based on 2-day mean FPG levels). Glycemic control, insulin dose, and hypoglycemic events were compared between algorithms. Overall, 1380 patients were included. In patients receiving metformin and SU at baseline, there were no significant differences in glycemic control between algorithms. Weight-adjusted dose was higher for algorithm 2 vs algorithms 1 and 3 (P = 0.0037 and P < 0.0001, respectively), though results were not significantly different when adjusted for reductions in HbA1c (0.36 IU/kg, 0.43 IU/kg, and 0.31 IU/kg for algorithms 1, 2, and 3, respectively). Yearly hypoglycemic event rates (confirmed blood glucose <56 mg/dL) were higher for algorithm 3 than algorithms 1 (P = 0.0003) and 2 (P < 0.0001). Three algorithms for initiation and titration of insulin glargine in patients with T2DM resulted in similar levels of glycemic control, with lower rates of hypoglycemia for patients treated using simpler algorithms 1 and 2. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion

PubMed Central

Polidori, David; Sha, Sue; Mudaliar, Sunder; Ciaraldi, Theodore P.; Ghosh, Atalanta; Vaccaro, Nicole; Farrell, Kristin; Rothenberg, Paul; Henry, Robert R.

2013-01-01

OBJECTIVE Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption. RESEARCH DESIGN AND METHODS This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, 3H-glucose, 14C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal. RESULTS Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0–2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0–6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups. CONCLUSIONS Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition. PMID:23412078

Failure to initiate early insulin therapy - A risk factor for diabetic retinopathy in insulin users with Type 2 diabetes mellitus: Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SN-DREAMS, Report number 35).

PubMed

Gupta, Aditi; Delhiwala, Kushal S; Raman, Rajiv P G; Sharma, Tarun; Srinivasan, Sangeetha; Kulothungan, Vaitheeswaran

2016-06-01

Insulin users have been reported to have a higher incidence of diabetic retinopathy (DR). The aim was to elucidate the factors associated with DR among insulin users, especially association between duration, prior to initiating insulin for Type 2 diabetes mellitus (DM) and developing DR. Retrospective cross-sectional observational study included 1414 subjects having Type 2 DM. Insulin users were defined as subjects using insulin for glycemic control, and insulin nonusers as those either not using any antidiabetic treatment or using diet control or oral medications. The duration before initiating insulin after diagnosis was calculated by subtracting the duration of insulin usage from the duration of DM. DR was clinically graded using Klein's classification. SPSS (version 9.0) was used for statistical analysis. Insulin users had more incidence of DR (52.9% vs. 16.3%, P < 0.0001) and sight threatening DR (19.1% vs. 2.4%, P < 0.0001) in comparison to insulin nonusers. Among insulin users, longer duration of DM (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.00-1.25, P = 0.044) and abdominal obesity (OR 1.15, 95% CI 1.02-1.29, P = 0.021) was associated with DR. The presence of DR was significantly associated with longer duration (≥5 years) prior to initiating insulin therapy, overall (38.0% vs. 62.0%, P = 0.013), and in subjects with suboptimal glycemic control (32.5% vs. 67.5%, P = 0.022). The presence of DR is significantly associated with longer duration of diabetes (>5 years) and sub-optimal glycemic control (glycosylated hemoglobin <7.0%). Among insulin users, abdominal obesity was found to be a significant predictor of DR; DR is associated with longer duration prior to initiating insulin therapy in Type 2 DM subjects with suboptimal glycemic control.

Delay of Treatment Initiation Does Not Adversely Affect Survival Outcome in Breast Cancer.

PubMed

Yoo, Tae-Kyung; Han, Wonshik; Moon, Hyeong-Gon; Kim, Jisun; Lee, Jun Woo; Kim, Min Kyoon; Lee, Eunshin; Kim, Jongjin; Noh, Dong-Young

2016-07-01

Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment. This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups. A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS. Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer.

Effect of insulin analog initiation therapy on LDL/HDL subfraction profile and HDL associated enzymes in type 2 diabetic patients.

PubMed

Aslan, Ibrahim; Kucuksayan, Ertan; Aslan, Mutay

2013-04-24

Insulin treatment can lead to good glycemic control and result in improvement of lipid parameters in type 2 diabetic patients. This study was designed to evaluate the effect of insulin analog initiation therapy on low-density lipoprotein (LDL)/ high-density lipoprotein (HDL) sub-fractions and HDL associated enzymes in type 2 diabetic patients during early phase. Twenty four type 2 diabetic patients with glycosylated hemoglobin (HbA1c) levels above 10% despite ongoing combination therapy with sulphonylurea and metformin were selected. Former treatment regimen was continued for the first day followed by substitution of sulphonylurea therapy with different insulin analogs (0.4 U/kg/day) plus metformin. Glycemic profiles were determined over 72 hours by continuous glucose monitoring system (CGMS) and blood samples were obtained from all patients at 24 and 72 hours. Plasma levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay (ELISA). Measurement of CETP and LCAT activity was performed via fluorometric analysis. Paraoxonase (PON1) enzyme activity was assessed from the rate of enzymatic hydrolysis of phenyl acetate to phenol formation. LDL and HDL subfraction analysis was done by continuous disc polyacrylamide gel electrophoresis. Mean blood glucose, total cholesterol (TC), triglyceride (TG) and very low-density lipoprotein cholesterol (VLDL-C) levels were significantly decreased while HDL-C levels were significantly increased after insulin treatment. Although LDL-C levels were not significantly different before and after insulin initiation therapy a significant increase in LDL-1 subgroup and a significant reduction in atherogenic LDL-3 and LDL-4 subgroups were observed. Insulin analog initiation therapy caused a significant increase in HDL-large, HDL- intermediate and a significant reduction in HDL-small subfractions

Functional silencing is initiated and maintained in immature anti-insulin B cells.

PubMed

Henry, Rachel A; Acevedo-Suárez, Carlos A; Thomas, James W

2009-03-15

Mechanisms of B cell tolerance act during development in the bone marrow and periphery to eliminate or restrict autoreactive clones to prevent autoimmune disease. B cells in the spleens of mice that harbor anti-insulin BCR transgenes (125Tg) are maintained in a functionally silenced or anergic state by endogenous hormone, but it is not clear when and where anergy is induced. An in vitro bone marrow culture system was therefore used to probe whether small protein hormones, a critical class of autoantigens, could interact with the BCR to induce anergy early during B cell development. Upon exposure to insulin, anti-insulin (125Tg) immature B cells show similar hallmarks of anergy as those observed in mature splenic B cells. These include BCR down-regulation, impaired proliferative responses to anti-CD40, and diminished calcium mobilization upon stimulation with BCR-dependent and independent stimuli. Inhibition of calcineurin also results in reduced immature B cell proliferation in a similar manner, suggesting a potential mechanism through which reduced intracellular calcium mobilization may be altering cellular proliferation. Signs of impairment appear after short-term exposure to insulin, which are reversible upon Ag withdrawal. This suggests that a high degree of functional plasticity is maintained at this stage and that constant Ag engagement is required to maintain functional inactivation. These findings indicate that tolerance observed in mature, splenic 125Tg B cells is initiated by insulin in the developing B cell compartment and thus highlight an important therapeutic window for the prevention of insulin autoimmunity.

Effect of flow rate and insulin priming on the recovery of insulin from microbore infusion tubing.

PubMed

Fuloria, M; Friedberg, M A; DuRant, R H; Aschner, J L

1998-12-01

A retrospective medical record review of 13 consecutive, hyperglycemic, extremely low birth weight (ELBW) infants treated with continuous insulin infusions revealed a 14- to 24-hour delay (mean, 19 hours) in blood glucose normalization despite stepwise increases in insulin infusion rates. This in vitro study examined the effects of flow rate and insulin priming on insulin recovery from polyvinyl chloride (PVC) tubing and polyethylene (PE)-lined PVC tubing infused with a standard insulin stock solution. Stock insulin solution (0.2 U/mL) was infused through microbore PVC or PE-lined tubing at flow rates of 0.05 and 0.2 mL/h. To determine if saturation of nonspecific binding sites would alter effluent insulin concentration, we compared insulin recovery from tubing previously flushed with the stock solution and tubing primed with 5 U/mL of insulin for 20 minutes. Effluent samples, which were collected at baseline and at six time points during a 24-hour period, were immediately frozen at -20 degreesC. Insulin concentration was measured by IMx immunoassay. Data were analyzed using general linear modeling with repeated measures. At 0.05 mL/h flow rate, insulin recovery from unprimed PVC tubing at 1, 2, 4, and 8 hours was 17%, 11%, 27%, and 55%, respectively, with 100% recovery at 24 hours. From insulin-primed tubing, insulin recovery was approximately 70% at 1, 2, and 4 hours, and close to 100% at 8 hours. At a faster flow rate of 0.2 mL/h, insulin recovery at 1, 2, 4, and 8 hours was 22%, 38%, 67%, and 75% vs 42%, 85%, 91% and 95% from unprimed and insulin-primed PVC tubing, respectively. Similar results were obtained from unprimed and insulin-primed PE-lined tubing at 0.2 mL/h flow rate. Priming of microbore tubing with 5 U/mL of insulin solution for 20 minutes to block nonspecific binding sites enhances delivery of a standard insulin stock at infusion rates typically used to treat hyperglycemic ELBW infants. We conclude that priming the tubing with a higher

Intranasal insulin improves memory in humans.

PubMed

Benedict, Christian; Hallschmid, Manfred; Hatke, Astrid; Schultes, Bernd; Fehm, Horst L; Born, Jan; Kern, Werner

2004-11-01

Previous studies have suggested an acutely improving effect of insulin on memory function. To study changes in memory associated with a prolonged increase in brain insulin activity in humans, here we used the intranasal route of insulin administration known to provide direct access of the substance to the cerebrospinal fluid compartment. Based on previous results indicating a prevalence of insulin receptors in limbic and hippocampal regions as well as improvements in memory with systemic insulin administration, we expected that intranasal administration of insulin improves primarily hippocampus dependent declaration memory function. Also, improvements in mood were expected. We investigated the effects of 8 weeks of intranasal administration of insulin (human regular insulin 4 x 40 IU/d) on declarative memory (immediate and delayed recall of word lists), attention (Stroop test), and mood in 38 healthy subjects (24 males) in a double blind, between-subject comparison. Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions. Delayed recall of words significantly improved after 8 weeks of intranasal insulin administration (words recalled, Placebo 2.92 +/- 1.00, Insulin 6.20 +/- 1.03, p < 0.05). Moreover, subjects after insulin reported signs of enhanced mood, such as reduced anger (p < 0.02) and enhanced self-confidence (p < 0.03). Results indicate a direct action of prolonged intranasal administration of insulin on brain functions, improving memory and mood in the absence of systemic side effects. These findings could be of relevance for the treatment of patients with memory disorders like in Alzheimer's disease.

The comprehensive electrophysiological study of curcuminoids on delayed-rectifier K+ currents in insulin-secreting cells.

PubMed

Kuo, Ping-Chung; Yang, Chia-Jung; Lee, Yu-Chi; Chen, Pei-Chun; Liu, Yen-Chin; Wu, Sheng-Nan

2018-01-15

Curcumin (CUR) has been demonstrated to induce insulin release from pancreatic β-cells; however, how curcuminoids (including demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)) exert any possible effects on membrane ion currents inherently in insulin-secreting cells remains largely unclear. The effects of CUR and other structurally similar curcuminoids on ion currents in rat insulin-secreting (INS-1) insulinoma cells were therefore investigated in this study. The effects of these compounds on ionic currents and membrane potential were studied by patch-clamp technique. CUR suppressed the amplitude of delayed-rectifier K + current (I K(DR) ) in a time-, state- and concentration-dependent manner in these cells and the inhibition was not reversed by diazoxide, nicorandil or chlorotoxin. The value of dissociation constant for CUR-induced suppression of I K(DR) in INS-1 cells was 1.26μM. Despite the inability of CUR to alter the activation rate of I K(DR) , it accelerated current inactivation elicited by membrane depolarization. Increasing CUR concentrations shifted the inactivation curve of I K(DR) to hyperpolarized potential and slowed the recovery of I K(DR) inactivation. CUR, DMC, and BDMC all exerted depressant actions on I K(DR) amplitude to a similar magnitude, although DMC and BDMC did not increase current inactivation clearly. CUR slightly suppressed the peak amplitude of voltage-gated Na + current. CUR, DMC and BDMC depolarized the resting potential and increased firing frequency of action potentials. The CUR-mediated decrease of I K(DR) and the increase of current inactivation also occurred in βTC-6 INS-1 cells. Taken these results together, these effects may be one of the possible mechanisms contributing their insulin-releasing effect. Copyright © 2017 Elsevier B.V. All rights reserved.

Relationship between treatment persistence and A1C trends among patients with type 2 diabetes newly initiating basal insulin

PubMed Central

Xie, Lin; Pan, Chunshen; Wang, Yuexi; Vaidya, Neel; Ye, Fen; Preblick, Ronald; Meneghini, Luigi

2018-01-01

This study examines the relationship between glycated haemoglobin (A1C) levels and treatment persistence with, or time to discontinuation of, basal insulin in patients with type 2 diabetes (T2D) newly initiating insulin. Claims data were extracted from the Optum Clinformatics database from January 2010 to June 2015. Adult patients with T2D initiating insulin glargine 100 U/mL (Gla‐100) or insulin detemir (DET) with ≥1 A1C measurement during 12‐month baseline and 18‐month follow‐up periods were included. Patients with a refill gap of >90 days were considered non‐persistent; otherwise, patients were considered persistent with insulin. The main outcome was A1C, measured closest to the end of each quarter during the follow‐up period. A total of 3993 of 109 934 patients met the inclusion criteria (43.0% persistent; 57.0% non‐persistent). Persistent patients were older (54.7 vs 52.7 years; P < .001), were more likely to be male (59.4% vs 54.4%; P = .002), and had significantly lower mean unadjusted A1C values at 18 months (8.26% vs 8.60%; P < .001) and quarterly. Only 43.0% of adults initiating basal insulin persisted with treatment for 18 months, with earlier discontinuation associated with higher A1C. PMID:29278460

How can insulin initiation delivery in a dual-sector health system be optimised? A qualitative study on healthcare professionals' views.

PubMed

Lee, Ping Yein; Lee, Yew Kong; Ng, Chirk Jenn

2012-04-30

The prevalence of type 2 diabetes is increasing at an alarming rate in developing countries. However, glycaemia control remains suboptimal and insulin use is low. One important barrier is the lack of an efficient and effective insulin initiation delivery approach. This study aimed to document the strategies used and proposed by healthcare professionals to improve insulin initiation in the Malaysian dual-sector (public-private) health system. In depth interviews and focus group discussions were conducted in Klang Valley and Seremban, Malaysia in 2010-11. Healthcare professionals consisting of general practitioners (n = 11), medical officers (n = 8), diabetes educators (n = 3), government policy makers (n = 4), family medicine specialists (n = 10) and endocrinologists (n = 2) were interviewed. We used a topic guide to facilitate the interviews, which were audio recorded, transcribed verbatim and analysed using a thematic approach. Three main themes emerged from the interviews. Firstly, there was a lack of collaboration between the private and public sectors in diabetes care. The general practitioners in the private sector proposed an integrated system for them to refer patients to the public health services for insulin initiation programmes. There could be shared care between the two sectors and this would reduce the disproportionately heavy workload at the public sector. Secondly, besides the support from the government health authority, the healthcare professionals wanted greater involvement of non-government organisations, media and pharmaceutical industry in facilitating insulin initiation in both the public and private sectors. The support included: training of healthcare professionals; developing and disseminating patient education materials; service provision by diabetes education teams; organising programmes for patients' peer group sessions; increasing awareness and demystifying insulin via public campaigns; and subsidising glucose

How can insulin initiation delivery in a dual-sector health system be optimised? A qualitative study on healthcare professionals’ views

PubMed Central

2012-01-01

Background The prevalence of type 2 diabetes is increasing at an alarming rate in developing countries. However, glycaemia control remains suboptimal and insulin use is low. One important barrier is the lack of an efficient and effective insulin initiation delivery approach. This study aimed to document the strategies used and proposed by healthcare professionals to improve insulin initiation in the Malaysian dual-sector (public–private) health system. Methods In depth interviews and focus group discussions were conducted in Klang Valley and Seremban, Malaysia in 2010–11. Healthcare professionals consisting of general practitioners (n = 11), medical officers (n = 8), diabetes educators (n = 3), government policy makers (n = 4), family medicine specialists (n = 10) and endocrinologists (n = 2) were interviewed. We used a topic guide to facilitate the interviews, which were audio recorded, transcribed verbatim and analysed using a thematic approach. Results Three main themes emerged from the interviews. Firstly, there was a lack of collaboration between the private and public sectors in diabetes care. The general practitioners in the private sector proposed an integrated system for them to refer patients to the public health services for insulin initiation programmes. There could be shared care between the two sectors and this would reduce the disproportionately heavy workload at the public sector. Secondly, besides the support from the government health authority, the healthcare professionals wanted greater involvement of non-government organisations, media and pharmaceutical industry in facilitating insulin initiation in both the public and private sectors. The support included: training of healthcare professionals; developing and disseminating patient education materials; service provision by diabetes education teams; organising programmes for patients’ peer group sessions; increasing awareness and demystifying insulin via public

The hybrid delay task: Can capuchin monkeys (Cebus apella) sustain a delay after an initial choice to do so?

PubMed Central

Paglieri, Fabio; Focaroli, Valentina; Bramlett, Jessica; Tierno, Valeria; McIntyre, Joseph M.; Addessi, Elsa; Evans, Theodore A.; Beran, Michael J.

2013-01-01

Choosing to wait for a better outcome (delay choice) and sustaining the delay prior to that outcome (delay maintenance) are both prerequisites for successful self control in intertemporal choices. However, most existing experimental methods test these skills in isolation from each other, and no significant correlation has been observed in performance across these tasks. In this study we introduce a new paradigm, the hybrid delay task, which combines an initial delay choice with a subsequent delay maintenance stage. This allows testing how often choosing to wait is paired with the actual ability to do so. We tested 18 capuchin monkeys (Cebus apella) from two laboratories in various conditions, and we found that subjects frequently chose the delayed reward but then failed to wait for it, due to poor delay maintenance. However, performance improved with experience and different behavioral responses for error correction were evident. These findings have far reaching implications: if such a high error rate was observed also in other species (possibly including Homo sapiens), this may indicate that delay choice tasks that make use of salient, prepotent stimuli do not reliably assess generalized self control, insofar as choosing to wait does not entail always being able to do so. PMID:23274585

Comparison Between Individually and Group-Based Insulin Pump Initiation by Time-Driven Activity-Based Costing

PubMed Central

Ridderstråle, Martin

2017-01-01

Background: Depending on available resources, competencies, and pedagogic preference, initiation of insulin pump therapy can be performed on either an individual or a group basis. Here we compared the two models with respect to resources used. Methods: Time-driven activity-based costing (TDABC) was used to compare initiating insulin pump treatment in groups (GT) to individual treatment (IT). Activities and cost drivers were identified, timed, or estimated at location. Medical quality and patient satisfaction were assumed to be noninferior and were not measured. Results: GT was about 30% less time-consuming and 17% less cost driving per patient and activity compared to IT. As a batch driver (16 patients in one group) GT produced an upward jigsaw-shaped accumulative cost curve compared to the incremental increase incurred by IT. Taking the alternate cost for those not attending into account, and realizing the cost of opportunity gained, suggested that GT was cost neutral already when 5 of 16 patients attended, and that a second group could be initiated at no additional cost as the attendance rate reached 15:1. Conclusions: We found TDABC to be effective in comparing treatment alternatives, improving cost control and decision making. Everything else being equal, if the setup is available, our data suggest that initiating insulin pump treatment in groups is far more cost effective than on an individual basis and that TDABC may be used to find the balance point. PMID:28366085

An exploratory trial of basal and prandial insulin initiation and titration for type 2 diabetes in primary care with adjunct retrospective continuous glucose monitoring: INITIATION study.

PubMed

Blackberry, Irene D; Furler, John S; Ginnivan, Louise E; Manski-Nankervis, Jo-Anne; Jenkins, Alicia; Cohen, Neale; Best, James D; Young, Doris; Liew, Danny; Ward, Glenn; O'Neal, David N

2014-11-01

To evaluate basal and prandial insulin initiation and titration in people with type 2 diabetes mellitus (T2DM) in primary care and to explore the feasibility of retrospective-continuous glucose monitoring (r-CGM) in guiding insulin dosing. The new model of care features General Practitioners (GPs) and Practice Nurses (PNs) working in an expanded role, with Credentialed Diabetes Educator - Registered Nurse (CDE-RN) support. Insulin-naïve T2DM patients (HbA1c >7.5% [>58 mmol/mol] despite maximal oral therapy) from 22 general practices in Victoria, Australia commenced insulin glargine, with glulisine added as required. Each was randomised to receive r-CGM or self-monitoring of blood glucose (SMBG). Glycaemic control (HbA1c) was benchmarked against specialist ambulatory patients referred for insulin initiation. Ninety-two patients mean age (range) 59 (28-77) years; 40% female; mean (SD) diabetes duration 10.5 (6.1) years participated. HbA1c decreased from (median (IQR)) 9.9 (8.8, 11.2)%; 85 (73, 99) mmol/mol to 7.3 (6.9, 7.8)%; 56 (52, 62) mmol/mol at 24 weeks (p < 0.0001). Comparing r-CGM (n = 46) with SMBG (n = 42), there were no differences in major hypoglycaemia (p=0.17) or ΔHbA1c (p = 0.31). More r-CGM than SMBG participants commenced glulisine (26/48 vs. 7/44; p < 0.001). Results were comparable to 82 benchmark patients, with similar low rates of major hypoglycaemia (2/89 vs. 0/82; p = 0.17) and less loss to follow up in the INITIATION group (3/92 vs. 14/82; p = 0.002). Insulin initiation and titration for T2DM patients in primary care was safe and improved HbA1c with low rates of major hypoglycaemia. CDE-RNs were effective in a new consultant role. r-CGM use in primary care was feasible and enhanced post-prandial hyperglycaemia recognition. Trial registration ACTRN12610000797077. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Delayed clearance of triglyceride‐rich lipoproteins in young, healthy obese subjects†

PubMed Central

Goll, R.; Lekahl, S.; Moen, O. S.; Florholmen, J.

2015-01-01

Summary Obesity is associated with the metabolic syndrome. The aims were, first, to study the postprandial triglyceride clearance in young, healthy obese subjects and, second, to investigate if fasting triglycerides can predict delayed postprandial triglyceride clearance. Eighteen apparently healthy, obese subjects with no clinical signs of metabolic disturbances participated. Controls were age‐ and sex‐matched, healthy, normal weight subjects. Subclinical markers of metabolic disturbances were assessed by measuring postprandial triglycerides in serum and in chylomicrons by oral fat tolerance test. Postprandial triglyceride clearance for 8 h was assessed indirectly as removal of the lipid from serum during the oral fat tolerance test. Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA‐IR). Twelve (66%) of the apparently healthy obese individuals had insulin resistance measured by HOMA‐IR. There was a delayed clearance of serum triglycerides and chylomicron triglycerides at 6 h when compared with the control group, while, at 8 h, the differences were only detected for the chylomicron triglyceride clearance. Triglyceride response was significantly greater in the obese subjects. Fasting triglycerides in upper normal level predicted a delayed postprandial triglyceride clearance and insulin resistance. In young, apparently healthy obese subjects early metabolic disturbances including insulin resistance and delayed postprandial triglyceride clearance can be detected. Fasting serum triglyceride in upper normal level predicted delayed postprandial triglyceride clearance and insulin resistance. PMID:26469529

Melatonin delays clutch initiation in a wild songbird

PubMed Central

Greives, Timothy J.; Kingma, Sjouke A.; Beltrami, Giulia; Hau, Michaela

2012-01-01

The hormone melatonin is known to play an important role in regulating many seasonal changes in physiology, morphology and behaviour. In birds, unlike in mammals, melatonin has thus far been thought to play little role in timing seasonal reproductive processes. This view is mainly derived from laboratory experiments on male birds. This study tests whether melatonin is capable of influencing the timing of clutch initiation in wild female songbirds. Free-living female great tits (Parus major) treated with melatonin-filled implants prior to the breeding season initiated their first clutch of the season significantly later than females carrying an empty implant. Melatonin treatment did not affect clutch size. Further, melatonin treatment did not delay the onset of daily activity in the wild nor adversely affect body mass in captivity compared with controls. These data suggest a previously unknown role for this hormone in regulating the timing of clutch initiation in the wild. PMID:22171024

Clinical inertia with regard to intensifying therapy in people with type 2 diabetes treated with basal insulin.

PubMed

Khunti, K; Nikolajsen, A; Thorsted, B L; Andersen, M; Davies, M J; Paul, S K

2016-04-01

To investigate whether clinical inertia, the failure to intensify treatment regimens when required, exists in people with type 2 diabetes treated with basal insulin. This was a retrospective cohort study involving patients with type 2 diabetes in the UK Clinical Practice Research Datalink database between January 2004 and December 2011, with follow-up until December 2013. A total of 11 696 patients were included in the analysis. Among all patients, 36.5% had their treatment intensified during the study period; of these, the treatment of 50.0, 42.5 and 7.4% was intensified with bolus or premix insulin or glucagon-like peptide-1 receptor agonists, respectively. The median time from initiation of basal insulin to treatment intensification was 4.3 years [95% confidence interval (CI) 4.1, 4.6]. Among patients clinically eligible for treatment intensification [glycated haemoglobin (HbA1c) ≥7.5% (58 mmol/mol)], 30.9% had their treatment regimen intensified. The median time to intensification in this group was 3.7 years (95% CI 3.4, 4.0). Increasing age, duration of diabetes, oral antihyperglycaemic agent usage and Charlson comorbidity index score were associated with a significant delay in the time to intensification (p < 0.05). Among patients with HbA1c ≥7.5% (58 mmol/mol), 32.1% stopped basal insulin therapy. Strategies should be developed to increase the number of patients undergoing therapy intensification and to reduce the delay in intensifying therapy for suitable patients on basal insulin. Initiatives to support patients continuing on insulin are also required. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Hypoglycemia in patients with type 2 diabetes newly initiated on basal insulin in the US in a community setting: impact on treatment discontinuation and hospitalization.

PubMed

Dalal, Mehul R; Kazemi, Mahmood R; Ye, Fen

2017-02-01

To evaluate the impact of 6 month hypoglycemia on treatment discontinuation and hospitalization of patients initiating basal insulin for type 2 diabetes (T2D) in real-world practice. This was a retrospective cohort study of patient-level data using electronic medical records (EMRs) in the Predictive Health Intelligence diabetes dataset. Data from adult patients with T2D initiating basal insulin glargine, insulin detemir, or Neutral Protamine Hagedorn insulin between January 2008 and March 2014 was analyzed. The date of first basal insulin prescription in an outpatient setting was the index date. A 12 month baseline prior to the index date was established; follow-up was 6-24 months from the index date. Patients were assigned to cohorts by experience of hypoglycemia (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code or blood glucose test) in the first 6 months following the index date; with hypoglycemia and without hypoglycemia cohorts were compared for basal insulin treatment discontinuation and hospitalization. Overall, 49,062 patients were included; 5159 (10.5%) experienced hypoglycemia in the 6 months following basal insulin initiation. In the first 12 months, 68.1% of patients in the with hypoglycemia cohort discontinued basal insulin versus 53.9% in the without hypoglycemia cohort (p < .0001); more patients in the with hypoglycemia cohort had at least one hospitalization in the first year of follow-up (50.1% vs. 14.6%; p < .0001). Patients with hypoglycemia soon after initiating basal insulin are at greater risk of discontinuation of their basal insulin therapy and hospitalization versus those who did not have hypoglycemic events within the first 6 months of basal insulin initiation. A limitation of this study is that it was a retrospective analysis of EMR data and the study may not be representative of all US patients with T2D on basal insulin and it cannot be assumed that every hypoglycemic event was

Initiation of nutritional support is delayed in critically ill obese patients: a multicenter cohort study.

PubMed

Borel, Anne-Laure; Schwebel, Carole; Planquette, Benjamin; Vésin, Aurélien; Garrouste-Orgeas, Maité; Adrie, Christophe; Clec'h, Christophe; Azoulay, Elie; Souweine, Bertrand; Allaouchiche, Bernard; Goldgran-Toledano, Dany; Jamali, Samir; Darmon, Michael; Timsit, Jean-François

2014-09-01

A high catabolic rate characterizes the acute phase of critical illness. Guidelines recommend an early nutritional support, regardless of the previous nutritional status. We aimed to assess whether the nutritional status of patients, which was defined by the body mass index (BMI) at admission in an intensive care unit (ICU), affected the time of nutritional support initiation. We conducted a cohort study that reported a retrospective analysis of a multicenter ICU database (OUTCOMEREA) by using data prospectively entered from January 1997 to October 2012. Patients who needed orotracheal intubation within the first 72 h and >3 d were included. Data from 3257 ICU stays were analyzed. The delay before feeding was different according to BMI groups (P = 0.035). The delay was longer in obese patients [BMI (in kg/m²) ≥30; n = 663] than in other patients with either low weight (BMI <20; n = 501), normal weight (BMI ≥20 and <25; n = 1135), or overweight (BMI ≥25 and <30; n = 958). The association between nutritional status and a delay in nutrition initiation was independent of potential confounding factors such as age, sex, and diabetes or other chronic diseases. In comparison with normal weight, the adjusted RR (95% CI) associated with a delayed nutrition initiation was 0.92 (0.86, 0.98) for patients with low weight, 1.00 (0.94, 1.05) for overweight patients, and 1.06 (1.00, 1.12) for obese patients (P = 0.004). The initiation of nutritional support was delayed in obese ICU patients. Randomized controlled trials that address consequences of early compared with delayed beginnings of nutritional support in critically ill obese patients are needed. © 2014 American Society for Nutrition.

Clinical characteristics of patients with type 2 diabetes mellitus at the time of insulin initiation: INSTIGATE observational study in Spain

PubMed Central

Dilla, Tatiana; Reviriego, Jesús; Castell, Conxa; Goday, Albert

2009-01-01

Little information is available on the management of patients with type 2 diabetes mellitus (DM2) in regular clinical practice, prior to and at the point of initiating treatment with insulin. The INSTIGATE study provides a description of the clinical profile of the patient with DM2 who begins treatment with insulin in both primary and secondary care. A total of 224 patients who had been diagnosed with DM2, were not responding to oral treatment, and began receiving insulin were included in the INSTIGATE study in Spain. Demographic data were collected, as well as data on macro- and microvascular complications of diabetes and comorbidities, past medical history of diabetes and oral treatment administered, the clinical severity of diabetes (HbA1c concentration) and insulin treatment initiated. Mean age of the sample was 65.4 years and 56.7% were men. There were 87% of patients who had a diagnosis of at least one significant comorbidity, notably hypertension and hyperlipidemia. The patient profile for metabolic syndrome was met by 75.1% of the patients. There was a higher incidence of macrovascular complications (38.4%) than microvascular complications (16.1%). Prior to insulin initiation, the most recent mean HbA1c was 9.2%. The majority of patients had been treated in the last 12 months with sulfonylureas and/or metformin (69.6 and 57.6%). The most common treatment prior to insulinization was the co-administration of two oral antidiabetics (OADs) (37.5%). Patients with DM2 observed in the study presented with elevated mean HbA1c and body mass index levels, comorbidities and complications related to diabetes at the time of insulin initiation. Changes and adjustments in treatment from diagnosis of diabetes occur when HbA1c levels are far above those recommended by the IDF (International Diabetes Federation), a factor which could be contributing to the development of both macrovascular and microvascular complications in the patient profile described in the study. PMID

Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus

PubMed Central

Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

2015-01-01

Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

Derivation and computation of discrete-delay and continuous-delay SDEs in mathematical biology.

PubMed

Allen, Edward J

2014-06-01

Stochastic versions of several discrete-delay and continuous-delay differential equations, useful in mathematical biology, are derived from basic principles carefully taking into account the demographic, environmental, or physiological randomness in the dynamic processes. In particular, stochastic delay differential equation (SDDE) models are derived and studied for Nicholson's blowflies equation, Hutchinson's equation, an SIS epidemic model with delay, bacteria/phage dynamics, and glucose/insulin levels. Computational methods for approximating the SDDE models are described. Comparisons between computational solutions of the SDDEs and independently formulated Monte Carlo calculations support the accuracy of the derivations and of the computational methods.

Can exercise ameliorate treatment toxicity during the initial phase of testosterone deprivation in prostate cancer patients? Is this more effective than delayed rehabilitation?

PubMed Central

2012-01-01

Background There has been substantial increase in use of androgen deprivation therapy as adjuvant management of prostate cancer. However, this leads to a range of musculoskeletal toxicities including reduced bone mass and increased skeletal fractures compounded with rapid metabolic alterations, including increased body fat, reduced lean mass, insulin resistance and negative lipoprotein profile, increased incidence of cardiovascular and metabolic morbidity, greater distress and reduced quality of life. Numerous research studies have demonstrated certain exercise prescriptions to be effective at preventing or even reversing these treatment toxicities. However, all interventions to date have been of rehabilitative intent being implemented after a minimum of 3 months since initiation of androgen deprivation, by which time considerable physical and psychological health problems have manifested. The pressing question is whether it is more efficacious to commence exercise therapy at the same time as initiating androgen deprivation, so treatment induced adverse effects can be immediately attenuated or indeed prevented. Methods/design We are proposing a multi-site randomized controlled trial with partial crossover to examine the effects of timing of exercise implementation (immediate or delayed) on preserving long-term skeletal health, reversing short- and long-term metabolic and cardiovascular risk factors, and supporting mental health in men receiving androgen deprivation therapy. 124 men who are about to initiate androgen deprivation for prostate cancer will be randomized to immediate or delayed groups. Immediate will commence a 6-month exercise program within 7–10 days of their first dose. Delayed will receive usual care for 6 months and then commence the exercise program for 6 months (partial cross-over). Immediate will be free to adopt the lifestyle of their choosing following the initial 6-month intervention. Measurements for primary and secondary endpoints will

Downhole delay assembly for blasting with series delay

DOEpatents

Ricketts, Thomas E.

1982-01-01

A downhole delay assembly is provided which can be placed into a blasthole for initiation of explosive in the blasthole. The downhole delay assembly includes at least two detonating time delay devices in series in order to effect a time delay of longer than about 200 milliseconds in a round of explosions. The downhole delay assembly provides a protective housing to prevent detonation of explosive in the blasthole in response to the detonation of the first detonating time delay device. There is further provided a connection between the first and second time delay devices. The connection is responsive to the detonation of the first detonating time delay device and initiates the second detonating time delay device. A plurality of such downhole delay assemblies are placed downhole in unfragmented formation and are initiated simultaneously for providing a round of explosive expansions. The explosive expansions can be used to form an in situ oil shale retort containing a fragmented permeable mass of formation particles.

Correlates of basal insulin persistence among insulin-naïve people with type 2 diabetes: results from a multinational survey.

PubMed

Peyrot, Mark; Perez-Nieves, Magaly; Ivanova, Jasmina; Cao, Dachuang; Schmerold, Luke; Kalirai, Samaneh; Hadjiyianni, Irene

2017-10-01

People with T2DM who initiate basal insulin therapy often stop therapy temporarily or permanently soon after initiation. This study analyzes the reasons for and correlates of stopping and restarting basal insulin therapy among people with T2DM. An online survey was completed by 942 insulin-naïve adults with self-reported T2DM from Brazil, France, Germany, Japan, Spain, UK, and US. Respondents had initiated basal insulin therapy within the 3-24 months before survey participation and met criteria for one of three persistence groups: continuers had no gaps of ≥7 days in basal insulin treatment; interrupters had at least one gap in insulin therapy of ≥7 days within the first 6 months after initiation and had since restarted basal insulin; and discontinuers stopped using basal insulin within the first 6 months after initiation and had not restarted. Physician recommendations and cost were strongly implicated in patients stopping and not resuming insulin therapy. Continuous persistence was lower for patients with more worries about insulin initiation, greater difficulties and weight gain while using insulin, and higher for those using pens and perceiving their diabetes as severe. Repeated interruption of insulin therapy was associated with hyperglycemia and treatment burden while using insulin. Resumption and perceived likelihood of resumption were associated with hyperglycemia upon insulin cessation. Perceived likelihood of resumption among discontinuers was associated with perceived benefits of insulin. Better understanding of the risk factors for patient cessation and resumption of basal insulin therapy may help healthcare providers improve persistence with therapy.

Glucose and Insulin Secretory Response Patterns Following Diet and Tolazamide Therapy in Diabetes

PubMed Central

Turtle, J. R.

1970-01-01

Glucose and insulin secretory response patterns during glucose tolerance tests were determined in 28 maturity-onset diabetics, and the sequential effects of diet and a sulphonylurea, tolazamide, were assessed. Untreated diabetics showed hyperglycaemia, increased serum immunoreactive insulin response patterns, delayed insulin release, and relative insulin deficiency. Diet alone partially corrected the hyperglycaemia and serum immunoreactive insulin response but had no effect on the delayed insulin release or relative insulin deficiency. Tolazamide plus diet restored all values towards normal. The net effect of maintenance tolazamide therapy was to (1) restore the insulin secretory response pattern to normal, (2) reduce total pancreatic insulin output, and (3) improve the efficiency of insulin secretion. The results suggest that there is a rational basis for the use of sulphonylurea in all maturity-onset diabetics, including patients with mild carbohydrate intolerance and those who are apparently controlled by diet alone. PMID:5470087

Branched chain amino acid suppressed insulin-initiated proliferation of human cancer cells through induction of autophagy.

PubMed

Wubetu, Gizachew Yismaw; Utsunomiya, Tohru; Ishikawa, Daichi; Ikemoto, Tetsuya; Yamada, Shinichiro; Morine, Yuji; Iwahashi, Shuichi; Saito, Yu; Arakawa, Yusuke; Imura, Satoru; Arimochi, Hideki; Shimada, Mitsuo

2014-09-01

Branched chain amino acid (BCAA) dietary supplementation inhibits activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis in diabetic animal models. However, the in vitro effect of BCAA on human cancer cell lines under hyper-insulinemic conditions remains unclear. Colon (HCT-116) and hepatic (HepG2) tumor cells were treated with varying concentrations of BCAA with or without fluorouracil (5-FU). The effect of BCAA on insulin-initiated proliferation was determined. Gene and protein expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. BCAA supplementation had no significant effect on cell proliferation and did not show significant synergistic or antagonistic effects with 5-FU. However, BCAA significantly decreased insulin-initiated proliferation of human colon and hepatic cancer cell lines in vitro. BCAA supplementation caused a marked decrease in activated IGF-IR expression and significantly enhanced both mRNA and protein expression of LC3-II and BECN1 (BECLIN-1). BCAA could be a useful chemopreventive modality for cancer in hyperinsulinemic conditions. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Preventing Delays in First-Case Starts on the Neurosurgery Service: A Resident-Led Initiative at an Academic Institution.

PubMed

Han, Seunggu J; Rolston, John D; Zygourakis, Corinna C; Sun, Matthew Z; McDermott, Michael W; Lau, Catherine Y; Aghi, Manish K

2016-01-01

On-time starts for the first case of the day are critical to maintaining efficiency in operating rooms (ORs). We studied whether a resident-led initiative to ensure on-time site marking and documentation of surgical consent could lead to improved first-case start time. In a resident-led initiative at a large 600-bed academic hospital with 25 ORs, we aimed to complete site marking and surgical consents half an hour before the scheduled start time for all first-case neurosurgical patients. We monitored the occurrence of delayed first starts and the length of delay during our initiative, and compared these cases to neurosurgical cases 3 months before the implementation of the initiative and to first-start nonneurosurgical cases. In the year of the initiative, both site marking and surgical consents were completed 30 minutes before the case start in 97% of neurosurgical cases. The average delay across all first-case starts was reduced to 7.17 minutes (N = 1271), compared with 9.67 minutes before the intervention (N = 345). During the study period, non-neurosurgical cases were delayed on average 10.3 minutes (N = 3592). There was a significant difference in latencies between the study period and the period before the initiative (p < 0.001), and also between neurosurgical cases and nonneurosurgical cases (p < 0.001). There was no reduction in delay times seen on the non-neurosurgical services in the study period when compared to the case 3 months before. Considering its effect across 1271 cases, this initiative over 1 year resulted in a total reduction of 52 hours and 57 minutes in delays. Through a resident-led quality improvement program, neurosurgical trainees successfully reduced delays in first-case starts on a surgical service. Engaging physician trainees in quality improvement and enhancing OR efficiency can be successfully achieved and can have a significant clinical and financial effect. Copyright © 2015 Association of Program Directors in Surgery. Published by

The Initiation of Smooth Pursuit is Delayed in Anisometropic Amblyopia.

PubMed

Raashid, Rana Arham; Liu, Ivy Ziqian; Blakeman, Alan; Goltz, Herbert C; Wong, Agnes M F

2016-04-01

Several behavioral studies have shown that the reaction times of visually guided movements are slower in people with amblyopia, particularly during amblyopic eye viewing. Here, we tested the hypothesis that the initiation of smooth pursuit eye movements, which are responsible for accurately keeping moving objects on the fovea, is delayed in people with anisometropic amblyopia. Eleven participants with anisometropic amblyopia and 14 visually normal observers were asked to track a step-ramp target moving at ±15°/s horizontally as quickly and as accurately as possible. The experiment was conducted under three viewing conditions: amblyopic/nondominant eye, binocular, and fellow/dominant eye viewing. Outcome measures were smooth pursuit latency, open-loop gain, steady state gain, and catch-up saccade frequency. Participants with anisometropic amblyopia initiated smooth pursuit significantly slower during amblyopic eye viewing (206 ± 20 ms) than visually normal observers viewing with their nondominant eye (183 ± 17 ms, P = 0.002). However, mean pursuit latency in the anisometropic amblyopia group during binocular and monocular fellow eye viewing was comparable to the visually normal group. Mean open-loop gain, steady state gain, and catch-up saccade frequency were similar between the two groups, but participants with anisometropic amblyopia exhibited more variable steady state gain (P = 0.045). This study provides evidence of temporally delayed smooth pursuit initiation in anisometropic amblyopia. After initiation, the smooth pursuit velocity profile in anisometropic amblyopia participants is similar to visually normal controls. This finding differs from what has been observed previously in participants with strabismic amblyopia who exhibit reduced smooth pursuit velocity gains with more catch-up saccades.

The Initiation of Smooth Pursuit is Delayed in Anisometropic Amblyopia

PubMed Central

Raashid, Rana Arham; Liu, Ivy Ziqian; Blakeman, Alan; Goltz, Herbert C.; Wong, Agnes M. F.

2016-01-01

Purpose Several behavioral studies have shown that the reaction times of visually guided movements are slower in people with amblyopia, particularly during amblyopic eye viewing. Here, we tested the hypothesis that the initiation of smooth pursuit eye movements, which are responsible for accurately keeping moving objects on the fovea, is delayed in people with anisometropic amblyopia. Methods Eleven participants with anisometropic amblyopia and 14 visually normal observers were asked to track a step-ramp target moving at ±15°/s horizontally as quickly and as accurately as possible. The experiment was conducted under three viewing conditions: amblyopic/nondominant eye, binocular, and fellow/dominant eye viewing. Outcome measures were smooth pursuit latency, open-loop gain, steady state gain, and catch-up saccade frequency. Results Participants with anisometropic amblyopia initiated smooth pursuit significantly slower during amblyopic eye viewing (206 ± 20 ms) than visually normal observers viewing with their nondominant eye (183 ± 17 ms, P = 0.002). However, mean pursuit latency in the anisometropic amblyopia group during binocular and monocular fellow eye viewing was comparable to the visually normal group. Mean open-loop gain, steady state gain, and catch-up saccade frequency were similar between the two groups, but participants with anisometropic amblyopia exhibited more variable steady state gain (P = 0.045). Conclusions This study provides evidence of temporally delayed smooth pursuit initiation in anisometropic amblyopia. After initiation, the smooth pursuit velocity profile in anisometropic amblyopia participants is similar to visually normal controls. This finding differs from what has been observed previously in participants with strabismic amblyopia who exhibit reduced smooth pursuit velocity gains with more catch-up saccades. PMID:27070109

Basal insulin persistence, associated factors, and outcomes after treatment initiation among people with type 2 diabetes mellitus in the US.

PubMed

Perez-Nieves, Magaly; Kabul, Samaneh; Desai, Urvi; Ivanova, Jasmina I; Kirson, Noam Y; Cummings, Alice Kate; Birnbaum, Howard G; Duan, Ran; Cao, Dachuang; Hadjiyianni, Irene

2016-01-01

To assess basal insulin persistence, associated factors, and economic outcomes for insulin-naïve people with type 2 diabetes mellitus (T2DM) in the US. People aged ≥18 years diagnosed with T2DM initiating basal insulin between April 2006 and March 2012 (index date), no prior insulin use, and continuous insurance coverage for 6 months before (baseline) and 24 months after index date (follow-up period) were selected using de-identified administrative claims data in the US. Based on whether there were ≥30 day gaps in basal insulin use in the first year post-index, patients were classified as continuers (no gap), interrupters (≥1 prescription after gap), and discontinuers (no prescription after gap). Factors associated with persistence - assessed using multinomial logistic regression model; annual healthcare resource use and costs during follow-up period - compared separately between continuers and interrupters, and continuers and discontinuers. Of the 19,110 people included in the sample (mean age: 59 years, ∼60% male), 20% continued to use basal insulin, 62% had ≥1 interruption, and 18% discontinued therapy in the year after initiation. Older age, multiple antihyperglycemic drug use, and injectable antihyperglycemic use during baseline were associated with significantly higher likelihoods of continuing basal insulin. Relative to interrupters and discontinuers, continuers had fewer emergency department visits, shorter hospital stays, and lower medical costs (continuers: $10,890, interrupters: $13,674, discontinuers: $13,021), but higher pharmacy costs (continuers: $7449, interrupters: $5239, discontinuers: $4857) in the first year post-index (p < 0.05 for all comparisons). Total healthcare costs were similar across the three cohorts. Findings for the second year post-index were similar. The majority of people in this study interrupted or discontinued basal insulin treatment in the year after initiation; and incurred higher medical resource use and

Insulin therapy refusal among type II diabetes mellitus patients in Kubang Pasu district, Kedah, Malaysia

PubMed Central

Tan, Wei Leong; Asahar, Siti Fairus; Harun, Noor Liani

2015-01-01

INTRODUCTION Diabetes mellitus is a rising non-communicable disease in Malaysia. Insulin therapy refusal is a challenge for healthcare providers, as it results in delayed insulin initiation. This study was conducted to determine the prevalence of insulin therapy refusal and its associated factors. METHODS This cross-sectional study was conducted at seven public health clinics in Kubang Pasu district of Kedah, Malaysia, from March to October 2012. A newly developed and validated questionnaire was used and participants were selected via systematic random sampling. Only patients diagnosed with type II diabetes mellitus (T2DM) and under the public health clinic care in Kubang Pasu were included in the study. Multiple logistic regression was used to study the association between insulin therapy refusal and its associated factors. RESULTS There were 461 respondents and the response rate was 100%. Among these 461 patients with T2DM, 74.2% refused insulin therapy. The most common reason given for refusal was a lack of confidence in insulin injection (85.4%). Multiple logistic regression revealed that respondents who had secondary education were 55.0% less likely to refuse insulin therapy than those who had primary education or no formal education (adjusted odds ratio [OR] 0.45, 95% confidence interval [CI] 0.25–0.82, p = 0.009). There was also a significant inverse association between glycated haemoglobin (HbA1c) level and insulin therapy refusal (adjusted OR 0.87, 95% CI 0.76–1.00, p = 0.047). CONCLUSION Insulin therapy refusal is common in Kubang Pasu. Educational status and HbA1c level should be taken into consideration when counselling patients on insulin therapy initiation. PMID:25532511

Immediate newborn care practices delay thermoregulation and breastfeeding initiation

PubMed Central

Sobel, Howard L; Silvestre, Maria Asuncion A; Mantaring, Jacinto Blas V; Oliveros, Yolanda E; Nyunt-U, Soe

2011-01-01

Aim A deadly nosocomial outbreak in a Philippine hospital drew nationwide attention to neonatal sepsis. Together with specific infection control measures, interventions that protect newborns against infection-related mortality include drying, skin-to-skin contact, delayed cord clamping, breastfeeding initiation and delayed bathing. This evaluation characterized hospital care in the first hours of life with the intent to drive policy change, strategic planning and hospital reform. Methods Trained physicians observed 481 consecutive deliveries in 51 hospitals using a standardized tool to record practices and timing of immediate newborn care procedures. Results Drying, weighing, eye care and vitamin K injections were performed in more than 90% of newborns. Only 9.6% were allowed skin-to-skin contact. Interventions were inappropriately sequenced, e.g. immediate cord clamping (median 12 sec), delayed drying (96.5%) and early bathing (90.0%). While 68.2% were put to the breast, they were separated two minutes later. Unnecessary suctioning was performed in 94.9%. Doctors trained in neonatal resuscitation were 2.5 (1.1–5.7) times more likely to unnecessarily suction vigorous newborns. Two per cent died and 5.7% developed sepsis/pneumonia. Conclusions This minute-by-minute observational assessment revealed that performance and timing of immediate newborn care interventions are below WHO standards and deprive newborns of basic protections against infection and death. PMID:21375583

Clinical and Economic Outcomes Associated With the Timing of Initiation of Basal Insulin in Patients With Type 2 Diabetes Mellitus Previously Treated With Oral Antidiabetes Drugs.

PubMed

Levin, Philip; Zhou, Steve; Durden, Emily; Farr, Amanda M; Gill, Jasvinder; Wei, Wenhui

2016-01-01

In patients with type 2 diabetes mellitus (T2DM) not achieving glycemic targets using oral antidiabetes drugs (OADs), studies suggest that timely insulin initiation has clinical benefits. Insulin initiation at the early versus late stage of disease progression has not been explored in detail. This retrospective database analysis investigated clinical and economic outcomes associated with the timing of insulin initiation in patients with T2DM treated with ≥1 OAD in a real-world US setting. This study linked data from the Truven Health MarketScan(®) Commercial database, Medicare Supplemental database, and Quintiles Electronic Medical Records database. A total of 1830 patients with T2DM were included. Patients were grouped according to their OAD use before basal insulin initiation (1, 2, or ≥3 OADs) as a proxy for the timing of insulin initiation. Clinical and economic outcomes were evaluated over 1 year of follow-up. During follow-up the 1 OAD group, compared with the 2 and ≥3 OADs groups, had a greater reduction in glycosylated hemoglobin A1c (-1.7% vs -1.0% vs -0.9%, respectively; P < 0.0001), greater achievement of glycemic target (38.2% vs 26.7% vs 19.6%, respectively; P < 0.0001), and a lower incidence of hypoglycemia (2.7% vs 6.6% vs 5.0%, respectively; P = 0.0002), with no difference in total health care costs ($21,167 vs $21,060 vs $20,133, respectively). This study shows that early insulin initiation (represented by the 1 OAD group) may be clinically beneficial to patients with T2DM not controlled with OADs, without adding to costs. This supports the call for timely initiation of individualized insulin therapy in this population. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Investigation of drug loading and in vitro release mechanisms of insulin-lauryl sulfate complex loaded PLGA nanoparticles.

PubMed

Shi, K; Cui, F; Yamamoto, H; Kawashima, Y

2008-12-01

Insulin, a water soluble peptide hormone, was hydrophobically ion-paired with sodium lauryl sulfate (SDS) at the stoichiometric molar ratio of 6:1. The obtained insulin-SDS complex precipitation was subsequently formulated in biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles by a modified spontaneous emulsion solvent diffusion method. Compared with a conventional method for free insulin encapsulation, direct dissolution of SDS-paired insulin in the non-aqueous organic phase led to an increase in drug recovery from 42.5% to 89.6%. The more hydrophobic complex contributes to the improved affinity of insulin to the polymer matrix, resulting in a higher drug content in the nanoparticles. The drug loading was investigated by determining initial burst release at the first 30 min. The results showed that 64.8% of recovered drug were preferentially surface bound on complex loaded nanoparticles. The in vitro drug release was characterized by an initial burst and subsequent delayed release in dissolution media of deionized water and phosphate buffer saline (PBS). Compared with that in PBS, nanoparticles in deionized water medium presented very low initial burst release (15% vs. 65%) and incomplete cumulative release (25% vs. 90%) of the drug. In addition, dialysis experiments were performed to clarify the form of the released insulin in the dissolution media. The results suggested that the ion-pair complex was sensitive to ionic strength, insulin was released from the particular matrix as complex form and subsequently suffered dissociation from SDS in buffer saline. Moreover, the in vivo bioactivity of the SDS-paired insulin and nanoparticulate formulations were evaluated in mice by estimation of their blood sugar levels. The results showed that the bioactivity of insulin was unaltered after the ion-pairing process.

Clinical utility of insulin and insulin analogs

PubMed Central

Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

2013-01-01

Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

Treatment of severe insulin resistance in pregnancy with 500 units per milliliter of concentrated insulin.

PubMed

Mendez-Figueroa, Hector; Maggio, Lindsay; Dahlke, Joshua D; Daley, Julie; Lopes, Vrishali V; Coustan, Donald R; Rouse, Dwight J

2013-07-01

To evaluate glycemic control and pregnancy outcomes among pregnant women with severe insulin resistance treated with 500 units/mL concentrated insulin. Retrospective analysis of gravid women with severe insulin resistance (need for greater than 100 units of insulin per injection or greater than 200 units/d) treated with either 500 units/mL concentrated insulin or conventional insulin therapy. We performed a two-part analysis: 1) between gravid women treated with and without 500 units/mL concentrated insulin; and 2) among gravid women treated with 500 units/mL concentrated insulin, comparing glycemic control before and after its initiation. Seventy-three pregnant women with severe insulin resistance were treated with 500 units/mL concentrated insulin and 78 with conventional insulin regimens. Patients treated with 500 units/mL concentrated insulin were older and more likely to have type 2 diabetes mellitus. Average body mass index was comparable between both groups (38.6 compared with 40.4, P=.11) as were obstetric and perinatal outcomes and glycemic control during the last week of gestation. Within the 500 units/mL concentrated insulin cohort, after initiation of this medication, fasting and postprandial blood glucose concentrations improved. However, the rates of blood glucose values less than 60 mg/dL and less than 50 mg/dL were higher in the 500 units/mL concentrated insulin group after initiation than before, 4.8% compared with 2.0% (P<.01) and 2.0% compared with 0.7% (P<.01), respectively. The use of 500 units/mL concentrated insulin in severely obese insulin-resistant pregnant women confers similar glycemic control compared with traditional insulin regimens but may increase the risk of hypoglycemia. II.

Influence of initial insulin dosage on blood glucose dynamics of children and adolescents with newly diagnosed type 1 diabetes mellitus.

PubMed

Wang, Yi; Gong, Chunxiu; Cao, Bingyan; Meng, Xi; Wei, Liya; Wu, Di; Liang, Xuejun; Li, Wenjing; Liu, Min; Gu, Yi; Su, Chang

2017-05-01

To investigate the effect of initial insulin dosage on blood glucose (BG) dynamics, β-cell protection, and oxidative stress in type 1 diabetes mellitus. Sixty newly diagnosed type 1 diabetes mellitus patients were randomly assigned to continuous subcutaneous insulin infusions of 0.6 ± 0.2 IU/kg/d (group 1), 1.0 ± 0.2 IU/kg/d (group 2), or 1.4 ± 0.2 IU/kg/d (group 3) for 3 wk. BG was monitored continuously for the first 10 d and the last 2 d of wk 2 and 3. A total of 24-hour urinary 8-iso-PGF2α was assayed on days 8, 9, and 10. The occurrence and duration of the honeymoon period were recorded. Fasting C-peptide and glycosylated hemoglobin (HbA1c) were assayed after 1, 6, and 12 months of insulin treatment. BG decreased to the target range by the end of wk 3 (group 1), wk 2 (group 2), or wk 1 (group 3). The actual insulin dosage over the 3 wk, frequency of hypoglycemia on wk 1 and 2, and median BG at the end of wk 1 differed significantly, but not 8-iso-PGF2α and the honeymoon period in the three groups. No severe hypoglycemia event was observed in any patient, but there was significant difference in the first occurrence of hypoglycemia. Differences in initial insulin dosage produced different BG dynamics in wk 1, equivalent BG dynamics on wk 2 and 3, but had no influence on short- and long-term BG control and honeymoon phase. The wide range of initial insulin dosage could be chosen if guided by BG monitoring. © 2016 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.

Optimizing the combination insulin bolus split for a high-fat, high-protein meal in children and adolescents using insulin pump therapy.

PubMed

Lopez, P E; Smart, C E; McElduff, P; Foskett, D C; Price, D A; Paterson, M A; King, B R

2017-10-01

To determine the optimum combination bolus split to maintain postprandial glycaemia with a high-fat and high-protein meal in young people with Type 1 diabetes. A total of 19 young people (mean age 12.9 ± 6.7 years) participated in a randomized, repeated-measures trial comparing postprandial glycaemic control across six study conditions after a high-fat and high-protein meal. A standard bolus and five different combination boluses were delivered over 2 h in the following splits: 70/30 = 70% standard /30% extended bolus; 60/40=60% standard/40% extended bolus; 50/50=50% standard/50% extended bolus; 40/60=40% standard/60% extended bolus; and 30/70=30% standard/70% extended bolus. Insulin dose was determined using the participant's optimized insulin:carbohydrate ratio. Continuous glucose monitoring was used to assess glucose excursions for 6 h after the test meal. Standard bolus and combination boluses 70/30 and 60/40 controlled the glucose excursion up to 120 min. From 240 to 300 min after the meal, the glucose area under the curve was significantly lower for combination bolus 30/70 compared with standard bolus (P=0.004). High-fat and high-protein meals require a ≥60% insulin:carbohydrate ratio as a standard bolus to control the initial postprandial rise. Additional insulin at an insulin:carbohydrate ratio of up to 70% is needed in the extended bolus for a high fat and protein meal to prevent delayed hyperglycaemia. © 2017 Diabetes UK.

Longitudinal Associations Among Religiousness, Delay Discounting, and Substance Use Initiation in Early Adolescence

PubMed Central

Kim-Spoon, Jungmeen; McCullough, Michael E.; Bickel, W. K.; Farley, Julee P.; Longo, Gregory S.

2014-01-01

Prior research indicates that religiousness is related negatively to adolescent health risk behaviors, yet how such protective effects operate is not well understood. This study examined the longitudinal associations among organizational and personal religiousness, delay discounting, and substance use initiation (alcohol, cigarette, and marijuana use). The sample comprised 106 early adolescents (10-13 years of age, 52% female) who were not using substances at Time 1. Path analyses suggested that high levels of personal religiousness at Time 1 were related to low levels of substance use at Time 2 (2.4 years later), mediated by low levels of delay discounting. Delay discounting appears to be an important contributor to the protective effect of religiousness on the development of substance use among adolescents. PMID:25750491

Longitudinal Associations Among Religiousness, Delay Discounting, and Substance Use Initiation in Early Adolescence.

PubMed

Kim-Spoon, Jungmeen; McCullough, Michael E; Bickel, W K; Farley, Julee P; Longo, Gregory S

2015-03-01

Prior research indicates that religiousness is related negatively to adolescent health risk behaviors, yet how such protective effects operate is not well understood. This study examined the longitudinal associations among organizational and personal religiousness, delay discounting, and substance use initiation (alcohol, cigarette, and marijuana use). The sample comprised 106 early adolescents (10-13 years of age, 52% female) who were not using substances at Time 1. Path analyses suggested that high levels of personal religiousness at Time 1 were related to low levels of substance use at Time 2 (2.4 years later), mediated by low levels of delay discounting. Delay discounting appears to be an important contributor to the protective effect of religiousness on the development of substance use among adolescents.

Insulin-like molecules in the beetle Tenebrio molitor.

PubMed

Sevala, V M; Sevala, V L; Loughton, B G

1993-07-01

Immunocytochemical staining of the nervous system of larva, pupa, and adult stage of Tenebrio molitor with anti-insulin serum demonstrated insulin-like peptides in the protocerebrum, corpora allata, and suboesophageal ganglion. During pupal development, marked changes in staining intensity of the protocerebral cells were detected. The staining pattern suggests release of insulin-like peptides early on day 0 and again on day 3 of the stadium. Injections of anti-insulin at these times caused significant delays in the timing of pupal/adult ecdysis. An immunoblot of haemolymph from day-3 pupae revealed a 6.5-kDa insulin-like molecule. These results suggest that the prothoracicotropic hormone of T. molitor is an insulin-like molecule.

Data on insulin therapy refusal among type II diabetes mellitus patients in Mashhad, Iran.

PubMed

Mostafavian, Zahra; Ghareh, Sahar; Torabian, Farnaz; Yazdi, Mohammad Sarafraz; Khazaei, Mahmood Reza

2018-06-01

Insulin has been considered as a therapy option of last resort in type 2 diabetes (T2DM) management. Delay in insulin therapy is common in these patients. This study collected the data on the factors associated with insulin refusal in poorly controlled T2DM patients prior to insulin therapy. The data collected from two endocrinology outpatient clinics affiliated by Islamic Azad University of Mashhad, Iran (IAUM) from January 2016 to September 2017. Study population was adults with non-insulin-using type 2 diabetes mellitus who refused insulin therapy. A 17-items researcher made questionnaire was used to obtain demographic data and information toward causes of insulin refusal. Data were analyzed using SPPS V.16 with descriptive and analytical tests such as multiple logistic regressions. The data of 110 patients with T2DM was recorded in this study. The most prevalent cause of insulin therapy refusal was reported to be painful insulin injection (78.2%) followed by this item "I'm afraid of injecting myself with a needle" (74.5%). Regression analysis revealed that education level had a significant association with the item of "Injecting insulin is painful" (P=0.033, OR=0.357). Also age (P=0.025, OR=1.076) and disease duration (P=0.024, OR=0.231) were significantly associated with the question "taking insulin makes life less flexible". Several causes have been found regarding misconceptions about insulin therapy in T2DM patients. Specialized educational interventions are recommended for initiating successful insulin therapy in these patients.

Hypoglycemia After Initiation of Basal Insulin in Patients with Type 2 Diabetes in the United States: Implications for Treatment Discontinuation and Healthcare Costs and Utilization.

PubMed

Dalal, Mehul R; Kazemi, Mahmood; Ye, Fen; Xie, Lin

2017-09-01

Hypoglycemia and fear of hypoglycemia may contribute to basal insulin discontinuation, poor glycemic control, and increased healthcare burden in patients with type 2 diabetes (T2D). This study aimed to determine the impact of hypoglycemia soon after basal insulin initiation on treatment discontinuation and economic outcomes in patients with T2D. Hypoglycemic events within 6 months of basal insulin initiation were identified using retrospective cohort data from patients with T2D, at least 18 years of age, initiated on basal insulin therapy in the Clinformatics™ Data Mart for Multiplan claims database from January 1, 2008, through August 31, 2012. Data were adjusted for baseline characteristics. Discontinuation was established for patients with 12-month follow-up data, while discontinuation risk was assessed in the extended analysis (6- to 24-month follow-up) by Cox regression analysis. Healthcare use and costs were determined. Of 55,608 patients, 4.5% experienced hypoglycemia within 6 months of basal insulin initiation. Patients with hypoglycemia were more likely to discontinue basal insulin within 12 months of initiation (79.0% vs. 74.2%; P < 0.001). Data, adjusted for baseline characteristics such as age, any baseline hypoglycemia, and use of oral antidiabetes drugs, showed that patients with hypoglycemia had a greater risk of discontinuation (hazard ratio 1.16; 95% confidence interval 1.03, 1.32; P = 0.0164), were more likely to have a hospitalization (41.0% vs. 24.3%; P < 0.001) or an ED visit (55.8% vs. 35.1%; P < 0.001), and had higher diabetes-related ($13,662 vs. $7506; P < 0.001) and all-cause ($30,719 vs. $19,079; P < 0.001) healthcare costs. US patients with T2D who experienced hypoglycemia within 6 months of basal insulin initiation were more likely to discontinue treatment, accompanied by a greater healthcare burden. Sanofi US, Inc.

Durations and Delays in Care Seeking, Diagnosis and Treatment Initiation in Uncomplicated Pulmonary Tuberculosis Patients in Mumbai, India.

PubMed

Mistry, Nerges; Rangan, Sheela; Dholakia, Yatin; Lobo, Eunice; Shah, Shimoni; Patil, Akshaya

2016-01-01

Timely diagnosis and treatment initiation are critical to reduce the chain of transmission of Tuberculosis (TB) in places like Mumbai, where almost 60% of the inhabitants reside in overcrowded slums. This study documents the pathway from the onset of symptoms suggestive of TB to initiation of TB treatment and examines factors responsible for delay among uncomplicated pulmonary TB patients in Mumbai. A population-based retrospective survey was conducted in the slums of 15 high TB burden administrative wards to identify 153 self-reported TB patients. Subsequently in-depth interviews of 76 consenting patients that fit the inclusion criteria were undertaken using an open-ended interview schedule. Mean total, first care seeking, diagnosis and treatment initiation duration and delays were computed for new and retreatment patients. Patients showing defined delays were divided into outliers and non-outliers for all three delays using the median values. The mean duration for the total pathway was 65 days with 29% of patients being outliers. Importantly the mean duration of first care seeking was similar in new (24 days) and retreatment patients (25 days). Diagnostic duration contributed to 55% of the total pathway largely in new patients. Treatment initiation was noted to be the least among the three durations with mean duration in retreatment patients twice that of new patients. Significantly more female patients experienced diagnostic delay. Major shift of patients from the private to public sector and non-allopaths to allopaths was observed, particularly for treatment initiation. Achieving positive behavioural changes in providers (especially non-allopaths) and patients needs to be considered in TB control strategies. Specific attention is required in counselling of TB patients so that timely care seeking is effected at the time of relapse. Prioritizing improvement of environmental health in vulnerable locations and provision of point of care diagnostics would be

Comparative Effectiveness of Insulin versus Combination Sulfonylurea and Insulin: a Cohort Study of Veterans with Type 2 Diabetes.

PubMed

Min, Jea Young; Griffin, Marie R; Hung, Adriana M; Grijalva, Carlos G; Greevy, Robert A; Liu, Xulei; Elasy, Tom; Roumie, Christianne L

2016-06-01

Type 2 diabetes patients often initiate treatment with a sulfonylurea and subsequently intensify their therapy with insulin. However, information on optimal treatment regimens for these patients is limited. To compare risk of cardiovascular disease (CVD) and hypoglycemia between sulfonylurea initiators who switch to or add insulin. This was a retrospective cohort assembled using national Veterans Health Administration (VHA), Medicare, and National Death Index databases. Veterans who initiated diabetes treatment with a sulfonylurea between 2001 and 2008 and intensified their regimen with insulin were followed through 2011. The association between insulin versus sulfonylurea + insulin and time to CVD or hypoglycemia were evaluated using Cox proportional hazard models in a 1:1 propensity score-matched cohort. CVD included hospitalization for acute myocardial infarction or stroke, or cardiovascular mortality. Hypoglycemia included hospitalizations or emergency visits for hypoglycemia, or outpatient blood glucose measurements <60 mg/dL. Subgroups included age < 65 and ≥ 65 years and estimated glomerular filtration rate ≥ 60 and < 60 ml/min. There were 1646 and 3728 sulfonylurea monotherapy initiators who switched to insulin monotherapy or added insulin, respectively. The 1596 propensity score-matched patients in each group had similar baseline characteristics at insulin initiation. The rate of CVD per 1000 person-years among insulin versus sulfonylurea + insulin users were 49.3 and 56.0, respectively [hazard ratio (HR) 0.85, 95 % confidence interval (CI) 0.64, 1.12]. Rates of first and recurrent hypoglycemia events per 1000 person-years were 74.0 and 100.0 among insulin users compared to 78.9 and 116.8 among sulfonylurea plus insulin users, yielding HR (95 % CI) of 0.94 (0.76, 1.16) and 0.87 (0.69, 1.10), respectively. Subgroup analysis results were consistent with the main findings. Compared to sulfonylurea users who added insulin, those who switched

Factors influencing initial choice of insulin therapy in a large international non-interventional study of people with type 2 diabetes

PubMed Central

Freemantle, N; Balkau, B; Danchin, N; Wang, E; Marre, M; Vespasiani, G; Kawamori, R; Home, P D

2012-01-01

Aim To use baseline characteristics of the Cardiovascular Risk Evaluation in people with type 2 Diabetes on Insulin Therapy study population to identify factors that could explain the choice of insulin therapy when beginning insulin. Methods The source, non-interventional, longitudinal, long-term study involves 314 centres in 12 countries in five regions. People were enrolled having started any insulin regimen in the previous 12 months. To identify factors associated with the choice of insulin regimen, multivariable backward logistic regression was performed on eligible physician and participant explanatory variables. Results Participants (N = 3031) had mean age 62 years, diabetes duration 11 years, body mass index 29.3 kg/m2 and an HbA1c of 9.5%. Participants in Japan had less hypertension, smoked more and used fewer concomitant medications than those of other regions. Only physician location (rural or urban) influenced the choice of insulin in Japan. In the other four-regions-combined, physician location, specialty, sex and practice type influenced choice of insulin as did participant location, baseline HbA1c, use of glucose-lowering therapies and prior insulin secretagogue use. Conclusion Choice of initial insulin regimen was influenced by several physician and participant characteristics in Canada and Europe, but only by physician location in Japan. PMID:22519930

Prepubertal exposure to arsenic(III) suppresses circulating insulin-like growth factor-1 (IGF-1) delaying sexual maturation in female rats.

PubMed

Reilly, Michael P; Saca, James C; Hamilton, Alina; Solano, Rene F; Rivera, Jesse R; Whitehouse-Innis, Wendy; Parsons, Jason G; Dearth, Robert K

2014-04-01

Arsenic (As) is a prevalent environmental toxin readily accessible for human consumption and has been identified as an endocrine disruptor. However, it is not known what impact As has on female sexual maturation. Therefore, in the present study, we investigated the effects of prepubertal exposure on mammary gland development and pubertal onset in female rats. Results showed that prepubertal exposure to 10 mg/kg of arsenite (As(III)) delayed vaginal opening (VO) and prepubertal mammary gland maturation. We determined that As accumulates in the liver, disrupts hepatocyte function and suppresses serum levels of the puberty related hormone insulin-like growth factor 1 (IGF-1) in prepubertal animals. Overall, this is the first study to show that prepubertal exposure to As(III) acts peripherally to suppress circulating levels of IGF-1 resulting in delayed sexual maturation. Furthermore, this study identifies a critical window of increased susceptibility to As(III) that may have a lasting impact on female reproductive function. Copyright © 2013 Elsevier Inc. All rights reserved.

Insulin therapy refusal among type II diabetes mellitus patients in Kubang Pasu district, the state of Kedah, Malaysia.

PubMed

Tan, Wei Leong; Asahar, Siti Fairus; Harun, Noor Liani

2015-04-01

Diabetes mellitus is a rising non-communicable disease in Malaysia. Insulin therapy refusal is a great challenge for healthcare providers, as it results in delayed insulin initiation. This study was conducted to determine the prevalence of insulin therapy refusal and its associated factors. This cross sectional study was conducted at seven public health clinics in Kubang Pasu district, Malaysia, from March to October 2012. A newly developed and validated questionnaire was used and participants were selected via systematic random sampling. Only patients diagnosed with type II diabetes mellitus (T2DM) and under the public health clinic care in Kubang Pasu were included in the study. Multiple logistic regressions were used to study the association between insulin therapy refusal and its associated factors. There were 461 respondents and the response rate was 100%. Among these 461 patients with T2DM, 74.2% refused insulin therapy. The most common reason given for refusal was a lack of confidence in insulin injection (85.4%). Multiple logistic regression revealed that respondents who had secondary education were 55.0% less likely to refuse insulin therapy than those who had primary or no formal education (p = 0.009, adjusted odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.25-0.82). There was also a significant inverse association between glycated haemoglobin (HbA1c) and insulin therapy refusal (p = 0.047, adjusted OR = 0.87, 95% CI = 0.76-1.00). Insulin therapy refusal is common in Kubang Pasu. Education status and HbA1c should be taken into consideration when counselling patients on insulin therapy initiation.

Comparison of prandial AIR inhaled insulin alone to intensified insulin glargine alone and to AIR insulin plus intensified insulin glargine in patients with type 2 diabetes previously treated with once-daily insulin glargine.

PubMed

Rosenstock, Julio; Eliaschewitz, Freddy G; Heilmann, Cory R; Muchmore, Douglas B; Hayes, Risa P; Belin, Ruth M

2009-09-01

Patients with type 2 diabetes often initiate insulin with once-daily basal insulin. Over time, many patients intensify their insulin regimens in an attempt to attain and sustain glycemic targets. This study compares three intensification approaches: changing insulin glargine to preprandial AIR inhaled insulin (developed by Alkermes, Inc. [Cambridge, MA] and Eli Lilly and Company [Indianapolis, IN]; AIR is a registered trademark of Alkermes, Inc.), intensifying glargine via validated titration algorithms (IG), or adding AIR insulin while intensifying glargine (AIR + IG). Five hundred sixty patients with hemoglobin A(1c) (A1C) of 7.5-10.5%, on one or more antihyperglycemic medications, and on once-daily insulin glargine for > or =4 months were randomly allocated to one of the three treatments lasting 52 weeks. The primary objective assessed between-group differences in A1C mean change from baseline to 24 weeks using last-observation-carried-forward (LOCF) in the intent-to-treat population. At 24 weeks, A1C was reduced from a mean baseline of 8.5% to 7.7%, 7.9%, and 7.5% for the AIR, IG, and AIR + IG groups, respectively. AIR produced 0.20% greater A1C decrease than IG (least-squares mean difference = -0.20%; 95% confidence interval [CI], -0.39, -0.02). AIR + IG had a 0.35% greater A1C decrease versus IG (95% CI, -0.57, -0.13). The -0.15% difference between AIR + IG versus AIR was not significant (P < 0.198). More hypoglycemia categorized as severe occurred with AIR alone versus IG alone at LOCF end points. More nocturnal hypoglycemia occurred with IG alone versus AIR alone and AIR + IG. Preprandial inhaled insulin provides an alternative for patients not optimized on insulin glargine alone. Glycemic control, hypoglycemic risk, delivery preference, and regimen complexity must be considered when selecting insulin initiation and optimization regimens.

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled With Newly Initiated and Continuously Titrated Basal Insulin Glargine

PubMed Central

Riddle, Matthew C.; Forst, Thomas; Aronson, Ronnie; Sauque-Reyna, Leobardo; Souhami, Elisabeth; Silvestre, Louise; Ping, Lin; Rosenstock, Julio

2013-01-01

OBJECTIVE When oral therapy for type 2 diabetes is ineffective, adding basal insulin improves glycemic control. However, when glycated hemoglobin (HbA1c) remains elevated because of postprandial hyperglycemia, the next therapeutic step is controversial. We examined the efficacy and safety of lixisenatide in patients with HbA1c still elevated after initiation of insulin glargine. RESEARCH DESIGN AND METHODS This double-blind, parallel-group trial enrolled patients with HbA1c 7–10% despite oral therapy. Insulin glargine was added and systematically titrated during a 12-week run-in, after which candidates with fasting glucose ≤7.8 mmol/L and HbA1c 7–9% were randomized to lixisenatide 20 µg or placebo for 24 weeks while insulin titration continued. The primary end point was HbA1c change after randomization. RESULTS The randomized population (n = 446) had mean diabetes duration of 9.2 years, BMI 31.8 kg/m2, and daily glargine dosage of 44 units. HbA1c had decreased during run-in from 8.6 to 7.6%; adding lixisenatide further reduced HbA1c by 0.71 vs. 0.40% with placebo (least squares mean difference, –0.32%; 95% CI, –0.46 to –0.17; P < 0.0001). More participants attained HbA1c <7% with lixisenatide (56 vs. 39%; P < 0.0001). Lixisenatide reduced plasma glucose 2 h after a standardized breakfast (difference vs. placebo –3.2 mmol/L; P < 0.0001) and had a favorable effect on body weight (difference vs. placebo –0.89 kg; P = 0.0012). Nausea, vomiting, and symptomatic hypoglycemia <3.3 mmol/L were more common with lixisenatide. CONCLUSIONS Adding lixisenatide to insulin glargine improved overall and postprandial hyperglycemia and deserves consideration as an alternative to prandial insulin for patients not reaching HbA1c goals with recently initiated basal insulin. PMID:23564915

Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.

PubMed

Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and

EADSG Guidelines: Insulin Therapy in Diabetes.

PubMed

Silver, Bahendeka; Ramaiya, Kaushik; Andrew, Swai Babu; Fredrick, Otieno; Bajaj, Sarita; Kalra, Sanjay; Charlotte, Bavuma M; Claudine, Karigire; Makhoba, Anthony

2018-04-01

A diagnosis of diabetes or hyperglycemia should be confirmed prior to ordering, dispensing, or administering insulin (A). Insulin is the primary treatment in all patients with type 1 diabetes mellitus (T1DM) (A). Typically, patients with T1DM will require initiation with multiple daily injections at the time of diagnosis. This is usually short-acting insulin or rapid-acting insulin analogue given 0 to 15 min before meals together with one or more daily separate injections of intermediate or long-acting insulin. Two or three premixed insulin injections per day may be used (A). The target glycated hemoglobin A1c (HbA1c) for all children with T1DM, including preschool children, is recommended to be < 7.5% (< 58 mmol/mol). The target is chosen aiming at minimizing hyperglycemia, severe hypoglycemia, hypoglycemic unawareness, and reducing the likelihood of development of long-term complications (B). For patients prone to glycemic variability, glycemic control is best evaluated by a combination of results with self-monitoring of blood glucose (SMBG) (B). Indications for exogenous insulin therapy in patients with type 2 diabetes mellitus (T2DM) include acute illness or surgery, pregnancy, glucose toxicity, contraindications to or failure to achieve goals with oral antidiabetic medications, and a need for flexible therapy (B). In T2DM patients, with regards to achieving glycemic goals, insulin is considered alone or in combination with oral agents when HbA1c is ≥ 7.5% (≥ 58 mmol/mol); and is essential for treatment in those with HbA1c ≥ 10% (≥ 86 mmol/mol), when diet, physical activity, and other antihyperglycemic agents have been optimally used (B). The preferred method of insulin initiation in T2DM is to begin by adding a long-acting (basal) insulin or once-daily premixed/co-formulation insulin or twice-daily premixed insulin, alone or in combination with glucagon-like peptide-1 receptor agonist (GLP-1 RA) or in combination with other oral antidiabetic

Consensus on Insulin Dose and Titration Algorithms in Ambulatory Care of Type 2 Diabetes in India.

PubMed

Kovil, Rajiv; Chawla, Manoj; Rajput, Rajesh; Singh, A K; Sinha, Binayak; Ghosal, Samit; Ballani, Piya; Gupta, Sunil; Tanna, Snehal; Bandukwala, S M; Shah, Tejas; Negalur, Vijay; Bhoraskar, Anil; Aravind, S R; Zargar, Abdul H; Kesavadev, Jothydev; Das, Ashok Kumar

2017-02-01

Insulin is the oldest of the currently available treatment options in Type 2 diabetes mellitus (T2DM) and is considered as the most effective glucose lowering agent. Despite this, decision on starting insulin therapy is often delayed in India as well as worldwide due to various barriers at both patient and physician levels. Appropriate insulin dosing and titration is also critical to the successful achievement of tight glycaemic control. To provide simple and easily implementable guidelines to primary care physicians on appropriate insulin dosing and titration of various insulin regimens for both initiation and intensification. Each insulin regimen (once daily [OD] basal, OD, twice daily and thrice daily premixed, basal-plus and basal-bolus) was presented and evaluated for dosing and titration based on established guidelines, data from approved pack inserts, and published scientific literature. These evaluations were then factored into the national context based on the expert committee representatives patient-physician experience in their clinical practice and common therapeutic practices followed in India. Recommendations for dosing and titration of basal, basal-plus, premixed and basal-bolus insulins were developed. The key recommendations are that insulin doses can be adjusted once or twice weekly; adjustment can be based on lowest/mean of three recent self-monitoring of plasma glucose pre-meal/fasting plasma glucose (FPG) values. The titration should be based on FPG or pre-meal value of 80-130 mg/dL and the dose should be reduced by 10-20% for patients reporting hypoglycaemia(<70mg/dL). The consensus based recommendations mentioned in this paper will be a useful reference tool for health care practitioners, to initiate, optimise and intensify insulin therapy and to successfully achieve optimal glucose control.

[Impact of care pathway on the delay for initiation of antituberculosis treatment in Conakry, Guinea].

PubMed

Camara, A; Bah-Sow, O Y; Baldé, N M; Camara, L M; Barry, I S; Bah, B; Diallo, M; Chaperon, J; Riou, F

2009-06-01

Complex care pathways can result in detrimental treatment delay particularly in tuberculosis patients. The purpose of this retrospective study was to assess the care pathways followed by tuberculosis patients prior to diagnosis and to assess impact on the delay for initiation of treatment in Conakry, Guinea. A total of 112 patients were interviewed at the time of first admission for pulmonary tuberculosis with positive bacilloscopy. Based on interview data, pathways were classified as conventional (use of health care facilities only) and mixed (use of health care facilities, self-medication, and traditional medicine). The correlation between patient characteristics and type of pathway was assessed by univariate and multivariate analysis and the two groups, i.e., conventional vs. mixed, were compared with regard to delay for initiation of treatment. The care pathway was classified as mixed in two out of three patients. Multivariate analysis showed that this type of pathway was only correlated with schooling (p=0.02). The mean delay for treatment was similar, i.e., 13.4 and 12.8 weeks for conventional and mixed pathways respectively (p<0.68). The percentage of pathways including three consultations at health care facilities was significantly higher in the conventional than mixed group (72% vs. 30%, p<0.001). The main reasons given for delayed use of health care facilities were poor knowledge of tuberculosis symptoms (26%) and high cost of care (12%). The findings of this study indicate that tuberculosis patients follow a variety of care pathways that can lead to delayed treatment. An information campaign is needed to increase awareness among the population and care providers.

Durations and Delays in Care Seeking, Diagnosis and Treatment Initiation in Uncomplicated Pulmonary Tuberculosis Patients in Mumbai, India

PubMed Central

Mistry, Nerges; Rangan, Sheela; Dholakia, Yatin; Lobo, Eunice; Shah, Shimoni; Patil, Akshaya

2016-01-01

Background Timely diagnosis and treatment initiation are critical to reduce the chain of transmission of Tuberculosis (TB) in places like Mumbai, where almost 60% of the inhabitants reside in overcrowded slums. This study documents the pathway from the onset of symptoms suggestive of TB to initiation of TB treatment and examines factors responsible for delay among uncomplicated pulmonary TB patients in Mumbai. Methods A population-based retrospective survey was conducted in the slums of 15 high TB burden administrative wards to identify 153 self-reported TB patients. Subsequently in-depth interviews of 76 consenting patients that fit the inclusion criteria were undertaken using an open-ended interview schedule. Mean total, first care seeking, diagnosis and treatment initiation duration and delays were computed for new and retreatment patients. Patients showing defined delays were divided into outliers and non-outliers for all three delays using the median values. Results The mean duration for the total pathway was 65 days with 29% of patients being outliers. Importantly the mean duration of first care seeking was similar in new (24 days) and retreatment patients (25 days). Diagnostic duration contributed to 55% of the total pathway largely in new patients. Treatment initiation was noted to be the least among the three durations with mean duration in retreatment patients twice that of new patients. Significantly more female patients experienced diagnostic delay. Major shift of patients from the private to public sector and non-allopaths to allopaths was observed, particularly for treatment initiation. Conclusion Achieving positive behavioural changes in providers (especially non-allopaths) and patients needs to be considered in TB control strategies. Specific attention is required in counselling of TB patients so that timely care seeking is effected at the time of relapse. Prioritizing improvement of environmental health in vulnerable locations and provision of

Body composition and concentrations of leptin, neuropeptide Y, beta-endorphin, growth hormone, insulin-like growth factor-I and insulin at menarche in girls with constitutional delay of puberty.

PubMed

Błogowska, Anna; Krzyzanowska-Swiniarska, Barbara; Zielińska, Dorota; Rzepka-Górska, Izabella

2006-05-01

Constitutional delay of puberty (CDP), a rare condition among girls, manifests as retarded sexual maturity past the 13th year of life. The clinical and endocrinological aspects of this interesting problem appear to have escaped attention in the literature. The purpose of the present study was to compare body composition and concentrations of leptin, neuropeptide Y (NPY), beta-endorphin, growth hormone (GH), insulin growth factor-I (IGF-I) and insulin at menarche in CDP girls and girls with normal pubertal development (NP). We enrolled 11 girls with CDP and 40 girls with NP. All participants were studied at or within 3 months of menarche. Age, height and weight were recorded. Body composition was established with a body composition analyzer. Radioimmunoassays were performed to measure concentrations of NPY, beta-endorphin, leptin, GH, IGF-I and insulin. The mean age at menarche in the CDP and NP groups was 16.1 and 12.5 years, respectively (p = 0.0001). CDP girls at menarche were taller (1.64 vs. 1.57 m; p = 0.012). The difference between groups in body weight (57.5 vs. 50.4 kg; p = 0.1), body mass index (BMI), fat mass, fat percentage (BF%) and lean mass was not significant, and nor was the difference in leptin, GH and insulin levels. However, CDP girls demonstrated significantly higher NPY concentrations (199.4+/-105.1 vs. 56.9+/-26.3 pg/ml; p = 0.001). NPY correlated with BF% (r = 0.60) in this group. IGF-I concentrations were significantly lower in CDP girls (524.8+/-50.6 ng/ml) than in NP girls (744.5+/-56.1 ng/ml; p = 0.024). Girls with CDP differed from NP girls only in age at menarche and height; they did not differ significantly with respect to BMI and body composition parameters. Higher concentrations of NPY in CDP girls may be responsible for CDP and reduced levels of IGF-I. Correlation of NPY with BF% suggests an involvement of this neuropeptide in the process of fat accumulation associated with CDP.

Interstitial fluid glucose dynamics during insulin-induced hypoglycaemia.

PubMed

Steil, G M; Rebrin, K; Hariri, F; Jinagonda, S; Tadros, S; Darwin, C; Saad, M F

2005-09-01

Glucose sensors often measure s.c. interstitial fluid (ISF) glucose rather than blood or plasma glucose. Putative differences between plasma and ISF glucose include a protracted delay during the recovery from hypoglycaemia and an increased gradient during hyperinsulinaemia. These have often been investigated using sensor systems that have delays due to signal smoothing, or require long equilibration times. The aim of the present study was to define these relationships during hypoglycaemia in a well-equilibrated system with no smoothing. Hypoglycaemia was induced by i.v. insulin infusion (360 pmol.m(-2).min(-1)) in ten non-diabetic subjects. Glucose was sequentially clamped at approximately 5, 4.2 and 3.1 mmol/l and allowed to return to normoglycaemia. Subjects wore two s.c. glucose sensors (Medtronic MiniMed, Northridge, CA, USA) that had been inserted for more than 12 h. A two-compartment model was used to quantify the delay and gradient. The delay during the fall in plasma glucose was not different from the delay during recovery (8.3+/-0.67 vs 6.3+/-1.1 min; p=0.27) and no differences were observed in the ratio of sensor current to plasma glucose at basal insulin (2.7+/-0.25 nA.mmol(-1).l) compared with any of the hyperinsulinaemic clamp phases (2.8+/-0.18, 2.7+/-0.021, 2.9+/-0.21; p=NS). The ratio was significantly elevated following recovery to normoglycaemia (3.1+/-0.2 nA.mmol(-1).l; p<0.001). The elevated ratio suggests that the plasma to ISF glucose gradient was decreased following hypoglycaemia, possibly due to increased skin blood flow. Recovery from hypoglycaemia is not accompanied by a protracted delay and insulin does not increase the plasma to s.c. ISF glucose gradient.

Misadventures in insulin therapy: are you at risk?

PubMed Central

Grissinger, Matthew; Lease, Michael

2003-01-01

About dollar 1 out of every dollar 7 spent on health care is related to diabetes mellitus, a leading cause of blindness and kidney failure and a strong risk factor for heart disease. Prevalence of the disease has increased by a third among adults in general in the last decade, but intensive therapy has been shown to delay the onset and slow the progression of diabetes-related complications. While insulin therapy remains key in the management of type 1 diabetes, many patients with type 2, or insulin-resistant, diabetes encounter insulin administration errors that compromise the quality of insulin delivery. Insulin errors are a major, but modifiable, barrier to dosing accuracy and optimal diabetes control for many patients. Future trends to combat the problem include increased use of insulin inhalers and smaller doses of rapid- or short-acting insulin to supplement longer-acting injections. PMID:12653373

Insulin use and persistence in patients with type 2 diabetes adding mealtime insulin to a basal regimen: a retrospective database analysis

PubMed Central

2011-01-01

Background The objective of this study was to characterize insulin use and examine factors associated with persistence to mealtime insulin among patients with type 2 diabetes (T2D) on stable basal insulin therapy initiating mealtime insulin therapy. Methods Insulin use among patients with T2D initiating mealtime insulin was investigated using Thomson Reuters MarketScan® research databases from July 2001 through September 2006. The first mealtime insulin claim preceded by 6 months with 2 claims for basal insulin was used as the index event. A total of 21 months of continuous health plan enrollment was required. Patients were required to have a second mealtime insulin claim during the 12-month follow-up period. Persistence measure 1 defined non-persistence as the presence of a 90-day gap in mealtime insulin claims, effective the date of the last claim prior to the gap. Persistence measure 2 required 1 claim per quarter to be persistent. Risk factors for non-persistence were assessed using logistic regression. Results Patients initiating mealtime insulin (n = 4752; 51% male, mean age = 60.3 years) primarily used vial/syringe (87%) and insulin analogs (60%). Patients filled a median of 2, 3, and 4 mealtime insulin claims at 3, 6, and 12 months, respectively, with a median time of 76 days between refills. According to measure 1, persistence to mealtime insulin was 40.7%, 30.2%, and 19.1% at 3, 6, and 12 months, respectively. Results for measure 2 were considerably higher: 74.3%, 55.3%, and 42.2% of patients were persistent at 3, 6, and 12 months, respectively. Initiating mealtime insulin with human insulin was a risk factor for non-persistence by both measures (OR < 0.80, p < 0.01). Additional predictors of non-persistence at 12 months included elderly age, increased insulin copayment, mental health comorbidity, and polypharmacy (p < 0.05 for all). Conclusions Mealtime insulin use and persistence were both considerably lower than expected, and were significantly lower

Delays before Diagnosis and Initiation of Treatment in Patients Presenting to Mental Health Services with Bipolar Disorder

PubMed Central

Patel, Rashmi; Shetty, Hitesh; Jackson, Richard; Broadbent, Matthew; Stewart, Robert; Boydell, Jane; McGuire, Philip; Taylor, Matthew

2015-01-01

Background Bipolar disorder is a significant cause of morbidity and mortality. Although existing treatments are effective, there is often a substantial delay before diagnosis and treatment initiation. We sought to investigate factors associated with the delay before diagnosis of bipolar disorder and the onset of treatment in secondary mental healthcare. Method Retrospective cohort study using anonymised electronic mental health record data from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register on 1364 adults diagnosed with bipolar disorder between 2007 and 2012. The following predictor variables were analysed in a multivariable Cox regression analysis: age, gender, ethnicity, compulsory admission to hospital under the UK Mental Health Act, marital status and other diagnoses prior to bipolar disorder. The outcomes were time to recorded diagnosis from first presentation to specialist mental health services (the diagnostic delay), and time to the start of appropriate therapy (treatment delay). Results The median diagnostic delay was 62 days (interquartile range: 17–243) and median treatment delay was 31 days (4–122). Compulsory hospital admission was associated with a significant reduction in both diagnostic delay (hazard ratio 2.58, 95% CI 2.18–3.06) and treatment delay (4.40, 3.63–5.62). Prior diagnoses of other psychiatric disorders were associated with increased diagnostic delay, particularly alcohol (0.48, 0.33–0.41) and substance misuse disorders (0.44, 0.31–0.61). Prior diagnosis of schizophrenia and psychotic depression were associated with reduced treatment delay. Conclusions Some individuals experience a significant delay in diagnosis and treatment of bipolar disorder after initiation of specialist mental healthcare, particularly those who have prior diagnoses of alcohol and substance misuse disorders. These findings highlight a need for further study on strategies to better identify

Delays before Diagnosis and Initiation of Treatment in Patients Presenting to Mental Health Services with Bipolar Disorder.

PubMed

Patel, Rashmi; Shetty, Hitesh; Jackson, Richard; Broadbent, Matthew; Stewart, Robert; Boydell, Jane; McGuire, Philip; Taylor, Matthew

2015-01-01

Bipolar disorder is a significant cause of morbidity and mortality. Although existing treatments are effective, there is often a substantial delay before diagnosis and treatment initiation. We sought to investigate factors associated with the delay before diagnosis of bipolar disorder and the onset of treatment in secondary mental healthcare. Retrospective cohort study using anonymised electronic mental health record data from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register on 1364 adults diagnosed with bipolar disorder between 2007 and 2012. The following predictor variables were analysed in a multivariable Cox regression analysis: age, gender, ethnicity, compulsory admission to hospital under the UK Mental Health Act, marital status and other diagnoses prior to bipolar disorder. The outcomes were time to recorded diagnosis from first presentation to specialist mental health services (the diagnostic delay), and time to the start of appropriate therapy (treatment delay). The median diagnostic delay was 62 days (interquartile range: 17-243) and median treatment delay was 31 days (4-122). Compulsory hospital admission was associated with a significant reduction in both diagnostic delay (hazard ratio 2.58, 95% CI 2.18-3.06) and treatment delay (4.40, 3.63-5.62). Prior diagnoses of other psychiatric disorders were associated with increased diagnostic delay, particularly alcohol (0.48, 0.33-0.41) and substance misuse disorders (0.44, 0.31-0.61). Prior diagnosis of schizophrenia and psychotic depression were associated with reduced treatment delay. Some individuals experience a significant delay in diagnosis and treatment of bipolar disorder after initiation of specialist mental healthcare, particularly those who have prior diagnoses of alcohol and substance misuse disorders. These findings highlight a need for further study on strategies to better identify underlying symptoms and offer appropriate treatment sooner

Insulin Oedema in Newly Diagnosed Type 1 Diabetes Mellitus

PubMed Central

Çetinkaya, Semra; Yılmaz Ağladıoğlu, Sebahat; Peltek Kendirici, Havva Nur; Bilgili, Hatice; Yıldırım, Nurdan; Aycan, Zehra

2010-01-01

Despite the essential role of insulin in the management of patients with insulin deficiency, insulin use can lead to adverse effects such as hypoglycaemia and weight gain. Rarely, crucial fluid retention can occur with insulin therapy, resulting in an oedematous condition. Peripheral or generalised oedema is an extremely rare complication of insulin therapy in the absence of heart, liver or renal involvement. It has been reported in newly diagnosed type 1 diabetes, in poorly controlled type 2 diabetes following the initiation of insulin therapy, and in underweight patients on large doses of insulin. The oedema occurs shortly after the initiation of intensive insulin therapy. We describe two adolescent girls with newly diagnosed type 1 diabetes, who presented with oedema of the lower extremities approximately one week after the initiation of insulin treatment; other causes of oedema were excluded. Spontaneous recovery was observed in both patients. Conflict of interest:None declared. PMID:21274337

Basal insulin initiation in primary vs. specialist care: similar glycaemic control in two different patient populations.

PubMed

Orozco-Beltran, D; Pan, C; Svendsen, A L; Faerch, L; Caputo, S

2016-03-01

To investigate the effect of healthcare provider (HCP) type (primary vs. specialist) on glycaemic control and other treatment parameters. Study of Once-Daily Levemir (SOLVE(™) ) is an international, 24-week, observational study of insulin initiation in people with type 2 diabetes. A total of 17,374 subjects were included, comprising 4144 (23.9%) primary care subjects. Glycaemic control improved in both HCP groups from baseline to final visit [glycated haemoglobin (HbA1c) -1.2 ± 1.4% (-13.1 ± 15.3 mmol/mol) and -1.3 ± 1.6% (-14.2 ± 17.5 mmol/mol), respectively]. After adjustment for known confounders, there was no statistically significant effect of HCP group on final HbA1c [-0.04%, 95% confidence interval (CI) -0.09 to -0.01 (-0.4 mmol/mol, 95% CI -1.0-0.1 mmol/mol), p = 0.1590]. However, insulin doses at the final visit were higher in primary care patients (+0.06, 95% CI 0.06-0.07 U/kg, p < 0.0001). Logistic regression demonstrated a significant effect of HCP type (primary vs. specialist care) on hypoglycaemia risk [odds ratio (OR) 0.75, 95% CI 0.64-0.87, p = 0.0002]. Primary care physicians took more time to train patients and had more frequent contact with patients than specialists (both p < 0.0001). Primary care physicians and specialists achieved comparable improvements in glycaemic control following insulin initiation. © 2016 The Authors. International Journal of Clinical Practice Published by John Wiley & Sons Ltd.

Expectations about insulin therapy, perceived insulin-delivery system social acceptability, and insulin treatment satisfaction contribute to decreases in insulin therapy self-efficacy in patients with type 2 diabetes after 36 weeks insulin therapy.

PubMed

Hayes, Risa P; Curtis, Bradley; Ilag, Liza; Nelson, David R; Wong, Mayme; Funnell, Martha

2013-09-01

Self-efficacy plays a critical role in diabetes self-care. Herein we explore factors contributing to decreased insulin therapy self-efficacy in insulin-naïve patients with type 2 diabetes mellitus (T2DM) initiating and managing insulin therapy over 36 weeks. The study was conducted within an international, randomized clinical trial comparing two insulin therapies administered by insulin pen in patients with T2DM inadequately controlled with oral antihyperglycemic medications. Patients completed the Self-Efficacy about Insulin Therapy Questionnaire (SEITQ) at baseline and endpoint. Patients also completed patient-reported measures assessing expectations about insulin therapy at baseline and perceptions about insulin therapy and insulin-delivery system (IDS) satisfaction at endpoint. Baseline and endpoint SEITQ scores were compared. Using prespecified criteria, patients were classified as having "decreased" or "no change/improved" insulin self-efficacy. Demographic, clinical, and patient-reported variables were entered into a logistic regression model with decreased insulin self-efficacy (yes or no) as the dependent variable. Baseline and endpoint SEITQ data were available for 450 insulin-naïve T2DM patients (mean age 59 years; 53% female; 57% Caucasian; mean baseline HbA1c 9.4%; 80.0 mmol/mol). Insulin therapy self-efficacy improved from baseline to endpoint (74.0 vs 77.5; P<0.001). Logistic regression analysis indicated that lower IDS satisfaction (P<0.0001), lower IDS social acceptability (P=0.004), and more positive expectations of insulin therapy (P<0.0001) were associated with decreased insulin self-efficacy. A candid discussion between clinicians and their insulin-naïve T2DM patients about the benefits and challenges of insulin therapy may prevent unrealistic expectations that could potentially undermine insulin self-efficacy. © 2013 Wiley Publishing Asia Pty Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.

Insulin and IGF1 Receptors Are Essential for XX and XY Gonadal Differentiation and Adrenal Development in Mice

PubMed Central

Romero, Yannick; Conne, Béatrice; Truong, Vy; Papaioannou, Marilena D.; Schaad, Olivier; Docquier, Mylène; Herrera, Pedro Luis; Wilhelm, Dagmar; Nef, Serge

2013-01-01

Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5. PMID:23300479

[Desensitization to human recombinant DNA insulin in an adolescent with insulin-dependent diabetes mellitus].

PubMed

Rosas Vargas, M A; Alvarez Amador, M; Alvarez Amador, L M; del Río Navarro, B E; Avila Castanón, L; Sienra Monge, J J

2001-01-01

Adverse reactions to drugs have increased in the last years, about 15% of all side effects are thought to be immune mediated according to the Coombs and Gell classification they can be type I (immediate) hypersensitivity, type II (cytotoxic) type III (immune complex mediated) or type IV (delay). Allergy to insulin is defined as an immunological response type I, and type II or III to exogenous insulin solutions occurring the 0.1% and 0.2% of the patients. A 13 year old female with a 4-year history of insulin-dependent diabetes mellitus who presented hypersensitivity against recombinant DNA (rDNA) insulin manifested with urticaria and itching. We used a premedication therapy without good response and impossibility to use alternative therapy for her metabolic control, so she needed desensitization with insulin. Skin prick testing with rapid insulin preparations 1:10 W/V dilution were positive. IgE antibodies to insulin weren't presented. IgE serum values were normal. We began the desensitization with a rapid 1:1000 UI insulin solution by intradermal route, than by subcutaneous route until reaching the accumulated doses necessary per day. During the process it appeared a papular rash and itching which were treated with an intravenous antihistaminic without troubles. The patient tolerated the desensitization procedure very well. For the past 14 months she has been treated uneventfully by subcutaneous administration of rDNA insulin. The desensitization against drugs is not a frequently process it only has to be used when it is impossible to substitute the treatment. Our patient showed probably hypersensitivity type 1 to insulin. However, we have to take into account the cytotoxic reaction caused by IgG or IgM antibodies or by immune complex. The desensitization finally was tolerated, 14 months after our patient accepts correctly her daily dose of human recombinant insulin.

Economic Impact of Treatment Duration and Persistence with Basal Insulin in Previously Insulin-Naive Users.

PubMed

Kalirai, Samaneh; Duan, Ran; Liu, Dongju; Reed, Beverly L

2017-03-01

Although insulin is a well-established therapy that is associated with improved clinical outcomes, adherence and persistence with insulin regimens are poor in patients with type 2 diabetes mellitus (T2DM). Diabetes-related health care costs and the impact of insulin persistence patterns on these health care costs have been previously studied; however, these aspects of insulin therapy have limited data beyond the first year of use and have not been characterized among patients previously naive to basal insulin. To (a) describe and compare medical- and pharmacy-related costs, health care resource utilization, and comorbidities and complications during the initial year and second (experienced) year of basal insulin therapy, and (b) describe and compare the impact of continuous versus interrupted basal insulin use during each year. This was a retrospective observational database analysis using claims from multiple U.S. commercial health plans (Truven Health MarketScan) in previously insulin-naive patients with T2DM who were initiated on basal insulin. Data collected included all-cause and diabetes-related medical and pharmacy costs, health care resource utilization (i.e., number and type of outpatient visits, hospitalization, emergency department [ED] visits), medication use, and preselected comorbidities and complications. This cost analysis described and compared health care costs and resource use between the initial and experienced years and further compared health care costs and resource use between continuers and interrupters within each of those years. A total of 23,645 patients were included in the analysis; 12,224 were classified as continuers and 11,421 were classified as interrupters. Among all patients, mean increases from the initial year to the experienced year were observed for all-cause medical costs ($12,690-$13,408; P = 0.048), all-cause pharmacy costs ($6,253-$6,559; P < 0.001), and all-cause health care costs ($18,943-$19,967; P = 0.006), after

Insulin Delivery System

NASA Technical Reports Server (NTRS)

1988-01-01

When Programmable Implantable Medication System (PIMS) is implanted in human body, it delivers precise programmed amounts of insulin over long periods of time. Mini-Med Technologies has been refining the Technologies since initial development at APL. The size of a hockey puck, and encased in titanium shell, PIMS holds about 2 1/2 teaspoons of insulin at a programmed basal rate. If a change in measured blood sugar level dictates a different dose, the patient can vary the amount of insulin delivered by holding a small radio transceiver over the implanted system and dialing in a specific program held in the PIMS computer memory. Insulin refills are accomplished approximately 4 times a year by hypodermic needle.

Patient-level meta-analysis of efficacy and hypoglycaemia in people with type 2 diabetes initiating insulin glargine 100U/mL or neutral protamine Hagedorn insulin analysed according to concomitant oral antidiabetes therapy.

PubMed

Owens, David R; Traylor, Louise; Mullins, Peter; Landgraf, Wolfgang

2017-02-01

Evaluate efficacy and hypoglycaemia according to concomitant oral antidiabetes drug (OAD) in people with type 2 diabetes initiating insulin glargine 100U/mL (Gla-100) or neutral protamine Hagedorn (NPH) insulin once daily. Four studies (target fasting plasma glucose [FPG] ⩽100mg/dL [⩽5.6mmol/L]; duration ⩾24weeks) were included. Standardised data from 2091 subjects (Gla-100, n=1024; NPH insulin, n=1067) were analysed. Endpoints included glycated haemoglobin (HbA1c) and FPG change, glycaemic target achievement, hypoglycaemia, weight change, and insulin dose. Mean HbA1c and FPG reductions were similar with Gla-100 and NPH insulin regardless of concomitant OAD (P=0.184 and P=0.553, respectively) and similar proportions of subjects achieved HbA1c <7.0% (P=0.603). There was a trend for more subjects treated with Gla-100 achieving FPG ⩽100mg/dL versus NPH insulin (relative risk [RR] 1.09 [95% confidence interval (CI) 0.97-1.23]; P=0.135). Plasma glucose confirmed (<70mg/dL) overall and nocturnal hypoglycaemia incidences and rates were lower with Gla-100 versus NPH insulin (overall RR 0.93 [95% CI 0.87-1.00]; P=0.041; nocturnal RR 0.73 [95% CI 0.65-0.83]; P<0.001). After 24weeks, weight gain and insulin doses were higher with Gla-100 versus NPH insulin (2.7kg vs 2.3kg, P=0.009 and 0.42U/kg vs 0.39U/kg; P=0.003, respectively). Insulin doses were higher when either insulin was added to sulfonylurea alone. Pooled results from treat-to-target trials in insulin-naïve people with type 2 diabetes demonstrate a significantly lower overall and nocturnal hypoglycaemia risk across different plasma glucose definitions with Gla-100 versus NPH insulin at similar glycaemic control. OAD therapy co-administered with Gla-100 or NPH insulin impacts glycaemic control and overall nocturnal hypoglycaemia risk. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin.

PubMed

Morris, Jill K; Vidoni, Eric D; Mahnken, Jonathan D; Montgomery, Robert N; Johnson, David K; Thyfault, John P; Burns, Jeffrey M

2016-03-01

Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p < 0.0001) and no change in performance on an additional task (delayed logical memory). In this study, although insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND

Effect of Different Insulin Response Patterns During Oral Glucose Tolerance Test on Glycemia in Individuals with Normal Glucose Tolerance.

PubMed

Praveen, Edavan Pulikkanath; Chouhan, Sunil; Sahoo, Jayaprakash; Goel, Sudhir K; Dwivedi, Sada Nand; Khurana, Madan Lal; Kulshreshtha, Bindu; Ammini, Ariachery C

2016-05-01

Research is still going on for detecting the earliest glucose homeostasis derangements in individuals, which is crucial for the prevention of glucose intolerance. This cross-sectional study analyzes different insulin response patterns during the oral glucose tolerance test (OGTT) and their implications on glycemia in normoglycemic individuals. The sample frame was the "Offspring of Individuals with Diabetes Study" database. All participants underwent OGTT. Blood samples were collected at 0, 30, 60, and 120 min for measurement of insulin, C-peptide, and proinsulin levels. Normal glucose tolerant individuals were selected for analysis. Four hundred fifty subjects (mean age, 25 years) were included and divided into two groups according to timing of plasma insulin peaking during OGTT: Group 1, peaking at 30 min; and Group 2, peaking at 60 or 120 min. Body mass index (BMI) and insulin resistance were comparable between the groups; however, Group 2 showed a significantly higher 60- and 120-min glucose level and lower disposition index. Based on the magnitude of the insulin levels, Group 1 was subdivided into Group N (normal pattern) and Group E (exaggerated pattern) with a 30-min insulin cutoff of 74 μU/mL (Group E, ≥74 μU/mL). Group 2 was subdivided into Group DL (delayed and limited pattern; 60-min insulin <73.0 μU/mL and 120-min insulin <80.0 μU/mL) and Group DE (delayed and exaggerated pattern; 60-min insulin ≥73.0 μU/mL or 120-min insulin ≥80.0 μU/mL). Group DE showed a significantly higher area under the curve (AUC) of glucose compared with the other groups and had a lower disposition index and high-density lipoprotein levels. Group DL had significantly lower insulin resistance and BMI compared with Group E but showed a similar AUC of glucose. A delayed insulin pattern was associated with higher postprandial glucose levels. Individuals with delayed and exaggerated insulin secretion may have a higher risk for glucose intolerance.

[Prospective observational study of insulin detemir in patients with poorly controlled type 2 diabetes mellitus initiating insulin therapy for the first time (SOLVE Study)].

PubMed

Orozco-Beltrán, Domingo; Artola-Menéndez, Sara

2016-02-01

Describe the experience in the primary care setting with insulin detemir in patients with poorly controlled type2 diabetes mellitus that need to add-on insulin to their oral antidiabetic drug therapy. Prospective observational study of 6 months of follow up, performed in 10 countries. In Spain, participating sites were only from the primary care setting. Eligible patients were those with poorly controlled type2 diabetes mellitus adding-on once-daily insulin detemir to their existing oral antidiabetic therapy in the month prior to their enrollment. The change of Hb1Ac and of weight at the end of the study and the incidence of hypoglycemia and adverse reactions, were analyzed. We report the results obtained in the Spanish cohort. Overall 17,374 patients were included, 973 in Spain [mean age 64.8 years (SE 12); duration of diabetes 9.4 years (SE 6.2); Hb1Ac 8.9% (DE 1.4)]. In the sample analyzed for efficacy (n=474) the mean change of Hb1Ac was -1.6% (95%CI: -1.75 to -1.42; P<.001), mean change of weight was -2.9 kg (95%CI: -3.72 to -2.08; P<.001). Only one episode of severe hypoglycemia was reported, which was also the only serious adverse reaction reported in the study. The incidence rate of non-severe hypoglycemia was 2.44 events/patient-year. In this cohort of patients with type 2 diabetes mellitus receiving newly initiated insulin therapy, once-daily detemir improved the glycemic control, with low incidence of hypoglycemia and a significant reduction of the weight. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes.

PubMed

Sun, Shishuo; Tan, Pengcheng; Huang, Xiaoheng; Zhang, Wei; Kong, Chen; Ren, Fangfang; Su, Xiong

2018-02-16

Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands, and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared with WT cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin-induced IRS1 degradation after CD36 knockdown. Overexpression of WT CD36, but not a ubiquitination-defective CD36 mutant, delayed IRS1 degradation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multisubunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin-induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA-sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Pharmacokinetic and Pharmacodynamic Properties of a Novel Inhaled Insulin

PubMed Central

Heinemann, Lutz; Baughman, Robert; Boss, Anders; Hompesch, Marcus

2016-01-01

Advances in insulin treatment options over recent decades have markedly improved the management of diabetes. Despite this, glycemic control remains suboptimal in many people with diabetes. Although postprandial glucose control has been improved with the development of subcutaneously injected rapid-acting insulin analogs, currently available insulins are not able to fully mimic the physiological time–action profile of endogenously secreted insulin after a meal. The delayed onset of metabolic action and prolonged period of effect induce the risk of postprandial hyperglycemia and late postprandial hypoglycemia. A number of alternative routes of insulin administration have been investigated over time in an attempt to overcome the limitations associated with subcutaneous administration and to provide an improved time–action insulin profile more closely simulating physiological prandial insulin release. Among these, pulmonary insulin delivery has shown the most promise. Technosphere® Inhaled Insulin (TI) is a rapid-acting inhaled human insulin recently approved by the FDA for prandial insulin therapy. In this article we discuss the pharmacokinetic and pharmacodynamic properties of TI, and, based on key studies performed during its clinical development, the implications for improved postprandial glucose control. PMID:27378794

Challenges constraining insulin access in Nepal-a country with no local insulin production.

PubMed

Sharma, Abhishek; Bhandari, Parash Mani; Neupane, Dipika; Kaplan, Warren A; Mishra, Shiva Raj

2018-05-01

Nepal is facing an increasing burden of diabetes and relies almost entirely on insulin imported through India. We employed a modified version of the WHO/Health Action International standard survey to assess insulin availability and prices, along with qualitative interviews with insulin retailers (pharmacists) and wholesalers in the Kathmandu Valley, Nepal. The mean availability of the two human insulins listed on the 2011 Nepal Essential Medicine List were 14.3% and 42.85% in the surveyed private- and public-sector pharmacies, respectively, compared with the WHO target of 80% availability. The median consumer price of human insulin cartridges, analogue insulin cartridges and pens was, respectively, 2.1, 4.6 and 5.3 times that of human insulin vials (US$5.54). The insulin cartridges made in India were less expensive (p<0.001) than those made elsewhere. The lowest-paid worker would need to spend between 3 and 17 days' wages to purchase a monthly insulin supply out of pocket. Insulin access is limited in Kathmandu owing to low availability and the highly unaffordable price. Insulin access could improve with the government exploring additional suppliers, pooling insulin tenders, auditing insulin utilization and developing independent prescribing guidelines. Furthermore, there is a need to educate physicians and develop a consensus statement on insulin initiation to curb the growing analogue use and promote rational use.

AMPK agonist AICAR delays the initial decline in lifetime-apex V̇o2 peak, while voluntary wheel running fails to delay its initial decline in female rats.

PubMed

Toedebusch, Ryan G; Ruegsegger, Gregory N; Braselton, Joshua F; Heese, Alexander J; Hofheins, John C; Childs, Tom E; Thyfault, John P; Booth, Frank W

2016-02-01

There has never been an outcome measure for human health more important than peak oxygen consumption (V̇o2 peak), yet little is known regarding the molecular triggers for its lifetime decline with aging. We examined the ability of physical activity or 5 wk of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) administration to delay the initial aging-induced decline in lifetime-apex V̇o2 peak and potential underlying molecular mechanisms. Experiment 1 consisted of female rats with (RUN) and without (NO RUN) running wheels, while experiment 2 consisted of female nonrunning rats getting the AMPK agonist AICAR (0.5 mg/g/day) subcutaneously for 5 wk beginning at 17 wk of age. All rats underwent frequent, weekly or biweekly V̇o2 peak tests beginning at 10 wk of age. In experiment 1, lifetime-apex V̇o2 peak occurred at 19 wk of age in both RUN and NO RUN and decreased thereafter. V̇o2 peak measured across experiment 1 was ∼25% higher in RUN than in NO RUN. In experiment 2, AICAR delayed the chronological age observed in experiment 1 by 1 wk, from 19 wk to 20 wk of age. RUN and NO RUN showed different skeletal muscle transcriptomic profiles both pre- and postapex. Additionally, growth and development pathways are differentially regulated between RUN and NO RUN. Angiomotin mRNA was downregulated postapex in RUN and NO RUN. Furthermore, strong significant correlations to V̇o2 peak and trends for decreased protein concentration supports angiomotin's potential importance in our model. Contrary to our primary hypothesis, wheel running was not sufficient to delay the chronological age of lifetime-apex V̇o2 peak decline, whereas AICAR delayed it 1 wk. Copyright © 2016 the American Physiological Society.

Weight gain in insulin-treated patients by body mass index category at treatment initiation: new evidence from real-world data in patients with type 2 diabetes.

PubMed

Paul, S K; Shaw, J E; Montvida, O; Klein, K

2016-12-01

To evaluate, in patients with type 2 diabetes (T2DM) treated with insulin, the extent of weight gain over 2 years of insulin treatment, and the dynamics of weight gain in relation to glycaemic achievements over time according to adiposity levels at insulin initiation. Patients with T2DM (n = 155 917), who commenced insulin therapy and continued it for at least 6 months, were selected from a large database of electronic medical records in the USA. Longitudinal changes in body weight and glycated haemoglobin (HbA1c) according to body mass index (BMI) category were estimated. Patients had a mean age of 59 years, a mean HbA1c level of 9.5%, and a mean BMI of 35 kg/m 2 at insulin initiation. The HbA1c levels at insulin initiation were significantly lower (9.2-9.4%) in the obese patients than in patients with normal body weight (10.0%); however, the proportions of patients with HbA1c >7.5% or >8.0% were similar across the BMI categories. The adjusted weight gain fell progressively with increasing baseline BMI category over 6, 12 and 24 months (p < .01). The adjusted changes in HbA1c were similar across BMI categories. A 1% decrease in HbA1c was associated with progressively less weight gain as pretreatment BMI rose, ranging from a 1.24 kg gain in those with a BMI <25 kg/m 2 to a 0.32 kg loss in those with a BMI > 40 kg/m 2 . During 24 months of insulin treatment, obese patients gained significantly less body weight than normal-weight and overweight patients, while achieving clinically similar glycaemic benefits. These data provide reassurance with regard to the use of insulin in obese patients. © 2016 John Wiley & Sons Ltd.

Insulin Resistance and Mitochondrial Dysfunction.

PubMed

Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

2017-01-01

Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

Impaired insulin/IGF-1 is responsible for diabetic gastroparesis by damaging myenteric cholinergic neurones and interstitial cells of Cajal.

PubMed

Yang, Shu; Wu, Bo; Sun, Haimei; Sun, Tingyi; Han, Kai; Li, Dandan; Ji, Fengqing; Zhang, Guoquan; Zhou, Deshan

2017-10-31

Diabetic gastroparesis is a common complication of diabetes mellitus (DM) that is characterized by decreased serum insulin and insulin-like growth factor-1 (IGF-1). Despite the fact that insulin treatment not glycemic control potently accelerated gastric emptying in type 1 DM patients, the role of insulin/InsR and IGF-1/IGF-1R signaling in diabetic gastroparesis remains incompletely elucidated. In the present study, type 1 DM mice were established and treated with insulin or Voglibose for 8 weeks. The gastric emptying was delayed from DM week 4 when the gastric InsR and IGF-1R were declined. Meanwhile, the gastric choline acetyltransferase (ChAT) was significantly reduced and the myenteric cholinergic neurones and their fibers were significantly diminished. The production of stem cell factor (SCF) was dramatically repressed in the gastric smooth muscles in DM week 6. TWereafter, interstitial cells of Cajal (ICC) were clearly lost and their networks were impaired in DM week 8. Significantly, compared with Voglibose, an 8-week treatment with insulin more efficiently delayed diabetic gastroparesis development by protecting the myenteric cholinergic neurones and ICC. In conclusion, diabetic gastroparesis was an aggressive process due to the successive damages of myenteric cholinergic neurones and ICC by impairing the insulin/InsR and IGF-1/IGF-1R signaling. Insulin therapy in the early stage may delay diabetic gastroparesis. © 2017 The Author(s).

Delay in initiation of treatment after diagnosis of pulmonary tuberculosis in primary health care setting: eight year cohort analysis from district Faridabad, Haryana, North India.

PubMed

Kant, Shashi; Singh, Arvind K; Parmeshwaran, Giridara G; Haldar, Partha; Malhotra, Sumit; Kaur, Ravneet

2017-01-01

Delay in initiation of tuberculosis (TB) treatment may have a tremendous impact on disease transmission, development of drug resistance, poor outcome and overall survival of TB patients. The delay can occur at various levels. Delay in initiation of treatment after diagnosis is mostly due to health system failure and has immense programmatic implications. It has not been studied extensively in the Indian setting. The authors did a cohort analysis of all TB patients initiated on treatment from two primary health centres (PHCs) at Ballabgarh Health and Demographic Surveillance System between January 2007 and December 2014. Diagnosis and treatment of TB in the study area was done as per the protocol envisaged in the national program. Information related to demography, details of diagnosis and treatment of TB and outcome of treatment were extracted from the TB register. Delay in initiation of treatment after diagnosis was considered if the gap between diagnosis and treatment was greater than 7 days. Bivariate and multivariate analyses were done to find the association of various factors with delay in initiation of treatment after diagnosis. Out of 885 patients, 662 patients started treatment for pulmonary TB. Mean time interval between diagnosis and initiation of treatment was 8.95 days. Only 57.7% of pulmonary TB patients were started on treatment within 7 days of diagnosis, and an additional 24.5% were started on treatment 8-14 days after diagnosis. Patients on retreatment regimens and those residing in villages without a PHC were more likely to have delayed initiation of treatment (odds ratio (OR)=1.82 (1.3-2.7, p=0.001) and OR=1.62 (1.1-2.5, p=0.01) respectively). Delay in initiation of treatment was also associated with unfavourable treatment outcome such as default, failure or death. There is a need to have healthcare changes related to TB care to enable initiation of treatment as early as possible. Pretreatment counselling especially for retreatment

Early versus delayed initiation of antiretroviral therapy for Indian HIV-Infected individuals with tuberculosis on antituberculosis treatment.

PubMed

Sinha, Sanjeev; Shekhar, Rahul C; Singh, Gurjeet; Shah, Nipam; Ahmad, Hafiz; Kumar, Narendra; Sharma, Surendra K; Samantaray, J C; Ranjan, Sanjai; Ekka, Meera; Sreenivas, Vishnu; Mitsuyasu, Ronald T

2012-07-31

For antiretroviral therapy (ART) naive human immunodeficiency virus (HIV) infected adults suffering from tuberculosis (TB), there is uncertainty about the optimal time to initiate highly active antiretroviral therapy (HAART) after starting antituberculosis treatment (ATT), in order to minimize mortality, HIV disease progression, and adverse events. In a randomized, open label trial at All India Institute of Medical Sciences, New Delhi, India, eligible HIV positive individuals with a diagnosis of TB were randomly assigned to receive HAART after 2-4 or 8-12 weeks of starting ATT, and were followed for 12 months after HAART initiation. Participants received directly observed therapy short course (DOTS) for TB, and an antiretroviral regimen comprising stavudine or zidovudine, lamivudine, and efavirenz. Primary end points were death from any cause, and progression of HIV disease marked by failure of ART. A total of 150 patients with HIV and TB were initiated on HAART: 88 received it after 2-4 weeks (early ART) and 62 after 8-12 weeks (delayed ART) of starting ATT. There was no significant difference in mortality between the groups after the introduction of HAART. However, incidence of ART failure was 31% in delayed versus 16% in early ART arm (p = 0.045). Kaplan Meier disease progression free survival at 12 months was 79% for early versus 64% for the delayed ART arm (p = 0.05). Rates of adverse events were similar. Early initiation of HAART for patients with HIV and TB significantly decreases incidence of HIV disease progression and has good tolerability. CTRI/2011/12/002260.

Heterotypic endosomal fusion as an initial trigger for insulin-induced glucose transporter 4 (GLUT4) translocation in skeletal muscle.

PubMed

Hatakeyama, Hiroyasu; Kanzaki, Makoto

2017-08-15

Comprehensive imaging analyses of glucose transporter 4 (GLUT4) behaviour in mouse skeletal muscle was conducted. Quantum dot-based single molecule nanometry revealed that GLUT4 molecules in skeletal myofibres are governed by regulatory systems involving 'static retention' and 'stimulus-dependent liberation'. Vital imaging analyses and super-resolution microscopy-based morphometry demonstrated that insulin liberates the GLUT4 molecule from its static state by triggering acute heterotypic endomembrane fusion arising from the very small GLUT4-containing vesicles in skeletal myofibres. Prior exposure to exercise-mimetic stimuli potentiated this insulin-responsive endomembrane fusion event involving GLUT4-containing vesicles, suggesting that this endomembranous regulation process is a potential site related to the effects of exercise. Skeletal muscle is the major systemic glucose disposal site. Both insulin and exercise facilitate translocation of the glucose transporter glucose transporter 4 (GLUT4) via distinct signalling pathways and exercise also enhances insulin sensitivity. However, the trafficking mechanisms controlling GLUT4 mobilization in skeletal muscle remain poorly understood as a resuly of technical limitations. In the present study, which employs various imaging techniques on isolated skeletal myofibres, we show that one of the initial triggers of insulin-induced GLUT4 translocation is heterotypic endomembrane fusion arising from very small static GLUT4-containing vesicles with a subset of transferrin receptor-containing endosomes. Importantly, pretreatment with exercise-mimetic stimuli potentiated the susceptibility to insulin responsiveness, as indicated by these acute endomembranous activities. We also found that AS160 exhibited stripe-like localization close to sarcomeric α-actinin and that insulin induced a reduction of the stripe-like localization accompanying changes in its detergent solubility. The results of the present study thus provide a

Design of insulin analogues for meal-related therapy.

PubMed

Brange, J

1993-01-01

The human insulin in replacement therapy has a hexameric structure. Hexamerization of the insulin molecule facilitates biosynthesis and beta-cell storage of insulin, but is unnecessary for biologic activity and appears to contribute to delayed absorption of exogenous insulin from the subcutis. Insulin analogues with reduced self-association that are produced through recombinant DNA techniques have been shown to have in vivo activity comparable to that of human insulin and absorption kinetics characterized by higher and more constant rates of disappearance from the subcutaneous injection site. In preliminary studies in patients receiving insulin therapy, monomeric insulin analogues have been found to provide glycemic control in the postprandial period that is at least equivalent to that of human insulin. Findings in these studies suggest that the use of such analogues may provide meal-related insulin effects closer to those observed in the physiologic state by limiting excessive postprandial glucose excursions and decreasing the risk of late hypoglycemia. Banting and Best revolutionized diabetes therapy 70 years ago with the extraction of insulin from animal pancreas glands (J Lab Clin Med 7:464-472, 1922). Since that time, many refinements of the therapeutic properties of pharmaceutical preparations of the hormone have been introduced. Until recently, however, such advances have been limited to improvements in insulin purity, insulin species, and adjustment of the composition of the vehicle with respect to auxiliary substances and other additives. With the advent of recombinant DNA techniques, it has become possible to optimize the insulin molecule itself for purposes of replacement therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Initiation of movement and energy expenditure in children with developmental delay: a case-control study.

PubMed

Chen, Chiao-Nan Joyce; Hwang, Ai-Wen; Lin, Shang-Ying; Lin, Yu-Chieh

2014-10-01

Lower levels of physical activity in children with developmental delay (DD) usually are attributed to higher energy costs. However, there is no evidence that children with DD spend more energy on daily physical activities, such as walking. The aim of this study was to compare energy costs during walking and movement initiation times in children with DD and children with typical development (TD) and matched for age. This was a case-control study. Children who were 3 and 5 years old and had DD (n=12) or TD (n=12) participated in the study. Measurements included ranges of motion in the lower extremities, physiological costs of walking, and movement initiation times. A task designed to evaluate the initiation of movement (the "go play with the toy" task) was used to examine the reaction times for children's goal-directed walking. The physiological costs of walking were similar in the 2 groups; however, children with DD walked at a lower speed than children with TD. Importantly, children with DD took more time to initiate goal-directed walking. The nature of the study design limited causal inference from the results. Children who were 3 to 5 years old and had DD had delays in goal-directed movement that may not have been attributable to motor impairments. The findings suggest that therapists should evaluate the movement initiation ability of 3- to 5-year-old children with DD as part of the design of an overall intervention plan. © 2014 American Physical Therapy Association.

Concepts and clinical use of ultra-long basal insulin.

PubMed

Eliaschewitz, Freddy Goldberg; Barreto, Tânia

2016-01-01

Diabetes mellitus (DM) is a public health issue, affecting around 382 million people worldwide. In order to achieve glycemic goals, insulin therapy is the frontline therapy for type 1 DM patients; for patients with type 2 DM, use of insulin therapy is an option as initial or add-on therapy for those not achieving glycemic control. Despite insulin therapy developments seen in the last decades, several barriers remain for insulin initiation and optimal maintenance in clinical practice. Fear of hypoglycemia, weight gain, pain associated with blood testing and injection-related pain are the most cited reasons for not starting insulin therapy. However, new generation of basal insulin formulations, with longer length of action, have shown the capability of providing adequate glycemic control with lower risk of hypoglycemia.

Central insulin administration improves odor-cued reactivation of spatial memory in young men.

PubMed

Brünner, Yvonne F; Kofoet, Anja; Benedict, Christian; Freiherr, Jessica

2015-01-01

Insulin receptors are ubiquitously found in the human brain, comprising the olfactory bulb, essential for odor processing, and the hippocampus, important for spatial memory processing. The present study aimed at examining if intranasal insulin, which is known to transiently increase brain insulin levels in humans, would improve odor-cued reactivation of spatial memory in young men. We applied a double-blind, placebo-controlled, counterbalanced within-subject design. The study was conducted at the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: Following intranasal administration of either insulin (40 I.U.) or placebo, male subjects (n = 18) were exposed to eight odors. During each odor exposure, a green-colored field was presented on a 17-in. computer screen. During immediate recall (comprising 3 runs), the participants were re-exposed to each odor cue, and were asked to select the corresponding field (with visual feedback after each response). The delayed recall was scheduled ∼10 min later (without feedback). To test if insulin's putative effect on odor-place memory would be domain-specific, participants also performed a separate place and odor recognition task. Intranasal insulin improved the delayed but not immediate odor-cued recall of spatial memory. This effect was independent of odor type and in the absence of systemic side effects (eg, fasting plasma glucose levels remained unaltered). Place and odor recognition were unaffected by the insulin treatment. These findings suggest that acute intranasal insulin improves odor-cued reactivation of spatial memory in young men.

PRECISION TIME-DELAY CIRCUIT

DOEpatents

Creveling, R.

1959-03-17

A tine-delay circuit which produces a delay time in d. The circuit a capacitor, an te back resistance, connected serially with the anode of the diode going to ground. At the start of the time delay a negative stepfunction is applied to the series circuit and initiates a half-cycle transient oscillatory voltage terminated by a transient oscillatory voltage of substantially higher frequency. The output of the delay circuit is taken at the junction of the inductor and diode where a sudden voltage rise appears after the initiation of the higher frequency transient oscillations.

Therapeutics of diabetes mellitus: focus on insulin analogues and insulin pumps.

PubMed

Valla, Vasiliki

2010-01-01

Inadequately controlled diabetes accounts for chronic complications and increases mortality. Its therapeutic management aims in normal HbA1C, prandial and postprandial glucose levels. This review discusses diabetes management focusing on the latest insulin analogues, alternative insulin delivery systems and the artificial pancreas. Intensive insulin therapy with multiple daily injections (MDI) allows better imitation of the physiological rhythm of insulin secretion. Longer-acting, basal insulin analogues provide concomitant improvements in safety, efficacy and variability of glycaemic control, followed by low risks of hypoglycaemia. Continuous subcutaneous insulin infusion (CSII) provides long-term glycaemic control especially in type 1 diabetic patients, while reducing hypoglycaemic episodes and glycaemic variability. Continuous subcutaneous glucose monitoring (CGM) systems provide information on postprandial glucose excursions and nocturnal hypo- and/or hyperglycemias. This information enhances treatment options, provides a useful tool for self-monitoring and allows safer achievement of treatment targets. In the absence of a cure-like pancreas or islets transplants, artificial "closed-loop" systems mimicking the pancreatic activity have been also developed. Individualized treatment plans for insulin initiation and administration mode are critical in achieving target glycaemic levels. Progress in these fields is expected to facilitate and improve the quality of life of diabetic patients.

Molecular Mechanisms of Insulin Resistance in Chronic Kidney Disease

PubMed Central

Thomas, Sandhya S.; Zhang, Liping; Mitch, William E.

2015-01-01

Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to its receptor, auto-phosphorylation of the insulin receptor is followed by kinase reactions that phosphorylate insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K) and Akt. In fact, low levels of Akt phosphorylation (p-Akt) identifies the presence of the insulin resistance that leads to metabolic defects in insulin-initiated metabolism of glucose, lipids and muscle proteins. Besides CKD, other complex conditions (e.g., inflammation, oxidative stress, metabolic acidosis, aging and excess angiotensin II) reduce p-Akt resulting in insulin resistance. Insulin resistance in each of these conditions is due to activation of different, E3 ubiquitin ligases which specifically conjugate ubiquitin to IRS-1 marking it for degradation in the ubiquitin-proteasome system (UPS). Consequently, IRS-1 degradation suppresses insulin-induced intracellular signaling, causing insulin resistance. Understanding mechanisms of insulin resistance could lead to therapeutic strategies that improve the metabolism of patients with CKD. PMID:26444029

The Association of Increased Total Glycosylated Hemoglobin Levels with Delayed Age at Menarche in Young Women with Type 1 Diabetes

PubMed Central

Danielson, Kirstie K.; Palta, Mari; Allen, Catherine; D’Alessio, Donn J.

2005-01-01

Context: Delayed menarche is associated with subsequent reproductive and skeletal complications. Previous research has found delayed growth and pubertal maturation with type 1 diabetes and with poor glycemic control. The effect of diabetes management on menarche is important to clarify because tighter control might prevent these complications. Objective: To investigate age at menarche in young women with type 1 diabetes, and examine the effect of diabetes management (e.g. total glycosylated hemoglobin (GHb) level, number of blood glucose checks, insulin therapy intensity, insulin dose) on age at menarche in those diagnosed before menarche. Design: The Wisconsin Diabetes Registry Project is a follow-up study of a type 1 diabetes population-based incident cohort initially enrolled 1987 – 1992. Setting: Twenty-eight counties in south-central Wisconsin. Patients or Other Participants: Recruited through referrals, self-report, and hospital/clinic ascertainment. Individuals with newly diagnosed type 1 diabetes, <30 years old, were invited to participate. Of 288 young women enrolled, 188 reported menarche by 2002; 105 were diagnosed before menarche. Interventions: Not applicable. Main Outcome Measure: Age at menarche. Results: Mean age at menarche was 12.78 years, compared to 12.54 years in the United States (p = 0.01). Ages at menarche and diagnosis were not associated. For those diagnosed before menarche, age at menarche was delayed 1.3 months with each one percent increase in mean total GHb level in the three years prior to menarche. Conclusions: Age at menarche was moderately delayed in young women with type 1 diabetes. Delayed menarche could potentially be minimized with improved GHb levels. PMID:16204372

Delayed Presentation of Ureteropelvic Junction Obstruction and Loss of Renal Function After Initially Mild (SFU Grade 1-2) Hydronephrosis.

PubMed

Bowen, Diana K; Yerkes, Elizabeth B; Lindgren, Bruce W; Gong, Edward M; Faasse, Mark A

2015-07-01

We report 4 pediatric cases of ureteropelvic junction obstruction involving delayed progression of initially mild postnatal hydronephrosis. All 4 children became symptomatic; however, 3 already had a substantial decrement of ipsilateral kidney function by the time of diagnosis. Two of these 3 patients had previous renal scintigraphy demonstrating normal differential function. We caution that counseling regarding hydronephrosis should emphasize the importance of prompt re-evaluation for any symptoms potentially referable to delayed presentation of ureteropelvic junction obstruction, irrespective of initial hydronephrosis grade. Future studies are needed to determine the optimal follow-up regimen for conservative management of hydronephrosis. Copyright © 2015 Elsevier Inc. All rights reserved.

Initiation of once daily insulin detemir is not associated with weight gain in patients with type 2 diabetes mellitus: results from an observational study

PubMed Central

2013-01-01

Background Obesity is common in type 2 diabetes (T2DM) and is associated with increased risk of morbidity and all-cause mortality. This analysis describes weight changes associated with insulin detemir initiation in real-life clinical practice. Methods Study of Once-Daily Levemir (SOLVE) was a 24-week international observational study of once-daily insulin detemir as add-on therapy in patients with T2DM receiving oral hypoglycaemic agents (OHAs). Results 17,374 participants were included in the analysis: mean age 62 ± 12 years; weight 80.8 ± 17.6 kg; body mass index (BMI) 29.2 ± 5.3 kg/m2; diabetes duration 10 ± 7 years; HbA1c 8.9 ± 1.6%. HbA1c decreased by 1.3 ± 1.5% during the study, with insulin doses of 0.27 ± 0.17 IU/kg. Patients with higher BMI had higher pre-insulin HbA1c, and similar reductions in HbA1c with insulin therapy. Weight decreased from 80.8 ± 17.6 kg to 80.3 ± 17.0 kg (change of -0.6 [95% CI -0.65; -0.47] kg), with 35% of patients losing >1 kg. Patients with the highest pre-insulin BMI lost the greatest amount of weight: BMI < 25: +0.8 [95% CI: 0.6; 0.9] kg, 25 ≤ BMI < 30: -0.2 [95% CI: -0.3; -0.8] kg, 30 ≤ BMI < 35: -1.0 [95% CI: -1.1; -0.8] kg; BMI ≥ 35: -1.9 [95% CI: -2.2; -1.6] kg. Minor hypoglycaemia decreased with increasing BMI: 2.3 and 1.3 events per patient year for BMI <25 and  ≥ 35, respectively. Conclusions Overall, patients with poorly controlled T2DM achieved significant reductions in HbA1c after initiation of once-daily insulin detemir therapy, without weight gain. The favourable impact of insulin detemir on weight may not apply to other insulin preparations. Trial registrations ClinicalTrials.gov, NCT00825643 and NCT00740519 PMID:24499517

Insulin sensitizer prevents and ameliorates experimental type 1 diabetes.

PubMed

Valitsky, Michael; Hoffman, Amnon; Unterman, Terry; Bar-Tana, Jacob

2017-12-01

Insulin-dependent type-1 diabetes (T1D) is driven by autoimmune β-cell failure, whereas systemic resistance to insulin is considered the hallmark of insulin-independent type-2 diabetes (T2D). In contrast to this canonical dichotomy, insulin resistance appears to precede the overt diabetic stage of T1D and predict its progression, implying that insulin sensitizers may change the course of T1D. However, previous attempts to ameliorate T1D in animal models or patients by insulin sensitizers have largely failed. Sensitization to insulin by MEthyl-substituted long-chain DICArboxylic acid (MEDICA) analogs in T2D animal models surpasses that of current insulin sensitizers, thus prompting our interest in probing MEDICA in the T1D context. MEDICA efficacy in modulating the course of T1D was verified in streptozotocin (STZ) diabetic rats and autoimmune nonobese diabetic (NOD) mice. MEDICA treatment normalizes overt diabetes in STZ diabetic rats when added on to subtherapeutic insulin, and prevents/delays autoimmune T1D in NOD mice. MEDICA treatment does not improve β-cell insulin content or insulitis score, but its efficacy is accounted for by pronounced total body sensitization to insulin. In conclusion, potent insulin sensitizers may counteract genetic predisposition to autoimmune T1D and amplify subtherapeutic insulin into an effective therapeutic measure for the treatment of overt T1D. Copyright © 2017 the American Physiological Society.

Insulin stimulation of rat ventricular K+ currents depends on the integrity of the cytoskeleton.

PubMed

Shimoni, Y; Ewart, H S; Severson, D

1999-02-01

1. The effect of insulin on K+ currents was studied with enzymatically dispersed ventricular myocytes from insulin-deficient (type I) diabetic rats. Diabetic conditions were induced by a single intravenous injection of streptozotocin (100 mg kg-1) given 8-13 days before the experiments. Measurements of plasma glucose and insulin levels confirmed the diabetic status of the animals. 2. A Ca2+-independent transient outward K+ current, It, and a slowly inactivating, quasi-steady-state current, Iss, which are depressed in diabetic myocytes, could be restored by exposure to 1, 10 or 100 nM insulin. This was only observed after a delay of 5-6 h, although an insulin exposure of only 1 h was sufficient to initiate its stimulatory action on It and Iss. The stimulatory effect of insulin on these K+ currents was prevented by 2 microM cycloheximide, which in itself had no direct effect on these currents. 3. Disruption of the actin microfilament network with 1 microM cytochalasin D (CD) also prevented the stimulatory effect of 100 nM insulin on both It and Iss. Since CD was added 1 h after insulin, inhibitory effects on insulin signalling were ruled out. Adding CD (1 microM) 5-9 h after insulin, when currents were already augmented, had no effect (up to 50 min exposure). Incubating control cells for 6-10 h with 1 microM CD had no effect on any of the currents measured. 4. Stabilization of the actin network by pre-exposure to 2.5 microM phalloidin restored the stimulatory effect of insulin, in the continued presence of CD, ruling out any effects of CD on components other than the cytoskeleton. 5. The stimulatory effect of insulin was also prevented by incubating cells with insulin in the presence of the microtubule-disrupting agent colchicine (5 microM). 6. These results suggest that the insulin-mediated augmentation of K+ currents in diabetic myocytes requires protein synthesis, possibly of K+ channels, as well as an intact cytoskeleton. The possibility that newly formed

Insulin aggregation tracked by its intrinsic TRES

NASA Astrophysics Data System (ADS)

Chung, Li Hung C.; Birch, David J. S.; Vyshemirsky, Vladislav; Ryadnov, Maxim G.; Rolinski, Olaf J.

2017-12-01

Time-resolved emission spectra (TRES) have been used to detect conformational changes of intrinsic tyrosines within bovine insulin at a physiological pH. The approach offers the ability to detect the initial stages of insulin aggregation at the molecular level. The data analysis has revealed the existence of at least three fluorescent species undergoing dielectric relaxation and significant spectral changes due to insulin aggregation. The results indicate the suitability of the intrinsic TRES approach for insulin studies and for monitoring its stability during storage and aggregation in insulin delivery devices.

Remifentanil maintains lower initial delayed nonmatching-to-sample accuracy compared to food pellets in male rhesus monkeys.

PubMed

Hutsell, Blake A; Banks, Matthew L

2017-12-01

Emerging human laboratory and preclinical drug self-administration data suggest that a history of contingent abused drug exposure impairs performance in operant discrimination procedures, such as delayed nonmatching-to-sample (DNMTS), that are hypothesized to assess components of executive function. However, these preclinical discrimination studies have exclusively used food as the reinforcer and the effects of drugs as reinforcers in these operant procedures are unknown. The present study determined effects of contingent intravenous remifentanil injections on DNMTS performance hypothesized to assess 1 aspect of executive function, working memory. Daily behavioral sessions consisted of 2 components with sequential intravenous remifentanil (0, 0.01-1.0 μg/kg/injection) or food (0, 1-10 pellets) availability in nonopioid dependent male rhesus monkeys (n = 3). Remifentanil functioned as a reinforcer in the DNMTS procedure. Similar delay-dependent DNMTS accuracy was observed under both remifentanil- and food-maintained components, such that higher accuracies were maintained at shorter (0.1-1.0 s) delays and lower accuracies approaching chance performance were maintained at longer (10-32 s) delays. Remifentanil maintained significantly lower initial DNMTS accuracy compared to food. Reinforcer magnitude was not an important determinant of DNMTS accuracy for either remifentanil or food. These results extend the range of experimental procedures under which drugs function as reinforcers. Furthermore, the selective remifentanil-induced decrease in initial DNMTS accuracy is consistent with a selective impairment of attentional, but not memorial, processes. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Integrated Demand Management: Minimizing Unanticipated Excessive Departure Delay while Ensuring Fairness from a Traffic Management Initiative

NASA Technical Reports Server (NTRS)

Yoo, Hyo-Sang; Brasil, Connie; Buckley, Nathan; Mohlenbrink, Christoph; Speridakos, Constantine; Parke, Bonny; Hodell, Gita; Lee, Paul U.; Smith, Nancy M.

2017-01-01

This paper introduces NASA's Integrated Demand Management (IDM) concept and presents the results from an early proof-of-concept evaluation and an exploratory experiment. An initial development of the concept was focused on integrating two systems - i.e. the FAA's newly deployed Traffic Flow Management System (TFMS) tool called the Collaborative Trajectory Options Program (CTOP) and the Time-Based Flow Management (TBFM) system with Extended Metering (XM) capabilities to manage projected heavy traffic demand into a capacity-constrained airport. A human-in-the-loop (HITL) simulation experiment was conducted to demonstrate the feasibility of the initial development of the concept by adapting it to an arrival traffic problem at Newark Liberty International Airport (EWR) during clear weather conditions. In this study, the CTOP was utilized to strategically plan the arrival traffic demand by controlling take-off times of both short- and long-haul flights (long-hauls specify aircraft outside TBFM regions and short-hauls specify aircraft within TBFM regions) in a way that results in equitable delays among the groups. Such strategic planning allows less airborne delay to occur within TBFM by feeding manageable long-haul traffic demand while reserving sufficient slots in the overhead streams for the short-haul departures. The manageable traffic demand indicates the TBFM scheduler assigns no more airborne delay than its assigned airspace is capable of absorbing. TBFM then uses its time-based metering capabilities to deliver the desirable throughput by tactically rescheduling the TBFM entered long-haul flights and short-haul departures. Additional research was also performed to explore use of Required Time of Arrival (RTA) capabilities as a potential control mechanism for the airborne flights to improve arrival traffic delivery accuracy of scheduled long-haul traffic demand. The study results show that both short- and long-haul flights received similar ground delays. In

Insulin Secretion Improves in Cystic Fibrosis Following Ivacaftor Correction of CFTR: A Small Pilot Study

PubMed Central

Bellin, Melena D.; Laguna, Theresa; Leschyshyn, Janice; Regelmann, Warren; Dunitz, Jordan; Billings, JoAnne; Moran, Antoinette

2013-01-01

Objective To determine whether the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector, ivacaftor. Methods This open-label pilot study was conducted in CF patients with the G551D mutation given new prescriptions for ivacaftor. At baseline and 4 weeks after daily ivacaftor therapy, intravenous (IVGTT) and oral glucose (OGTT) tolerance tests were performed. Results Five patients age 6–52 were studied. After 1 month on ivacaftor, the insulin response to oral glucose improved by 66–178% in all subjects except one with long-standing diabetes. OGTT glucose levels were not lower in the two individuals with diabetes or the two with normal glucose tolerance (NGT), but the glucose tolerance category in the subject with impaired glucose tolerance (IGT) improved to NGT after treatment. In response to intravenous glucose, the only patient whose acute insulin secretion did not improve had newly diagnosed, untreated CFRD. The others improved by 51–346%. Acute insulin secretion was partially restored in two subjects with no measurable acute insulin response at baseline, including the one with IGT and the one with long-standing diabetes. Conclusions This small pilot study suggests there is a direct role of CFTR in human insulin secretion. Larger, long-term longitudinal studies are necessary to determine whether early initiation of CFTR correction, particularly in young children with CF who have not yet lost considerable beta-cell mass, will delay or prevent development of diabetes in this high risk population. PMID:23952705

Roles and relationships between health professionals involved in insulin initiation for people with type 2 diabetes in the general practice setting: a qualitative study drawing on relational coordination theory.

PubMed

Manski-Nankervis, Jo-Anne; Furler, John; Blackberry, Irene; Young, Doris; O'Neal, David; Patterson, Elizabeth

2014-01-31

The majority of care for people with type 2 diabetes occurs in general practice, however when insulin initiation is required it often does not occur in this setting or in a timely manner and this may have implications for the development of complications. Increased insulin initiation in general practice is an important goal given the increasing prevalence of type 2 diabetes and a relative shortage of specialists. Coordination between primary and secondary care, and between medical and nursing personnel, may be important in achieving this. Relational coordination theory identifies key concepts that underpin effective interprofessional work: communication which is problem solving, timely, accurate and frequent and relationships between professional roles which are characterized by shared goals, shared knowledge and mutual respect. This study explores roles and relationships between health professionals involved in insulin initiation in order to gain an understanding of factors which may impact on this task being carried out in the general practice setting. 21 general practitioners, practice nurses, diabetes nurse educators and physicians were purposively sampled to participate in a semi-structured interview. Transcripts of the interviews were analysed using framework analysis. There were four closely interlinked themes identified which impacted on how health professionals worked together to initiate people with type 2 diabetes on insulin: 1. Ambiguous roles; 2. Uncertain competency and capacity; 3. Varying relationships and communication; and 4. Developing trust and respect. This study has shown that insulin initiation is generally recognised as acceptable in general practice. The role of the DNE and practice nurse in this space and improved communication and relationships between health professionals across organisations and levels of care are factors which need to be addressed to support this clinical work. Relational coordination provides a useful framework for

Oscillatory dynamics of an intravenous glucose tolerance test model with delay interval

NASA Astrophysics Data System (ADS)

Shi, Xiangyun; Kuang, Yang; Makroglou, Athena; Mokshagundam, Sriprakash; Li, Jiaxu

2017-11-01

Type 2 diabetes mellitus (T2DM) has become prevalent pandemic disease in view of the modern life style. Both diabetic population and health expenses grow rapidly according to American Diabetes Association. Detecting the potential onset of T2DM is an essential focal point in the research of diabetes mellitus. The intravenous glucose tolerance test (IVGTT) is an effective protocol to determine the insulin sensitivity, glucose effectiveness, and pancreatic β-cell functionality, through the analysis and parameter estimation of a proper differential equation model. Delay differential equations have been used to study the complex physiological phenomena including the glucose and insulin regulations. In this paper, we propose a novel approach to model the time delay in IVGTT modeling. This novel approach uses two parameters to simulate not only both discrete time delay and distributed time delay in the past interval, but also the time delay distributed in a past sub-interval. Normally, larger time delay, either a discrete or a distributed delay, will destabilize the system. However, we find that time delay over a sub-interval might not. We present analytically some basic model properties, which are desirable biologically and mathematically. We show that this relatively simple model provides good fit to fluctuating patient data sets and reveals some intriguing dynamics. Moreover, our numerical simulation results indicate that our model may remove the defect in well known Minimal Model, which often overestimates the glucose effectiveness index.

Initial Misdiagnosis of Proximal Pancreatic Adenocarcinoma Is Associated with Delay in Diagnosis and Advanced Stage at Presentation.

PubMed

Swords, Douglas S; Mone, Mary C; Zhang, Chong; Presson, Angela P; Mulvihill, Sean J; Scaife, Courtney L

2015-10-01

Delay in diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with decreased survival. The effect of an initial misdiagnosis on delay in diagnosis and stage of PDAC is unknown. This study is a retrospective review (2000-2010) from a University-based cancer center of new diagnoses of proximal PDAC. Of 313 patients, 98 (31.3 %) had an initial misdiagnosis. Misdiagnosed patients were younger, 62.8 ± 12.6 vs. 68.0 ± 10.1 (p < 0.001). The most common initial misdiagnoses were: gallbladder disease, gastroesophageal reflux disease, and peptic ulcer disease. After excluding patients with prior cholecystectomy, 14.2 % were misdiagnosed with gallbladder disease and underwent cholecystectomy before PDAC diagnosis. Misdiagnosed patients had higher rates of abdominal pain (p < 0.001), weight loss (p = 0.04), and acute pancreatitis (p < 0.001) and lower rate of jaundice (p < 0.001). Median time between symptoms to PDAC diagnosis was longer in misdiagnosed: 4.2 months vs. 1.4 (p < 0.001). Median time from contact with medical provider to axial imaging was longer in misdiagnosed (p < 0.001). Rate of stages III-IV disease at diagnosis was higher in misdiagnosed: 61.2 vs. 43.7 % (p = 0.004), with a 1.4 (95 % confidence interval (CI), 1.12-1.74) higher risk of stages III-IV disease at diagnosis; however, there was no difference in median overall survival in misdiagnosed patients (9.6 months in misdiagnosed vs. 10.3 months in correctly diagnosed, p = 0.69). Initial misdiagnosis of patients with proximal PDAC is associated with delay in diagnosis and higher risk of locally advanced or advanced disease at time of PDAC diagnosis.

Cost-effectiveness of insulin detemir compared with NPH insulin in people with type 2 diabetes in Denmark, Finland, Norway, and Sweden.

PubMed

Ridderstråle, Martin; Jensen, Marie Markert; Gjesing, Rasmus Prior; Niskanen, Leo

2013-01-01

To assess the cost-effectiveness of insulin detemir compared with Neutral Protamine Hagedorn (NPH) insulin when initiating insulin treatment in people with type 2 diabetes mellitus (T2DM) in Denmark, Finland, Norway, and Sweden. Efficacy and safety data were derived from a 20-week multi-centre randomized controlled head-to-head clinical trial comparing insulin detemir and NPH insulin in insulin naïve people with T2DM, and short-term (1-year) cost effectiveness analyses were performed. As no significant differences in HbA1c were observed between the two treatment arms, the model was based on significant differences in favour of insulin detemir in frequency of hypoglycaemia (Rate-Ratio = 0.52; CI = 0.44-0.61) and weight gain (Δ = 0.9 kg). Model outcomes were measured in Quality Adjusted Life Years (QALYs) using published utility estimates. Acquisition costs for insulin and direct healthcare costs associated with non-severe hypoglycaemic events were obtained from National Health Service public sources. One-way and probabilistic sensitivity analyses were performed. Based on lower incidence of non-severe hypoglycaemic events and less weight gain, the QALY gain from initiating treatment with insulin detemir compared with NPH insulin was 0.01 per patient per year. Incremental cost-effectiveness ratios for the individual countries were: Denmark, Danish Kroner 170,852 (€22,933); Finland, €28,349; Norway, Norwegian Kroner 169,789 (€21,768); and Sweden, Swedish Krona 226,622 (€25,097) per QALY gained. Possible limitations of the study are that data on hypoglycaemia and relative weight benefits from a clinical trial were combined with hypoglycaemia incidence data from observational studies. These populations may have slightly different patient characteristics. The lower risk of non-severe hypoglycaemia and less weight gain associated with using insulin detemir compared with NPH insulin when initiating insulin treatment in insulin naïve patients with

Treatment intensification using long-acting insulin -predictors of future basal insulin supported oral therapy in the DIVE registry.

PubMed

Danne, Thomas; Bluhmki, Tobias; Seufert, Jochen; Kaltheuner, Matthias; Rathmann, Wolfgang; Beyersmann, Jan; Bramlage, Peter

2015-10-07

In patients with type-2 diabetes receiving oral antidiabetic drugs (OADs), the addition of insulin is frequently required to achieve sufficient control over blood glucose levels. It is, however, difficult to predict if, when and in which patients insulin therapy will be needed. We aimed to identify patient related variables associated with the addition of basal insulin to oral therapy resulting in a basal supported oral therapy (BOT). DIVE (DIabetes Versorgungs-Evaluation) is a prospective, observational, multi-centre diabetes registry established in Germany in 2011. For the present explorative analysis, 31,008 patients with type-2 diabetes prescribed at least one OAD were included. Patients who had previously received insulin and those over 90 years old were excluded. The event of interest was defined as the initiation of BOT during the observational period. Cause-specific Cox proportional hazards models based on a competing risk framework were applied for risk quantification. Multivariable adjusted hazard ratios demonstrated that longer diabetes duration, higher BMI, poorer glycaemic control, documentation of any micro- or macrovascular comorbidity, the presence of concomitant non-antidiabetic pharmacotherapies, and greater numbers of prescribed OADs increased the likelihood of BOT initiation. On the other hand BOT initiation was less likely in patients with older age and female gender. Analysing the likelihood of OAD termination without initiation of BOT provided supportive evidence for the variables predictive of BOT initiation. Analysis of the DIVE registry has resulted in the identification of a number of factors that may be predictive for the initiation of BOT for type-2 diabetes patients initially prescribed one or more OADs. Poor glycaemic control, the presence of vascular comorbidities and concomitant medications, and a greater number of OADs were all detected to increase the risk of a switch to BOT. Female gender and younger age showed protective

Administration technique and storage of disposable insulin pens reported by patients with diabetes.

PubMed

Mitchell, Virginia D; Porter, Kyle; Beatty, Stuart J

2012-01-01

The purpose of the study was to evaluate insulin injection technique and storage of insulin pens as reported by patients with diabetes and to compare correct pen use to initial education on injection technique, hemoglobin A1C, duration of insulin therapy, and duration of insulin pen. Cross-sectional questionnaire orally administered to patients at a university-affiliated primary care practice. Subjects were patients with diabetes who were 18 years or older and prescribed a disposable insulin pen for at least 4 weeks. A correct usage score was calculated for each patient based on manufacturer recommendations for disposable insulin pen use. Associations were made between the correct usage score and certainty in technique, initial education, years of insulin therapy, duration of pen use, and hemoglobin A1C. Sixty-seven patients completed the questionnaire, reporting total use of 94 insulin pens. The 3 components most often neglected by patients were priming pen needle, holding for specific count time before withdrawal of pen needle from skin, and storing an in-use pen. For three-fourths of the insulin pens being used, users did not follow the manufacturer's instructions for proper administration and storage of insulin pens. Correct usage scores were significantly higher if initial education on insulin pens was performed by a pharmacist or nurse. The majority of patients may be ignoring or unaware of key components for consistent insulin dosing using disposable insulin pens; therefore, initial education and reeducation on correct use of disposable insulin pens by health care professionals are needed.

Internalization and localization of basal insulin peglispro in cells.

PubMed

Moyers, Julie S; Volk, Catherine B; Cao, Julia X C; Zhang, Chen; Ding, Liyun; Kiselyov, Vladislav V; Michael, M Dodson

2017-10-15

Basal insulin peglispro (BIL) is a novel, PEGylated insulin lispro that has a large hydrodynamic size compared with insulin lispro. It has a prolonged duration of action, which is related to a delay in insulin absorption and a reduction in clearance. Given the different physical properties of BIL compared with native insulin and insulin lispro, it is important to assess the cellular internalization characteristics of the molecule. Using immunofluorescent confocal imaging, we compared the cellular internalization and localization patterns of BIL, biosynthetic human insulin, and insulin lispro. We assessed the effects of BIL on internalization of the insulin receptor (IR) and studied cellular clearance of BIL. Co-localization studies using antibodies to either insulin or PEG, and the early endosomal marker EEA1 showed that the overall internalization and subcellular localization pattern of BIL was similar to that of human insulin and insulin lispro; all were rapidly internalized and co-localized with EEA1. During ligand washout for 4 h, concomitant loss of insulin, PEG methoxy group, and PEG backbone immunostaining was observed for BIL, similar to the loss of insulin immunostaining observed for insulin lispro and human insulin. Co-localization studies using an antibody to the lysosomal marker LAMP1 did not reveal evidence of lysosomal localization for insulin lispro, human insulin, BIL, or PEG using either insulin or PEG immunostaining reagents. BIL and human insulin both induced rapid phosphorylation and internalization of human IR. Our findings show that treatment of cells with BIL stimulates internalization and localization of IR to early endosomes. Both the insulin and PEG moieties of BIL undergo a dynamic cellular process of rapid internalization and transport to early endosomes followed by loss of cellular immunostaining in a manner similar to that of insulin lispro and human insulin. The rate of clearance for the insulin lispro portion of BIL was slower than

Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment

PubMed Central

Craft, Suzanne; Baker, Laura D.; Montine, Thomas J.; Minoshima, Satoshi; Watson, G. Stennis; Claxton, Amy; Arbuckle, Matthew; Callaghan, Maureen; Tsai, Elaine; Plymate, Stephen R.; Green, Pattie S.; Leverenz, James; Cross, Donna; Gerton, Brooke

2011-01-01

Objective To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). Design Randomized, double-blind, placebo-controlled trial. Setting Clinical research unit of a Veterans Affairs medical center. Participants The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). Main Outcome Measures Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease’s Assessment Scale–cognitive subscale (ADAS-cog) score and the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment. Results Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein–to–Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18

Insulin delivery route for the artificial pancreas: subcutaneous, intraperitoneal, or intravenous? Pros and cons.

PubMed

Renard, Eric

2008-07-01

Insulin delivery is a crucial component of a closed-loop system aiming at the development of an artificial pancreas. The intravenous route, which has been used in the bedside artificial pancreas model for 30 years, has clear advantages in terms of pharmacokinetics and pharmacodynamics, but cannot be used in any ambulatory system so far. Subcutaneous (SC) insulin infusion benefits from the broad expansion of insulin pump therapy that promoted the availability of constantly improving technology and fast-acting insulin analog use. However, persistent delays of insulin absorption and action, variability and shortterm stability of insulin infusion from SC-inserted catheters generate effectiveness and safety issues in view of an ambulatory, automated, glucose-controlled, artificial beta cell. Intraperitoneal insulin delivery, although still marginally used in diabetes care, may offer an interesting alternative because of its more-physiological plasma insulin profiles and sustained stability and reliability of insulin delivery.

Tissue-specific Insulin Signaling in the Regulation of Metabolism and Aging

PubMed Central

Zhang, Jingjing

2014-01-01

In mammals, insulin signaling regulates glucose homeostasis and plays an essential role in metabolism, organ growth, development, fertility, and lifespan. Defects in this signaling pathway contribute to various metabolic diseases such as type 2 diabetes, polycystic ovarian disease, hypertension, hyperlipidemia, and atherosclerosis. However, reducing the insulin signaling pathway has been found to increase longevity and delay the aging-associated diseases in various animals, ranging from nematodes to mice. These seemly paradoxical findings raise an interesting question as to how modulation of the insulin signaling pathway could be an effective approach to improve metabolism and aging. In this review, we summarize current understanding on tissue-specific functions of insulin signaling in the regulation of metabolism and lifespan. We also discuss potential benefits and limitations in modulating tissue-specific insulin signaling pathway to improve metabolism and healthspan. PMID:25087968

Delayed peak response of cortisol to insulin tolerance test in patients with Prader-Willi syndrome.

PubMed

Oto, Yuji; Matsubara, Keiko; Ayabe, Tadayuki; Shiraishi, Masahisa; Murakami, Nobuyuki; Ihara, Hiroshi; Matsubara, Tomoyo; Nagai, Toshiro

2018-06-01

Deaths among children with Prader-Willi syndrome (PWS) are often related to only mild or moderate upper respiratory tract infections, and many causes of death remain unexplained. Several reports have hypothesized that patients with PWS may experience latent central adrenal insufficiency. However, whether PWS subjects suffer from alteration of the hypothalamus-pituitary-adrenal (HPA) axis remains unclear. This study aimed to explore the HPA axis on PWS. We evaluated the HPA axis in 36 PWS patients (24 males, 12 females; age range, 7 months to 12 years; median age 2.0 years; interquartile range [IQR], 1.5-3.4 years) using an insulin tolerance test (ITT) in the morning between 08:00 and 11:00. For comparison, ITT results in 37 age-matched healthy children evaluated for short stature were used as controls. In PWS patients, basal levels of adrenocorticotropic hormone (ACTH) were 13.5 pg/ml (IQR, 8.3-27.5 pg/ml) and basal levels of cortisol were 18.0 μg/dl (IQR, 14.2-23.7 μg/dl). For all patients, cortisol levels at 60 min after stimulation were within the reference range (>18.1 μg/dl), with a median peak of 41.5 μg/dl (IQR, 32.3-48.6 μg/dl). Among control children, basal level of ACTH and basal and peak levels of cortisol were 10.9 (IQR, 8.5-22.0 pg/ml), 15.6 (IQR, 11.9-21.6 μg/dl), and 27.8 μg/dl (IQR, 23.7-30.5 μg/dl), respectively. Basal and peak levels of cortisol were all within normal ranges, but peak response of cortisol to ITT was delayed in the majority of PWS patients (64%). Although the mechanism remains unclear, this delay may signify the existence of central obstacle in adjustment of the HPA axis. © 2018 Wiley Periodicals, Inc.

Initiation of insulin glargine therapy in type 2 diabetes subjects suboptimally controlled on oral antidiabetic agents: results from the AT.LANTUS trial.

PubMed

Davies, M; Lavalle-González, F; Storms, F; Gomis, R

2008-05-01

For many patients with type 2 diabetes, oral antidiabetic agents (OADs) do not provide optimal glycaemic control, necessitating insulin therapy. Fear of hypoglycaemia is a major barrier to initiating insulin therapy. The AT.LANTUS study investigated optimal methods to initiate and maintain insulin glargine (LANTUS, glargine, Sanofi-aventis, Paris, France) therapy using two treatment algorithms. This subgroup analysis investigated the initiation of once-daily glargine therapy in patients suboptimally controlled on multiple OADs. This study was a 24-week, multinational (59 countries), multicenter (611), randomized study. Algorithm 1 was a clinic-driven titration and algorithm 2 was a patient-driven titration. Titration was based on target fasting blood glucose < or =100 mg/dl (< or =5.5 mmol/l). Algorithms were compared for incidence of severe hypoglycaemia [requiring assistance and blood glucose <50 mg/dl (<2.8 mmol/l)] and baseline to end-point change in haemoglobin A(1c) (HbA(1c)). Of the 4961 patients enrolled in the study, 865 were included in this subgroup analysis: 340 received glargine plus 1 OAD and 525 received glargine plus >1 OAD. Incidence of severe hypoglycaemia was <1%. HbA(1c) decreased significantly between baseline and end-point for patients receiving glargine plus 1 OAD (-1.4%, p < 0.001; algorithm 1 -1.3% vs. algorithm 2 -1.5%; p = 0.03) and glargine plus >1 OAD (-1.7%, p < 0.001; algorithm 1 -1.5% vs. algorithm 2 -1.8%; p = 0.001). This study shows that initiation of once-daily glargine with OADs results in significant reduction of HbA(1c) with a low risk of hypoglycaemia. The greater reduction in HbA(1c) was seen in patients randomized to the patient-driven algorithm (algorithm 2) on 1 or >1 OAD.

Insulin structure and stability.

PubMed

Brange, J; Langkjoer, L

1993-01-01

Insulin is composed of 51 amino acids in two peptide chains (A and B) linked by two disulfide bonds. The three-dimensional structure of the insulin molecule (insulin monomer), essentially the same in solution and in solid phase, exists in two main conformations. These differ in the extent of helix in the B chain which is governed by the presence of phenol or its derivatives. In acid and neutral solutions, in concentrations relevant for pharmaceutical formulation, the insulin monomer assembles to dimers and at neutral pH, in the presence of zinc ions, further to hexamers. Many crystalline modifications of insulin have been identified but only those with the hexamer as the basic unit are utilized in preparations for therapy. The insulin hexamer forms a relatively stable unit but some flexibility remains within the individual molecules. The intrinsic flexibility at the ends of the B chain plays an important role in governing the physical and chemical stability of insulin. A variety of chemical changes of the primary structure (yielding insulin derivatives), and physical modifications of the secondary to quaternary structures (resulting in "denaturation," aggregation, and precipitation) are known to affect insulin and insulin preparations during storage and use (Fig. 8). The tendency of insulin to undergo structural transformation resulting in aggregation and formation of insoluble insulin fibrils has been one of the most intriguing and widely studied phenomena in relation to insulin stability. Although the exact mechanism of fibril formation is still obscure, it is now clear that the initial step is an exposure of certain hydrophobic residues, normally buried in the three-dimensional structure, to the surface of the insulin monomer. This requires displacement of the COOH-terminal B-chain residues from their normal position which can only be accomplished via monomerization of the insulin. Therefore, most methods stabilizing insulin against fibrillation share the

COMPARISON OF THREE ALGORITHMS FOR BASAL INSULIN IN TRANSITIONING STABLE POST-CARDIOTHORACIC SURGERY PATIENTS FROM INTRAVENOUS TO SUBCUTANEOUS INSULIN

PubMed Central

Dungan, Kathleen; Hall, Christine; Schuster, Dara; Osei, Kwame

2011-01-01

Objective The objective was to determine the efficacy of an algorithim containing aspart dosed according to carbohydrate intake and one of 3 initial doses of detemir in stable cardiac surgery patients requiring intravenous (IV) insulin. Methods Patients were extubated, off pressors and otherwise stable, requiring at least 1 unit/hr of IV insulin at least 48 hours following surgery. Subjects were randomized to once daily detemir at 50, 65, or 80% of IV basal insulin requirements and received aspart according to carbohydrate intake. The dose of detemir was adjusted daily over 72 hours. Results The number of patients with an initial morning glucose 80–130 mg/dl was 36, 63, and 56% of patients at the 50, 65, and 80% doses (p=0.12) (n=82). However, the mean overall glucose at 24 and 72 hours was similar between groups, and 86, 93, and 92% achieved a mean glucose 80–180 mg/dl at 72 hours (p=0.60). Hypoglycemia (<65 mg/dl) only occurred in the 65% (21%) and 80% (12%) groups over the first 72 hours (p=0.02 in the 50% compared to the 65 and 80% groups combined) with one event <40 mg/dl in the 80% group. There was no loss of glycemic control by the end of the once daily dosing interval. Conclusions Glycemic targets can be achieved without hypoglycemia by 72 hours in most cardiac surgery patients requiring IV insulin with a regimen containing an initial detemir dose of 50% of basal IV insulin requirements and prandial and supplemental insulin. PMID:21550950

Treatment duration (persistence) of basal insulin supported oral therapy (BOT) in Type-2 diabetic patients: comparison of insulin glargine with NPH insulin.

PubMed

Quinzler, Renate; Ude, Miriam; Franzmann, Alexandra; Feldt, Sandra; Schüssel, Katrin; Leuner, Kristina; Müller, Walter E; Dippel, Franz-Werner; Schulz, Martin

2012-01-01

To compare the persistence (treatment duration) of basal insulin supported oral therapy (BOT) using insulin glargine (GLA) or NPH insulin (NPH) in Type-2 diabetic patients. This retrospective cohort study reports results from an analysis of claims data from prescriptions for ambulatory patients within the German Statutory Health Insurance scheme. The study is based on claims data from more than 80% of German community pharmacies. Treatment duration until switching to a basal bolus treatment regimen (intensified conventional insulin therapy: ICT) was determined in insulin-naïve patients who began treatment with BOT using GLA or NPH between 01/2003 and 12/2006. A total of 97,998 patients (61,070 GLA and 36,928 NPH) were included. Within the observation period, 23.5% of GLA patients and 28.0% of NPH patients switched from BOT to ICT. The upper quartile of probability of continuation of therapy (the 75th percentile) was reached after 769 days in GLA patients and after 517 days in NPH patients. Therefore, the risk of switching to ICT was significantly higher with NPH compared to GLA: hazard ratios were 1.34 (99% CI: 1.29-1.38; unadjusted) and 1.22 (99% CI: 1.18-1.27) after adjustment for predefined covariates. Various sensitivity analyses using modified inclusion criteria and endpoint definitions were applied and these confirmed the initial results. Type-2 diabetic patients under BOT with GLA stayed significantly longer on the initial therapy before switching to ICT than patients on BOT using NPH.

Insulin algorithms in the self-management of insulin-dependent diabetes: the interactive 'Apple Juice' program.

PubMed

Williams, A G

1996-01-01

The 'Apple Juice' program is an interactive diabetes self-management program which runs on a lap-top Macintosh Powerbook 100 computer. The dose-by-dose insulin advisory program was initially designed for children with insulin-dependent (type 1) diabetes mellitus. It utilizes several different insulin algorithms, measurement formulae, and compensation factors for meals, activity, medication and the dawn phenomenon. It was developed to assist the individual with diabetes and/or care providers, in determining specific insulin dosage recommendations throughout a 24 h period. Information technology functions include, but are not limited to automated record keeping, data recall, event reminders, data trend/pattern analyses and education. This paper highlights issues, observations and recommendations surrounding the use of the current version of the software, along with a detailed description of the insulin algorithms and measurement formulae applied successfully with the author's daughter over a six year period.

Pharmacokinetic Model of the Transport of Fast-Acting Insulin From the Subcutaneous and Intradermal Spaces to Blood.

PubMed

Lv, Dayu; Kulkarni, Sandip D; Chan, Alice; Keith, Stephen; Pettis, Ron; Kovatchev, Boris P; Farhi, Leon S; Breton, Marc D

2015-07-01

Pharmacokinetic (PK) models describing the transport of insulin from the injection site to blood assist clinical decision making and are part of in silico platforms for developing and testing of insulin delivery strategies for treatment of patients with diabetes. The ability of these models to accurately describe all facets of the in vivo insulin transport is therefore critical for their application. Here, we propose a new model of fast-acting insulin analogs transport from the subcutaneous and intradermal spaces to blood that can accommodate clinically observed biphasic appearance and delayed clearance of injected insulin, 2 phenomena that are not captured by existing PK models. To develop the model we compare 9 insulin transport PK models which describe hypothetical insulin delivery pathways potentially capable of approximating biphasic appearance of exogenous insulin. The models are tested with respect to their ability to describe clinical data from 10 healthy volunteers which received 1 subcutaneous and 2 intradermal insulin injections on 3 different occasions. The optimal model, selected based on information and posterior identifiability criteria, assumes that insulin is delivered at the administrative site and is then transported to the bloodstream via 2 independent routes (1) diffusion-like process to the blood and (2) combination of diffusion-like processes followed by an additional compartment before entering the blood. This optimal model accounts for biphasic appearance and delayed clearance of exogenous insulin. It agrees better with the clinical data as compared to commonly used models and is expected to improve the in silico development and testing of insulin treatment strategies, including artificial pancreas systems. © 2015 Diabetes Technology Society.

An Information Theoretical Analysis of Human Insulin-Glucose System Toward the Internet of Bio-Nano Things.

PubMed

Abbasi, Naveed A; Akan, Ozgur B

2017-12-01

Molecular communication is an important tool to understand biological communications with many promising applications in Internet of Bio-Nano Things (IoBNT). The insulin-glucose system is of key significance among the major intra-body nanonetworks, since it fulfills metabolic requirements of the body. The study of biological networks from information and communication theoretical (ICT) perspective is necessary for their introduction in the IoBNT framework. Therefore, the objective of this paper is to provide and analyze for the first time in the literature, a simple molecular communication model of the human insulin-glucose system from ICT perspective. The data rate, channel capacity, and the group propagation delay are analyzed for a two-cell network between a pancreatic beta cell and a muscle cell that are connected through a capillary. The results point out a correlation between an increase in insulin resistance and a decrease in the data rate and channel capacity, an increase in the insulin transmission rate, and an increase in the propagation delay. We also propose applications for the introduction of the system in the IoBNT framework. Multi-cell insulin glucose system models may be based on this simple model to help in the investigation, diagnosis, and treatment of insulin resistance by means of novel IoBNT applications.

Insulin production rate in normal man as an estimate for calibration of continuous intravenous insulin infusion in insulin-dependent diabetic patients.

PubMed

Waldhäusl, W K; Bratusch-Marrain, P R; Francesconi, M; Nowotny, P; Kiss, A

1982-01-01

This study examines the feasibility of deriving the 24-h insulin requirement of insulin-dependent diabetic patients who were devoid of any endogenous insulin release (IDD) from the insulin-production rate (IPR) of healthy man (basal, 17 mU/min; stimulated 1.35 U/12.5 g glucose). To this end, continuous intravenous insulin infusion (CIVII) was initiated at a precalculated rate of 41.2 +/- 4.6 (SD) U/24 h in IDD (N - 12). Blood glucose profiles were compared with those obtained during intermittent subcutaneous (s.c.) insulin therapy (IIT) and those of healthy controls (N = 7). Regular insulin (Hoechst CS) was infused with an adapted Mill Hill Infuser at a basal infusion rate of 1.6 U/h (6:00 a.m. to 8:00 p.m.), and of 0.8 U/h from 8:00 p.m. to 6:00 a.m. Preprandial insulin (3.2-6.4 U) was added for breakfast, lunch, and dinner. Daily individual food intake totaled 7688 +/- 784 kJ (1836 +/- 187 kcal)/24 h including 184 +/- 37 g of glucose. Proper control of blood glucose (BG) (mean BG 105 +/- 10 mg/dl; mean amplitude of glycemic excursions 54 +/- 18 mg/dl; and 1 h postprandial BG levels not exceeding 160 mg/dl) and of plasma concentrations of beta-hydroxybutyrate and lactate was maintained by 41.4 +/- 4.4 U insulin/24 h. Although BG values only approximated the upper normal range as seen in healthy controls, they were well within the range reported by others during CIVII. Therefore, we conclude that in adult IDD completely devoid of endogenous insulin (1) the IPR of normal man can be used during CIVII as an estimate for the patient's minimal insulin requirement per 24 h, and (2) this approach allows for a blood glucose profile close to the upper range of a normal control group. Thus, deriving a patient's daily insulin dose from the insulin production rate of healthy man may add an additional experimental protocol which aids in making general calculations of a necessary insulin dose instead of using trial and error or a closed-loop insulin infusion system.

Learning From Past Failures of Oral Insulin Trials.

PubMed

Michels, Aaron W; Gottlieb, Peter A

2018-07-01

Very recently one of the largest type 1 diabetes prevention trials using daily administration of oral insulin or placebo was completed. After 9 years of study enrollment and follow-up, the randomized controlled trial failed to delay the onset of clinical type 1 diabetes, which was the primary end point. The unfortunate outcome follows the previous large-scale trial, the Diabetes Prevention Trial-Type 1 (DPT-1), which again failed to delay diabetes onset with oral insulin or low-dose subcutaneous insulin injections in a randomized controlled trial with relatives at risk for type 1 diabetes. These sobering results raise the important question, "Where does the type 1 diabetes prevention field move next?" In this Perspective, we advocate for a paradigm shift in which smaller mechanistic trials are conducted to define immune mechanisms and potentially identify treatment responders. The stage is set for these interventions in individuals at risk for type 1 diabetes as Type 1 Diabetes TrialNet has identified thousands of relatives with islet autoantibodies and general population screening for type 1 diabetes risk is under way. Mechanistic trials will allow for better trial design and patient selection based upon molecular markers prior to large randomized controlled trials, moving toward a personalized medicine approach for the prevention of type 1 diabetes. © 2018 by the American Diabetes Association.

Predictors of insulin uptake among adults with type 2 diabetes in the Stepping Up Study.

PubMed

Holmes-Truscott, Elizabeth; Furler, John; Blackberry, Irene; O'Neal, David N; Speight, Jane

2017-11-01

We aimed to investigate predictors of insulin uptake, and change in insulin appraisals, among adults with type 2 diabetes mellitus (T2DM) who participated in the Stepping Up trial. The Stepping Up model of care, supporting timely insulin initiation in primary care, was evaluated in a two-armed cluster-randomised controlled trial. Participants were 266 adults (mean±SD age 62±10years; 39% women) with T2DM (median (IQR) duration 8.5 (5, 13)years) from 74 primary care practices (Stepping Up intervention: 57%, control 43%). At 12months, 47% (n=126) had commenced insulin. Controlling for randomisation, logistic regression was used to explore baseline predictors of insulin uptake, including: demographic and clinical characteristics, emotional wellbeing (depressive symptoms and diabetes-related distress), insulin treatment appraisals, and, 'willingness' to initiate insulin. Two-way analysis of variance examined effects of, and interaction between, randomisation and insulin uptake on 12-month change in insulin appraisals. Participants using insulin at 12months were more likely (all p<0.05) than those with non-insulin-treated T2DM to report: lower socioeconomic status, higher baseline HbA1c (median difference: 0.3%; 3mmol/mol), greater willingness to commence insulin (very willing: 27% vs 12%), and less negative and more positive insulin appraisals. All contributed significantly to the final model (χ 2 (8)=92.1, p<0.001) except insulin appraisals. Regardless of trial allocation, those initiating insulin reported significantly greater reductions in negative insulin appraisals. Controlling for randomisation, 12-month insulin use was predicted by higher baseline HbA1c and 'willingness' to use insulin if recommended. Negative insulin appraisals reduced following insulin initiation. Copyright © 2017 Elsevier B.V. All rights reserved.

Insulin resistance, β-cell dysfunction and differences in curves of plasma glucose and insulin in the intermediate points of the standard glucose tolerance test in adults with cystic fibrosis.

PubMed

Cano Megías, Marta; González Albarrán, Olga; Guisado Vasco, Pablo; Lamas Ferreiro, Adelaida; Máiz Carro, Luis

2015-02-01

diabetes has become a co-morbidity with a negative impact on nutritional status, lung function and survival in cystic fibrosis. To identify any changes in intermediate points after a 2-hour oral glucose tolerance test (OGTT), pancreatic β-cell dysfunction, and insulin resistance in cystic fibrosis-related diabetes. It was carried out a retrospective analysis in a cohort of 64 patients affected of cystic fibrosis, older than 14 years, using the first pathological OGTT. Peripheral insulin resistance was measured using the homeostasis model assessment for insulin resistance (HOMA- IR), and pancreatic β-cell function was calculated according to Wareham. Time to maximum plasma insulin and glucose levels and area under the curve (AUC0-120) were also measured. Twenty-eight women and 36 men with a mean age of 26.8 years were enrolled, of whom 26.7% had normal glucose tolerance (NGT), 18.3% cystic fibrosis-related diabetes without fasting hyperglycemia (CFRD w/o FPG), 10% indeterminate (INDET), and 45% impaired glucose tolerance (IGT). HOMA-IR values were not significantly different between the diagnostic categories. Patients with any pathological change had worse β cell function, with a significant delay in insulin secretion, although there were no differences in total insulin production (AUC0-120). Time to maximum glucose levels was significantly shorter in NGT patients as compared to other categories, with glucose AUC0-120 being higher in the different diagnostic categories as compared to NGT. In over half the cases, peak blood glucose levels during a standard OGTT are reached in the intermediate time points, rather than at the usual time of 120minutes. Patients with cystic fibrosis and impaired glucose metabolism have a delayed insulin secretion during the standard OGTT due to loss of first-phase insulin secretion, with no differences in total insulin production. Absence of significant changes in HOMA-IR suggests that β-cell dysfunction is the main pathogenetic

A prospective, randomized, open-label study comparing the efficacy and safety of preprandial and prandial insulin in combination with acarbose in elderly, insulin-requiring patients with type 2 diabetes mellitus.

PubMed

Yang, Guang; Li, Chunlin; Gong, Yanping; Li, Jian; Cheng, Xiaoling; Tian, Hui

2013-06-01

By delaying absorption of carbohydrates, acarbose can reduce preprandial hyperglycemia and delay the emergence of postprandial hyperglycemia. To evaluate whether acarbose can shorten the desirable time interval between insulin injection and meals, 60 elderly (≥60 years) patients with unsatisfactorily controlled type 2 diabetes mellitus despite insulin use were enrolled in a randomized, open-label study of 16 weeks' duration. Two groups (n=20 each) were randomized to receive isophane protamine biosynthetic human insulin 70/30 injections twice daily 30 min before meals plus acarbose 50 mg once daily (Group A) or three times daily (Group B) before meals, whereas the third group (n=20) received isophane protamine biosynthetic human insulin 70/30 injections twice daily immediately before meals plus acarbose 50 mg three times daily before meals (Group C). The required insulin dosage at study end was significantly less in Groups B and C than in Group A. Both continuous glucose monitoring data and the patients' self-monitoring data indicated that blood glucose variability parameters were significantly improved in Groups B and C in comparison with Group A, but there were no significant differences between Groups B and C. The incidence of hypoglycemia was low in all three groups. The absence of a significant difference in glucose variability between Groups B and C suggests that the addition of acarbose permitted adjustment of the insulin administration time from 30 min before meals to immediately before meals-which may be more convenient for patients-without affecting glycemic control.

The Effect of Fasting Duration on Baseline Blood Glucose Concentration, Blood Insulin Concentration, Glucose/Insulin Ratio, Oral Sugar Test, and Insulin Response Test Results in Horses.

PubMed

Bertin, F R; Taylor, S D; Bianco, A W; Sojka-Kritchevsky, J E

2016-09-01

Published descriptions of the oral sugar test (OST) and insulin response test (IRT) have been inconsistent when specifying the protocol for fasting horses before testing. The purpose of our study was to examine the effect of fasting duration on blood glucose concentration, blood insulin concentration, glucose/insulin ratio, OST, and IRT results in horses. Ten healthy adult horses. Both OST and IRT were performed on horses without fasting and after fasting for 3, 6, and 12 hours. Thus, 8 tests were performed per horse in a randomized order. Blood collected at the initial time point of the OST was analysed for both blood glucose and serum insulin concentrations so that baseline concentrations and the glucose/insulin ratio could be determined. Unless fasted, horses had free-choice access to grass hay. There was no effect of fasting and fasting duration on blood glucose concentration, serum insulin concentration, glucose/insulin ratio, or the OST. Response to insulin in the IRT was decreased in fasted horses. The effect increased with fasting duration, with the least response to insulin administration after a 12-hour fast. These data indicate that insulin sensitivity is not a fixed trait in horses. Fasting a horse is not recommended for a glucose/insulin ratio or IRT, and fasting a horse for 3 hours is recommended for the OST. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

[Comparison of initial and delayed myocardial imaging with beta-methyl-p-[123I]-iodophenylpentadecanoic acid in acute myocardial infarction].

PubMed

Naruse, H; Yoshimura, N; Yamamoto, J; Morita, M; Fukutake, N; Ohyanagi, M; Iwasaki, T; Fukuchi, M

1994-01-01

Myocardial imaging using beta-methyl-p-[123I]-iodophenylpentadecanoic acid (BMIPP) of 15 patients with acute myocardial infarction was performed to assess "fill-in" and "washout" defects in the delayed myocardial image. The initial and delayed images were evaluated by a visual and quantitative washout rate method. Visual judgement found 8/180 (4%) segments showed "fill-in" defects, and 24/180 segments (13%) showed "washout" defects. There was no relationship between days from onset to the study and the frequency of fill-in and washout defects. The mean washout rate in the segments with "fill-in" defects was 9.0 +/- 16.6%, and that of "washout" defects was 24.9 +/- 18.1% which was significantly higher than in controls (8.7 +/- 15.4%, p < 0.05). There was no correlation between mean washout rate and total blood lipids, total cholesterol, triglyceride and HDL-cholesterol. Therefore, neither time from onset nor blood lipids level was related to changes from the initial image to the delayed image. These changes may be due to relative (false) findings due to changes in circumference, and may be based on myocardial characteristics after myocardial infarction and/or reperfusion.

Insulin oedema in a child with newly diagnosed diabetes mellitus.

PubMed

Aravamudhan, Avinash; Gardner, Chris; Smith, Claire; Senniappan, Senthil

2014-05-01

Insulin oedema is a rare complication of insulin therapy for diabetes mellitus. It has been reported in type 1 diabetes mellitus, in poorly controlled type 2 diabetes mellitus following either the initiation or intensification of insulin therapy and in underweight patients on large doses of insulin. There are only a few case reports since it was first described in 1928, showing that it is an uncommon and probably an under-reported complication. The majority of those reports have been in the adult population. The generalised oedema tends to develop shortly after initiation or intensification of insulin therapy and resolves spontaneously within few weeks. We present one of the youngest patients reported in the literature, a 9-year-old boy who developed insulin oedema within few days of presenting with diabetic ketoacidosis. The case highlights the importance of recognising this generally transient and self-resolving complication and differentiating it from other serious causes of oedema.

Self-management support for insulin therapy in type 2 diabetes.

PubMed

Funnell, Martha M; Kruger, Davida F; Spencer, Mary

2004-01-01

The purpose of this article is to describe the self-management support that can be provided by diabetes educators for type 2 diabetes patients who are transitioning from therapy with oral hypoglycemic agents to insulin. The role of the diabetes educator in patient education and self-management support during all aspects of insulin therapy is discussed. Phases during which support may be especially important include the decision-making process, initiation, and maintenance. Although some patients make the decision fairly easily, the introduction of insulin therapy is likely to raise many issues and questions for many type 2 diabetes patients. The more reluctant patients may experience psychological insulin resistance, a syndrome where insulin therapy is viewed as a threat or failure, which can affect health professionals as well. The diabetes educator can provide support and approaches to help diminish this resistance and make the transition to insulin therapy easier and more effective for patients with type 2 diabetes. Education and ongoing self-management support are needed for informed decision making and the initiation and maintenance of insulin therapy. Therefore, diabetes educators have a critical role to play during both the decision-making process and the safe transition to insulin therapy.

Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

PubMed

Vora, J P; Owens, D R; Dolben, J; Atiea, J A; Dean, J D; Kang, S; Burch, A; Brange, J

1988-11-12

To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. Study in normal people at a diabetes research unit and a university department of medical physics. Seven healthy male volunteers aged 20-39 not receiving any other drugs. After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U/kg respectively. The response of glucagon substantiated the earlier and

Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

PubMed Central

Vora, J. P.; Owens, D. R.; Dolben, J.; Atiea, J. A.; Dean, J. D.; Kang, S.; Burch, A.; Brange, J.

1988-01-01

OBJECTIVE--To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. DESIGN--Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. SETTING--Study in normal people at a diabetes research unit and a university department of medical physics. SUBJECTS--Seven healthy male volunteers aged 20-39 not receiving any other drugs. INTERVENTIONS--After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. END POINT--To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U

Effects of background statin therapy on glycemic response and cardiovascular events following initiation of insulin therapy in type 2 diabetes: a large UK cohort study.

PubMed

Anyanwagu, Uchenna; Mamza, Jil; Donnelly, Richard; Idris, Iskandar

2017-08-22

Statins may increase the risk of new-onset diabetes and adversely affect glycaemic control, but their effects on the glycemic response and mortality outcomes following commencement of insulin therapy in patients with Type 2 Diabetes (T2D) are unclear. A retrospective cohort study was conducted in 12,725 insulin initiators with T2D using The Health Improvement Network (THIN) UK database. Changes in HbA1c at 6, 12, 24 and 36 months, and the 5-year risk of mortality and (3-point) major adverse cardiovascular events (MACE), were compared between prior users (n = 10,682) and non-users (n = 2043) of statin therapy who were newly commenced on insulin treatment. Cox proportional hazard models were used to estimate the hazard ratios of the different outcomes. Mean age of the cohort was 58.7 ± 14.0 years (51% male) and mean baseline HbA1c was 8.7 ± 1.8%. A greater initial reduction in HbA1c was observed following insulin initiation in the non-users of statins compared with the users, which was significant in the short term (-0.34% vs -0.26% at 6 months; mean diff = -0.09%, p = 0.004) but not in the long term: -0.31% versus -0.35% at 3 years (mean diff = 0.05%, p = 0.344). CV events (3-point MACE) were 878 versus 217 in statin users versus non-users (20.7 vs 30.9 per 1000 person-years; adjusted Hazard Ratio (aHR) 1.36 (95% CI 1.15-1.62; p < 0.0001). In a subgroup analysis of individual statins, HbA1c was higher throughout the study duration with all statins relative to non-users of statin therapy (p < 0.05). The aHRs for 3-point MACE for atorvastatin, simvastatin, rosuvastatin and pravastatin were 0.82 (95% CI 0.68-0.98), 0.67 (0.55-0.82), 0.56 (0.39-0.81) and 0.78 (0.60-1.01), respectively. Following initiation of insulin therapy in patients with T2D in routine care, concurrent use of a statin was associated with less good glycaemic control in the short-term but a much lower risk of major adverse CV events.

Fenofibrate Decreases Insulin Clearance and Insulin Secretion to Maintain Insulin Sensitivity*

PubMed Central

Ramakrishnan, Sadeesh K.; Russo, Lucia; Ghanem, Simona S.; Patel, Payal R.; Oyarce, Ana Maria; Heinrich, Garrett; Najjar, Sonia M.

2016-01-01

High fat diet reduces the expression of CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a transmembrane glycoprotein that promotes insulin clearance and down-regulates fatty acid synthase activity in the liver upon its phosphorylation by the insulin receptor. Because peroxisome proliferator-activated receptor α (PPARα) transcriptionally suppresses CEACAM1 expression, we herein examined whether high fat down-regulates CEACAM1 expression in a PPARα-dependent mechanism. By activating PPARα, the lipid-lowering drug fenofibrate reverses dyslipidemia and improves insulin sensitivity in type 2 diabetes in part by promoting fatty acid oxidation. Despite reducing glucose-stimulated insulin secretion, fenofibrate treatment does not result in insulin insufficiency. To examine whether this is mediated by a parallel decrease in CEACAM1-dependent hepatic insulin clearance pathways, we fed wild-type and Pparα−/− null mice a high fat diet supplemented with either fenofibrate or Wy14643, a selective PPARα agonist, and examined their effect on insulin metabolism and action. We demonstrated that the decrease in insulin secretion by fenofibrate and Wy14643 is accompanied by reduction in insulin clearance in wild-type but not Pparα−/− mice, thereby maintaining normoinsulinemia and insulin sensitivity despite continuous high fat intake. Intact insulin secretion in L-CC1 mice with protected hepatic insulin clearance and CEACAM1 levels provides in vivo evidence that insulin secretion responds to changes in insulin clearance to maintain physiologic insulin and glucose homeostasis. These results also emphasize the relevant role of hepatic insulin extraction in regulating insulin sensitivity. PMID:27662905

Insulin effects on honeybee appetitive behaviour.

PubMed

Mengoni Goñalons, Carolina; Guiraud, Marie; de Brito Sanchez, María Gabriela; Farina, Walter M

2016-10-01

Worker honeybees (Apis mellifera) carry out multiple tasks throughout their adult lifespan. It has been suggested that the insulin/insulin-like signalling pathway participates in regulating behavioural maturation in eusocial insects. Insulin signalling increases as the honeybee worker transitions from nurse to food processor to forager. As behavioural shifts require differential usage of sensory modalities, our aim was to assess insulin effects on olfactory and gustatory responsiveness as well as on olfactory learning in preforaging honeybee workers of different ages. Adults were reared in the laboratory or in the hive. Immediately after being injected with insulin or vehicle (control), and focusing on the proboscis extension response, bees were tested for their spontaneous response to odours, sucrose responsiveness and ability to discriminate odours through olfactory conditioning. Bees injected with insulin have higher spontaneous odour responses. Sucrose responsiveness and odour discrimination are differentially affected by treatment according to age: whereas insulin increases gustatory responsiveness and diminishes learning abilities of younger workers, it has the opposite effect on older bees. In summary, insulin can improve chemosensory responsiveness in young workers, but also worsens their learning abilities to discriminate odours. The insulin signalling pathway is responsive in young workers, although they are not yet initiating outdoor activities. Our results show strong age-dependent effects of insulin on appetitive behaviour, which uncover differences in insulin signalling regulation throughout the honeybee worker's adulthood. © 2016. Published by The Company of Biologists Ltd.

Addition of or switch to insulin therapy in people treated with glucagon-like peptide-1 receptor agonists: A real-world study in 66 583 patients.

PubMed

Montvida, Olga; Klein, Kerenaftali; Kumar, Sudhesh; Khunti, Kamlesh; Paul, Sanjoy K

2017-01-01

Real world outcomes of addition or switch to insulin therapy in type 2 diabetes (T2DM) patients on glucagon-like paptide-1 receptor agonist (GLP-1RA) with inadequately controlled hyperglycaemia, are not known. Patients with T2DM (n = 66 583) with a minimum of 6 months of GLP-1RA treatment and without previous insulin treatment were selected. Those who added insulin (n = 39 599) or switched to insulin after GLP-1RA cessation (n = 4706) were identified. Adjusted changes in glycated haemoglobin (HbA1c), weight, systolic blood pressure (SBP), and LDL cholesterol were estimated over 24 months follow-up. Among those who continued with GLP-1RA treatment without adding or switching to insulin, the highest adjusted mean HbA1c change was achieved within 6 months, with no further glycaemic benefits observed during 24 months of follow-up. Addition of insulin within 6 months of GLP-1RA initiation was associated with 18% higher odds of achieving HbA1c <7% at 24 months, compared with adding insulin later. At 24 months, those who added insulin reduced HbA1c significantly by 0.55%, while no glycaemic benefit was observed in those who switched to insulin. Irrespective of intensification with insulin, weight, SBP and LDL cholesterol were significantly reduced by 3 kg, 3 mm Hg, and 0.2 mmol/L, respectively, over 24 months. Significant delay in intensification of treatment by addition of insulin is observed in patients with T2DM inadequately controlled with GLP-1RA. Earlier addition of insulin is associated with better glycaemic control, while switching to insulin is not clinically beneficial during 2 years of treatment. Non-responding patients on GLP-1RA would benefit from adding insulin therapy, rather than switching to insulin. © 2016 John Wiley & Sons Ltd.

Reasons for delaying or engaging in early sexual initiation among adolescents in Nigeria

PubMed Central

Ankomah, Augustine; Mamman-Daura, Fatima; Omoregie, Godpower; Anyanti, Jennifer

2011-01-01

Background Annually, over 1 million births in Nigeria are to teenage mothers. Many of these pregnancies are unwanted and these mothers are also exposed to the risk of human immunodeficiency virus (HIV) infection. Sexual abstinence is a critical preventative health strategy. Several quantitative studies in Nigeria have identified the correlates and determinants of early sex, yet few have explored in depth the underlying reasons for early sex. This paper explores both the key factors that motivate some unmarried young people to engage in early sex and reasons why some delay. Methods This qualitative study was based on data from 30 focus group discussions held with unmarried 14- to 19-year-olds in four geographically and culturally dispersed Nigerian states. Focus groups were stratified by sexual experience to capture variations among different subgroups. Results Several reasons for early premarital sex were identified. The “push” factors included situations where parents exposed young female adolescents to street trading. “Pull” factors, particularly for males, included the pervasive viewing of locally produced movies, peer pressure and, for females, transactional sex (where adolescent girls exchange sex for gifts, cash, or other favors). Also noted were overtly coercive factors, including rape. There were also myths and misconceptions that “justified” early sexual initiation. Reasons cited for delay included religious injunction against premarital sex; disease prevention (especially HIV/acquired immunodeficiency syndrome); fear of pregnancy, and linked to this, the fear of dropping out of school; and, for females, the fear of bringing shame to the family, which could lead to their inability to get a “good” husband in the future. Conclusion The differences observed between sexually active and abstinent adolescents were that the latter were more confident, had greater determination, and, most important, deployed refusal skills to delay first sex

Factors associated with reaching or not reaching target HbA1c after initiation of basal or premixed insulin in patients with type 2 diabetes.

PubMed

Scheen, A J; Schmitt, H; Jiang, H H; Ivanyi, T

2017-02-01

To evaluate factors associated with reaching or not reaching target glycated haemoglobin (HbA 1c ) levels by analysing the respective contributions of fasting hyperglycaemia (FHG), also referred to as basal hyperglycaemia, vs postprandial hyperglycaemia (PHG) before and after initiation of a basal or premixed insulin regimen in patients with type 2 diabetes. This post-hoc analysis of insulin-naïve patients in the DURABLE study randomised to receive either insulin glargine or insulin lispro mix 25 evaluated the percentages of patients achieving a target HbA 1c of <7.0% (<53mmol/mol) per baseline HbA 1c quartiles, and the effect of each insulin regimen on the relative contributions of PHG and FHG to overall hyperglycaemia. Patients had comparable demographic characteristics and similar HbA 1c and FHG values at baseline in each HbA 1c quartile regardless of whether they reached the target HbA 1c . The higher the HbA 1c quartile, the greater was the decrease in HbA 1c , but also the smaller the percentage of patients achieving the target HbA 1c . HbA 1c and FHG decreased more in patients reaching the target, resulting in significantly lower values at endpoint in all baseline HbA 1c quartiles with either insulin treatment. Patients not achieving the target HbA 1c had slightly higher insulin doses, but lower total hypoglycaemia rates. Smaller decreases in FHG were associated with not reaching the target HbA 1c , suggesting a need to increase basal or premixed insulin doses to achieve targeted fasting plasma glucose and improve patient response before introducing more intensive prandial insulin regimens. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

PubMed Central

2015-01-01

Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24–48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise. PMID:26487009

Delayed Intervention With Pyridoxamine Improves Metabolic Function and Prevents Adipose Tissue Inflammation and Insulin Resistance in High-Fat Diet-Induced Obese Mice.

PubMed

Maessen, Dionne E; Brouwers, Olaf; Gaens, Katrien H; Wouters, Kristiaan; Cleutjens, Jack P; Janssen, Ben J; Miyata, Toshio; Stehouwer, Coen D; Schalkwijk, Casper G

2016-04-01

Obesity is associated with an increased risk for the development of type 2 diabetes and vascular complications. Advanced glycation end products are increased in adipose tissue and have been associated with insulin resistance, vascular dysfunction, and inflammation of adipose tissue. Here, we report that delayed intervention with pyridoxamine (PM), a vitamin B6 analog that has been identified as an antiglycating agent, protected against high-fat diet (HFD)-induced body weight gain, hyperglycemia, and hypercholesterolemia, compared with mice that were not treated. In both HFD-induced and db/db obese mice, impaired glucose metabolism and insulin resistance were prevented by PM supplementation. PM inhibited the expansion of adipose tissue and adipocyte hypertrophy in mice. In addition, adipogenesis of murine 3T3-L1 and human Simpson-Golabi-Behmel Syndrome preadipocytes was dose- and time-dependently reduced by PM, as demonstrated by Oil Red O staining and reduced expression of adipogenic differentiation genes. No ectopic fat deposition was found in the liver of HFD mice. The high expression of proinflammatory genes in visceral adipose tissue of the HFD group was significantly attenuated by PM. Treatment with PM partially prevented HFD-induced mild vascular dysfunction. Altogether, these findings highlight the potential of PM to serve as an intervention strategy in obesity. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Initial 60Fe Abundance in the Solar Nebula Constrained by Delayed Onset of a Planetesimal Dynamo

NASA Astrophysics Data System (ADS)

Wang, H.; Weiss, B. P.; Crowley, J.

2017-12-01

The paleomagnetism of meteorites provides evidence for advecting metallic core dynamos and large-scale differentiation on their parent planetesimals. Their small sizes relative to planets enable new opportunities to understand the physics of dynamo generation. Wang et al. [2017] studied the paleomagnetism of three volcanic angrites (D'Orbigny, 4563.37±0.12 Ma; Sahara 99555, 4563.54±0.14 Ma; Asuka 881371, 4562.4±1.6 Ma) and one plutonic angrite (Angra dos Reis, 4556.51±0.11 Ma). Their results show that the older volcanic angrites recorded no detectable paleomagnetic field, while the younger plutonic angrite recorded a paleomagnetic field of 17 µT interpreted as evidence of a core dynamo on the angrite parent body (APB). This indicates that the initiation of the APB dynamo was delayed until sometime between 4 and 11 My after the formation of calcium aluminum-rich inclusions (CAIs) at 4567.30 ± 0.16 Ma. This late timing is consistent with recent planetesimal thermal evolution models invoking shallow magma oceans [Neumann et al. 2014], which predict that planetesimal dynamos would not initiate until the core began to crystallize. It is also consistent with thermal evolution models invoking large-scale magma oceans that considered thermal blanketing of the core by 26Al decay in the mantle [Roberts et al. 2013, Sterenborg and Crowley 2013], which would delay thermal convection dynamos until several My after accretion (occurred <0.25 My after CAIs for the APB [Schiller et al. 2015]) and differentiation. Because the presence of even a small amount of 60Fe in the core could effectively remove the thermal blanketing effect of mantle 26Al, we can use the delay in timing of the dynamo to constrain the abundance of 60Fe on the APB. Our planetesimal thermal evolution models show that if the initial solar nebula 60Fe/56Fe ratio was greater than 5×10-9, the APB core dynamo would have to start earlier than 4 My after CAIs, in contradiction to the paleomagnetic constraints

Continuous Subcutaneous Insulin Infusion in Children: A Pilot Study Validating a Protocol to Avoid Hypoglycemia at Initiation.

PubMed

Manousaki, Despoina; Deladoëy, Johnny; Geoffroy, Louis; Olivier, Patricia

2017-01-01

The occurrence of hypoglycemia and hyperglycemia during the first days after transition to continuous subcutaneous insulin infusion (CSII) in patients with type 1 diabetes has not been systematically studied in children. The aim of this prospective study was to demonstrate that the protocol applied in our diabetes clinic is safe at CSII initiation in children. We assessed 22 pediatric patients with type 1 diabetes, using continuous glucose monitoring (CGM) before and after CSII initiation (±3 days). After CSII initiation, there was no difference in the rates of hypoglycemic events expressed as relative rates (RRs) per person-reading (RR = 0.85, p  = 0.52, 95% CI 0.52-1.39), as well as in the number of prolonged hypoglycemic events (>1 h) per day (RR = 1.12, p  = 0.56, 95% CI 0.75-1.68). We observed only a trend toward prolonged episodes of hyperglycemia after pump initiation (RR = 1.52, p  = 0.06, 95% CI 0.97-2.35). Our study is the first to assess, through CGM and in a prospective way, the impact of a CSII initiation protocol on glycemic values. Our protocol provides a safe model to avoid hypoglycemia at CSII initiation in children. www.ClinicalTrials.gov, identifier NCT01840358.

Insulin accelerates global and mitochondrial protein synthesis rates in neonatal muscle during sepsis

USDA-ARS?s Scientific Manuscript database

In neonatal pigs, sepsis decreases protein synthesis in skeletal muscle by decreasing translation initiation. However, insulin stimulates muscle protein synthesis despite persistent repression of translation initiation signaling. To determine whether the insulin-induced increase in global rates of m...

Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study.

PubMed

Peyrot, M; Barnett, A H; Meneghini, L F; Schumm-Draeger, P-M

2012-05-01

To examine patient and physician beliefs regarding insulin therapy and the degree to which patients adhere to their insulin regimens. Internet survey of 1250 physicians (600 specialists, 650 primary care physicians) who treat patients with diabetes and telephone survey of 1530 insulin-treated patients (180 with Type 1 diabetes, 1350 with Type 2 diabetes) in China, France, Japan, Germany, Spain, Turkey, the UK or the USA. One third (33.2%) of patients reported insulin omission/non-adherence at least 1 day in the last month, with an average of 3.3 days. Three quarters (72.5%) of physicians report that their typical patient does not take their insulin as prescribed, with a mean of 4.3 days per month of basal insulin omission/non-adherence and 5.7 days per month of prandial insulin omission/non-adherence. Patients and providers indicated the same five most common reasons for insulin omission/non-adherence: too busy; travelling; skipped meals; stress/emotional problems; public embarrassment. Physicians reported low patient success at initiating insulin in a timely fashion and adjusting insulin doses. Most physicians report that many insulin-treated patients do not have adequate glucose control (87.6%) and that they would treat more aggressively if not for concern about hypoglycaemia (75.5%). Although a majority of patients (and physicians) regard insulin treatment as restrictive, more patients see insulin treatment as having positive than negative impacts on their lives. Glucose control is inadequate among insulin-treated patients, in part attributable to insulin omission/non-adherence and lack of dose adjustment. There is a need for insulin regimens that are less restrictive and burdensome with lower risk of hypoglycaemia. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Short-term fasting promotes insulin expression in rat hypothalamus.

PubMed

Dakic, Tamara B; Jevdjovic, Tanja V; Peric, Mina I; Bjelobaba, Ivana M; Markelic, Milica B; Milutinovic, Bojana S; Lakic, Iva V; Jasnic, Nebojsa I; Djordjevic, Jelena D; Vujovic, Predrag Z

2017-07-01

In the hypothalamus, insulin takes on many roles involved in energy homoeostasis. Therefore, the aim of this study was to examine hypothalamic insulin expression during the initial phase of the metabolic response to fasting. Hypothalamic insulin content was assessed by both radioimmunoassay and Western blot. The relative expression of insulin mRNA was examined by qPCR. Immunofluorescence and immunohistochemistry were used to determine the distribution of insulin immunopositivity in the hypothalamus. After 6-h fasting, both glucose and insulin levels were decreased in serum but not in the cerebrospinal fluid. Our study showed for the first time that, while the concentration of circulating glucose and insulin decreased, both insulin mRNA expression and insulin content in the hypothalamic parenchyma were increased after short-term fasting. Increased insulin immunopositivity was detected specifically in the neurons of the hypothalamic periventricular nucleus and in the ependymal cells of fasting animals. These novel findings point to the complexity of mechanisms regulating insulin expression in the CNS in general and in the hypothalamus in particular. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

NMR studies of muscle glycogen synthesis in insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus immediately after glycogen-depleting exercise.

PubMed Central

Price, T B; Perseghin, G; Duleba, A; Chen, W; Chase, J; Rothman, D L; Shulman, R G; Shulman, G I

1996-01-01

To examine the impact of insulin resistance on the insulin-dependent and insulin-independent portions of muscle glycogen synthesis during recovery from exercise, we studied eight young, lean, normoglycemic insulin-resistant (IR) offspring of individuals with non-insulin-dependent diabetes mellitus and eight age-weight matched control (CON) subjects after plantar flexion exercise that lowered muscle glycogen to approximately 25% of resting concentration. After approximately 20 min of exercise, intramuscular glucose 6-phosphate and glycogen were simultaneously monitored with 31P and 13C NMR spectroscopies. The postexercise rate of glycogen resynthesis was nonlinear. Glycogen synthesis rates during the initial insulin independent portion (0-1 hr of recovery) were similar in the two groups (IR, 15.5 +/- 1.3 mM/hr and CON, 15.8 +/- 1.7 mM/hr); however, over the next 4 hr, insulin-dependent glycogen synthesis was significantly reduced in the IR group [IR, 0.1 +/- 0.5 mM/hr and CON, 2.9 +/- 0.2 mM/hr; (P < or = 0.001)]. After exercise there was an initial rise in glucose 6-phosphate concentrations that returned to baseline after the first hour of recovery in both groups. In summary, we found that following muscle glycogen-depleting exercise, IR offspring of parents with non-insulin-dependent diabetes mellitus had (i) normal rates of muscle glycogen synthesis during the insulin-independent phase of recovery from exercise and (ii) severely diminished rates of muscle glycogen synthesis during the subsequent recovery period (2-5 hr), which has previously been shown to be insulin-dependent in normal CON subjects. These data provide evidence that exercise and insulin stimulate muscle glycogen synthesis in humans by different mechanisms and that in the IR subjects the early response to stimulation by exercise is normal. PMID:8643574

An Audit of Insulin Usage and Insulin Injection Practices in a Large Indian Cohort

PubMed Central

Baruah, Manash P.; Kalra, Sanjay; Bose, Saptarshi; Deka, Jumi

2017-01-01

Introduction: Insulin remains the cornerstone of therapy in a substantial number of patients with type 2 diabetes mellitus (T2DM). Inadequate knowledge regarding insulin usage is likely to influence its acceptance and adherence, and outcome of therapy, underscoring great need to investigate knowledge, attitude, and practice of insulin usage in patients with T2DM. Methodology: A cross-sectional registry-based retrospective study analyzed data collected from 748 respondents (male: 466, female: 282), mostly from high or middle economic status, who were enrolled as outpatient in a referral clinic during last 10 years (2006–2016), to assess the general characteristics of patients with type 2 diabetes and their baseline knowledge, attitude, and practice of insulin usage and injection practices. Results: Mean ± standard deviation (SD) of duration of diabetes was 12.24 ± 7.60 years and mean ± SD duration of insulin therapy was 3.42 ± 4.18 years, which was initiated after a mean ± SD diabetes duration of 8.80 ± 6.42 years. Mean insulin dose per kilogram of body weight/day was 0.51 ± 0.27 units. Total daily dose of insulin was 33.36 ± 18.44 units and number of injections/day (mean ± SD) was 2.06 ± 0.73. Among the respondents, 58.96% were on human insulin and 35.70% were on analog insulin. Pen devices were used by 66.08% of the population whereas 31.76% used insulin syringes. The prevalence of lipohypertrophy (LH) was 12.57%, which was significantly (P < 0.001) associated with wrong technique with regard to injection angle (10.45% vs. 23.02%), site of injection (7.00% vs. 30.51%), rotation of site of injection (0.88% vs. 17.66%), and reuse of needle (5.77% vs. 15.19%). LH was also significantly (P < 0.05) associated with the use of human (14.74%) compared to analog insulin (8.24%). Conclusion: The current study highlights the unique patterns of insulin usage and associated high prevalence of LH among insulin users in India. PMID:28553603

Third Exposure to a Reduced Carbohydrate Meal Lowers Evening Postprandial Insulin and GIP Responses and HOMA-IR Estimate of Insulin Resistance.

PubMed

Lin, Po-Ju; Borer, Katarina T

2016-01-01

30% compared to no such changes after three 60%-carbohydrate meals, an effect that was independent of pre-meal exercise. The parallel timing and magnitude of postprandial insulin and GIP changes suggest their dependence on a delayed intestinal adaptation to a low-carbohydrate diet. Pre-meal exercise exacerbated glucose intolerance with both diets most likely due to impairment of insulin signaling by pre-meal elevation of FFAs.

Probing the mechanism of insulin fibril formation with insulin mutants.

PubMed

Nielsen, L; Frokjaer, S; Brange, J; Uversky, V N; Fink, A L

2001-07-27

The molecular basis of insulin fibril formation was investigated by studying the structural properties and kinetics of fibril formation of 20 different human insulin mutants at both low pH (conditions favoring monomer/dimer) and at pH 7.4 (conditions favoring tetramer/hexamer). Small-angle X-ray scattering showed insulin to be monomeric in 20% acetic acid, 0.1 M NaCl, pH 2. The secondary structure of the mutants was assessed using far-UV circular dichroism, and the tertiary structure was determined using near-UV circular dichroism, quenching of intrinsic fluorescence by acrylamide and interactions with the hydrophobic probe 1-anilino-8-naphthalene-sulfonic acid (ANS). The kinetics of fibril formation were monitored with the fluorescent dye, Thioflavin T. The results indicate that the monomer is the state from which fibrils arise, thus under some conditions dissociation of hexamers may be rate limiting or partially rate limiting. The insulin mutants were found to retain substantial nativelike secondary and tertiary structure under all conditions studied. The results suggest that fibril formation of the insulin mutants is controlled by specific molecular interactions that are sensitive to variations in the primary structure. The observed effects of several mutations on the rate of fibril formation are inconsistent with a previously suggested model for fibrillation [Brange, J., Whittingham, J., Edwards, D., Youshang, Z., Wollmer, A., Brandenburg, D., Dodson, G., and Finch, J. (1997) Curr. Sci. 72, 470-476]. Two surfaces on the insulin monomer are identified as potential interacting sites in insulin fibrils, one consisting of the residues B10, B16, and B17 and the other consisting of at least the residues A8 and B25. The marked increase in the lag time for fibril formation with mutations to more polar residues, as well as mutations to charged residues, demonstrates the importance of both hydrophobic and electrostatic interactions in the initial stages of fibrillation

The impact of insulin therapy and attitudes towards insulin intensification among adults with type 2 diabetes: A qualitative study.

PubMed

Holmes-Truscott, Elizabeth; Browne, Jessica L; Speight, Jane

2016-08-01

As type 2 diabetes (T2DM) is a progressive chronic condition, regular clinical review and treatment intensification are critical for prevention of long-term complications. Our aim was to explore the personal impact of insulin therapy, both positive and negative consequences, and attitudes towards future insulin intensification. Twenty face-to-face interviews were conducted, and transcripts were analysed using thematic inductive analysis. Eligible participants were adults with T2DM, using insulin injections for <4years. Participants were mostly men (n=13, 65%), (median (range)) aged 65 (43-76) years, living with T2DM for 11.5 (2-27) years. Five themes emerged regarding the consequences (positive and negative) of insulin therapy, including: physical impact, personal control, emotional well-being, freedom/flexibility, (concerns about) others' reactions. Increased inconvenience and the perceived seriousness of using fast-acting insulin were both reported as barriers to future insulin intensification, despite most participants being receptive to the idea of administering additional injections. Positive and negative experiences of insulin therapy were reported by adults with T2DM and most were receptive to insulin intensification despite reported barriers. These findings may inform clinical interactions with people with T2DM and interventions to promote receptiveness to insulin initiation and intensification. Copyright © 2016 Elsevier Inc. All rights reserved.

Long-term outcome of individuals treated with oral insulin: diabetes prevention trial-type 1 (DPT-1) oral insulin trial.

PubMed

Vehik, Kendra; Cuthbertson, David; Ruhlig, Holly; Schatz, Desmond A; Peakman, Mark; Krischer, Jeffrey P

2011-07-01

To evaluate the long-term intervention effects of oral insulin on the development of type 1 diabetes and to assess the rate of progression to type 1 diabetes before and after oral insulin treatment was stopped in the Diabetes Prevention Trial-Type 1 (DPT-1). The follow-up included subjects who participated in the early intervention of oral insulin (1994-2003) to prevent or delay type 1 diabetes. A telephone survey was conducted in 2009 to determine whether diabetes had been diagnosed and, if not, an oral glucose tolerance test (OGTT), hemoglobin A1c (HbA1c), and autoantibody levels were obtained on all subjects who agreed to participate. Of 372 subjects randomized, 97 developed type 1 diabetes before follow-up; 75% of the remaining 275 subjects were contacted. In the interim, 77 subjects had been diagnosed with type 1 diabetes and 54 of the remainder have had an OGTT; 10 of these were diagnosed with type 1 diabetes, subsequently. Among individuals meeting the original criteria for insulin autoantibodies (IAAs) (≥80 nU/mL), the overall benefit of oral insulin remained significant (P=0.05). However, the hazard rate in this group increased (from 6.4% [95% CI 4.5-9.1] to 10.0% [7.1-14.1]) after cessation of therapy, which approximated the rate of individuals treated with placebo (10.2% [7.1-14.6]). Overall, the oral insulin treatment effect in individuals with confirmed IAA≥80 nU/mL appeared to be maintained with additional follow-up; however, once therapy stopped, the rate of developing diabetes in the oral insulin group increased to a rate similar to that in the placebo group.

Mechanisms of the effects of grains on insulin and glucose responses.

PubMed

Hallfrisch, J; Facn; Behall, K M

2000-06-01

Consumption of a number of grains and grain extracts has been reported to control or improve glucose tolerance and reduce insulin resistance. The inability of the body to maintain normal glucose levels or to require excessive levels of insulin to do so has been called glucose intolerance, impaired glucose tolerance and insulin resistance. These conditions are associated with obesity and may be preliminary steps in the progression to type 2 diabetes mellitus. Although dietary goals recommend the consumption of three servings of whole grains per day, average consumption in the United States is less than one serving per day. There are a number of mechanisms by which grains may improve glucose metabolism and delay or prevent the progression of impaired glucose tolerance to insulin resistance and diabetes. These mechanisms are related to the physical properties and structure of grains. The composition of the grain, including particle size, amount and type of fiber, viscosity, amylose and amylopectin content all affect the metabolism of carbohydrates from grains. Increasing whole grain intake in the population can result in improved glucose metabolism and delay or reduce the risk of developing type 2 diabetes mellitus. Whole grains can provide a substantial contribution to the improvement of the diets of Americans. A number of whole grain foods and grain fiber sources are beneficial in reduction of insulin resistance and improvement in glucose tolerance. Form, amount and method of cooking of these foods as well as the health characteristics, age and gender of the group of subjects studied are all important factors in the effectiveness of the foods in altering these responses. Dietary recommendations of health organizations suggest consumption of three servings a day of whole grain foods; however, Americans generally fall below this standard. Recent research using various grains and grain products effective in improving insulin resistance or lowering glycemic index will

Clathrin-dependent entry and vesicle-mediated exocytosis define insulin transcytosis across microvascular endothelial cells

PubMed Central

Azizi, Paymon M.; Zyla, Roman E.; Guan, Sha; Wang, Changsen; Liu, Jun; Bolz, Steffen-Sebastian; Heit, Bryan; Klip, Amira; Lee, Warren L.

2015-01-01

Transport of insulin across the microvasculature is necessary to reach its target organs (e.g., adipose and muscle tissues) and is rate limiting in insulin action. Morphological evidence suggests that insulin enters endothelial cells of the microvasculature, and studies with large vessel–derived endothelial cells show insulin uptake; however, little is known about the actual transcytosis of insulin and how this occurs in the relevant microvascular endothelial cells. We report an approach to study insulin transcytosis across individual, primary human adipose microvascular endothelial cells (HAMECs), involving insulin uptake followed by vesicle-mediated exocytosis visualized by total internal reflection fluorescence microscopy. In this setting, fluorophore-conjugated insulin exocytosis depended on its initial binding and uptake, which was saturable and much greater than in muscle cells. Unlike its degradation within muscle cells, insulin was stable within HAMECs and escaped lysosomal colocalization. Insulin transcytosis required dynamin but was unaffected by caveolin-1 knockdown or cholesterol depletion. Instead, insulin transcytosis was significantly inhibited by the clathrin-mediated endocytosis inhibitor Pitstop 2 or siRNA-mediated clathrin depletion. Accordingly, insulin internalized for 1 min in HAMECs colocalized with clathrin far more than with caveolin-1. This study constitutes the first evidence of vesicle-mediated insulin transcytosis and highlights that its initial uptake is clathrin dependent and caveolae independent. PMID:25540431

When Intensive Insulin Therapy (MDI) Fails in Patients With Type 2 Diabetes: Switching to GLP-1 Receptor Agonist Versus Insulin Pump.

PubMed

Cohen, Ohad; Filetti, Sebastiano; Castañeda, Javier; Maranghi, Marianna; Glandt, Mariela

2016-08-01

Treatment with insulin, alone or with oral or injectable hypoglycemic agents, is becoming increasingly common in patients with type 2 diabetes. However, approximately 40% of patients fail to reach their glycemic targets with the initially prescribed regimen and require intensification of insulin therapy, which increases the risks of weight gain and hypoglycemia. Many of these patients eventually reach a state in which further increases in the insulin dosage fail to improve glycemic control while increasing the risks of weight gain and hypoglycemia. The recently completed OpT2mise clinical trial showed that continuous subcutaneous insulin infusion (CSII) is more effective in reducing glycated hemoglobin (HbA1c) than intensification of multiple daily injection (MDI) insulin therapy in patients with type 2 diabetes who do not respond to intensive insulin therapy. CSII therapy may also be useful in patients who do not reach glycemic targets despite multidrug therapy with basal-bolus insulin and other agents, including glucagon-like peptide (GLP)-1 receptor agonists; current guidelines offer no recommendations for the treatment of such patients. Importantly, insulin and GLP-1 receptor agonists have complementary effects on glycemia and, hence, can be used either sequentially or in combination in the initial management of diabetes. Patients who have not previously failed GLP-1 receptor agonist therapy may show reduction in weight and insulin dose, in addition to moderate improvement in HbA1c, when GLP-1 receptor agonist therapy is added to MDI regimens. In subjects with long-standing type 2 diabetes who do not respond to intensive insulin therapies, switching from MDI to CSII and/or the addition of GLP-1 receptor agonists to MDI have the potential to improve glycemic control without increasing the risk of adverse events. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for

Importance of Insulin Immunoassays in the Diagnosis of Factitious Hypoglycemia

PubMed Central

Nalbantoğlu Elmas, Özlem; Demir, Korcan; Soylu, Nusret; Çelik, Nilüfer; Özkan, Behzat

2014-01-01

We report two cases emphasizing the importance of insulin assays for evaluation of hypoglycemia in diabetic patients. Case 1 was a 96/12-year-old female patient with type 1 diabetes mellitus and case 2 was a 1010/12-year-old male patient with DIDMOAD. Both patients were on a basal-bolus insulin regimen. Both were admitted because of persistent hypoglycemia. Analyses of serum samples obtained at the time of hypoglycemia initially showed low insulin and C-peptide levels. Recurrent episodes of unexplained hypoglycemia necessitated measurement of insulin levels by using different insulin assays, which revealed hyperinsulinemic hypoglycemia with low C-peptide levels, findings which confirmed a diagnosis of factitious hypoglycemia. Surreptitious administration of insulin should not be excluded in diabetic patients with hypoglycemia without taking into account the rate of cross-reactivity of insulin analogues with the insulin assay used. PMID:25541899

Inhaled Insulin: A Clinical and Historical Review.

PubMed

Chan, Jason; Cheng-Lai, Angela

Insulin is the most effective blood glucose lowering agent and remains one of the cornerstones of diabetes management. However, many individuals with diabetes are either reluctant to initiate or are nonadherent to their insulin therapy for various reasons, including fear of frequent injections. Technosphere Insulin (TI) is a novel inhaled insulin powder that is approved by the United States Food and Drug Administration for the management of diabetes. The results from 2 phase III clinical trials have shown that TI was noninferior to subcutaneous insulin aspart and superior to inhaled placebo in lowering HbA1c in patients with diabetes mellitus types 1 and 2, respectively. Across both studies, TI appears to be generally well tolerated, with the most common adverse events being hypoglycemia and cough. However, long-term pulmonary safety concerns have not been addressed and additional studies are needed. Overall, TI appears to be a promising noninvasive prandial insulin alternative for individuals with diabetes who are at risk for medication nonadherence due to aversion to frequent injections. This article provides a review of the historical development of TI, its safety and efficacy data, and its advantages and disadvantages over traditional injectable insulins.

Reduction of Sulfonylurea with the Initiation of Basal Insulin in Patients with Inadequately Controlled Type 2 Diabetes Mellitus Undergoing Long-Term Sulfonylurea-Based Treatment.

PubMed

Yang, Yeoree; Shin, Jeong Ah; Yang, Hae Kyung; Lee, Seung Hwan; Ko, Seung Hyun; Ahn, Yu Bae; Yoon, Kun Ho; Cho, Jae Hyoung

2016-12-01

There were a limited number of studies about β-cell function after insulin initiation in patients exposed to long durations of sulfonylurea treatment. In this study, we aimed to evaluate the recovery of β-cell function and the efficacy of concurrent sulfonylurea use after the start of long-acting insulin. In this randomized controlled study, patients with type 2 diabetes mellitus (T2DM), receiving sulfonylurea for at least 2 years with glycosylated hemoglobin (HbA1c) >7%, were randomly assigned to two groups: sulfonylurea maintenance (SM) and sulfonylurea reduction (SR). Following a 75-g oral glucose tolerance test (OGTT), we administered long-acting basal insulin to the two groups. After a 6-month follow-up, we repeated the OGTT. Among 69 enrolled patients, 57 completed the study and were analyzed: 31 in the SM and 26 in the SR group. At baseline, there was no significant difference except for the longer duration of diabetes and lower triglycerides in the SR group. After 6 months, the HbA1c was similarly reduced in both groups, but there was little difference in the insulin dose. In addition, insulin secretion during OGTT was significantly increased by 20% to 30% in both groups. A significant weight gain was observed in the SM group only. The insulinogenic index was more significantly improved in the SR group. Long-acting basal insulin replacement could improve the glycemic status and restore β-cell function in the T2DM patients undergoing sulfonylurea-based treatment, irrespective of the sulfonylurea dose reduction. The dose reduction of the concurrent sulfonylurea might be beneficial with regard to weight grain.

Evaluation of a randomized intervention to delay sexual initiation among fifth-graders followed through the sixth grade

PubMed Central

Koo, Helen P.; Rose, Allison; El-Khorazaty, M. Nabil; Yao, Qing; Jenkins, Renee R.; Anderson, Karen M.; Davis, Maurice; Walker, Leslie R.

2011-01-01

US adolescents initiate sex at increasingly younger ages, yet few pregnancy prevention interventions for children as young as 10–12 years old have been evaluated. Sixteen Washington, DC schools were randomly assigned to intervention versus control conditions. Beginning in 2001/02 with fifth-grade students and continuing during the sixth grade, students completed pre-intervention and post-intervention surveys each school year. Each year, the intervention included 10–13 classroom sessions related to delaying sexual initiation. Linear hierarchical models compared outcome changes between intervention and control groups by gender over time. Results show the intervention significantly decreased a rise over time in the anticipation of having sex in the next 12 months among intervention boys versus control boys, but it had no other outcome effects. Among girls, the intervention had no significant outcome effects. One exception is that for both genders, compared with control students, intervention students increased their pubertal knowledge. In conclusion, a school-based curriculum to delay sexual involvement among fifth-grade and sixth-grade high-risk youths had limited impact. Additional research is necessary to outline effective interventions, and more intensive, comprehensive interventions may be required to counteract adverse circumstances in students’ lives and pervasive influences toward early sex. ClinicalTrials. gov identifier: NCT00341471 PMID:21857793

Insulin oedema and treatment-induced neuropathy occurring in a 20-year-old patient with Type 1 diabetes commenced on an insulin pump.

PubMed

Rothacker, K M; Kaye, J

2014-01-01

Oedema may occur following initiation or intensification of insulin therapy in patients with Type 1 and Type 2 diabetes. Mild oedema is thought to be not uncommon, but under-reported, whilst generalized oedema with involvement of serous cavities has rarely been described. Multiple pathogenic mechanisms have been proposed, including insulin-induced sodium and water retention. Patients at greater risk for insulin oedema include those with poor glycaemic control. Dramatic improvement in glycaemic control is also associated with sensory and autonomic neuropathy. We describe a case of generalized oedema occurring in a 20-year-old, low body weight patient with Type 1 diabetes with poor glycaemic control 3 days following commencement of an insulin pump; blood sugars had dramatically improved with this treatment. Alternative causes for oedema were excluded. Oedema slowly improved with insulin dose reduction with higher blood sugar targets plus frusemide treatment. Subsequent to oedema resolution, the patient unfortunately developed generalized neuropathic pain, thought to be another manifestation of rapid improvement in glycaemic control. Caution should be taken when a patient with diabetes that is poorly controlled has an escalation in therapy that may dramatically improve their blood sugar levels; this includes the initiation of an insulin pump. Clinicians and patients should be aware of the potential risk of insulin oedema, treatment-induced neuropathy and worsening of diabetic retinopathy in the setting of rapid improvement in glycaemic control. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

Contingency Tracking during Unsignaled Delayed Reinforcement

ERIC Educational Resources Information Center

Keely, Josue; Feola, Tyler; Lattal, Kennon A.

2007-01-01

Three experiments were conducted with rats in which responses on one lever (labeled the functional lever) produced reinforcers after an unsignaled delay period that reset with each response during the delay. Responses on a second, nonfunctional, lever did not initiate delays, but, in the first and third experiments, such responses during the last…

Interrelations between glucose-induced insulin response, metabolic indicators, and time of first ovulation in high-yielding dairy cows.

PubMed

Bossaert, P; Leroy, J L M R; De Vliegher, S; Opsomer, G

2008-09-01

High-yielding dairy cows are more susceptible to metabolic and reproductive disorders than low-yielding cows. Insulin plays a pivotal role in the development of both problems. In the present study, we aimed to assess the glucose-induced insulin responses of dairy cows at different time points relative to calving and to relate this to the metabolic status and the time of first ovulation. Twenty-three healthy, multiparous Holstein-Friesian cows with a high genetic merit for milk yield were studied from 14 d prepartum to 42 d postpartum. Intravenous glucose tolerance tests were performed on -14, 14, and 42 d relative to calving to evaluate the plasma insulin and glucose responses to a glucose load, as estimated by the peak concentration, the area under the curve (AUC), and the clearance rates of insulin and glucose. Blood samples were obtained at 3-d intervals and analyzed for glucose, insulin, and nonesterified fatty acids (NEFA). The time of first ovulation was defined by transrectal ultrasonography and plasma progesterone analysis. Glucose-induced insulin AUC and peak concentration decreased and glucose clearance increased during lactation compared with the dry period. Plasma NEFA concentrations were negatively related to insulin AUC and peak concentrations. Fourteen cows ovulated within 42 d postpartum, and the remaining 9 cows suffered from delayed resumption of ovarian function. Survival analysis demonstrated that cows with lower NEFA concentrations during the dry period tended to have earlier resumption of ovarian activity. In conclusion, our data suggest a decreased plasma insulin response to glucose postpartum in high-yielding dairy cows, possibly contributing to metabolic stress during the early postpartum period. It is hypothesized that NEFA impair glucose-induced insulin secretion in dairy cows. Additionally, our results suggest the importance of lipolysis during the transition period as a risk factor for delayed ovulation.

Effects of Insulin and Octreotide on Memory and Growth Hormone in Alzheimer's Disease

PubMed Central

Watson, G. Stennis; Baker, Laura D.; Cholerton, Brenna A.; Rhoads, Kristoffer W.; Merriam, George R.; Schellenberg, Gerard D.; Asthana, PhD;Sanjay; Cherrier, Monique; Craft, Suzanne

2009-01-01

Both insulin alone and the somatostatin analogue octreotide alone facilitate memory in patients with Alzheimer's disease (AD). Since octreotide inhibits endogenous insulin secretion, the cognitive effects of insulin and octreotide may not be independent. This study tested the individual and interactive effects of insulin and octreotide on memory and plasma growth hormone (GH) levels in older adults. Participants were 16 memory-impaired (AD=7, amnestic mild cognitive impairment=9; apolipoprotein E [APOE] ε4- [no ε4 alleles]=9, ε4+ [1-2 ε4 alleles]=7) and 19 cognitively-intact older adults (APOE ε4-=17, ε4+=1). On separate days, fasting participants received counterbalanced infusions of (1) insulin (1 mU·kg-1·min-1) and dextrose to maintain euglycemia, (2) octreotide (150 μg/h), (3) insulin, dextrose, and octreotide, or (4) saline. Story recall was the principal endpoint. Insulin alone facilitated delayed recall for ε4-patients, relative to ε4+ patients (P=0.0012). Furthermore, ε4- patients with higher Mattis Dementia Rating Scale (DRS) scores had greater octreotide-induced memory facilitation (P=0.0298). For healthy adults, octreotide facilitated memory (P=0.0122). Unexpectedly, hyperinsulinemia with euglycemia increased GH levels in healthy controls (P=0.0299). Thus, insulin and octreotide appear to regulate memory in older adults. APOE ε4 genotype modulates responses to insulin and octreotide. Finally, insulin may regulate GH levels during euglycemia. PMID:19625744

Clinical and economic outcomes in patients with type 2 diabetes initiating insulin glargine disposable pen versus exenatide BID.

PubMed

Baser, Onur; Wei, Wenhui; Baser, Erdem; Xie, Lin

2011-01-01

To evaluate clinical and economic outcomes in patients with type 2 diabetes mellitus (T2DM) who failed oral anti-diabetic drug (OAD) therapy and initiated either insulin glargine with disposable pen (GLA-P) or exenatide BID (EXE). This retrospective study used data from a large US-managed care claims database and included adult T2DM patients initiating treatment with GLA-P or EXE in 2007 or 2008. Propensity score matching was used to control observed baseline differences between treatment groups. Primary study end-points included treatment persistence, A1C, healthcare utilization, and healthcare costs during the 1-year follow-up period. Two thousand three hundred and thirty nine patients were included in the study (GLA-P: 381; EXE: 1958); 626 patients were in the 1:1 matched cohort (54% male; mean age: 54 years; mean A1C: 9.2%). At follow-up, patients in the GLA-P group were significantly more persistent in treatment than EXE patients (48% vs 15% in persistence rate and 252 vs 144 days in persistence days; both p<0.001). GLA-P patients also had significantly lower A1C at follow-up (8.02% vs 8.32%; p=0.042) and greater A1C reduction from baseline (-1.23% vs -0.92%; p=0.038). There were no significant differences in claims-based hypoglycemia rates and overall diabetes-related healthcare utilization and cost. Since this was a retrospective analysis, causality of treatment benefits cannot be established. The study was specific to two treatments and may not generalize to other models of insulin administration. Some of the results, although statistically significant, may not be found clinically important. In a real-world setting among T2DM patients who failed to achieve or sustain glycemic goal with OADs, initiation of GLA-P instead of EXE may be a more effective option because it was associated with greater treatment persistence, greater A1C reduction without a significantly higher rate of hypoglycemia, and similar healthcare costs.

Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding.

PubMed

Papaioannou, Anastasios; Kuyucak, Serdar; Kuncic, Zdenka

2015-01-01

A sequence of complex conformational changes is required for insulin to bind to the insulin receptor. Recent experimental evidence points to the B chain C-terminal (BC-CT) as the location of these changes in insulin. Here, we present molecular dynamics simulations of insulin that reveal new insights into the structural changes occurring in the BC-CT. We find three key results: 1) The opening of the BC-CT is inherently stochastic and progresses through an open and then a "wide-open" conformation--the wide-open conformation is essential for receptor binding, but occurs only rarely. 2) The BC-CT opens with a zipper-like mechanism, with a hinge at the Phe24 residue, and is maintained in the dominant closed/inactive state by hydrophobic interactions of the neighboring Tyr26, the critical residue where opening of the BC-CT (activation of insulin) is initiated. 3) The mutation Y26N is a potential candidate as a therapeutic insulin analogue. Overall, our results suggest that the binding of insulin to its receptor is a highly dynamic and stochastic process, where initial docking occurs in an open conformation and full binding is facilitated through interactions of insulin receptor residues with insulin in its wide-open conformation.

Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse

PubMed Central

Ning, Jie; Hong, Tao; Yang, Xuefeng; Mei, Shuang; Liu, Zhenqi; Liu, Hui-Yu

2011-01-01

The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes. PMID:21586696

Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice.

PubMed Central

Karounos, D G; Bryson, J S; Cohen, D A

1997-01-01

The purpose of this study was to determine the relative importance of the metabolic effects of insulin for diabetes prevention by administering insulin or an inactive insulin analog by daily subcutaneous injections to prediabetic mice. A recombinant monomeric human insulin analog, which does not bind to the insulin receptor as a consequence of an alteration of a single amino acid at position 25 of the B chain, was shown to be equally effective at diabetes prevention as was intact insulin. In contrast to native insulin, the insulin analog did not cause hypoglycemia after subcutaneous injection. The insulin analog, however, protected young adult mice from diabetes, even when it was initiated after the onset of extensive lymphocytic infiltration of the islets. Thus, preventative therapy by daily subcutaneous injections of insulin does not require the hypoglycemic response, or binding to the insulin receptor to prevent the onset of type I diabetes. PMID:9294099

Does availability of AIR insulin increase insulin use and improve glycemic control in patients with type 2 diabetes?

PubMed

Bergenstal, Richard M; Freemantle, Nick; Leyk, Malgorzata; Cutler, Gordon B; Hayes, Risa P; Muchmore, Douglas B

2009-09-01

In the concordance model, physician and patient discuss treatment options, explore the impact of treatment decisions from the patient's perspective, and make treatment choices together. We tested, in a concordance setting, whether the availability of AIR inhaled insulin (developed by Alkermes, Inc. [Cambridge, MA] and Eli Lilly and Company [Indianapolis, IN]; AIR is a registered trademark of Alkermes, Inc.), as compared with existing treatment options alone, leads to greater initiation and maintenance of insulin therapy and improves glycemic control in patients with type 2 diabetes. This was a 9-month, multicenter, parallel, open-label study in adult, nonsmoking patients with diabetes not optimally controlled by two or more oral antihyperglycemic medications. Patients were randomized to the Standard Options group (n = 516), in which patients chose a regimen from drugs in each major treatment class excluding inhaled insulin, or the Standard Options + AIR insulin group (n = 505), in which patients had the same choices plus AIR insulin. The primary end points were the proportion of patients in each group using insulin at end point and change in hemoglobin A1C (A1C) from baseline to end point. At end point, 53% of patients in the Standard Options group and 59% in the Standard Options + AIR insulin group were using insulin (P = 0.07). Both groups reduced A1C by about 1.2% and reported increased well-being and treatment satisfaction. The most common adverse event with AIR insulin was transient cough. The opportunity to choose AIR insulin did not affect overall use of insulin at end point or A1C outcomes. Regardless of group assignment, utilizing a shared decision-making approach to treatment choices (concordance model), resulted in improved treatment satisfaction and A1C values at end point. Therefore, increasing patient involvement in treatment decisions may improve outcomes.

Short communication: The effect of delayed colostrum feeding on plasma concentrations of glucagon-like peptide 1 and 2 in newborn calves.

PubMed

Inabu, Y; Fischer, A; Song, Y; Guan, L L; Oba, M; Steele, M A; Sugino, T

2018-07-01

Glucagon-like peptide (GLP)-1 is involved in glucose homeostasis via its role in stimulating insulin secretion, whereas GLP-2 increases mucosal growth of the small intestine. To our knowledge, the effect of delayed colostrum feeding on plasma GLP-1 and GLP-2 in neonatal calves has not been evaluated. To investigate the effect of delayed colostrum feeding on plasma concentrations of GLP-1 and GLP-2 in newborn calves, we randomly assigned 27 Holstein bull calves to 1 of 3 treatment groups: those fed colostrum within 1 h after birth (control), 6 h after birth (6H), and 12 h after birth (12H; n = 9 for each treatment). Blood samples were obtained before the colostrum feeding and every 3 h after each colostrum feeding for a 36-h period, and plasma concentrations of GLP-1, GLP-2, insulin, and glucose were measured. Plasma GLP-1 concentration at 12 h after colostrum feeding was lower in 12H than in control calves. In addition, plasma insulin concentration was lower in the 6H and 12H calves than in the controls. Plasma glucose and GLP-2 concentrations were, however, not affected by treatment. These results indicate that delayed colostrum feeding can decrease plasma GLP-1 and insulin concentrations without affecting glucose or GLP-2 concentration. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Introduction to Focus Issue: Time-delay dynamics

NASA Astrophysics Data System (ADS)

Erneux, Thomas; Javaloyes, Julien; Wolfrum, Matthias; Yanchuk, Serhiy

2017-11-01

The field of dynamical systems with time delay is an active research area that connects practically all scientific disciplines including mathematics, physics, engineering, biology, neuroscience, physiology, economics, and many others. This Focus Issue brings together contributions from both experimental and theoretical groups and emphasizes a large variety of applications. In particular, lasers and optoelectronic oscillators subject to time-delayed feedbacks have been explored by several authors for their specific dynamical output, but also because they are ideal test-beds for experimental studies of delay induced phenomena. Topics include the control of cavity solitons, as light spots in spatially extended systems, new devices for chaos communication or random number generation, higher order locking phenomena between delay and laser oscillation period, and systematic bifurcation studies of mode-locked laser systems. Moreover, two original theoretical approaches are explored for the so-called Low Frequency Fluctuations, a particular chaotical regime in laser output which has attracted a lot of interest for more than 30 years. Current hot problems such as the synchronization properties of networks of delay-coupled units, novel stabilization techniques, and the large delay limit of a delay differential equation are also addressed in this special issue. In addition, analytical and numerical tools for bifurcation problems with or without noise and two reviews on concrete questions are proposed. The first review deals with the rich dynamics of simple delay climate models for El Nino Southern Oscillations, and the second review concentrates on neuromorphic photonic circuits where optical elements are used to emulate spiking neurons. Finally, two interesting biological problems are considered in this Focus Issue, namely, multi-strain epidemic models and the interaction of glucose and insulin for more effective treatment.

Systemic absorption of insulin and glucagon applied topically to the eyes of rats and a diabetic dog.

PubMed

Pillion, D J; Wang, P; Yorks, J; McCann, P; Meezan, E

1995-01-01

Nondiabetic rats were anesthetized with xylazine/ketamine to induce hyperglycemia and systemic insulin absorption from eyedrops formulated with dodecylmaltoside was quantitated by both a decrease in serum levels of D-glucose and an increase in immunoreactive insulin levels. When insulin eyedrop administration was delayed until 60 minutes after the administration of eyedrops containing 0.25% dodecylmaltoside, the enhanced systemic absorption of insulin was maintained, suggesting that dodecylmaltoside had an effect directly on the permeability of the nasal sinus epithelium. When glucagon was formulated in eyedrops or nosedrops containing dodecylmaltoside, systemic absorption of glucagon could be measured in the form of an increase in the serum D-glucose concentration following nasal application, but not after ocular application. Eyedrops containing insulin plus 0.125% dodecylmaltoside were administered to a diabetic dog; a dose of 20 units of regular insulin caused a modest decrease in serum D-glucose concentration and a concomitant increase in serum immunoreactive insulin content. These results provide evidence that peptide drugs such as insulin can be formulated in eyedrops with low concentrations of dodecylmaltoside, a mild nonionic surfactant.

A Drosophila model for fetal alcohol syndrome disorders: role for the insulin pathway

PubMed Central

McClure, Kimberly D.; French, Rachael L.; Heberlein, Ulrike

2011-01-01

SUMMARY Prenatal exposure to ethanol in humans results in a wide range of developmental abnormalities, including growth deficiency, developmental delay, reduced brain size, permanent neurobehavioral abnormalities and fetal death. Here we describe the use of Drosophila melanogaster as a model for exploring the effects of ethanol exposure on development and behavior. We show that developmental ethanol exposure causes reduced viability, developmental delay and reduced adult body size. We find that flies reared on ethanol-containing food have smaller brains and imaginal discs, which is due to reduced cell division rather than increased apoptosis. Additionally, we show that, as in mammals, flies reared on ethanol have altered responses to ethanol vapor exposure as adults, including increased locomotor activation, resistance to the sedating effects of the drug and reduced tolerance development upon repeated ethanol exposure. We have found that the developmental and behavioral defects are largely due to the effects of ethanol on insulin signaling; specifically, a reduction in Drosophila insulin-like peptide (Dilp) and insulin receptor expression. Transgenic expression of Dilp proteins in the larval brain suppressed both the developmental and behavioral abnormalities displayed by ethanol-reared adult flies. Our results thus establish Drosophila as a useful model system to uncover the complex etiology of fetal alcohol syndrome. PMID:21303840

Insulin and insulin-like growth factor-1 (lGF-1) inhibit repair of potentially lethal radiation damage and chromosome aberrations and later DNA repair kinetics in plateau-phase A549 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jayanth, V.R.; Belfi, C.A.; Swick, A.R.

1995-08-01

Plateau-phase A549 cells exhibit a high capacity for repair of potentially lethal radiation damage (PLD) when allowed to recover in their own spent medium. Addition of either insulin or insulin-like growth factor-1 (IGF-1) to the spent medium 60 to 120 min before irradiation significantly inhibits PLD repair. The 9-h recovery factor (survival with holding/survival without holding)is reduced from 10.8 {plus_minus} 0.7 to 3.4 {plus_minus}0.3 by insulin and to 3.0 {plus_minus} 0.4 by IGF-1. Neither growth factor alters the cell age distribution of the plateau-phase cells, increases the rate of incorporation of 5-bromo-2{prime}-deoxyuridine into DNA, or alters the extent of radiation-inducedmore » mitotic delay in cells subcultured immediately after irradiation. Both insulin and IGF-1 alter the kinetics for rejoining of DNA double-strand breaks (DSBs), slowing the fast component of rejoining significantly. However, these growth factors have no effect on the initial level of DSBs or on the percentage of residual unrejoined breaks at 120 min postirradiation. Both growth factors affect repair of lesions leading to dicentric, but not to acentric, chromosome aberrations significantly. In control cells (treated with phosphate-buffered saline, 90 min prior to irradiation), the half-time for disappearance of dicentrics was 4.1 h (3.4 to 5.1 h), and 47.1 {plus_minus} 3.7% of the residual damage remained at 24 h postirradiation. Insulin and IGF-1 increased the half-time for disappearance of dicentrics to 5.2 h (3.9 to 7.7 h) and 5.7 h (5.5 to 5.9 h), respectively, and increased residual damage to 56.1 {plus_minus}5.9% and 60.8 {plus_minus} 6.0%, respectively. Overall, these data show that insulin and IGF-1 inhibit PLD repair in A54j9 cells by mechanisms which are independent of changes in cell cycle parameters. The data suggest that the growth factors act by inducing changes in chromatin conformation which promote misrepair of radiation-damaged DNA. 49 refs., 5 figs., 4 tabs.« less

Extensive intramuscular manifestation of sarcoidosis with initially missed diagnosis and delayed therapy: a case report.

PubMed

Meyer, Niklaus; Sutter, Reto; Schirp, Udo; Gutzeit, Andreas

2017-08-24

Sarcoidosis is a multisystemic granulomatous disorder, which in nearly all cases involves the lungs and other organs. Isolated forms of sarcoidosis within the muscles, but without lung involvement, are extremely rare and can lead to delayed or even false diagnosis. A 52-year-old white, Swiss man presented with painful arm cramps and a history of symptoms over the previous 3 years. In the initial clinical investigation, our patient also showed edema in both legs without any other complaints. After performing an magnetic resonance imaging scan of his extremities and a positron emission tomography/computed tomography scan, diffuse myositis was described. The subsequent muscle biopsy provided the surprising diagnosis of muscle sarcoidosis, without involvement of the lungs or any other organ. After starting therapy with glucocorticoids, his symptoms improved immediately. Sarcoidosis is a common disorder, which in most cases affects the lungs. In this case report an isolated sarcoidosis is described without lung involvement, but with involvement of the muscles of the extremities and the trunk. Reported cases of sarcoidosis only involving skeletal muscle and without lung involvement are extremely rare. Radiologists should consider this presentation of sarcoidosis to avoid delayed diagnosis and therapy.

Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity.

PubMed

Yamamoto, Soh; Kuramoto, Kenta; Wang, Nan; Situ, Xiaolei; Priyadarshini, Medha; Zhang, Weiran; Cordoba-Chacon, Jose; Layden, Brian T; He, Congcong

2018-06-12

Autophagy, a stress-induced lysosomal degradative pathway, has been assumed to exert similar metabolic effects in different organs. Here, we establish a model where autophagy plays different roles in insulin-producing β cells versus insulin-responsive cells, utilizing knockin (Becn1 F121A ) mice manifesting constitutively active autophagy. With a high-fat-diet challenge, the autophagy-hyperactive mice unexpectedly show impaired glucose tolerance, but improved insulin sensitivity, compared to mice with normal autophagy. Autophagy hyperactivation enhances insulin signaling, via suppressing ER stress in insulin-responsive cells, but decreases insulin secretion by selectively sequestrating and degrading insulin granule vesicles in β cells, a process we term "vesicophagy." The reduction in insulin storage, insulin secretion, and glucose tolerance is reversed by transient treatment of autophagy inhibitors. Thus, β cells and insulin-responsive tissues require different autophagy levels for optimal function. To improve insulin sensitivity without hampering secretion, acute or intermittent, rather than chronic, activation of autophagy should be considered in diabetic therapy development. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Voluntary Exercise Impairs Initial Delayed Spatial Alternation Performance in Estradiol Treated Ovariectomized Middle-Aged Rats

PubMed Central

Neese, Steven L.; Korol, Donna L.; Schantz, Susan L.

2013-01-01

Estrogens differentially modulate behavior in the adult female rodent. Voluntary exercise can also impact behavior, often reversing age associated decrements in memory processes. Our research group has published a series of papers reporting a deficit in the acquisition of an operant working memory task, delayed spatial alternation (DSA), following 17β-estradiol treatment to middle-aged ovariectomized (OVX) rats. The current study examined if voluntary exercise could attenuate the 17β-estradiol induced deficits on DSA performance. OVX 12-month old Long- Evans rats were implanted with a Silastic capsule containing 17β-estradiol (10% in cholesterol: low physiological range) or with a blank capsule. A subset of the 17β-estradiol and OVX untreated rats were given free access to a running wheel in their home cage. All rats were tested for 40 sessions on the DSA task. Surprisingly, we found running wheel access to impair initial acquisition of the DSA task in 17β-estradiol treated rats, an effect not seen in OVX untreated rats given running wheel access. This deficit was driven by an increase in perseverative responding on a lever no longer associated with reinforcement. We also report for the first time a 17β-estradiol induced impairment on the DSA task following a long intertrial delay (18-sec), an effect revealed following more extended testing than in our previous studies (15 additional sessions). Overall, running wheel access increased initial error rate on the DSA task in 17β-estradiol treated middle-aged OVX rats, and failed to prevent the 17β-estradiol induced deficits in performance of the operant DSA task in later testing sessions. PMID:24013039

Growth hormone, insulin and aging: The benefits of endocrine defects

PubMed Central

Bartke, Andrzej

2012-01-01

Longevity of mice can be increased by spontaneous or experimentally induced mutations that interfere with the biosynthesis or actions of growth hormone (GH), insulin-like growth factor 1 (IGF-1), or insulin in the adipose tissue. The effects of GH resistance and deficiency of GH (along with thyrotropin and prolactin) on aging and lifespan are the most pronounced and best established of these mutations. Potential mechanisms linking these endocrine deficits with delayed aging and extended longevity include increased stress resistance, alterations in insulin and mammalian target of rapamycin (mTOR) signaling and metabolic adjustments. Physiological relationships deduced from the extreme phenotypes of long-lived mouse mutants appear to apply broadly, encompassing genetically normal (“wild-type”) mice and other mammalian species. The role of GH in the control of human aging continues to be hotly debated, but recent data indicate that reduced somatotropic signaling provides protection from cancer and other age-related diseases and may promote old age survival. PMID:20851173

Addition of rapid-acting insulin to basal insulin therapy in type 2 diabetes: indications and modalities.

PubMed

Monnier, L; Colette, C

2006-02-01

There are many reasons to believe that in the near future, the treatment of patients with Type 2 diabetes will be characterised by an increased use of insulin therapy. To ensure that insulin regimens are acceptable to patients, and implemented by physicians, they should be as simple and efficient as possible. Simplicity is synonymous with the regimen of once-daily basal insulin glargine given at any time of the day (at the same time each day). With such a strategy, the dose is adjusted by titrating to target fasting blood glucose values of 5.0 - 7.2 mmol/L (90 - 130 mg/dL). When these targets can no longer be achieved with reasonable doses of long-acting insulin, a rapid-acting insulin analogue should be added at meal times. A step-by-step strategy can be used; it is recommended that initially, a single daily prandial bolus of a rapid-acting insulin analogue is administered before the meal that leads to the highest post-meal blood glucose excursions. Further boluses can be added at other meal times as necessary, i.e, when post-meal blood glucose values remain above 10.0 mmol/L (180 mg/dL) and 7.8 mmol/L (140 mg/dL) at mid-morning and 2h-post-lunch or post-dinner times, respectively. This stepwise strategy may eventually lead to a standard basal-bolus regimen with 3 pre-meal injections of rapid-acting insulin analogues, a potentially small trade-off for achieving fairly-well controlled diabetes.

Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial.

PubMed

Craft, Suzanne; Baker, Laura D; Montine, Thomas J; Minoshima, Satoshi; Watson, G Stennis; Claxton, Amy; Arbuckle, Matthew; Callaghan, Maureen; Tsai, Elaine; Plymate, Stephen R; Green, Pattie S; Leverenz, James; Cross, Donna; Gerton, Brooke

2012-01-01

To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). Randomized, double-blind, placebo-controlled trial. Clinical research unit of a Veterans Affairs medical center. The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention  Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment. Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus

Comparison of the physiological relevance of systemic vs. portal insulin delivery to evaluate whole body glucose flux during an insulin clamp

PubMed Central

Farmer, Tiffany D.; Jenkins, Erin C.; O'Brien, Tracy P.; McCoy, Gregory A.; Havlik, Allison E.; Nass, Erik R.; Nicholson, Wendell E.; Printz, Richard L.

2014-01-01

To understand the underlying pathology of metabolic diseases, such as diabetes, an accurate determination of whole body glucose flux needs to be made by a method that maintains key physiological features. One such feature is a positive differential in insulin concentration between the portal venous and systemic arterial circulation (P/S-IG). P/S-IG during the determination of the relative contribution of liver and extra-liver tissues/organs to whole body glucose flux during an insulin clamp with either systemic (SID) or portal (PID) insulin delivery was examined with insulin infusion rates of 1, 2, and 5 mU·kg−1·min−1 under either euglycemic or hyperglycemic conditions in 6-h-fasted conscious normal rats. A P/S-IG was initially determined with endogenous insulin secretion to exist with a value of 2.07. During an insulin clamp, while inhibiting endogenous insulin secretion by somatostatin, P/S-IG remained at 2.2 with PID, whereas, P/S-IG disappeared completely with SID, which exhibited higher arterial and lower portal insulin levels compared with PID. Consequently, glucose disappearance rates and muscle glycogen synthetic rates were higher, but suppression of endogenous glucose production and liver glycogen synthetic rates were lower with SID compared with PID. When the insulin clamp was performed with SID at 2 and 5 mU·kg−1·min−1 without managing endogenous insulin secretion under euglycemic but not hyperglycemic conditions, endogenous insulin secretion was completely suppressed with SID, and the P/S-IG disappeared. Thus, compared with PID, an insulin clamp with SID underestimates the contribution of liver in response to insulin to whole body glucose flux. PMID:25516552

Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats

PubMed Central

Cummings, Bethany P; Bettaieb, Ahmed; Graham, James L; Stanhope, Kimber; Haj, Fawaz G; Havel, Peter J

2015-01-01

There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset. PMID:24627447

Insulin Secretagogues

MedlinePlus

... the Spikes Is mealtime insulin right for you? Insulin Secretagogues September 2017 Download PDFs English Espanol Editors ... Additional Resources Affordable Insulin Project FDA What are insulin secretagogues? Insulin secretagogues are one type of medicine ...

How does brain insulin resistance develop in Alzheimer's disease?

PubMed

De Felice, Fernanda G; Lourenco, Mychael V; Ferreira, Sergio T

2014-02-01

Compelling preclinical and clinical evidence supports a pathophysiological connection between Alzheimer's disease (AD) and diabetes. Altered metabolism, inflammation, and insulin resistance are key pathological features of both diseases. For many years, it was generally considered that the brain was insensitive to insulin, but it is now accepted that this hormone has central neuromodulatory functions, including roles in learning and memory, that are impaired in AD. However, until recently, the molecular mechanisms accounting for brain insulin resistance in AD have remained elusive. Here, we review recent evidence that sheds light on how brain insulin dysfunction is initiated at a molecular level and why abnormal insulin signaling culminates in synaptic failure and memory decline. We also discuss the cellular basis underlying the beneficial effects of stimulation of brain insulin signaling on cognition. Discoveries summarized here provide pathophysiological background for identification of novel molecular targets and for development of alternative therapeutic approaches in AD. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

β-Cell Hyperplasia Induced by Hepatic Insulin Resistance

PubMed Central

Escribano, Oscar; Guillén, Carlos; Nevado, Carmen; Gómez-Hernández, Almudena; Kahn, C. Ronald; Benito, Manuel

2009-01-01

OBJECTIVE Type 2 diabetes results from a combination of insulin resistance and impaired insulin secretion. To directly address the effects of hepatic insulin resistance in adult animals, we developed an inducible liver-specific insulin receptor knockout mouse (iLIRKO). RESEARCH DESIGN AND METHODS Using this approach, we were able to induce variable insulin receptor (IR) deficiency in a tissue-specific manner (liver mosaicism). RESULTS iLIRKO mice presented progressive hepatic and extrahepatic insulin resistance without liver dysfunction. Initially, iLIRKO mice displayed hyperinsulinemia and increased β-cell mass, the extent of which was proportional to the deletion of hepatic IR. Our studies of iLIRKO suggest a cause-and-effect relationship between progressive insulin resistance and the fold increase of plasma insulin levels and β-cell mass. Ultimately, the β-cells failed to secrete sufficient insulin, leading to uncontrolled diabetes. We observed that hepatic IGF-1 expression was enhanced in iLIRKO mice, resulting in an increase of circulating IGF-1. Concurrently, the IR-A isoform was upregulated in hyperplastic β-cells of iLIRKO mice and IGF-1–induced proliferation was higher than in the controls. In mouse β-cell lines, IR-A, but not IR-B, conferred a proliferative capacity in response to insulin or IGF-1, providing a potential explanation for the β-cell hyperplasia induced by liver insulin resistance in iLIRKO mice. CONCLUSIONS Our studies of iLIRKO mice suggest a liver-pancreas endocrine axis in which IGF-1 functions as a liver-derived growth factor to promote compensatory pancreatic islet hyperplasia through IR-A. PMID:19136656

Insulin secretion and insulin action in non-insulin-dependent diabetes mellitus: which defect is primary?

PubMed

Reaven, G M

1984-01-01

Defects in both insulin secretion and insulin action exist in patients with non-insulin-dependent diabetes mellitus (NIDDM). The loss of the acute plasma insulin response to intravenous glucose is seen in patients with relatively mild degrees of fasting hyperglycemia, but patients with severe fasting hyperglycemia also demonstrate absolute hypoinsulinemia in response to an oral glucose challenge. In contrast, day-long circulating insulin levels are within normal limits even in severely hyperglycemic patients with NIDDM. The relationship between NIDDM and insulin action in NIDDM is less complex, and is a characteristic feature of the syndrome. This metabolic defect is independent of obesity, and the severity of the resistance to insulin-stimulated glucose uptake increases with magnitude of hyperglycemia. Control of hyperglycemia with exogenous insulin ameliorates the degree of insulin resistance, and reduction of insulin resistance with weight loss in obese patients with NIDDM leads to an enhanced insulin response. Since neither therapeutic intervention is capable of restoring all metabolic abnormalities to normal, these observations do not tell us which of these two defects is primarily responsible for the development of NIDDM. Similarly, the observation that most patients with impaired glucose tolerance are hyperinsulinemic and insulin resistant does not prove that insulin resistance is the primary defect in NIDDM. In conclusion, reduction in both insulin secretion and action is seen in patients with NIDDM, and the relationship between these two metabolic abnormalities is very complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of morphine on the expression of insulin receptor and protein levels of insulin/IGFs in rat neural stem cells.

PubMed

Salarinasab, Sadegh; Nourazarian, AliReza; Nikanfar, Masoud; Abdyazdani, Nima; Kazemi, Masoumeh; Feizy, Navid; Rahbarghazi, Reza

2017-11-01

Alzheimer's disease is correlated with neuronal degeneration and loss of neuronal precursors in different parts of the brain. It has been found disturbance in the homeostasis neural stem cells (NSCs) can cause neurodegeneration. Morphine, an analgesic agent, can disrupt the dynamic and normal state of NSCs. However, more investigations are required to clearly address underlying mechanisms. The current experiment aimed to investigate the effects of morphine on the cell distribution of insulin factor and receptor and insulin-like growth factors (IGF1, IGF2) in NSCs. NSCs were isolated from rats and stemness feature confirmed by antibodies against nestin and Sox2. The cells were exposed to 100μM morphine, 50μM naloxone and combination of these two drugs for 72h. The neural cell growth, changes in levels of insulin and insulin-like growth factors secreted by NSCs as well as the insulin-receptor-gene expression were assessed by flow cytometry, ELlSA, and real-time PCR, respectively. Cell cycle assay revealed the exposure of cells to morphine for 72h increased cell apoptosis and decreased neural stem cell growth. The biosynthesis of insulin, insulin-like growth factors, and insulin receptor were reduced (p<0.05) after NSCs exposure to morphine at the concentration of 100μM for 24, 48 and 72h. Naloxone is a competitive antagonist which binds MOR where morphine (and endogenous opioids) bind, and reversed the detrimental effects of morphine. It can be concluded that morphine initiated irregularity in NSCs kinetics and activity by reducing the secretion of insulin and insulin-like growth factors and down-regulation of insulin receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

Common Standards of Basal Insulin Titration in T2DM

PubMed Central

Arnolds, Sabine; Heise, Tim; Flacke, Frank; Sieber, Jochen

2013-01-01

Type 2 diabetes mellitus has become a worldwide major health problem, and the number of people affected is steadily increasing. Thus, not all patients suffering from the disease can be treated by specialized diabetes centers or outpatient clinics, but by primary care physicians. The latter, however, might have time constraints and have to deal with many kinds of diseases or with multimorbid patients, so their focus is not so much on lowering high blood glucose values. Thus, the physicians, as well as the patients themselves, are often reluctant to initiate and adjust insulin therapy, although basal insulin therapy is considered the appropriate strategy after oral antidiabetic drug failure, according to the latest international guidelines. A substantial number of clinical studies have shown that insulin initiation and optimization can be managed successfully by using titration algorithms—even in cases where patients themselves are the drivers of insulin titration. Nevertheless, tools and strategies are needed to facilitate this process in the daily life of both primary health care professionals and patients with diabetes. PMID:23759411

Routine delayed voiding cystourethography after initial successful endoscopic treatment with Dextranomer/Hialuronic Acid Copolimer (Dx/HA) of vesicoureteral reflux (VUR). Is it necessary?

PubMed

García-Aparicio, L; Blázquez-Gómez, E; Vila Santandreu, A; Camacho Diaz, J A; Vila-Cots, J; Ramos Cebrian, M; de Haro, I; Martin, O; Tarrado, X

2016-12-01

Some guidelines recommend an early voiding cystourethrography (VCUG) after endoscopic treatment of vesicoureteral reflux (VUR), but there's no consensus if it's necessary a long-term follow-up in these patients. The aim of our study is analyze if it's necessary a delayed VCUG after initial successful treatment with Dx/HA. We have reviewed all medical charts of patients that underwent Dx/HA treatment from 2006 to 2010. We have selected patients with initial successful treatment and more than 3 years of radiological and clinical follow-up. We have analyzed late clinical and radiological outcomes. One hundred and sixty children with 228 refluxing ureters underwent Dx/HA endoscopic treatment with a mean follow-up of 52.13 months. Early VCUG was performed in 215 ureters with an initial successful rate of 84.1%. The group of study was 94/215 ureters with more than 3 years of follow-up with a delayed VCUG. VUR was still resolved in 79,8% of the ureters. Clinical success rate was 91.7%. The incidence of febrile urinary tract infection in those patients with cured VUR and those with a relapsed VUR was 8 and 15%, respectively; but there were no significant differences. We have not found any variable related with relapsed VUR except those ureters that initially received 2 injections (P<.05). If our objective in the treatment of VUR is to reduce the incidence of febrile urinary tract infection it is not necessary to perform a delayed VCUG even though the long-term radiological outcomes is worse than clinical outcome. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes

PubMed Central

Schatz, Desmond A.; Bundy, Brian; Skyler, Jay S.; Greenbaum, Carla J.

2017-01-01

Importance Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. Objective To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Design, Setting, and Participants Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Interventions Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). Main Outcome and Measures The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Results Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7-12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in

The Brain Response to Peripheral Insulin Declines with Age: A Contribution of the Blood-Brain Barrier?

PubMed Central

Heni, Martin; Maetzler, Walter; Fritsche, Andreas; Häring, Hans-Ulrich; Hennige, Anita M.

2015-01-01

Objectives It is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity. Methods Insulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements. Results In humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved. Conclusions This study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system. PMID:25965336

Effect of glyburide on in vivo recycling of the hepatic insulin receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frank, H.J.; Donohoe, M.T.; Morris, W.L.

1985-09-20

Sulfonylureas affect insulin action at both receptor and post-receptor sites, but their exact mechanism is poorly understood. In these studies, a novel technique was used to examine the influence of glyburide on in vivo cycling of the hepatic insulin receptor. Rats were gavage-fed with 5 mg/kg per day of glyburide solubilized in 60 percent polyethylene glycol and 40 percent phosphate buffer. Control rats were fed polyethylene glycol and buffer alone. After seven days, each rat was anesthetized, the abdomen was surgically exposed, and the animal was given a saturating bolus of 30 micrograms of unlabeled insulin via the portal vein.more » At seven specified times from 10 seconds to 45 minutes later, a second portal vein injection of a mixture of 1.5 microCi (0.015 micrograms) SVI-labeled insulin and 15 microCi THOH (a highly diffusible internal reference marker) was administered; 18 seconds later (time for one circulation), the right lobe of the liver was removed, and SVI and TH values were counted. The liver uptake index and the turnover half-time were then calculated. Glyburide caused a doubling of the turnover half-time for the receptor. This suggests that sulfonylureas potentiate the action of insulin either by increasing the dwell time of insulin on its receptor or by affecting an intracellular event that delays the recycling of the insulin receptor back to the cell surface plasma membrane.« less

Insulin non-persistence among people with type 2 diabetes: how to get your patients to stay on insulin therapy.

PubMed

Garnero, Theresa L; Davis, Nichola J; Perez-Nieves, Magaly; Hadjiyianni, Irene; Cao, Dachuang; Ivanova, Jasmina I; Peyrot, Mark

2018-05-01

Continuing use of medication is key to effective treatment and positive health outcomes, particularly in chronic conditions such as diabetes. However, in primary care, non-persistence (i.e. discontinuing or interrupting treatment) with insulin therapy is a common problem among patients with type 2 diabetes. To help primary care physicians manage patients who are non-persistent or likely not to be persistent, this review aimed to provide an overview of modifiable and non-modifiable factors associated with insulin non-persistence as well as practical strategies to address them. Data were extracted from published studies evaluating factors associated with non-persistence among patients with type 2 diabetes. A targeted literature review was performed using PubMed to identify recent studies (2000-2016) reporting measures of non-persistence with insulin therapy. Practical strategies to identify and prevent non-persistence were based on the authors' direct experience in primary care. Non-modifiable factors associated with non-persistence included gender, age, prior treatments, and cost of therapy. Before/at insulin initiation, modifiable factors included patients' perception of diabetes, preference for oral medication, and concerns/expectations about treatment complexity, inconvenience, or side effects. After initiation, modifiable factors included syringe use, difficulties during the first week of therapy, side effects, and insufficient glycemic control. Open-ended and patient-centered questions and a blame-free environment can help physicians identify, prevent, and reduce non-persistence behaviors. Possible questions to start a conversation with patients are provided. Effective physician-patient communication is essential to the management of diabetes. Primary care physicians should be familiar with the most common reasons for insulin non-persistence.

[Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

PubMed

Kolychev, A P; Ternovskaya, E E; Arsenieva, A V; Shapkina, E V

2013-01-01

Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates.

Does Insulin Explain the Relation between Maternal Obesity and Poor Lactation Outcomes? An Overview of the Literature1234

PubMed Central

2016-01-01

It is well established that obese women are at increased risk of delayed lactogenesis and short breastfeeding duration, but the underlying causal contributors remain unclear. This review summarizes the literature examining the role of insulin in lactation outcomes. Maternal obesity is a strong risk factor for insulin resistance and prediabetes, but until recently a direct role for insulin in milk production had not been elucidated. Over the past 6 y, studies in both animal models and humans have shown insulin-sensitive gene expression to be dramatically upregulated specifically during the lactation cycle. Insulin is now considered to play a direct role in lactation, including essential roles in secretory differentiation, secretory activation, and mature milk production. At the same time, emerging clinical research suggests an important association between suboptimal glucose tolerance and lactation difficulty. To develop effective interventions to support lactation success in obese women further research is needed to identify how, when, and for whom maternal insulin secretion and sensitivity affect lactation ability. PMID:26980825

Stimulation of muscle protein synthesis by somatotropin in pigs is independent of the somatotropin-induced increase in circulating insulin.

PubMed

Wilson, Fiona A; Orellana, Renán A; Suryawan, Agus; Nguyen, Hanh V; Jeyapalan, Asumthia S; Frank, Jason; Davis, Teresa A

2008-07-01

Chronic treatment of growing pigs with porcine somatotropin (pST) promotes protein synthesis and doubles postprandial levels of insulin, a hormone that stimulates translation initiation. This study aimed to determine whether the pST-induced increase in skeletal muscle protein synthesis was mediated through an insulin-induced stimulation of translation initiation. After 7-10 days of pST (150 microg x kg(-1) x day(-1)) or control saline treatment, pancreatic glucose-amino acid clamps were performed in overnight-fasted pigs to reproduce 1) fasted (5 microU/ml), 2) fed control (25 microU/ml), and 3) fed pST-treated (50 microU/ml) insulin levels while glucose and amino acids were maintained at baseline fasting levels. Fractional protein synthesis rates and indexes of translation initiation were examined in skeletal muscle. Effectiveness of pST treatment was confirmed by reduced urea nitrogen and elevated insulin-like growth factor I levels in plasma. Skeletal muscle protein synthesis was independently increased by both insulin and pST. Insulin increased the phosphorylation of protein kinase B and the downstream effectors of the mammalian target of rapamycin, ribosomal protein S6 kinase, and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1). Furthermore, insulin reduced inactive 4E-BP1.eIF4E complex association and increased active eIF4E.eIF4G complex formation, indicating enhanced eIF4F complex assembly. However, pST treatment did not alter translation initiation factor activation. We conclude that the pST-induced stimulation of skeletal muscle protein synthesis in growing pigs is independent of the insulin-associated activation of translation initiation.

Representing delayed force feedback as a combination of current and delayed states.

PubMed

Avraham, Guy; Mawase, Firas; Karniel, Amir; Shmuelof, Lior; Donchin, Opher; Mussa-Ivaldi, Ferdinando A; Nisky, Ilana

2017-10-01

To adapt to deterministic force perturbations that depend on the current state of the hand, internal representations are formed to capture the relationships between forces experienced and motion. However, information from multiple modalities travels at different rates, resulting in intermodal delays that require compensation for these internal representations to develop. To understand how these delays are represented by the brain, we presented participants with delayed velocity-dependent force fields, i.e., forces that depend on hand velocity either 70 or 100 ms beforehand. We probed the internal representation of these delayed forces by examining the forces the participants applied to cope with the perturbations. The findings showed that for both delayed forces, the best model of internal representation consisted of a delayed velocity and current position and velocity. We show that participants relied initially on the current state, but with adaptation, the contribution of the delayed representation to adaptation increased. After adaptation, when the participants were asked to make movements with a higher velocity for which they had not previously experienced with the delayed force field, they applied forces that were consistent with current position and velocity as well as delayed velocity representations. This suggests that the sensorimotor system represents delayed force feedback using current and delayed state information and that it uses this representation when generalizing to faster movements. NEW & NOTEWORTHY The brain compensates for forces in the body and the environment to control movements, but it is unclear how it does so given the inherent delays in information transmission and processing. We examined how participants cope with delayed forces that depend on their arm velocity 70 or 100 ms beforehand. After adaptation, participants applied opposing forces that revealed a partially correct representation of the perturbation using the current and the

The interplay between noncoding RNAs and insulin in diabetes.

PubMed

Tian, Yan; Xu, Jia; Du, Xiao; Fu, Xianghui

2018-04-10

Noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs and circular RNAs, regulate various biological processes and are involved in the initiation and progression of human diseases. Insulin, a predominant hormone secreted from pancreatic β cells, is an essential factor in regulation of systemic metabolism through multifunctional insulin signaling. Insulin production and action are tightly controlled. Dysregulations of insulin production and action can impair metabolic homeostasis, and eventually lead to the development of multiple metabolic diseases, especially diabetes. Accumulating data indicates that ncRNAs modulate β cell mass, insulin synthesis, secretion and signaling, and their role in diabetes is dramatically emerging. This review summarizes our current knowledge of ncRNAs as regulators of insulin, with particular emphasis on the implications of this interplay in the development of diabetes. We outline the role of ncRNAs in pancreatic β cell mass and function, which is critical for insulin production and secretion. We also highlight the involvement of ncRNAs in insulin signaling in peripheral tissues including liver, muscle and adipose, and discuss ncRNA-mediated inter-organ crosstalk under diabetic conditions. A more in-depth understanding of the interplay between ncRNAs and insulin may afford valuable insights and novel therapeutic strategies for treatment of diabetes, as well as other human diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Central insulin signaling is attenuated by long-term insulin exposure via insulin receptor substrate-1 serine phosphorylation, proteasomal degradation, and lysosomal insulin receptor degradation.

PubMed

Mayer, Christopher M; Belsham, Denise D

2010-01-01

Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR.

Temporal-contextual processing in working memory: evidence from delayed cued recall and delayed free recall tests.

PubMed

Loaiza, Vanessa M; McCabe, David P

2012-02-01

Three experiments are reported that addressed the nature of processing in working memory by investigating patterns of delayed cued recall and free recall of items initially studied during complex and simple span tasks. In Experiment 1, items initially studied during a complex span task (i.e., operation span) were more likely to be recalled after a delay in response to temporal-contextual cues, relative to items from subspan and supraspan list lengths in a simple span task (i.e., word span). In Experiment 2, items initially studied during operation span were more likely to be recalled from neighboring serial positions during delayed free recall than were items studied during word span trials. Experiment 3 demonstrated that the number of attentional refreshing opportunities strongly predicts episodic memory performance, regardless of whether the information is presented in a spaced or massed format in a modified operation span task. The results indicate that the content-context bindings created during complex span trials reflect attentional refreshing opportunities that are used to maintain items in working memory.

IG20/MADD Plays a Critical Role in Glucose-Induced Insulin Secretion

PubMed Central

Li, Liang-cheng; Wang, Yong; Carr, Ryan; Haddad, Christine Samir; Li, Ze; Qian, Lixia; Oberholzer, Jose; Maker, Ajay V.; Wang, Qian; Prabhakar, Bellur S.

2014-01-01

Pancreatic β-cell dysfunction is a common feature of type 2 diabetes. Earlier, we had cloned IG20 cDNA from a human insulinoma and had shown that IG20/MADD can encode six different splice isoforms that are differentially expressed and have unique functions, but its role in β-cell function was unexplored. To investigate the role of IG20/MADD in β-cell function, we generated conditional knockout (KMA1ko) mice. Deletion of IG20/MADD in β-cells resulted in hyperglycemia and glucose intolerance associated with reduced and delayed glucose-induced insulin production. KMA1ko β-cells were able to process insulin normally but had increased insulin accumulation and showed a severe defect in glucose-induced insulin release. These findings indicated that IG20/MADD plays a critical role in glucose-induced insulin release from β-cells and that its functional disruption can cause type 2 diabetes. The clinical relevance of these findings is highlighted by recent reports of very strong association of the rs7944584 single nucleotide polymorphism (SNP) of IG20/MADD with fasting hyperglycemia/diabetes. Thus, IG20/MADD could be a therapeutic target for type 2 diabetes, particularly in those with the rs7944584 SNP. PMID:24379354

Insulin microcrystal suspension as a long-acting formulation for pulmonary delivery.

PubMed

Kwon, Jai-Hyun; Lee, Byung-Ha; Lee, Jae-Jeong; Kim, Chan-Wha

2004-06-01

Pulmonary delivery provides the most promising non-parenteral route of insulin administration. Insulin was used as a model protein to demonstrate the feasibility of using protein crystals for the pulmonary delivery of a sustained-release protein drug formulation. Insulin microcrystals with a mean diameter of 3 microm were prepared using a seed zone method. The yield of crystallization was very high (95.8 +/- 0.97%), and the microcrystals were recovered with high efficiency (>98%) by centrifugation. Morphological examination using scanning electron microphotography showed the microcrystals to be of a homogeneous rhombohedral shape, with some rhombus forms, without aggregates. After the administration of 32 U/kg of the microcrystal suspension to STZ-induced diabetic SD rats by intratracheal instillation, the blood glucose levels were reduced and hypoglycemia was prolonged over 13 h, as compared to the insulin solution. The percent minimum reductions of the blood glucose concentration (% MRBG) produced by the microcrystal suspension and insulin solution reached 36.5 and 37.2%, respectively, of the initial level, and the percent total reductions in blood glucose (% TRBG(13 h)) were 34.4 and 25.0%, respectively. In the case of inhalation using a sieve-type ultrasonic nebulizer, the % MRBG produced by the microcrystal suspension and insulin solution were 21.7 and 26.3%, respectively, of the initial level, and the % TRBG(13 h) were 66.7 and 58.4%, respectively. However, the hypoglycemic effects of the microcrystal suspension were prolonged over 7 h, which compares favorably with the insulin solution (P<0.5 by unpaired t-test). These results could be attributed to the sustained-release of insulin from the microcrystals, which were deposited widely throughout the entire lung.

Use of complementary and alternative medicines is associated with delay to initiation of disease-modifying anti-rheumatic drug therapy in early inflammatory arthritis.

PubMed

Lahiri, Manjari; Santosa, Amelia; Teoh, Lay Kheng; Clayton, Jane A; Lim, Sheen Yee; Teng, Gim Gee; Cheung, Peter P M

2017-05-01

To study the predictors of complementary and alternative medicine (CAM) use in patients with early inflammatory arthritis (EIA), and its impact on delay to initiation of disease-modifying anti-rheumatic drugs (DMARD). Data were collected prospectively from EIA patients aged ≥ 21 years. Current or prior CAM use was ascertained by face-to-face interview. Predictors of CAM use and its effect on time to DMARD initiation were determined by multivariate logistic regression and Cox proportional hazards, respectively. One hundred and eighty patients (70.6% female, 58.3% Chinese), of median (interquartile range [IQR]) age 51.1 (40.9-59.8) years and symptom duration 16.6 (9.2-26.6) weeks were included: 83.9% had rheumatoid arthritis, 57% were seropositive. Median (IQR) Disease Activity Score in 28-joints (DAS28) was 4.3 (2.8-5.7), modified Health Assessment Questionnaire (mHAQ) was 0.38 (0.0-0.88) and 41.3% were CAM users. Chinese race (odds ratio [OR] 5.76 [95%CI 2.53-13.1]), being non-English speaking (OR 2.68 [95% CI 1.18-6.09]), smoking (OR 3.35 [95% CI 1.23-9.15] and high DAS28 (OR 2.73 [95% CI 1.05-7.09] were independent predictors of CAM use. CAM users initiated DMARD later (median [IQR] 21.5 [13.1-30.4] vs. 15.6 [9.4-22.7] weeks in non-users, P = 0.005). CAM use and higher DAS28 were associated with a longer delay to DMARD initiation (hazard ratio [HR] 0.69, 95% CI 0.50-0.95 and 0.63, 95% CI 0.43-0.91, respectively) while higher mHAQ was associated with a shorter delay (HR 1.59, 95% CI 1.08-2.34) and race, education level, being non-English speaking, smoking and seropositivity were not associated. Healthcare professionals should be aware of the unique challenges in treating patients with EIA in Asia. Healthcare beliefs regarding CAM may need to be addressed to reduce treatment delay. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Utilization of a Cloud-Based Diabetes Management Program for Insulin Initiation and Titration Enables Collaborative Decision Making Between Healthcare Providers and Patients.

PubMed

Hsu, William C; Lau, Ka Hei Karen; Huang, Ruyi; Ghiloni, Suzanne; Le, Hung; Gilroy, Scott; Abrahamson, Martin; Moore, John

2016-02-01

Overseeing proper insulin initiation and titration remains a challenging task in diabetes care. Recent advances in mobile technology have enabled new models of collaborative care between patients and healthcare providers (HCPs). We hypothesized that the adoption of such technology could help individuals starting basal insulin achieve better glycemic control compared with standard clinical practice. This was a 12 ± 2-week randomized controlled study with 40 individuals with type 2 diabetes who were starting basal insulin due to poor glycemic control. The control group (n = 20) received standard face-to-face care and phone follow-up as needed in a tertiary center, whereas the intervention group (n = 20) received care through the cloud-based diabetes management program where regular communications about glycemic control and insulin doses were conducted via patient self-tracking tools, shared decision-making interfaces, secure text messages, and virtual visits (audio, video, and shared screen control) instead of office visits. By intention-to-treat analysis, the intervention group achieved a greater hemoglobin A1c decline compared with the control group (3.2 ± 1.5% vs. 2.0% ± 2.0%; P = 0.048). The Diabetes Treatment Satisfaction Questionnaire showed a significant improvement in the intervention group compared with the control group (an increase of 10.1 ± 11.7 vs. 2.1 ± 6.5 points; P = 0.01). HCPs spent less time with patients in the intervention group compared with those in the control group (65.9 min per subject vs. 81.6 min per subject). However, the intervention group required additional training time to use the mobile device. Mobile health technology could be an effective tool in sharing data, enhancing communication, and improving glycemic control while enabling collaborative decision making in diabetes care.

Insulin Restores Gestational Diabetes Mellitus–Reduced Adenosine Transport Involving Differential Expression of Insulin Receptor Isoforms in Human Umbilical Vein Endothelium

PubMed Central

Westermeier, Francisco; Salomón, Carlos; González, Marcelo; Puebla, Carlos; Guzmán-Gutiérrez, Enrique; Cifuentes, Fredi; Leiva, Andrea; Casanello, Paola; Sobrevia, Luis

2011-01-01

OBJECTIVE To determine whether insulin reverses gestational diabetes mellitus (GDM)–reduced expression and activity of human equilibrative nucleoside transporters 1 (hENT1) in human umbilical vein endothelium cells (HUVECs). RESEARCH DESIGN AND METHODS Primary cultured HUVECs from full-term normal (n = 44) and diet-treated GDM (n = 44) pregnancies were used. Insulin effect was assayed on hENT1 expression (protein, mRNA, SLC29A1 promoter activity) and activity (initial rates of adenosine transport) as well as endothelial nitric oxide (NO) synthase activity (serine1177 phosphorylation, l-citrulline formation). Adenosine concentration in culture medium and umbilical vein blood (high-performance liquid chromatography) as well as insulin receptor A and B expression (quantitative PCR) were determined. Reactivity of umbilical vein rings to adenosine and insulin was assayed by wire myography. Experiments were in the absence or presence of l-NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) or ZM-241385 (an A2A-adenosine receptor antagonist). RESULTS Umbilical vein blood adenosine concentration was higher, and the adenosine- and insulin-induced NO/endothelium-dependent umbilical vein relaxation was lower in GDM. Cells from GDM exhibited increased insulin receptor A isoform expression in addition to the reported NO–dependent inhibition of hENT1-adenosine transport and SLC29A1 reporter repression, and increased extracellular concentration of adenosine and NO synthase activity. Insulin reversed all these parameters to values in normal pregnancies, an effect blocked by ZM-241385 and l-NAME. CONCLUSIONS GDM and normal pregnancy HUVEC phenotypes are differentially responsive to insulin, a phenomenon where insulin acts as protecting factor for endothelial dysfunction characteristic of this syndrome. Abnormal adenosine plasma levels, and potentially A2A-adenosine receptors and insulin receptor A, will play crucial roles in this phenomenon in GDM. PMID:21515851

Insulin restores gestational diabetes mellitus-reduced adenosine transport involving differential expression of insulin receptor isoforms in human umbilical vein endothelium.

PubMed

Westermeier, Francisco; Salomón, Carlos; González, Marcelo; Puebla, Carlos; Guzmán-Gutiérrez, Enrique; Cifuentes, Fredi; Leiva, Andrea; Casanello, Paola; Sobrevia, Luis

2011-06-01

To determine whether insulin reverses gestational diabetes mellitus (GDM)-reduced expression and activity of human equilibrative nucleoside transporters 1 (hENT1) in human umbilical vein endothelium cells (HUVECs). Primary cultured HUVECs from full-term normal (n = 44) and diet-treated GDM (n = 44) pregnancies were used. Insulin effect was assayed on hENT1 expression (protein, mRNA, SLC29A1 promoter activity) and activity (initial rates of adenosine transport) as well as endothelial nitric oxide (NO) synthase activity (serine(1177) phosphorylation, l-citrulline formation). Adenosine concentration in culture medium and umbilical vein blood (high-performance liquid chromatography) as well as insulin receptor A and B expression (quantitative PCR) were determined. Reactivity of umbilical vein rings to adenosine and insulin was assayed by wire myography. Experiments were in the absence or presence of l-N(G)-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) or ZM-241385 (an A(2A)-adenosine receptor antagonist). Umbilical vein blood adenosine concentration was higher, and the adenosine- and insulin-induced NO/endothelium-dependent umbilical vein relaxation was lower in GDM. Cells from GDM exhibited increased insulin receptor A isoform expression in addition to the reported NO-dependent inhibition of hENT1-adenosine transport and SLC29A1 reporter repression, and increased extracellular concentration of adenosine and NO synthase activity. Insulin reversed all these parameters to values in normal pregnancies, an effect blocked by ZM-241385 and l-NAME. GDM and normal pregnancy HUVEC phenotypes are differentially responsive to insulin, a phenomenon where insulin acts as protecting factor for endothelial dysfunction characteristic of this syndrome. Abnormal adenosine plasma levels, and potentially A(2A)-adenosine receptors and insulin receptor A, will play crucial roles in this phenomenon in GDM.

Does Insulin Explain the Relation between Maternal Obesity and Poor Lactation Outcomes? An Overview of the Literature.

PubMed

Nommsen-Rivers, Laurie A

2016-03-01

It is well established that obese women are at increased risk of delayed lactogenesis and short breastfeeding duration, but the underlying causal contributors remain unclear. This review summarizes the literature examining the role of insulin in lactation outcomes. Maternal obesity is a strong risk factor for insulin resistance and prediabetes, but until recently a direct role for insulin in milk production had not been elucidated. Over the past 6 y, studies in both animal models and humans have shown insulin-sensitive gene expression to be dramatically upregulated specifically during the lactation cycle. Insulin is now considered to play a direct role in lactation, including essential roles in secretory differentiation, secretory activation, and mature milk production. At the same time, emerging clinical research suggests an important association between suboptimal glucose tolerance and lactation difficulty. To develop effective interventions to support lactation success in obese women further research is needed to identify how, when, and for whom maternal insulin secretion and sensitivity affect lactation ability. © 2016 American Society for Nutrition.

Stimulation of muscle protein synthesis by somatotropin in pigs is independent of the somatotropin-induced increase in circulating insulin

PubMed Central

Wilson, Fiona A.; Orellana, Renán A.; Suryawan, Agus; Nguyen, Hanh V.; Jeyapalan, Asumthia S.; Frank, Jason; Davis, Teresa A.

2008-01-01

Chronic treatment of growing pigs with porcine somatotropin (pST) promotes protein synthesis and doubles postprandial levels of insulin, a hormone that stimulates translation initiation. This study aimed to determine whether the pST-induced increase in skeletal muscle protein synthesis was mediated through an insulin-induced stimulation of translation initiation. After 7–10 days of pST (150 μg·kg−1·day−1) or control saline treatment, pancreatic glucose-amino acid clamps were performed in overnight-fasted pigs to reproduce 1) fasted (5 μU/ml), 2) fed control (25 μU/ml), and 3) fed pST-treated (50 μU/ml) insulin levels while glucose and amino acids were maintained at baseline fasting levels. Fractional protein synthesis rates and indexes of translation initiation were examined in skeletal muscle. Effectiveness of pST treatment was confirmed by reduced urea nitrogen and elevated insulin-like growth factor I levels in plasma. Skeletal muscle protein synthesis was independently increased by both insulin and pST. Insulin increased the phosphorylation of protein kinase B and the downstream effectors of the mammalian target of rapamycin, ribosomal protein S6 kinase, and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1). Furthermore, insulin reduced inactive 4E-BP1·eIF4E complex association and increased active eIF4E·eIF4G complex formation, indicating enhanced eIF4F complex assembly. However, pST treatment did not alter translation initiation factor activation. We conclude that the pST-induced stimulation of skeletal muscle protein synthesis in growing pigs is independent of the insulin-associated activation of translation initiation. PMID:18460595

Ultrasound mediated transdermal insulin delivery in pigs using a lightweight transducer.

PubMed

Park, E J; Werner, Jacob; Smith, Nadine Barrie

2007-07-01

In previous studies, ultrasound mediated transdermal drug delivery has shown a promising potential as a method for noninvasive drug administration. For prospective future human application, this study was designed to determine the feasibility of lightweight cymbal transducer array as a practical device for noninvasive transdermal insulin delivery in large pigs. Six Yorkshire pigs (100-140 lbs) were divided into two groups. As the control (n = 3), the first group did not receive any ultrasound exposure with the insulin. The second group (n = 3) was treated with ultrasound and insulin at 20 kHz with an I(sptp) = 100 mW/cm(2) at a 20% duty cycle for 60 min. With the pigs in lateral recumbency after anesthesia, the ultrasound transducer with insulin was placed on the axillary area of the pig. At the beginning and every 15 min up to 90 min, the blood glucose level was determined using a glucose monitoring system. To compare the results of individual animals, the change of blood glucose level was normalized to each animal's initial glucose value at the start of the experiment. Although each animal had a different initial glucose level, the mean and standard error for the six animals was 146 +/- 13 mg/dl. For the control group, the blood glucose level increased to 31 +/- 21 mg/dl compared to the initial baseline over the 90 min experiment. However for the ultrasound with insulin treated group, the glucose level decreased to -72 +/- 5 mg/dl at 60 min (p < 0.05) and continued to decrease to -91 +/- 23 mg/dl in 90 min (p < 0.05). The results indicate the feasibility of ultrasound mediated transdermal insulin delivery using the cymbal transducer array in animal with a similar size and weight to a human. Based on these result, the cymbal array has potential as a practical ultrasound system for noninvasive transdermal insulin delivery for diabetes management.

Monomeric insulins and their experimental and clinical implications.

PubMed

Brange, J; Owens, D R; Kang, S; Vølund, A

1990-09-01

hypoglycemic response with the analogues were observed. The monomeric insulin had no lag phase and followed a monoexponential course throughout the absorption process. In contrast, two phases in rate of absorption were identified for the dimer and three for the normal hexameric human insulin. The initial lag phase and the subsequent accelerated absorption of soluble insulin can now be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process. In the light of these results, the effects of insulin concentration, injected volume, temperature, and massage on the absorption process are now also understood.(ABSTRACT TRUNCATED AT 400 WORDS)

Biosimilar insulins.

PubMed

Heinemann, Lutz

2012-08-01

Until now most insulin used in developed countries is manufactured and distributed by a small number of multinational companies. Other pharmaceutical companies - many of these are located in countries such as India or China - are also able to manufacture insulin with modern biotechnological methods. Additionally, the patents for many insulin formulations have expired or are going to expire soon. This enables such companies to produce insulins and to apply for market approval of these as biosimilar insulins (BIs) in highly regulated markets such as the EU or the US. To understand the complexity of BIs' approval and usage, scientific and regulatory aspects have to be discussed. Differences in the manufacturing process (none of the insulin-manufacturing procedures are identical) result in the fact that all insulin that might become BIs differ from the originator insulin to some extent. The question is, have such differences in the structure of the insulin molecule and or the purity and so on clinically relevant consequences for the biological effects induced or not. The guidelines already in place in the EU for market approval require that the manufacturer demonstrates that his insulin has a safety and efficacy profile that is similar to that of the 'original' insulin formulation. Recently guidelines for biosimilars were issued in the US; however, these do not cover insulin. Although a challenging approval process for insulins to become BI might be regarded as a hurdle to keep companies out of certain markets, it is fair to say that the potential safety and efficacy issues surrounding BI are substantial and relevant, and do warrant a careful and evidence-driven approval process. Nevertheless, it is very likely that in the next years, BIs will come to the market also in highly regulated markets.

Delay banking for air traffic management

NASA Technical Reports Server (NTRS)

Green, Steven M. (Inventor)

2007-01-01

A method and associated system for time delay banking for aircraft arrival time, aircraft departure time and/or en route flight position. The delay credit value for a given flight may decrease with passage of time and may be transferred to or traded with other flights having the same or a different user (airline owner or operator). The delay credit value for a given aircraft flight depends upon an initial delay credit value, which is determined by a central system and depends upon one or more other flight characteristics. Optionally, the delay credit value decreases with passage of time. Optionally, a transaction cost is assessed against a delay credit value that is used on behalf of another flight with the same user or is traded with a different user.

Future therapeutic directions; new medications and insulin delivery in a changing world for effective diabetes management.

PubMed

Modi, Pankaj

2009-09-01

Insulin remains a key to the management of diabetes. The early addition of insulin to oral therapy in type-2 patients is recognized as an effective option that can help improve glycemic control and reduces the complications and contribute to more favorable outcomes. Controlling blood glucose levels within acceptable limits is crucial to the long-term health of patients with diabetes. The benefits of patient education and chronic disease management tools cannot be underestimated as many patients will require education and help in initiation of insulin therapy to achieve glycemic targets. The wide choice of insulin formulations and the ever-expanding range of delivery methods are now available. These methods made insulin administration easier, less painful, more discreet, and more accurate than ever before thus providing important tools to overcome barriers to insulin initiation and improve achievement of glycemic goals. In addition, exciting developments in newer therapeutics have increased the potential for optimal glycemic control. This review discusses how these approaches can help patients manage their diabetes effectively by considering new insulin formulations and delivery devices and newer therapeutics.

Personalized Care and the Role of Insulin as a Vehicle to Optimizing Treatments in Diabetes Care.

PubMed

Bieszk, Nella; Grabner, Michael; Wei, Wenhui; Barron, John; Quimbo, Ralph; Yan, Tingjian; Biel, Beth; Chu, James W

2017-11-01

In patients with type 2 diabetes (T2D) with poor glycemic control, there is an unmet need for treatment optimization involving the initiation and/or intensification of insulin therapy, which is often delayed because of clinical inertia. Educational initiatives that target patients and physicians might be one way to address this need. To evaluate the effectiveness of educational materials mailed to physicians and their patients in affecting initiation of insulin therapy and other health care outcomes. This study, named PIVOTs (Personalized care and the role of Insulin as a Vehicle to Optimizing Treatments), used integrated medical and pharmacy claims data from the U.S.-based HealthCore Integrated Research Database between January 1, 2006, and April 4, 2014, to identify patients who were potential candidates for insulin therapy. Eligible patients were aged 18-75 years, currently enrolled in a commercial or Medicare Advantage health plan, with T2D diagnosis codes. Patients selected for insulin treatment education had glycated hemoglobin A1c (A1c) > 10%, irrespective of the number of noninsulin antihyperglycemic drugs used, or A1c > 8.0% and ≤ 10% while receiving ≥ 2 noninsulin antihyperglycemic drugs. For each identified patient, a corresponding treating physician was identified on a hierarchical basis. Physician-level randomization was conducted to assign physicians and their linked patients to the following 4 cohorts: (1) a cross-sectional cohort in which educational materials were sent to patients and physicians on a single outreach date; (2) a longitudinal cohort in which educational materials were sent to patients and physicians on 2 occasions, 3 months apart; (3) an enhanced cohort in which patients and physicians received the same mailings as the longitudinal cohort, plus physicians were invited to attend a 1:1 video conference academic detailing session; and (4) a control cohort in which patients and physicians did not receive any educational materials

[The effect of mineral water on serotonin and insulin production (an experimental study)].

PubMed

Polushina, N D

1998-01-01

Radioimmunoassay (DRG kits) and orthotoluidine test were conducted to measure blood serotonin, insulin and glucose in 70 intact Wistar rat males before and after a course of drinking mineral water Essentuki 17 (MW). After the MW drinking course, a single dose of mineral water increases basal levels of serotonin and insulin, sensitivity of endocrine cells to MW. Serotonin and insulin rose maximally on minute 5 after the drink while in contrast to minute 15 and 30 before initiation of the MW drinking course. A direct correlation was found between blood concentrations of serotonin and insulin.

Facilitating the safe use of insulin pens in hospitals through a mentored quality-improvement program.

PubMed

Lutz, Mark F; Haines, Stuart T; Lesch, Christine A; Szumita, Paul M

2016-10-01

Results of the MENTORED QUALITY IMPROVEMENT IMPACT PROGRAM℠ (MQIIP) on Ensuring Insulin Pen Safety in Hospitals, which was part of an ASHP educational initiative aimed at ensuring the safe use of insulin pens in hospitals, are described. During this ASHP initiative, which also included continuing-education activities and Web-based resources, distance mentoring by pharmacists with expertise in the safe use of insulin pens was provided to interprofessional teams at 14 hospitals between September 2014 and May 2015. The results of baseline assessments of nursing staff knowledge of insulin pen use, insulin pen storage and labeling audits, and insulin pen injection observations conducted in September and October 2014 were the basis for insulin pen quality-improvement plans. Postintervention data were collected in April and May 2015. Compared with the baseline period, significant improvements in nurses' knowledge of insulin pen use, insulin pen labeling and storage, and insulin pen administration were observed in the postintervention period despite the relatively short time frame for implementation of quality-improvement plans. Program participants are committed to sustaining and building on improvements achieved during the program. The outcome measures described in this report could be adapted by other health systems to identify opportunities to improve the safety of insulin pen use. Focused attention on insulin pen safety through an interprofessional team approach during the MQIIP enabled participating sites to detect potential safety issues based on collected data, develop targeted process changes, document improvements, and identify areas requiring further intervention. A sustained organizational commitment is required to ensure the safe use of insulin pen devices in hospitals. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog.

PubMed

Su, Chih-Ting; Lin, Yi-Chun

2016-01-01

Insulin antibodies (IA) associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA) found in insulin autoimmune syndrome (IAS), which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%), high insulin concentration (111.9 IU/mL) and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly. Insulin autoimmune syndrome (IAS) or IAS-like situation should be one of the differential diagnosis in patients with hyperinsulinemic hypoglycemia.Although less reported, insulin antibodies (IA) caused by exogenous insulin analog should be considered as the cause of hypoglycemia.Patients with suspected insulin autoimmune syndrome (IAS) should be screened for drugs related to autoimmunity to endogenous insulin.

Observations on early and delayed colostomy closure.

PubMed

Tade, A O; Salami, B A; Ayoade, B A

2011-06-01

Traditional treatment of a variety of colorectal pathologies had included a diverting colostomy that was closed eight or more weeks later during a readmission. The aim of this retrospective study was to determine the outcomes of early colostomy closure and delayed colostomy closure in patients with temporary colostomies following traumatic and non-traumatic colorectal pathologies. In this study early colostomy closure was the closure of a colostomy within three weeks of its construction, while delayed colostomy closure referred to closure after 3 weeks. Complete records of the 37 adult patients who had temporary colostomy constructed and closed between Jan. 1997 December 2003 for various colorectal pathologies were studied. Fourteen patients had early colostomy closure while 23 had delayed closure. In the early colostomy closure group there were 10 men and 4 women. The mean age of the patients was 28yr with a range of 18-65yr. Colostomies were closed 9-18 days after initial colostomy construction. There was no mortality. Morbidity rate 28.6% (4 out of 14). There were two faecal fistulas (14.3%). Twenty-three patients had delayed colostomy closure 8 weeks to 18 months after initial colostomy construction. These were patients unfit for early surgery after initial colostomy construction because of carcinoma, significant weight loss, or sepsis. There was no mortality. Morbidity rate was 26.1%. There were 3 faecal fistulas (13.2%). Outcomes following early colostomy closure and delayed closure were comparable. Patients fit for surgery should have early closure whilst patients who may have compromised health should have delayed closure.

Using a patient decision aid for insulin initiation in patients with type 2 diabetes: a qualitative analysis of doctor–patient conversations in primary care consultations in Malaysia

PubMed Central

Syed, Ayeshah; Mohd Don, Zuraidah; Ng, Chirk Jenn; Lee, Yew Kong; Khoo, Ee Ming; Lee, Ping Yein; Lim Abdullah, Khatijah; Zainal, Azlin

2017-01-01

Objective To investigate whether the use of apatient decision aid (PDA) for insulin initiation fulfils its purpose of facilitating patient-centred decision-making through identifying how doctors and patients interact when using the PDA during primary care consultations. Design Conversation analysis of seven single cases of audio-recorded/video-recorded consultations between doctors and patients with type 2 diabetes, using a PDA on starting insulin. Setting Primary care in three healthcare settings: (1) one private clinic; (2) two public community clinics and (3) one primary care clinic in a public university hospital, in Negeri Sembilan and the Klang Valley in Malaysia. Participants Clinicians and seven patients with type 2 diabetes to whom insulin had been recommended. Purposive sampling was used to select a sample high in variance across healthcare settings, participant demographics and perspectives on insulin. Primary outcome measures Interaction between doctors and patients in a clinical consultation involving the use of a PDA about starting insulin. Results Doctors brought the PDA into the conversation mainly by asking information-focused ‘yes/no’ questions, and used the PDA for information exchange only if patients said they had not read it. While their contributions were limited by doctors’ questions, some patients disclosed issues or concerns. Although doctors’ PDA-related questions acted as a presequence to deliberation on starting insulin, their interactional practices raised questions on whether patients were informed and their preferences prioritised. Conclusions Interactional practices can hinder effective PDA implementation, with habits from ordinary conversation potentially influencing doctors’ practices and complicating their implementation of patient-centred decision-making. Effective interaction should therefore be emphasised in the design and delivery of PDAs and in training clinicians to use them. PMID:28490553

Treatment persistence in the use of basal insulins in Poland and Germany
.

PubMed

Rathmann, Wolfgang; Czech, Marcin; Franek, Edward; Kostev, Karel

2017-02-01

To compare short-term basal insulin therapy persistence and its predictors in Poland and Germany. Persistence was defined as proportions of patients remaining on the initial basal insulin (analogs: Poland: n = 6,889, Germany: n = 454,067; neutral protamine Hagedorn (NPH) insulins: Poland: n = 50,761, Germany: n = 226,064) over 2 years based on nationwide prescription databases (LRx; IMS Health) in Poland and Germany from 2013 to 2015. Persistence was evaluated by Kaplan-Meier curves (log-rank tests). Risk of discontinuation of initial basal insulin was investigated using Cox regression models adjusting for age, sex, comedication with other glucose-lowering agents and baseline or comedication with antihypertensives, lipid-lowering drugs, antidepressants, and antiepileptics. In Poland, 2-year persistence was 83.0% in analog insulin and 73.3% in NPH users (p < 0.001). In Germany, persistence was also higher in patients with analog insulins (92.6% vs. 79.0%; p < 0.001). Analog insulin users were less likely to discontinue basal insulin compared with NPH users (adjusted hazard ratio (95%CI): Poland: 0.73 (0.67 - 0.79); Germany: 0.27 (0.27 - 0.28)). Higher age (> 75 vs. ≤ 60 years: Poland: 1.24 (1.16 - 1.33), Germany: 1.09 (1.07 - 1.11)) and GLP-1 receptor agonist use (Poland: 2.76 (1.38 - 5.53), Germany: 1.21 (1.16 - 1.26)) were related to higher risk of discontinuation. Male sex, metformin, sulfonylurea, thiazolidinedione, and short-acting insulin prescriptions as well as antihypertensive, anti-epileptic, and lipid-lowering drug use were associated with lower risk of discontinuation in both countries (all p < 0.05). This real-world study shows that both in Poland and Germany treatment persistence of newly-prescribed basal insulin is influenced by type of insulin (analog vs. NPH) and by glucose-lowering and other comedications.
.

Remission of Diabetes by Insulin Gene Therapy Using a Hepatocyte-specific and Glucose-responsive Synthetic Promoter

PubMed Central

Han, Jaeseok; McLane, Brienne; Kim, Eung-Hwi; Yoon, Ji-Won; Jun, Hee-Sook

2011-01-01

Efficient production of insulin in response to changes in glucose levels has been a major issue for insulin gene therapy to treat diabetes. To express target genes in response to glucose specifically in hepatocytes, we generated a synthetic promoter library containing hepatocyte nuclear factor-1, CAAT/enhancer-binding protein (C/EBP) response element, and glucose-response element. Combinations of these three cis-elements in 3-, 6-, or 9-element configurations were screened for transcriptional activity and then glucose responsiveness in vitro. The most effective promoter (SP23137) was selected for further study. Intravenous administration of a recombinant adenovirus expressing furin-cleavable rat insulin under control of the SP23137 promoter into streptozotocin (STZ)-induced diabetic mice resulted in normoglycemia, which was maintained for >30 days. Glucose tolerance tests showed that treated mice produced insulin in response to glucose and cleared exogenous glucose from the blood in a manner similar to nondiabetic control mice, although the clearance was somewhat delayed. Insulin expression was seen specifically in the liver and not in other organs. These observations indicate the potential of this synthetic, artificial promoter to regulate glucose-responsive insulin production and remit hyperglycemia, thus providing a new method of liver-directed insulin gene therapy for type 1 diabetes. PMID:21119621

Remission of diabetes by insulin gene therapy using a hepatocyte-specific and glucose-responsive synthetic promoter.

PubMed

Han, Jaeseok; McLane, Brienne; Kim, Eung-Hwi; Yoon, Ji-Won; Jun, Hee-Sook

2011-03-01

Efficient production of insulin in response to changes in glucose levels has been a major issue for insulin gene therapy to treat diabetes. To express target genes in response to glucose specifically in hepatocytes, we generated a synthetic promoter library containing hepatocyte nuclear factor-1, CAAT/enhancer-binding protein (C/EBP) response element, and glucose-response element. Combinations of these three cis-elements in 3-, 6-, or 9-element configurations were screened for transcriptional activity and then glucose responsiveness in vitro. The most effective promoter (SP23137) was selected for further study. Intravenous administration of a recombinant adenovirus expressing furin-cleavable rat insulin under control of the SP23137 promoter into streptozotocin (STZ)-induced diabetic mice resulted in normoglycemia, which was maintained for >30 days. Glucose tolerance tests showed that treated mice produced insulin in response to glucose and cleared exogenous glucose from the blood in a manner similar to nondiabetic control mice, although the clearance was somewhat delayed. Insulin expression was seen specifically in the liver and not in other organs. These observations indicate the potential of this synthetic, artificial promoter to regulate glucose-responsive insulin production and remit hyperglycemia, thus providing a new method of liver-directed insulin gene therapy for type 1 diabetes.

Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated.

PubMed

Suryawan, Agus; Orellana, Renan A; Nguyen, Hanh V; Jeyapalan, Asumthia S; Fleming, Jillian R; Davis, Teresa A

2007-12-01

Insulin and amino acids act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs, and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to translation initiation and how these responses change with development. Overnight-fasted 6- (n = 4/group) and 26-day-old (n = 6/ group) pigs were studied during 1) euinsulinemic-euglycemiceuaminoacidemic conditions (controls), 2) euinsulinemic-euglycemichyperaminoacidemic clamps (AA), and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps (INS). INS, but not AA, increased the phosphorylation of protein kinase B (PKB) and tuberous sclerosis 2 (TSC2). Both INS and AA increased protein synthesis and the phosphorylation of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase-1, and eukaryotic initiation factor (eIF)4E-binding protein 1 (4E-BP1), and these responses were higher in 6-day-old compared with 26-day-old pigs. Both INS and AA decreased the binding of 4E-BP1 to eIF4E and increased eIF4E binding to eIF4G; these effects were greater in 6-day-old than in 26-day-old pigs. Neither INS nor AA altered the composition of mTORC1 (raptor, mTOR, and GbetaL) or mTORC2 (rictor, mTOR, and GbetaL) complexes. Furthermore, neither INS, AA, nor age had any effect on the abundance of Rheb and the phosphorylation of AMP-activated protein kinase and eukaryotic elongation factor 2. Our results suggest that the activation by insulin and amino acids of signaling components leading to translation initiation is developmentally regulated and parallels the developmental decline in protein synthesis in skeletal muscle of neonatal pigs.

Activation by Insulin and Amino Acids of Signaling Components Leading to Translation Initiation in Skeletal Muscle of Neonatal Pigs Is Developmentally Regulated

PubMed Central

Suryawan, Agus; Orellana, Renan A.; Nguyen, Hanh V.; Jeyapalan, Asumthia S.; Fleming, Jillian R.; Davis, Teresa A.

2009-01-01

Insulin (INS) and amino acids (AA) act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to translation initiation and how these responses change with development. Overnight fasted 6-day-old (n=4/group) and 26-day-old (n=6/group) pigs were studied during: 1) euinsulinemic-euglycemic-euaminoacidemic conditions (controls), 2) euinsulinemic-euglycemic-hyperaminoacidemic clamps (AA), and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps (INS). INS, but not AA, increased the phosphorylation of protein kinase B (PKB) and tuberous sclerosis 2 (TSC2). Both INS and AA increased protein synthesis and the phosphorylation of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase-1, and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and these responses were higher in 6-day-old compared to 26-day-old pigs. Both INS and AA decreased the binding of 4E-BP1 to eIF4E and increased eIF4E binding to eIF4G; these effects were greater in 6-day-old than in 26-day-old pigs. Neither INS nor AA altered the composition of mTORC1 (raptor, mTOR, and GβL) or mTORC2 (rictor, mTOR, and GβL) complexes. Furthermore, neither INS, AA, nor age had any effect on the abundance of Rheb and the phosphorylation of AMP-activated kinase (AMPK) and eukaryotic elongation factor 2 (eEF2). Our results suggest that the activation by insulin and amino acids of signaling components leading to translation initiation is developmentally regulated and parallels the developmental decline in protein synthesis in skeletal muscle of neonatal pigs. PMID:17878222

Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents.

PubMed

Home, Philip D; Dain, Marie-Paule; Freemantle, Nick; Kawamori, Ryuzo; Pfohl, Martin; Brette, Sandrine; Pilorget, Valérie; Scherbaum, Werner A; Vespasiani, Giacomo; Vincent, Maya; Balkau, Beverley

2015-05-01

It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats.

PubMed

Begg, Denovan P; Mul, Joram D; Liu, Min; Reedy, Brianne M; D'Alessio, David A; Seeley, Randy J; Woods, Stephen C

2013-03-01

Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.

[Comparison between basal insulin glargine and NPH insulin in patients with diabetes type 1 on conventional intensive insulin therapy].

PubMed

Pesić, Milica; Zivić, Sasa; Radenković, Sasa; Velojić, Milena; Dimić, Dragan; Antić, Slobodan

2007-04-01

Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin) for basal insulin supply in patients with type 1 diabetes. A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IT) were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15); 2. NPH insulin twice daily (n = 15); 3. insulin glargine once daily (n = 18). Meal time insulin aspart was continued in all groups. Fasting blood glucose (FBG) was lower in the glargine group (7.30+/-0.98 mmol/1) than in the twice daily NPH group (7.47+/-1.06 mmol/1), but without significant difference. FBG was significantly higher in the once daily NPH group (8.44+/-0.85 mmol/l; p < 0.05). HbAlc after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72+/-0.86% to 6.87+/-0.50%), as well as in the twice daily NPH group (from 7.80+/-0.83% to 7.01+/-0.63%). Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56+/-2.09) than in both NPH groups (9.0+/-1.65 in twice daily NPH group and 8.13+/-1.30 in other NPH group) (episodes/patients-month, p < 0.05). Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbAlc and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.

Implications of delayed initiation of radiotherapy: accelerated repopulation after induction chemotherapy for stage III non-small cell lung cancer.

PubMed

Chen, Chien P; Weinberg, Vivian K; Jahan, Thierry M; Jablons, David M; Yom, Sue S

2011-11-01

For patients with stage III non-small cell lung cancer treated with induction chemotherapy (ICT), delayed initiation of subsequent radiotherapy (RT) may allow for repopulation in the interval between treatment modalities and during the early phase of RT. We quantified the impact of postinduction RT timing by evaluating the pace of tumor regrowth. Institutionally approved retrospective review identified 21 analyzable patients with stage III non-small cell lung cancer who had platinum-based ICT followed by RT+/- chemotherapy from 2002 to 2009. Radiographic response was determined by RECIST criteria and the volume of the single largest tumor mass on the pre-ICT, post-ICT, and RT-planning computed tomography scans. After ICT, the median percent volume change from pre-ICT baseline was -41% (range -86 to +86%). By the RT-planning computed tomography scan, the median percent volume change from the post-ICT timepoint was +40% (range -11 to +311%) and the median volume change was +20 ml (range -4 to 102 ml); these changes were significant (p = 0.0002). Similar results were seen for tumor diameter. A correlation was observed between the amount of delay and degree of regrowth for percent volume (p = 0.0006) and percent diameter change (p = 0.003). A delay greater than 21 days produced greater increases in percent volume change (p = 0.002) and percent diameter (p = 0.055) than lesser delays. After ICT, tumor regrowth can occur within a few weeks. Radiation treatment planning should begin as soon as possible after the administration of ICT to maximize the benefits of cytoreduction.

Delayed Temporal Lobe Hemorrhage After Initiation of Acyclovir in an Immunocompetent Patient with Herpes Simplex Virus-2 Encephalitis: A Case Report.

PubMed

Mueller, Kyle; Ryan, Joshua E; Tai, Alex; Armonda, Rocco A

2017-01-15

Herpes simplex virus (HSV) is the most common cause of non-epidemic, sporadic, acute focal encephalitis in the United States. Inflammation of the vasculature makes them friable and susceptible to hemorrhage. Massive hemorrhage, though rare, can present in a delayed fashion after initiation of acyclovir and often requires surgical intervention. We report a unique case of delayed temporal lobe hemorrhage after initiation of acyclovir in an immunocompetent patient, specifically for its presentation, virology, and surgical management. A 40-year-old left-handed Caucasian female with chronic headaches, along with a 20-pack-year smoking history, presented to an outside facility with one week of diffuse, generalized headache, fever, nausea, and vomiting. Initial cranial imaging was negative for hemorrhage. Cerebrospinal fluid (CSF) studies showed a lymphocytic pleocytosis with elevated protein, along with polymerase chain reaction (PCR) positive staining for HSV, establishing the diagnosis of HSV-2 encephalitis, which is less common in adults. Acyclovir was initiated and one week later while still hospitalized, the patient developed acute altered mental status with cranial imaging showing a large right temporal lobe hemorrhage with significant midline shift. She was transferred to our facility for surgical intervention. Computed tomography angiography (CTA) was negative for any underlying vascular lesion. She was taken to the operating room for a decompressive unilateral (right) hemicraniectomy and temporal lobectomy. She had no postoperative complications and completed a three-week course of acyclovir. She was discharged to acute rehab with plans to return at a later date for cranioplasty. Intracerebral hemorrhage is an uncommon, although possible sequela, of herpes encephalitis. Despite initiation of early antiviral therapy, close monitoring is warranted, given the pathophysiology of the vasculature. Any decline in the neurological exam and/or increasing symptomatology

Relationship between Weather, Traffic and Delay Based on Empirical Methods

NASA Technical Reports Server (NTRS)

Sridhar, Banavar; Swei, Sean S. M.

2006-01-01

The steady rise in demand for air transportation over the years has put much emphasis on the need for sophisticated air traffic flow management (TFM) within the National Airspace System (NAS). The NAS refers to hardware, software and people, including runways, radars, networks, FAA, airlines, etc., involved in air traffic management (ATM) in the US. One of the metrics that has been used to assess the performance of NAS is the actual delays provided through FAA's Air Traffic Operations Network (OPSNET). The OPSNET delay data includes those reportable delays, i.e. delays of 15 minutes or more experienced by Instrument Flight Rule (IFR) flights, submitted by the FAA facilities. These OPSNET delays are caused by the application of TFM initiatives in response to, for instance, weather conditions, increased traffic volume, equipment outages, airline operations, and runway conditions. TFM initiatives such as, ground stops, ground delay programs, rerouting, airborne holding, and miles-in-trail restrictions, are actions which are needed to control the air traffic demand to mitigate the demand-capacity imbalance due to the reduction in capacity. Consequently, TFM initiatives result in NAS delays. Of all the causes, weather has been identified as the most important causal factor for NAS delays. Therefore, in order to accurately assess the NAS performance, it has become necessary to create a baseline for NAS performance and establish a model which characterizes the relation between weather and NAS delays.

Action of insulin on the surface morphology of hepatocytes: role of phosphatidylinositol 3-kinase in insulin-induced shape change of microvilli.

PubMed

Lange, K; Brandt, U; Gartzke, J; Bergmann, J

1998-02-25

primary products, PIP and PIP2. Thus, activated PI 3-kinase may direct a flux of profilin-actin complexes to the membrane locations of activated insulin receptors, where, due to the release of actin monomers after binding of profilactin to PI(3,4)P2 and PI(3,4,5)P3, massive actin polymerization is initiated. As a consequence, PI 3-kinase activation initiates a vectorial reorganization of the cellular actin system to membrane sites neighboring activated insulin receptors, giving rise to local membrane stress as visualized by extensive surface deformations and shortening of microvilli. In addition, extensive high-affinity binding of F-actin-barbed endcapping proteins enhances the cytoplasmic concentration of rapidly polymerizing filament ends. Consequently, the actin monomer concentration is lowered and the (cytoplasmic) pointed ends of the microvillar shaft bundle depolymerize and become shorter. The observations presented strengthen the previously postulated diffusion-barrier concept of glucose- and ion-uptake regulation and provide a mechanistic basis for explaining the action of insulin and other growth factors on transport processes across the plasma membrane.

High-mix insulins

PubMed Central

Kalra, Sanjay; Farooqi, Mohammad Hamed; El-Houni, Ali E.

2015-01-01

Premix insulins are commonly used insulin preparations, which are available in varying ratios of different molecules. These drugs contain one short- or rapid-acting, and one intermediate- or long-acting insulin. High-mix insulins are mixtures of insulins that contain 50% or more than 50% of short-acting insulin. This review describes the clinical pharmacology of high-mix insulins, including data from randomized controlled trials. It suggests various ways, in which high-mix insulin can be used, including once daily, twice daily, thrice daily, hetero-mix, and reverse regimes. The authors provide a rational framework to help diabetes care professionals, identify indications for pragmatic high-mix use. PMID:26425485

Anti-insulin antibody test

MedlinePlus

Insulin antibodies - serum; Insulin Ab test; Insulin resistance - insulin antibodies; Diabetes - insulin antibodies ... You appear to have an allergic response to insulin Insulin no longer seems to control your diabetes

Effect of time delay on flying qualities: An update

NASA Technical Reports Server (NTRS)

Smith, R. E.; Sarrafian, S. K.

1986-01-01

Flying qualities problems of modern, full-authority electronic flight control systems are most often related to the introduction of additional time delay in aircraft response to a pilot input. These delays can have a significant effect on the flying qualities of the aircraft. Time delay effects are reexamined in light of recent flight test experience with aircraft incorporating new technology. Data from the X-29A forward-swept-wing demonstrator, a related preliminary in-flight experiment, and other flight observations are presented. These data suggest that the present MIL-F-8785C allowable-control system time delay specifications are inadequate or, at least, incomplete. Allowable time delay appears to be a function of the shape of the aircraft response following the initial delay. The cockpit feel system is discussed as a dynamic element in the flight control system. Data presented indicate that the time delay associated with a significant low-frequency feel system does not result in the predicted degradation in aircraft flying qualities. The impact of the feel system is discussed from two viewpoints: as a filter in the control system which can alter the initial response shape and, therefore, the allowable time delay, and as a unique dynamic element whose delay contribution can potentially be discounted by special pilot loop closures.

Mixed model of dietary fat effect on postprandial glucose-insulin metabolism from carbohydrates in type 1 diabetes.

PubMed

Yamamoto Noguchi, Claudia Cecilia; Kunikane, Noriaki; Hashimoto, Shogo; Furutani, Eiko

2015-08-01

In this study we introduce an extension of a previously developed model of glucose-insulin metabolism in type 1 diabetes (T1D) from carbohydrates that includes the effect of dietary fat on postprandial glycemia. We include two compartments that represent plasma triglyceride and nonesterified fatty acid (NEFA) concentration, in addition to a mathematical representation of delayed gastric emptying and insulin resistance, which are the most well-known effects of dietary fat metabolism. Simulation results show that postprandial glucose as well as lipid levels in our model approximates clinical data from T1D patients.

Development and implementation of mass media campaigns to delay sexual initiation among African American and White youth.

PubMed

Noar, Seth M; Zimmerman, Rick S; Palmgreen, Philip; Cupp, Pamela K; Floyd, Brenikki R; Mehrotra, Purnima

2014-01-01

Reducing new HIV/STD infections among at-risk adolescents requires developing and evaluating evidence-based health communication approaches. Research overwhelmingly supports the conclusion that early sexual initiation is associated with STDs and other negative outcomes in later years (e.g., unintended pregnancy). The authors' research group secured funding from the National Institute of Mental Health to develop, implement, and rigorously evaluate televised mass media campaigns to delay initiation of sexual intercourse among African American and White adolescents in two cities in the Southeastern United States. The focus of the present study is on the development and implementation of the campaigns, including (a) rationale and theoretical underpinnings; (b) collection, screening, and assessment of existing public service announcements; (c) development of new public service announcements; (d) study design and campaign airing plan; and (e) message exposure achieved in the campaigns. Health communication campaigns hold much promise in reaching at-risk adolescent populations with targeted, timely, and relevant risk-reduction messages.

Preoperative oral carbohydrates and postoperative insulin resistance.

PubMed

Nygren, J; Soop, M; Thorell, A; Sree Nair, K; Ljungqvist, O

1999-04-01

Infusions of carbohydrates before surgery have been shown to reduce postoperative insulin resistance. Presently, we investigated the effects of a carbohydrate drink, given shortly before surgery, on postoperative insulin sensitivity. Insulin sensitivity and glucose turnover ([6, 6,(2)H(2)]-D-glucose) were measured using hyper-insulinemic, normoglycemic clamps before and after elective surgery. Sixteen patients undergoing total hip replacement were randomly assigned to preoperative oral carbohydrate administration (CHO-H, n = 8) or the same amount of a placebo drink (placebo, n = 8) before surgery. Insulin sensitivity was measured before and immediately after surgery. Patients undergoing elective colorectal surgery were studied before surgery and 24 h postoperatively (CHO-C (n = 7), and fasted (n = 7), groups). The fasted group underwent surgery after an overnight fast. In both studies, the CHO groups received 800 ml of an isoosmolar carbohydrate rich beverage the evening before the operation (100g carbohydrates), as well as another 400 ml (50g carbohydrates) 2 h before the initiation of anesthesia. Immediately after surgery, insulin sensitivity was reduced 37% in the placebo group (P < 0.05 vs. preoperatively) while no significant change was found in the CHO-H group (-16%, p = NS). During clamps performed 24h postoperatively, insulin sensitivity and whole-body glucose disposal was reduced in both groups, but the reduction was greater compared to that in the CHO-C group (-49 +/- 6% vs. -26 +/- 8%, P> 0.05 fasted vs. CHO-C). Patients given a carbohydrate drink shortly before elective surgery displayed less reduced insulin sensitivity after surgery as compared to patients undergoing surgery after an overnight fast. Copyright 1999 Harcourt Publishers Ltd.

Variability of Directly Measured First-Pass Hepatic Insulin Extraction and its Association With Insulin Sensitivity and Plasma Insulin.

PubMed

Asare-Bediako, Isaac; Paszkiewicz, Rebecca L; Kim, Stella P; Woolcott, Orison O; Kolka, Cathryn M; Burch, Miguel A; Kabir, Morvarid; Bergman, Richard N

2018-05-11

While the β-cells secrete insulin, it is the liver with its first-pass insulin extraction (FPE) that regulates the amount of insulin allowed into circulation for action on target tissues. The metabolic clearance rate of insulin, of which FPE is the dominant component, is reported to be a major determinant of insulin sensitivity (SI). We studied the intricate relationship between FPE, SI and fasting insulin. We used a direct method of measuring FPE, the paired portal/peripheral infusion protocol (PPII) where insulin is infused step-wise, either via the portal vein or a peripheral vein in healthy young dogs (n =12). FPE is calculated as the difference in clearance rates (slope of infusion rate vs. steady insulin plot) between the paired experiments. Significant correlations were found between FPE vs. clamp assessed SI (r s = 0.74); FPE vs. fasting insulin (r s = -0.64) and SI vs. fasting insulin (r s = - 0.67). Also, we found a wide variance in FPE (22.4 -77.2%; mean ± SD of 50.4 ± 19.1%) which is reflected in the variability of plasma insulin (48.1 ± 30.9pM) and SI (9.4 ± 5.8 x10 4 dL * kg -1 * min -1 * pM -1 ). FPE could be the nexus of regulation of both plasma insulin and SI. © 2018 by the American Diabetes Association.

Vitamin C and E chronic supplementation differentially affect hepatic insulin signaling in rats.

PubMed

Ali, Mennatallah A; Eid, Rania M H M; Hanafi, Mervat Y

2018-02-01

Vitamin C and vitamin E supplementations and their beneficial effects on type 2 diabetes mellitus (T2DM) have been subjected to countless controversial data. Hence, our aim is to investigate the hepatic molecular mechanisms of any diabetic predisposing risk of the chronic administration of different doses of vitamin E or vitamin C in rats. The rats were supplemented with different doses of vitamin C or vitamin E for eight months. Vitamin C and vitamin E increased fasting blood glucose, insulin, and homeostasis model assessment index for insulin resistance (HOMA). Vitamin C disrupted glucose tolerance by attenuating upstream hepatic insulin action through impairing the phosphorylation and activation of insulin receptor and its subsequent substrates; however, vitamin E showed its effect downstream insulin receptor in the insulin signaling pathway, reducing hepatic glucose transporter-2 (GLUT2) and phosphorylated protein kinase (p-Akt). Moreover, both vitamins showed their antioxidant capabilities [nuclear factor-erythroid-2-related factor 2 (Nrf2), total and reduced glutathione] and their negative effect on Wnt pathway [phosphorylated glycogen synthase kinase-3β (p-GSK-3β)], by altering the previously mentioned parameters, inevitably leading to severe reduction of reactive oxygen species (ROS) below the physiological levels. In conclusion, a detrimental effect of chronic antioxidant vitamins supplementation was detected; leading to insulin resistance and impaired glucose tolerance obviously through different mechanisms. Overall, these findings indicate that the conventional view that vitamins promote health benefits and delay chronic illnesses and aging should be modified or applied with caution. Copyright © 2017. Published by Elsevier Inc.

A model of insulin fibrils derived from the x-ray crystal structure of a monomeric insulin (despentapeptide insulin).

PubMed

Brange, J; Dodson, G G; Edwards, D J; Holden, P H; Whittingham, J L

1997-04-01

The crystal structure of despentapeptide insulin, a monomeric insulin, has been refined at 1.3 A spacing and subsequently used to predict and model the organization in the insulin fibril. The model makes use of the contacts in the densely packed despentapeptide insulin crystal, and takes into account other experimental evidence, including binding studies with Congo red. The dimensions of this model fibril correspond well with those measured experimentally, and the monomer-monomer contacts within the fibril are in accordance with the known physical chemistry of insulin fibrils. Using this model, it may be possible to predict mutations in insulin that might alleviate problems associated with fibril formation during insulin therapy.

Management of type-1 and type-2 diabetes by insulin injections in diabetology clinics - a scientific research review.

PubMed

Aziz, Kamran M A

2012-05-01

Better control of the diabetic metabolic state will prevent the diabetes complications. However in current clinical practice, it is sometimes difficult to achieve this goal. Additionally, physicians find themselves in an equivocal position to initiate insulin therapy, its selection, combining with Oral agents and further management. The current article was written to focus on diabetes pathogenesis at molecular level, its classification and management by insulin injections. Knowledge of basic biochemistry, pharmacology with kinetics of Insulin is essential for diabetes management. Nonetheless, it should be a priority to search for evidence based clinical methodologies for selecting the patients for initiating, modifying or combining the insulin therapy. Type-1 diabetic patients are best controlled on basal bolus insulin regimens. However in type-2 diabetes, metformin with lifestyle modifications should be the first line therapy, thereafter combined with oral hypoglycemic agents or shifting to insulin gradually if diabetes remains uncontrolled. Metformin is recommended to be prescribed with insulin as compared to oral hypoglycemic agents which should be discontinued while starting insulin. Monitoring the insulin therapy on regular visits to diabetologist and diabetes multidisciplinary team remains the integral part of diabetes management. The review also outlines relevant and recent insulin analogue patents for the management of Diabetes.

Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.

PubMed

Rodriguez-Rodriguez, Patricia; Sandebring-Matton, Anna; Merino-Serrais, Paula; Parrado-Fernandez, Cristina; Rabano, Alberto; Winblad, Bengt; Ávila, Jesús; Ferrer, Isidre; Cedazo-Minguez, Angel

2017-12-01

Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity

PubMed Central

Eisenstein, Sarah A.; Gredysa, Danuta M.; Antenor–Dorsey, Jo Ann; Green, Leonard; Arbeláez, Ana Maria; Koller, Jonathan M.; Black, Kevin J.; Perlmutter, Joel S.; Moerlein, Stephen M.; Hershey, Tamara

2015-01-01

Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [11C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic

Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity.

PubMed

Eisenstein, Sarah A; Gredysa, Danuta M; Antenor-Dorsey, Jo Ann; Green, Leonard; Arbeláez, Ana Maria; Koller, Jonathan M; Black, Kevin J; Perlmutter, Joel S; Moerlein, Stephen M; Hershey, Tamara

2015-01-01

Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [11C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic

Insulin Therapy

MedlinePlus

... Your Health Resources Drugs, Procedures & Devices Prescription Medicines Insulin Therapy Insulin Therapy Share Print When you digest food, your ... you eat into glucose (a form of sugar). Insulin allows this glucose to enter all the cells ...

Practical Focus on American Diabetes Association/European Association for the Study of Diabetes Consensus Algorithm in Patients with Type 2 Diabetes Mellitus: Timely Insulin Initiation and Titration (Iran-AFECT).

PubMed

Khamseh, Mohammad Ebrahim; Yousefzadeh, Gholamreza; Banazadeh, Zahra; Ghareh, Sahar

2017-02-01

The aim of this study was to evaluate the safety and effectiveness of insulin glargine in a large population from a variety of clinical care in Iranian people with type 2 diabetes mellitus (T2DM) and to measure the percentage of patients achieving glycosylated hemoglobin (HbA1c) <7% by the end of 24 weeks of treatment in routine clinical practice. This study was a 24 week, observational study of patients with T2DM, for whom the physician had decided to initiate or to switch to insulin glargine. The safety and efficacy of glargine were assessed at baseline and at week 24. Seven hundred and twenty-five people with T2DM (63% female) including both insulin naïve and prior insulin users were recruited in this study. The mean age of the participants was 54.2±11.2 years, and the mean HbA1c level was 8.88%±0.93% at baseline. By the end of the study, 27% of the entire participants reached to HbA1c target of less than 7% and 52% had HbA1c ≤7.5%. No serious adverse event was reported in this study. Furthermore, overall hypoglycemia did not increase in prior insulin users and the entire cohort. In addition, body weight did not change in participants while lipid profile improved significantly. Treatment with insulin glargine could improve glycemic control without increasing the risk of hypoglycemic events in people with T2DM. In addition, a significant clinical improvement was observed in lipid profile. Copyright © 2017 Korean Diabetes Association

Evaluation of efficiency of insulin suppository formulations containing sodium salicylate or sodium cholate in insulin dependent diabetic patients.

PubMed

Hosny, Ehab A; Al-Marzouki, Zohair M H; Metwally, Mohammed E S; Souaida, Mamdouh Y S; Alshaik, Abdel Rhman A M

2003-10-01

Two formulations of insulin suppositories were prepared to contain different amounts of sodium salicylate and sodium cholate as absorption promoters and also of insulin with the purpose of obtaining the most effective formulation in reducing plasma glucose levels after rectal administration to diabetic patients. The results show that insulin suppositories containing 100 mg sodium salicylate and 100 or 200 U of crystalline insulin showed no significant difference in AUC, Cmax and Tmax and both formulations showed significant reduction in plasma glucose level compared to initial values within 1.5-2 h. The results from experiments carried out in health volunteers showed that 100 mg sodium salicylate is the optimum amount to be included in insulin suppositories producing significantly higher Cmax and AUC compared to those produced after rectal administration of insulin suppositories containing 50 or 200 mg sodium salicylate. The results also show that using sodium cholate in 50 mg amount did not produce any significant reduction in plasma glucose levels of insulin dependent diabetic patients given suppositories containing 100 U of insulin, but this amount in suppositories containing 200 U of insulin was able to produce significant (p < 0.05) reduction in plasma glucose level within 1 h which lasted till end of experiment producing Cmax of 29.7 +/- 6.61% at Tmax of 1.5 +/- 0.61 h. On increasing the amount of sodium cholate to 100 mg in the suppositories, a marked (p < 0.01) reduction in plasma glucose level took place and the Cmax increased to 47.7 +/- 12.24% at Tmax of 1.5 +/- 0.63 h. This resulted in AUC of 86.7 +/- 22.4 mg%h which was non significantly higher from that produced after administration of suppositories containing 50 mg sodium cholate and 200 U insulin (62.5 +/- 17.6 mg%h). The results also show that insulin suppositories containing 100 mg sodium cholate and 200 U insulin resulted in a non significant differences in Cmax and AUC from those produced by S

Is the current standard of care leading to cost-effective outcomes for patients with type 2 diabetes requiring insulin? A long-term health economic analysis for the UK.

PubMed

Valentine, W J; Curtis, B H; Pollock, R F; Van Brunt, K; Paczkowski, R; Brändle, M; Boye, K S; Kendall, D M

2015-07-01

The aim of the analysis was to investigate whether insulin intensification, based on the use of intensive insulin regimens as recommended by the current standard of care in routine clinical practice, would be cost-effective for patients with type 2 diabetes in the UK. Clinical data were derived from a retrospective analysis of 3185 patients with type 2 diabetes on basal insulin in The Health Improvement Network (THIN) general practice database. In total, 48% (614 patients) intensified insulin therapy, defined by adding bolus or premix insulin to a basal regimen, which was associated with a reduction in HbA1c and an increase in body mass index. Projections of clinical outcomes and costs (2011 GBP) over patients' lifetimes were made using a recently validated type 2 diabetes model. Immediate insulin intensification was associated with improvements in life expectancy, quality-adjusted life expectancy and time to onset of complications versus no intensification or delaying intensification by 2, 4, 6, or 8 years. Direct costs were higher with the insulin intensification strategy (due to the acquisition costs of insulin). Incremental cost-effectiveness ratios for insulin intensification were GBP 32,560, GBP 35,187, GBP 40,006, GBP 48,187 and GBP 55,431 per QALY gained versus delaying intensification 2, 4, 6 and 8 years, and no intensification, respectively. Although associated with improved clinical outcomes, insulin intensification as practiced in the UK has a relatively high cost per QALY and may not lead to cost-effective outcomes for patients with type 2 diabetes as currently defined by UK cost-effectiveness thresholds. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Trivalent Chromium has no Effect on Delaying Azoxymethane-Induced Colorectal Cancer in FVB/NJ Mice.

PubMed

White, Pandora E; Deng, Ge; Kuykendall, M Kaitlyn; Tadros, Abbey M; Dyroff, Samantha L; Honan, Rachel E; Robertson, Preshus M; Vincent, John B; Rasco, Jane F

2015-11-01

As Cr(III) compounds have been shown to increase insulin sensitivity and decrease plasma cholesterol and triglycerides in rodent models of diabetes and insulin resistance and as colorectal cancer risk has been associated with insulin resistance and diabetes, the effects of the Cr(III) compound Cr3 ([Cr3O(O2CCH2CH3)6(H2O)3](+)) were investigated in male and female FVB/NJ mice with azoxymethane-induced colorectal cancer. In contrast to a previous study on the effects of Cr3 on 1,2-dimethylhydrazine-induced colorectal cancer in Sprague Dawley rats, no effects of Cr3 at daily doses of 1 and 10 mg Cr/kg body mass were observed, leaving in question whether administration of Cr(III) compounds can delay or prevent the onset of colorectal cancer.

Baseline and 1-year interim follow-up assessment of Japanese patients initiating insulin therapy who were enrolled in the cardiovascular risk evaluation in people with type 2 diabetes on insulin therapy study: an international, multicenter, observational study.

PubMed

Kawamori, Ryuzo; Node, Koichi; Hanafusa, Toshiaki; Atsumi, Yoshihito; Naito, Yusuke; Oka, Yoshitomo

2013-09-08

21.8% of patients over 6 to 12 months. Our results suggest that insulin treatment is an effective and safe therapeutic option in Japanese patients with T2DM, and earlier insulin initiation might be associated with better glycemic control.

[Delays in diagnosing and treating tuberculosis in Croatia].

PubMed

Jurčev-Savičević, Anamarija; Popović-Grle, Sanja; Mulić, Rosanda; Smoljanović, Mladen; Miše, Kornelija

2012-09-01

The aim of this study was to determine factors causing delay in tuberculosis diagnosis and treatment in Croatia. It included 240 adults with pulmonary tuberculosis, who were interviewed for demographics, socioeconomic, lifestyle, and personal health data. Total delay was defined as a number of days from the onset of symptoms to the initiation of therapy. The median and the 75th percentile of the total delay were 68 and 120 days, respectively: 16.7 % of the patients initiated treatment within the first month, 23.8 % within the second month, 23.3 % within the third month, 12.9 % within the fourth month, and 23.3 % more than four months after the symptoms appeared. Long delay (exceeding median delay) was strongly associated with drug abuse (p=0.021). Extreme delay (75th percentile of delay) was significantly associated with the lowest level of education (p=0.021), below minimal income (p=0.039), minimal to average income (p=0.020), current smoking (p=0.050), and co-morbidity (p=0.048). In the multivariate model, long delay remained associated with drug abuse, while extreme delay was associated with the lowest level of education (p=0.033) and current (p=0.017) and ex-smoking (p=0.045).In a setting with decreasing TB incidence, the reported delay can be reduced by increasing health education, not only about tuberculosis per se, but about health in general and attitudes towards prevention and early care. It is also important to increase tuberculosis knowledge among healthcare workers as well as their diagnostic skills.

Insulin resistance in obesity can be reliably identified from fasting plasma insulin.

PubMed

ter Horst, K W; Gilijamse, P W; Koopman, K E; de Weijer, B A; Brands, M; Kootte, R S; Romijn, J A; Ackermans, M T; Nieuwdorp, M; Soeters, M R; Serlie, M J

2015-12-01

Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely measured variables. We assembled data from non-obese (n=112) and obese (n=100) men who underwent two-step EHCs using [6,6-(2)H2]glucose as tracer (insulin infusion dose 20 and 60 mU m(-2) min(-1), respectively). Reference ranges for hepatic and peripheral insulin sensitivity were calculated from healthy non-obese men. Based on these reference values, obese men with preserved insulin sensitivity or insulin resistance were identified. Cutoff points for insulin-mediated suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disappearance rate (Rd) were 46.5% and 37.3 μmol kg(-)(1) min(-)(1), respectively. Most obese men (78%) had EGP suppression within the reference range, whereas only 12% of obese men had Rd within the reference range. Obese men with Rd <37.3 μmol kg(-1) min(-1) did not differ from insulin-sensitive obese men in age, body mass index (BMI), body composition, fasting glucose or cholesterol, but did have higher fasting insulin (110±49 vs 63±29 pmol l(-1), P<0.001) and homeostasis model assessment of insulin resistance (HOMA-IR) (4.5±2.2 vs 2.7±1.4, P=0.004). Insulin-resistant obese men could be identified with good sensitivity (80%) and specificity (75%) from fasting insulin >74 pmol l(-1). Most obese men have hepatic insulin sensitivity within the range of non-obese controls, but below-normal peripheral insulin sensitivity, that is, insulin resistance. Fasting insulin (>74 pmol l(-1) with current insulin immunoassay) may be used for identification of insulin-resistant (or metabolically unhealthy) obese men in research and clinical settings.

Challenges and unmet needs in basal insulin therapy: lessons from the Asian experience.

PubMed

Chan, Wing Bun; Chen, Jung Fu; Goh, Su-Yen; Vu, Thi Thanh Huyen; Isip-Tan, Iris Thiele; Mudjanarko, Sony Wibisono; Bajpai, Shailendra; Mabunay, Maria Aileen; Bunnag, Pongamorn

2017-01-01

Basal insulin therapy can improve glycemic control in people with type 2 diabetes. However, timely initiation, optimal titration, and proper adherence to prescribed basal insulin regimens are necessary to achieve optimal glycemic control. Even so, glycemic control may remain suboptimal in a significant proportion of patients. Unique circumstances in Asia (eg, limited resources, management of diabetes primarily in nonspecialist settings, and patient populations that are predominantly less educated) coupled with the limitations of current basal insulin options (eg, risk of hypoglycemia and dosing time inflexibility) amplify the challenge of optimal basal insulin therapy in Asia. Significant progress has been made with long-acting insulin analogs (insulin glargine 100 units/mL and insulin detemir), which provide longer coverage and less risk of hypoglycemia over intermediate-acting insulin (Neutral Protamine Hagedorn insulin). Furthermore, recent clinical evidence suggests that newer long-acting insulin analogs, new insulin glargine 300 units/mL and insulin degludec, may address some of the unmet needs of current basal insulin options in terms of risk of hypoglycemia and dosing time inflexibility. Nevertheless, more can be done to overcome barriers to basal insulin therapy in Asia, through educating both patients and physicians, developing better patient support models, and improving accessibility to long-acting insulin analogs. In this study, we highlight the unique challenges associated with basal insulin therapy in Asia and, where possible, propose strategies to address the unmet needs by drawing on clinical experiences and perspectives in Asia.

Challenges and unmet needs in basal insulin therapy: lessons from the Asian experience

PubMed Central

Chan, Wing Bun; Chen, Jung Fu; Goh, Su-Yen; Vu, Thi Thanh Huyen; Isip-Tan, Iris Thiele; Mudjanarko, Sony Wibisono; Bajpai, Shailendra; Mabunay, Maria Aileen; Bunnag, Pongamorn

2017-01-01

Basal insulin therapy can improve glycemic control in people with type 2 diabetes. However, timely initiation, optimal titration, and proper adherence to prescribed basal insulin regimens are necessary to achieve optimal glycemic control. Even so, glycemic control may remain suboptimal in a significant proportion of patients. Unique circumstances in Asia (eg, limited resources, management of diabetes primarily in nonspecialist settings, and patient populations that are predominantly less educated) coupled with the limitations of current basal insulin options (eg, risk of hypoglycemia and dosing time inflexibility) amplify the challenge of optimal basal insulin therapy in Asia. Significant progress has been made with long-acting insulin analogs (insulin glargine 100 units/mL and insulin detemir), which provide longer coverage and less risk of hypoglycemia over intermediate-acting insulin (Neutral Protamine Hagedorn insulin). Furthermore, recent clinical evidence suggests that newer long-acting insulin analogs, new insulin glargine 300 units/mL and insulin degludec, may address some of the unmet needs of current basal insulin options in terms of risk of hypoglycemia and dosing time inflexibility. Nevertheless, more can be done to overcome barriers to basal insulin therapy in Asia, through educating both patients and physicians, developing better patient support models, and improving accessibility to long-acting insulin analogs. In this study, we highlight the unique challenges associated with basal insulin therapy in Asia and, where possible, propose strategies to address the unmet needs by drawing on clinical experiences and perspectives in Asia. PMID:29276400

Delayed Partial Nephrectomy for Hydronephrosis After Renal Trauma.

PubMed

Setia, Shaan; Jackson, Jessica Nicole; Herndon, C D Anthony; Corbett, Sean T

2017-03-01

Delayed sequelae following conservative management of renal trauma in the pediatric population are uncommon. Reports of delayed operations to manage these sequelae are even less common. Here we present the case of a 16-year-old male patient who had delayed development of upper urinary tract obstruction with recurrent infections following high-grade renal trauma managed conservatively. Ultimately, he required a robotic-assisted partial nephrectomy 2 years after initial nonoperative management. This is unique as no prior studies to our knowledge have described delayed hydronephrosis and delayed partial nephrectomy over a year following renal trauma. Copyright © 2016 Elsevier Inc. All rights reserved.

Is there an association between suicide attempt and delay of initiation of mood stabilizers in bipolar I disorder?

PubMed

Nery-Fernandes, Fabiana; Quarantini, Lucas C; Guimarães, José L; de Oliveira, Irismar R; Koenen, Karestan C; Kapczinski, Flavio; Miranda-Scippa, Ângela

2012-02-01

Little is known about the extent to which delay of initiation of mood-stabilizing treatment may influence outcomes in bipolar patients (BP). In this study, our aim was to investigate the association between delay of mood stabilizer treatment in bipolar patients and lifetime history of suicide attempts. A consecutive sample of 268 bipolar I outpatients from two teaching hospitals in Brazil was recruited. The assessment included a socio-demographic history form, a clinical interview regarding clinical variables and the Structured Clinical Interview for DSM-IV. Participants were divided into three groups: BP that initiated the first mood stabilizer in the same year of the first episode of the disease (FMS≤1), between 1 and 5 years after the first episode of the disease (15). The mean time from the first episode until the first mood stabilizer medication was 8.6 years (SD 9.8 years). The FMS>5 group, showed a higher lifetime prevalence of suicide attempts than the other two groups (PR=1.75, 95% CI: 1.24-2.47), p=0.001. These results remained significant after adjusting for potential confounders, (PR=1.82, 95% CI: 1.29-2.60), p=0.001. This study evaluated patients retrospectively and does not permit a cause-effect relationship. The present study supports the importance of early diagnosis and early intervention for BP in order to limit the potentially lethal impact of the disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Improved Glycemic Control Achieved by Switching to Insulin Degludec in Insulin-Treated Patients with Type 2 Diabetes in a Real-World Setting: a Non-interventional, Retrospective Cohort Study.

PubMed

Melzer Cohen, Cheli; Thorsted, Brian Larsen; Wolden, Michael Lyng; Chodick, Gabriel; Karasik, Avraham

2017-10-01

Retrospective cohort study evaluating the clinical effectiveness of insulin degludec (IDeg) in insulin-treated patients with type 2 diabetes switching from other insulins to IDeg in a real-world setting. Data were drawn from the Maccabi Health Management Organization in Israel and included patients treated with IDeg between 1 September 2014 and 29 February 2016. Main inclusion criteria were age ≥18 years, diagnosis of type 2 diabetes, and treated with insulin for at least 1 year prior to IDeg initiation. HbA1c, insulin dose, body weight, and body mass index were recorded before and 90 and 180 days post-switch. Of 211 eligible patients, 57% were male, mean age ± SD 62.2 ± 12.1 years, and diabetes duration >10 years. Switching to IDeg decreased HbA1c from a mean 8.8 ± 1.5% (73.0 ± 16.4 mmol/mol) baseline by 0.58 ± 1.0% (6.3 ± 10.9 mmol/mol) (p < 0.001). Baseline HbA1c of >8.5% (69.0 mmol/mol) and daily insulin dose of ≥50 U were associated with a greater reduction in HbA1c [1.0 ± 1.1% (10.9 ± 12.0 mmol/mol) and 1.2 ± 1.1% (13.1 ± 12.0 mmol/mol), respectively] compared with the total population. At 180 days post-switch, the mean daily basal insulin dose increased by 2 U compared with pre-switch. There was no significant change in body weight post-switch. In a real-world setting, switching from another insulin to IDeg significantly improved glycemic control in patients with type 2 diabetes, without significant weight gain and with only a modest increase in insulin dose after IDeg initiation. Novo Nordisk.

Effects of intranasal insulin on endogenous glucose production in insulin-resistant men.

PubMed

Xiao, Changting; Dash, Satya; Stahel, Priska; Lewis, Gary F

2018-03-14

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m 2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP. © 2018 John Wiley & Sons Ltd.

Impaired Insulin Secretion and Enhanced Insulin Sensitivity in Cholecystokinin-Deficient Mice

PubMed Central

Lo, Chun-Min; Obici, Silvana; Dong, H. Henry; Haas, Michael; Lou, Dawnwen; Kim, Dae Hyun; Liu, Min; D’Alessio, David; Woods, Stephen C.; Tso, Patrick

2011-01-01

OBJECTIVE Cholecystokinin (CCK) is released in response to lipid intake and stimulates insulin secretion. We hypothesized that CCK deficiency would alter the regulation of insulin secretion and glucose homeostasis. RESEARCH DESIGN AND METHODS We used quantitative magnetic resonance imaging to determine body composition and studied plasma glucose and insulin secretion of CCK gene knockout (CCK-KO) mice and their wild-type controls using intraperitoneal glucose and arginine infusions. The area of anti-insulin staining in pancreatic islets was measured by immunohistochemistry. Insulin sensitivity was assessed with euglycemic-hyperinsulemic clamps. RESULTS CCK-KO mice fed a low-fat diet had a reduced acute insulin response to glucose but a normal response to arginine and normal glucose tolerance, associated with a trend toward greater insulin sensitivity. However, when fed a high-fat diet (HFD) for 10 weeks, CCK-KO mice developed glucose intolerance despite increased insulin sensitivity that was associated with low insulin secretion in response to both glucose and arginine. The deficiency of insulin secretion in CCK-KO mice was not associated with changes in β-cell or islet size. CONCLUSIONS CCK is involved in regulating insulin secretion and glucose tolerance in mice eating an HFD. The impaired insulin response to intraperitoneal stimuli that do not typically elicit CCK release suggests that this hormone has chronic effects on β-cell adaptation to diet in addition to acute incretin actions. PMID:21602512

Improving Procedure Start Times and Decreasing Delays in Interventional Radiology: A Department's Quality Improvement Initiative.

PubMed

Villarreal, Monica C; Rostad, Bradley S; Wright, Richard; Applegate, Kimberly E

2015-12-01

To identify and reduce reasons for delays in procedure start times, particularly the first cases of the day, within the interventional radiology (IR) divisions of the Department of Radiology using principles of continuous quality improvement. An interdisciplinary team representative of the IR and preprocedure/postprocedure care area (PPCA) health care personnel, managers, and data analysts was formed. A standardized form was used to document both inpatient and outpatient progress through the PPCA and IR workflow in six rooms and to document reasons for delays. Data generated were used to identify key problems areas, implement improvement interventions, and monitor their effects. Project duration was 6 months. The average number of on-time starts for the first case of the day increased from 23% to 56% (P value < .01). The average number of on-time, scheduled outpatients increased from 30% to 45% (P value < .01). Patient wait time to arrive at treatment room once they were ready for their procedure was reduced on average by 10 minutes (P value < .01). Patient care delay duration per 100 patients was reduced from 30.3 to 21.6 hours (29% reduction). Number of patient care delays per 100 patients was reduced from 46.6 to 40.1 (17% reduction). Top reasons for delay included waiting for consent (26% of delays duration) and laboratory tests (12%). Many complex factors contribute to procedure start time delays within an IR practice. A data-driven and patient-centered, interdisciplinary team approach was effective in reducing delays in IR. Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.

Insulin compatibility with polymer materials used in external pump infusion systems.

PubMed

Melberg, S G; Havelund, S; Villumsen, J; Brange, J

1988-04-01

In a study designed to mimic actual user conditions for external insulin pump infusion, the insulin quality after passage through the infusion set was assessed by various analytical methods, including high performance liquid chromatography. The two infusion sets tested consisted of, firstly, a polyvinylchloride/rubber syringe and a polyvinylchloride catheter sterilized by gamma irradiation and, secondly, a polyethylene/polypropylene syringe connected to a polyethylene catheter and sterilized by ethylene oxide. The insulin solution delivered through the PVC infusion set showed a reduction of preservative to less than 30% of the initial content and increased formation of chemical transformation products of insulin varying from twice the reference level during the first day to more than three times on the third day. By contrast, the polyethylene/polypropylene infusion system showed only a minor decrease in preservative content and no increase in chemical transformation. These effects were observed irrespective of the brand of insulin and were not affected by increase of the zinc content of the insulin solution. Investigation of the influence of the sterilization methods performed on polyvinylchloride and polyethylene catheters revealed that gamma irradiated polyvinylchloride catheters were markedly harmful to the insulin solution, whereas ethylene oxide sterilization did not influence the chemical stability of insulin.

Use of short-acting insulin aspart in managing older people with diabetes

PubMed Central

Marouf, Eltayeb; Sinclair, Alan J

2009-01-01

Type 2 diabetes mellitus affects 5.9% of the world adult population, with older people and some ethnic groups disproportionately affected. Treatment of older people with diabetes differs in many ways from that in younger adults since the majority have type 2 disease and are at particular risk of macrovascular rather than disabling microvascular disease. Insulin therapy, the most effective of diabetes medications, can reduce any level of elevated HBA1c if used in adequate doses. However, some clinicians are often reluctant to initiate insulin therapy in older people with diabetes mainly out of their concerns about adverse reactions to insulin, particularly hypoglycemia. There is evidence suggesting that insulin aspart appears to act similarly to regular human insulin in older people with type 2 diabetes mellitus. Insulin aspart can be used in the treatment of older people with diabetes, but this should be individualized. There is evidence that it improves postprandial glucose control, improves long-term metabolic control, reduces risk of major nocturnal hypoglycemia and increases patient satisfaction compared with soluble insulin. PMID:19503780

Treatment of hypertriglyceridemia-induced acute pancreatitis with insulin

PubMed Central

Erkan, Nazif; Yakan, Savas; Yildirim, Mehmet; Carti, Erdem; Ucar, Deniz; Oymaci, Erkan

2015-01-01

Introduction Hypertriglyceridaemia (HT)-induced pancreatitis rarely occurs unless triglyceride levels exceed 1000 mg/dl. Hypertriglyceridaemia over 1,000 mg/dl can provoke acute pancreatitis (AP) and its persistence can worsen the clinical outcome. In contrast, a rapid decrease in triglyceride level is beneficial. Insulin-stimulated lipoprotein lipase is known to decrease serum triglyceride levels. However, their efficacy in HT-induced AP is not well documented. Aim To present 12 cases of AP successfully treated by insulin administration. Material and methods Three hundred and forty-three cases of AP were diagnosed at our clinic between 2005 and 2012. Twelve (3.5%) of these cases were HT-induced AP. Twelve patients who suffered HT-induced AP are reported. Initial blood triglyceride levels were above 1000 mg/dl. Besides the usual treatment of AP, insulin was administered intravenously in continuous infusion. The patients’ medical records were retrospectively evaluated in this study. Results Serum triglyceride levels decreased to < 500 mg/dl within 2–3 days. No complications of treatment were seen and good clinical outcome was observed. Conclusions Our results are compatible with the literature. Insulin may be used safely and effectively in HT-induced AP therapy. Administration of insulin is efficient when used to reduce triglyceride levels in patients with HT-induced AP. PMID:25960810

Low-melting elemental metal or fusible alloy encapsulated polymerization initiator for delayed initiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hermes, Robert E.

2017-08-15

An encapsulated composition for polymerization includes an initiator composition for initiating a polymerization reaction, and a capsule prepared from an elemental metal or fusible alloy having a melting temperature from about 20.degree. C. to about 200.degree. C. A fluid for polymerization includes the encapsulated composition and a monomer. When the capsule melts or breaks open, the initiator is released.

Insulin glargine 300 U/mL for basal insulin therapy in type 1 and type 2 diabetes mellitus.

PubMed

Lau, Ip Tim; Lee, Ka Fai; So, Wing Yee; Tan, Kathryn; Yeung, Vincent Tok Fai

2017-01-01

To review published clinical studies on the efficacy and safety of new insulin glargine 300 units/mL (Gla-300), a new long-acting insulin analog, for the treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DM). Data sources comprised primary research articles on Gla-300, including pharmacodynamic, pharmacokinetic, and clinical studies. In pharmacodynamic and pharmacokinetic studies, Gla-300 showed a flatter time-action profile and longer duration of action than Gla-100. Noninferiority of Gla-300 versus Gla-100 for lowering of glycated hemoglobin was demonstrated in Phase III clinical studies covering a range of T1DM and T2DM patient populations. Over 6-12 months of follow-up, Gla-300 consistently showed comparable glycemic efficacy with less hypoglycemia vs Gla-100, even during the first 8 weeks of treatment. Although titrated insulin doses were 11%-17% higher with Gla-300 vs Gla-100, changes in body weight were similar or favored Gla-300. Clinical studies provide evidence that the pharmacodynamic and pharmacokinetic properties of Gla-300 may translate into clinical benefits in both T1DM and T2DM. Gla-300 may provide a new option for people initiating basal insulin, those requiring higher basal insulin doses, those with T1DM, and those who may be at increased risk for hypoglycemia, such as people with chronic kidney disease, the elderly, and those with cardiovascular comorbidities.

Insulin glargine 300 U/mL for basal insulin therapy in type 1 and type 2 diabetes mellitus

PubMed Central

Lau, Ip Tim; Lee, Ka Fai; So, Wing Yee; Tan, Kathryn; Yeung, Vincent Tok Fai

2017-01-01

Objective To review published clinical studies on the efficacy and safety of new insulin glargine 300 units/mL (Gla-300), a new long-acting insulin analog, for the treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DM) Materials and methods Data sources comprised primary research articles on Gla-300, including pharmacodynamic, pharmacokinetic, and clinical studies. Results In pharmacodynamic and pharmacokinetic studies, Gla-300 showed a flatter time–action profile and longer duration of action than Gla-100. Noninferiority of Gla-300 versus Gla-100 for lowering of glycated hemoglobin was demonstrated in Phase III clinical studies covering a range of T1DM and T2DM patient populations. Over 6–12 months of follow-up, Gla-300 consistently showed comparable glycemic efficacy with less hypoglycemia vs Gla-100, even during the first 8 weeks of treatment. Although titrated insulin doses were 11%–17% higher with Gla-300 vs Gla-100, changes in body weight were similar or favored Gla-300. Conclusion Clinical studies provide evidence that the pharmacodynamic and pharmacokinetic properties of Gla-300 may translate into clinical benefits in both T1DM and T2DM. Gla-300 may provide a new option for people initiating basal insulin, those requiring higher basal insulin doses, those with T1DM, and those who may be at increased risk for hypoglycemia, such as people with chronic kidney disease, the elderly, and those with cardiovascular comorbidities. PMID:28721081

Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

PubMed

Argirion, Ilona; Weinstein, Stephanie J; Männistö, Satu; Albanes, Demetrius; Mondul, Alison M

2017-10-01

Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk. Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer. Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12-3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99-3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio ( P trend = 0.55 and P trend = 0.27, respectively). Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development. Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519-24. ©2017 AACR . ©2017 American Association for Cancer Research.

Impact of improving postprandial glycemic control with intensifying insulin therapy in type 2 diabetes.

PubMed

Yacoub, Tamer

2017-11-01

Worldwide, many people with type 2 diabetes are not at recommended glycemic targets and remain at increased risk of microvascular and macrovascular complications. Reaching recommended glycemic targets requires normalizing both fasting and postprandial glucose (PPG). For some patients, this will require addition of a prandial insulin delivered by injection to control PPG excursions. Evidence from epidemiological studies suggests an association between postprandial hyperglycemia and cardiovascular disease, and thus, expert guidelines recommend that treatment for elevated PPG not be delayed. Indeed, studies have demonstrated that PPG makes the greatest contribution to HbA 1c in patients who are approaching, but have not yet reached HbA 1c <7.0%. Appropriately timed exposure of the liver to insulin is critical in suppressing hepatic glucose output (and therefore PPG levels) after a meal. Rapid-acting insulin analogs, with their faster onset and shorter duration of action, offer advantages over regular human insulin. Unfortunately, even with improved pharmacokinetic/pharmacodynamic characteristics, rapid-acting insulin analogs are still unable to fully reproduce the rapid release of insulin into the portal circulation and suppression of hepatic glucose output that occurs in the individual without diabetes after starting a meal. The next generation of rapid-acting insulin analogs will have an even more favorable pharmacokinetic profile that should allow patients to further improve glycemic control. Continuous subcutaneous insulin infusion (CSII) represents another option for intensifying therapy and improving postprandial control in some patients, and studies have shown that the benefits are sustainable long-term. However, it is currently unclear which patients stand to benefit the most from the extra expense and complexity of a CSII regimen, and further studies are needed.

Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial.

PubMed

Krischer, Jeffrey P; Schatz, Desmond A; Bundy, Brian; Skyler, Jay S; Greenbaum, Carla J

2017-11-21

Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7-12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes

A Prospective Evaluation of Insulin and Insulin-like Growth Factor-I as Risk Factors for Endometrial Cancer

PubMed Central

Gunter, Marc J.; Hoover, Donald R.; Yu, Herbert; Wassertheil-Smoller, Sylvia; Manson, JoAnn E.; Li, Jixin; Harris, Tiffany G.; Rohan, Thomas E.; Xue, XiaoNan; Ho, Gloria Y.F.; Einstein, Mark H.; Kaplan, Robert C.; Burk, Robert D.; Wylie-Rosett, Judith; Pollak, Michael N.; Anderson, Garnet; Howard, Barbara V.; Strickler, Howard D.

2011-01-01

Obesity is a major risk factor for endometrial cancer, a relationship thought to be largely explained by the prevalence of high estrogen levels in obese women. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed whether insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with endometrial cancer while accounting for estrogen levels. We therefore conducted a case-cohort study of incident endometrial cancer in the Women’s Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. The study involved all 250 incident cases and a random subcohort of 465 subjects for comparison. Insulin, total IGF-I, free IGF-I, IGF-binding protein-3, glucose, and estradiol levels were measured in fasting baseline serum specimens. Cox models were used to estimate associations with endometrial cancer, particularly endometrioid adenocarcinomas, the main histologic type (n = 205). Our data showed that insulin levels were positively associated with endometrioid adenocarcinoma [hazard ratio contrasting highest versus lowest quartile (HRq4-q1), 2.33; 95% confidence interval (95% CI), 1.13–4.82] among women not using hormone therapy after adjustment for age and estradiol. Free IGF-I was inversely associated with endometrioid adenocarcinoma (HRq4-q1, 0.53; 95% CI, 0.31–0.90) after adjustment for age, hormone therapy use, and estradiol. Both of these associations were stronger among overweight/obese women, especially the association between insulin and endometrioid adenocarcinoma (HRq4-q1, 4.30; 95% CI, 1.62–11.43). These data indicate that hyperinsulinemia may represent a risk factor for endometrioid adenocarcinoma that is independent of estradiol. Free IGF-I levels were inversely associated with endometrioid adenocarcinoma, consistent with prior cross-sectional data. PMID:18398032

Economic benefits of improved insulin stability in insulin pumps.

PubMed

Weiss, Richard C; van Amerongen, Derek; Bazalo, Gary; Aagren, Mark; Bouchard, Jonathan R

2011-05-01

Insulin pump users discard unused medication and infusion sets according to labeling and manufacturer's instructions. The stability labeling for insulin aspart (rDNA origin] (Novolog) was increased from two days to six. The associated savings was modeled from the perspective of a hypothetical one-million member health plan and the total United States population. The discarded insulin volume and the number of infusion sets used under a two-day stability scenario versus six were modeled. A mix of insulin pumps of various reservoir capacities with a range of daily insulin dosages was used. Average daily insulin dose was 65 units ranging from 10 to 150 units. Costs of discarded insulin aspart [rDNA origin] were calculated using WAC (Average Wholesale Price minus 16.67%). The cost of pump supplies was computed for the two-day scenario assuming a complete infusion set change, including reservoirs, every two days. Under the six-day scenario complete infusion sets were discarded every six days while cannulas at the insertion site were changed midway between complete changes. AWP of least expensive supplies was used to compute their costs. For the hypothetical health plan (1,182 pump users) the annual reduction in discarded insulin volume between scenarios was 19.8 million units. The corresponding cost reduction for the plan due to drug and supply savings was $3.4 million. From the U.S. population perspective, savings of over $1 billion were estimated. Using insulin that is stable for six days in pump reservoirs can yield substantial savings to health plans and other payers, including patients.

Safety of once-daily insulin detemir in patients with type 2 diabetes treated with oral hypoglycemic agents in routine clinical practice.

PubMed

Ross, Stuart; Dzida, Grzegorz; Ji, Qiuhe; Kaiser, Marcel; Ligthelm, Robert; Meneghini, Luigi; Nazeri, Avideh; Orozco-Beltran, Domingo; Pan, Changyu; Svendsen, Anne Louise

2014-05-01

The aim of the present study was to identify demographic and treatment factors that were predictive of hypoglycemia in a large cohort of type 2 diabetic patients initiating insulin detemir. The present 24-week observational study of insulin initiation included 17 374 participants from 10 countries. Severe hypoglycemia was defined as an event requiring third party assistance; minor hypoglycemia was defined as a daytime or nocturnal glucose measurement <3.1 mmol/L. Prior to initiating insulin therapy, 4.9% of the cohort reported hypoglycemia (pre-insulin hypoglycemia), with most (94.2%) reporting minor events and 9.6% reporting severe events. Compared with patients without pre-insulin hypoglycemia, those with pre-insulin hypoglycemia had a higher incidence of events of minor hypoglycemia (1.72 vs 4.46 events per patient-year [ppy], respectively), nocturnal hypoglycemia (0.25 vs 1.09 events ppy, respectively), and severe hypoglycemia (<0.01 vs 0.04 events ppy, respectively) at final visit. Age (P < 0.047), body mass index (P < 0.001), a prior history of microvascular disease (P < 0.001), pre-insulin hypoglycemia (P < 0.001), increased number of oral hypoglycemic agents (OHAs; P < 0.001), OHA intensification (P < 0.001), and the use of glinides (P = 0.004) were all found to be independently associated with the occurrence of hypoglycemia during the study. Once-daily insulin detemir therapy was safe and effective, and rates of hypoglycemia were low. Concerns about hypoglycemia should not deter the initiation of basal insulin analogs. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Role of genetic variation in insulin-like growth factor 1 receptor on insulin resistance and arterial hypertension.

PubMed

Sookoian, Silvia; Gianotti, Tomas Fernandez; Gemma, Carolina; Burgueño, Adriana L; Pirola, Carlos J

2010-06-01

To perform a two-stage study to explore the role of gene variants in the risk of insulin resistance and arterial hypertension. The selection of variants was performed by a first stage of in-silico analysis of the original genome-wide association data sets on genes involved in metabolic syndrome components, granted by the Diabetes Genetics Initiative and the Wellcome Trust Case-Control Consortium. We started by identifying single-nucleotide polymorphisms with a cutoff for association (P < 0.05) in both data sets after the application of a computational algorithm of gene prioritization. Among the more promising variants, six single-nucleotide polymorphisms in IGF1R (rs11247362, rs10902606, rs1317459, rs11854132, rs2684761, and rs2715416) were selected for further evaluation in our population. Altogether, 1094 men, aged 34.4 +/- 8.6 years, were included in a population-based study. Genotypes of rs2684761 showed significant association with insulin resistance (as a discrete trait, odds ratio per G allele 1.27, 95% confidence interval 1.03-1.56, P = 0.026; and homeostasis model assessment-insulin resistance as a continuous trait, P = 0.01). A significant association of rs2684761 with arterial hypertension was also observed (odds ratio per G allele 1.29, 95% confidence interval 1.02-1.64, P = 0.037) after adjusting for age and homeostasis model assessment-insulin resistance. Our study suggests for the first time a putative role of IGF1R variants in individual susceptibility to metabolic syndrome-related phenotypes, in particular on the risk of having insulin resistance and arterial hypertension.

Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

PubMed

Højlund, Kurt

2014-07-01

Type 2 diabetes, obesity and polycystic ovary syndrome (PCOS) are common metabolic disorders which are observed with increasing prevalences, and which are caused by a complex interplay between genetic and environmental factors, including increased calorie intake and physical inactivity. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes and cardiovascular disease. In several studies, we have investigated insulin action on glucose and lipid metabolism, and at the molecular level, insulin signaling to glucose transport and glycogen synthesis in skeletal muscle from healthy individuals and in obesity, PCOS and type 2 diabetes. Moreover, we have described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance. Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin action on glucose uptake and glycogen synthesis is impaired. This suggests that the defects in glucose and lipid oxidation in the common metabolic disorders are secondary to other factors. In young women with PCOS, the degree of insulin resistance was similar to that seen in middle-aged patients with type 2 diabetes. This supports the hypothesis of an unique pathogenesis of insulin resistance in PCOS. Insulin in physiological concentrations stimulates glucose uptake in human skeletal

In vivo studies on insulin permeability of an immunoisolation device intended for islet transplantation using the microdialysis technique.

PubMed

Rafael, E; Wernerson, A; Arner, P; Tibell, A

1999-01-01

In this study, insulin was injected into Theracyte immunoisolation devices to analyze changes in the permeability of the device over time after implantation. The recovery of insulin was studied after subcutaneous implantation of the devices in rats, using the microdialysis technique. The area under the insulin concentration vs. time curves (AUC) after insulin injection in devices implanted 1 day previously did not differ significantly from the AUC after subcutaneous injection. At 1, 2 and 4 weeks after implantation, the recovery of insulin was significantly reduced, but at 3 months, the AUC was not significantly different from that in the control group. Histological examination showed that the number of vascular profiles within 15 microm of the device were significantly higher at 2, 4 weeks and 3 months after transplantation when compared to numbers at 1 week. The design of the device allows transplantation of cells at a chosen time point after its implantation. Delayed filling of the device would allow neovascularization of the device surface before graft implantation and we suggest that such a schedule might improve function of the encapsulated graft.

Pregestational diabetes with extreme insulin resistance: use of U-500 insulin in pregnancy.

PubMed

Zuckerwise, Lisa C; Werner, Erika F; Pettker, Christian M; McMahon-Brown, Erin K; Thung, Stephen F; Han, Christina S

2012-08-01

Increased insulin requirements in pregnancy can hinder attainment of glycemic control in diabetic patients. U-500 insulin is a concentrated form of regular insulin that can be a valuable tool in the treatment of patients with severe insulin resistance. A 24-year-old woman with pregestational diabetes mellitus experienced increasing insulin requirements during pregnancy, peaking at 650 units daily. The frequent, large-volume injections of standard-concentration insulin were poorly tolerated by the patient and resulted in nonadherence. She subsequently achieved glycemic control on thrice-daily U-500 insulin. Pregnancy exacerbates insulin resistance in diabetic patients, and these patients may require high doses of insulin. U-500 insulin is an effective alternative for patients with severe insulin resistance and should be considered for pregnant women with difficulty achieving glycemic control.

Management Strategies to Facilitate Optimal Outcomes for Patients Treated with Delayed-release Dimethyl Fumarate.

PubMed

Mayer, Lori; Fink, Mary Kay; Sammarco, Carrie; Laing, Lisa

2018-04-01

Delayed-release dimethyl fumarate is an oral disease-modifying therapy that has demonstrated significant efficacy in adults with relapsing-remitting multiple sclerosis. Incidences of flushing and gastrointestinal adverse events are common in the first month after delayed-release dimethyl fumarate initiation. Our objective was to propose mitigation strategies for adverse events related to initiation of delayed-release dimethyl fumarate in the treatment of patients with multiple sclerosis. Studies of individually developed mitigation strategies and chart reviews were evaluated. Those results, as well as mitigation protocols developed at multiple sclerosis care centers, are summarized. Key steps to optimize the effectiveness of delayed-release dimethyl fumarate treatment include education prior to and at the time of delayed-release dimethyl fumarate initiation, initiation dose protocol gradually increasing to maintenance dose, dietary suggestions for co-administration with food, gastrointestinal symptom management with over-the-counter medications, flushing symptom management with aspirin, and temporary dose reduction. Using the available evidence from clinical trials and evaluations of post-marketing studies, these strategies to manage gastrointestinal and flushing symptoms can be effective and helpful to the patient when initiating delayed-release dimethyl fumarate.

Insulin Infusion Set: The Achilles Heel of Continuous Subcutaneous Insulin Infusion

PubMed Central

Heinemann, Lutz; Krinelke, Lars

2012-01-01

Continuous subcutaneous insulin infusion from an insulin pump depends on reliable transfer of the pumped insulin to the subcutaneous insulin depot by means of an insulin infusion set (IIS). Despite their widespread use, the published knowledge about IISs and related issues regarding the impact of placement and wear time on insulin absorption/insulin action is relatively small. We also have to acknowledge that our knowledge is limited with regard to how often patients encounter issues with IISs. Reading pump wearer blogs, for instance, suggests that these are a frequent source of trouble. There are no prospective clinical studies available on current IIS and insulin formulations that provide representative data on the type and frequency of issues with infusion sets. The introduction of new IISs and patch pumps may foster a reassessment of available products and of patient problems related to their use. The aim of this review is to summarize the current knowledge and recommendations about IISs and to highlight potential directions of IIS development in order to make insulin absorption safer and more efficient. PMID:22920824

Determinants of High Fasting Insulin and Insulin Resistance Among Overweight/Obese Adolescents.

PubMed

Ling, Jerri Chiu Yun; Mohamed, Mohd Nahar Azmi; Jalaludin, Muhammad Yazid; Rampal, Sanjay; Zaharan, Nur Lisa; Mohamed, Zahurin

2016-11-08

Hyperinsulinaemia is the earliest subclinical metabolic abnormality, which precedes insulin resistance in obese children. An investigation was conducted on the potential predictors of fasting insulin and insulin resistance among overweight/obese adolescents in a developing Asian country. A total of 173 overweight/obese (BMI > 85 th percentile) multi-ethnic Malaysian adolescents aged 13 were recruited from 23 randomly selected schools in this cross-sectional study. Waist circumference (WC), body fat percentage (BF%), physical fitness score (PFS), fasting glucose and fasting insulin were measured. Insulin resistance was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). Adjusted stepwise multiple regression analysis was performed to predict fasting insulin and HOMA-IR. Covariates included pubertal stage, socioeconomic status, nutritional and physical activity scores. One-third of our adolescents were insulin resistant, with girls having significantly higher fasting insulin and HOMA-IR than boys. Gender, pubertal stage, BMI, WC and BF% had significant, positive moderate correlations with fasting insulin and HOMA-IR while PFS was inversely correlated (p < 0.05). Fasting insulin was primarily predicted by gender-girls (Beta = 0.305, p < 0.0001), higher BMI (Beta = -0.254, p = 0.02) and greater WC (Beta = 0.242, p = 0.03). This study demonstrated that gender, BMI and WC are simple predictors of fasting insulin and insulin resistance in overweight/obese adolescents.

Design of an Insulin Analog with Enhanced Receptor Binding Selectivity

PubMed Central

Zhao, Ming; Wan, Zhu-li; Whittaker, Linda; Xu, Bin; Phillips, Nelson B.; Katsoyannis, Panayotis G.; Ismail-Beigi, Faramarz; Whittaker, Jonathan; Weiss, Michael A.

2009-01-01

Insulin binds with high affinity to the insulin receptor (IR) and with low affinity to the type 1 insulin-like growth factor (IGF) receptor (IGFR). Such cross-binding, which reflects homologies within the insulin-IGF signaling system, is of clinical interest in relation to the association between hyperinsulinemia and colorectal cancer. Here, we employ nonstandard mutagenesis to design an insulin analog with enhanced affinity for the IR but reduced affinity for the IGFR. Unnatural amino acids were introduced by chemical synthesis at the N- and C-capping positions of a recognition α-helix (residues A1 and A8). These sites adjoin the hormone-receptor interface as indicated by photocross-linking studies. Specificity is enhanced more than 3-fold on the following: (i) substitution of GlyA1 by d-Ala or d-Leu, and (ii) substitution of ThrA8 by diaminobutyric acid (Dab). The crystal structure of [d-AlaA1,DabA8]insulin, as determined within a T6 zinc hexamer to a resolution of 1.35 Å, is essentially identical to that of human insulin. The nonstandard side chains project into solvent at the edge of a conserved receptor-binding surface shared by insulin and IGF-I. Our results demonstrate that modifications at this edge discriminate between IR and IGFR. Because hyperinsulinemia is typically characterized by a 3-fold increase in integrated postprandial insulin concentrations, we envisage that such insulin analogs may facilitate studies of the initiation and progression of cancer in animal models. Future development of clinical analogs lacking significant IGFR cross-binding may enhance the safety of insulin replacement therapy in patients with type 2 diabetes mellitus at increased risk of colorectal cancer. PMID:19773552

Insulin resistance in the liver: Deficiency or excess of insulin?

PubMed Central

Bazotte, Roberto B; Silva, Lorena G; Schiavon, Fabiana PM

2014-01-01

In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states. PMID:25486190

Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

PubMed Central

Richey, Joyce M.; Castro, Ana Valeria B.; Broussard, Josiane L.; Ionut, Viorica; Bergman, Richard N.

2015-01-01

Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. Previously, we have shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model and measured the appearance of insulin in the lymph as a means to sample muscle interstitium under hyperinsulinemic euglycemic clamp conditions. Although lipid infusion lowered the glucose infusion rate and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the lymph. Interestingly, despite a significant, 10-fold increase in plasma FFA, we detected little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. Thus, we conclude that experimental insulin resistance induced by lipid infusion does not reduce insulin access to skeletal muscle under clamp conditions. This would suggest that the peripheral insulin resistance is likely due to reduced cellular sensitivity to insulin in this model, and yet we did not detect a change in the tissue microenvironment that could contribute to cellular insulin resistance. PMID:25852002

Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements.

PubMed

Pearson, Scott M; Trujillo, Jennifer M

2018-04-01

We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U-300 (Gla-300) or insulin degludec. This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla-100 to either Gla-300 ( n = 95) or insulin degludec ( n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1-12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19-60 interquartile range (IQR)] units at baseline to 34.5 (19-70 IQR) units after follow up ( p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different ( p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 ( p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Patients who transitioned from Gla-100 to Gla-300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different.

Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements

PubMed Central

Trujillo, Jennifer M.

2018-01-01

Background: We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U-300 (Gla-300) or insulin degludec. Methods: This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla-100 to either Gla-300 (n = 95) or insulin degludec (n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1–12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Results: Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19–60 interquartile range (IQR)] units at baseline to 34.5 (19–70 IQR) units after follow up (p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different (p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 (p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Conclusions: Patients who transitioned from Gla-100 to Gla-300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different. PMID:29619208

Insulin released from titanium discs with insulin coatings-Kinetics and biological activity.

PubMed

Malekzadeh, B Ö; Ransjo, M; Tengvall, P; Mladenovic, Z; Westerlund, A

2017-10-01

Local administration of insulin from a titanium surface has been demonstrated to increase bone formation in non-diabetic rats. The authors hypothesized that insulin was released from the titanium surface and with preserved biological activity after the release. Thus, in the present in vitro study, human recombinant insulin was immobilized onto titanium discs, and the insulin release kinetics was evaluated using Electro-chemiluminescence immunoassay. Neutral Red uptake assay and mineralization assay were used to evaluate the biological effects of the released insulin on human osteoblast-like MG-63 cells. The results confirmed that insulin was released from titanium surfaces during a six-week period. Etching the disc prior to insulin coating, thickening of the insulin coating and incubation of the discs in serum-enriched cell culture medium increased the release. However, longer storage time decreased the release of insulin. Furthermore, the released insulin had retained its biological activity, as demonstrated by the significant increase in cell number and a stimulated mineralization process, upon exposure to released insulin. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1847-1854, 2017. © 2016 Wiley Periodicals, Inc.

Comparison of utilization, cost, adherence, and hypoglycemia in patients with type 2 diabetes initiating rapid-acting insulin analog with prefilled pen versus vial/syringe.

PubMed

Lee, Lauren J; Li, Qian; Reynolds, Matthew W; Pawaskar, Manjiri D; Corrigan, Sheila M

2011-01-01

Studies examining outcomes of different insulin delivery systems are limited. The objective of this study was to compare healthcare utilization, costs, adherence, and hypoglycemia rates in patients with type 2 diabetes mellitus (T2DM) initiating rapid-acting insulin analog (RAIA) using prefilled pen versus vial/syringe. A retrospective analysis was conducted using a US claims database (1/1/2007 to 12/31/2008). Inclusion criteria were: ≥18 years old, with T2DM, ≥12 months of continuous eligibility, and new to RAIA. Difference-in-difference analyses after propensity score matching were conducted to compare changes in outcomes from 6 months prior to and 6 months after initiating RAIA with a prefilled pen versus vial/syringe (Wilcoxon rank-sum test for costs and t-test for other outcomes). Categories of utilization and costs (2009 USD) included total and diabetes-related inpatient, outpatient, and emergency room. Adherence was measured by proportion of days covered (PDC). Hypoglycemia was identified using ICD-9-CM codes. Baseline characteristics were similar between the prefilled pen (n = 239) and vial/syringe (n = 590) cohorts after matching. Adherence to RAIA was greater in the prefilled pen cohort than the vial/syringe cohort (PDC: 54.6 vs. 45.2%, p < 0.001). While the increase in diabetes-related pharmacy costs from before to after initiating RAIA was greater in the prefilled pen cohort than the vial/syringe cohort (+$900 vs. +$607, p < 0.001), the prefilled pen cohort was associated with greater reductions in the total diabetes-related costs (-$235 vs. +$61, p = 0.006) and the utilization of oral anti-hyperglycemic agents (-1.3 vs. -0.7, p = 0.016). There were no significant differences in other outcomes. Claims databases do not provide optimal measures for adherence or T2DM severity, and only capture hypoglycemia events requiring clinical intervention. Initiating RAIA with a prefilled pen was associated with better adherence and

Clinical use of the co-formulation of insulin degludec and insulin aspart.

PubMed

Kumar, A; Awata, T; Bain, S C; Ceriello, A; Fulcher, G R; Unnikrishnan, A G; Arechavaleta, R; Gonzalez-Gálvez, G; Hirose, T; Home, P D; Kaku, K; Litwak, L; Madsbad, S; Pinget, M; Mehta, R; Mithal, A; Tambascia, M; Tibaldi, J; Christiansen, J S

2016-08-01

To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins. © 2016 John Wiley & Sons Ltd.

Delayed risk stratification, to include the response to initial treatment (surgery and radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer patients.

PubMed

Castagna, Maria Grazia; Maino, Fabio; Cipri, Claudia; Belardini, Valentina; Theodoropoulou, Alexandra; Cevenini, Gabriele; Pacini, Furio

2011-09-01

After initial treatment, differentiated thyroid cancer (DTC) patients are stratified as low and high risk based on clinical/pathological features. Recently, a risk stratification based on additional clinical data accumulated during follow-up has been proposed. To evaluate the predictive value of delayed risk stratification (DRS) obtained at the time of the first diagnostic control (8-12 months after initial treatment). We reviewed 512 patients with DTC whose risk assessment was initially defined according to the American (ATA) and European Thyroid Association (ETA) guidelines. At the time of the first control, 8-12 months after initial treatment, patients were re-stratified according to their clinical status: DRS. Using DRS, about 50% of ATA/ETA intermediate/high-risk patients moved to DRS low-risk category, while about 10% of ATA/ETA low-risk patients moved to DRS high-risk category. The ability of the DRS to predict the final outcome was superior to that of ATA and ETA. Positive and negative predictive values for both ATA (39.2 and 90.6% respectively) and ETA (38.4 and 91.3% respectively) were significantly lower than that observed with the DRS (72.8 and 96.3% respectively, P<0.05). The observed variance in predicting final outcome was 25.4% for ATA, 19.1% for ETA, and 62.1% for DRS. Delaying the risk stratification of DTC patients at a time when the response to surgery and radioiodine ablation is evident allows to better define individual risk and to better modulate the subsequent follow-up.

Baseline and 1-year interim follow-up assessment of Japanese patients initiating insulin therapy who were enrolled in the cardiovascular risk evaluation in people with type 2 diabetes on insulin therapy study: an international, multicenter, observational study

PubMed Central

2013-01-01

diabetes control at the 1-year follow-up (P < .05 for trend). Symptomatic hypoglycemic episodes occurred in 21.8% of patients over 6 to 12 months. Conclusions Our results suggest that insulin treatment is an effective and safe therapeutic option in Japanese patients with T2DM, and earlier insulin initiation might be associated with better glycemic control. PMID:24011395

Insulin therapy in neonatal diabetes mellitus: a review of the literature.

PubMed

Rabbone, Ivana; Barbetti, Fabrizio; Gentilella, Raffaella; Mossetto, Gilberto; Bonfanti, Riccardo; Maffeis, Claudio; Iafusco, Dario; Piccinno, Elvira

2017-07-01

Neonatal diabetes mellitus (NDM) is a rare disorder, and guidance is limited regarding its optimal management. We reviewed insulin usage in NDM, with a focus on continuous subcutaneous insulin infusion (CSII). A PubMed search identified 40 reports of patients with NDM treated with insulin published between 1994 and 2016. Data concerning treatment of NDM are limited. CSII resolves some of the issues associated with insulin therapy in neonates. No clinical trials of CSII in NDM have been reported. Case reports suggest that CSII is a safe and effective means of treating NDM. CSII was initiated to improve glycaemic control, for practicality and convenience, and to overcome difficulties associated with the maintenance of long-term intravenous catheters. CSII can provide better glycaemic control than multiple daily injections, with few hypoglycaemic events. Continuous glucose monitoring integrated with the pump helps provide more precise control of blood glucose levels. CSII generally uses short-acting insulin or rapid-acting insulin analogues, and those that are approved for use in neonates appear to be appropriate for the treatment of NDM using an insulin pump. Information from case reports indicates that CSII is safe and effective for the management of NDM. Copyright © 2017 Elsevier B.V. All rights reserved.

Adaptive and Personalized Plasma Insulin Concentration Estimation for Artificial Pancreas Systems.

PubMed

Hajizadeh, Iman; Rashid, Mudassir; Samadi, Sediqeh; Feng, Jianyuan; Sevil, Mert; Hobbs, Nicole; Lazaro, Caterina; Maloney, Zacharie; Brandt, Rachel; Yu, Xia; Turksoy, Kamuran; Littlejohn, Elizabeth; Cengiz, Eda; Cinar, Ali

2018-05-01

The artificial pancreas (AP) system, a technology that automatically administers exogenous insulin in people with type 1 diabetes mellitus (T1DM) to regulate their blood glucose concentrations, necessitates the estimation of the amount of active insulin already present in the body to avoid overdosing. An adaptive and personalized plasma insulin concentration (PIC) estimator is designed in this work to accurately quantify the insulin present in the bloodstream. The proposed PIC estimation approach incorporates Hovorka's glucose-insulin model with the unscented Kalman filtering algorithm. Methods for the personalized initialization of the time-varying model parameters to individual patients for improved estimator convergence are developed. Data from 20 three-days-long closed-loop clinical experiments conducted involving subjects with T1DM are used to evaluate the proposed PIC estimation approach. The proposed methods are applied to the clinical data containing significant disturbances, such as unannounced meals and exercise, and the results demonstrate the accurate real-time estimation of the PIC with the root mean square error of 7.15 and 9.25 mU/L for the optimization-based fitted parameters and partial least squares regression-based testing parameters, respectively. The accurate real-time estimation of PIC will benefit the AP systems by preventing overdelivery of insulin when significant insulin is present in the bloodstream.

Characteristics Predictive for a Successful Switch from Insulin Analogue Therapy to Oral Hypoglycemic Agents in Patients with Type 2 Diabetes

PubMed Central

Kim, Gyuri; Lee, Yong-ho; Kang, Eun Seok; Cha, Bong-Soo; Lee, Hyun Chul

2016-01-01

Purpose The objective of this study was to investigate clinical and laboratory parameters that could predict which patients could maintain adequate glycemic control after switching from initial insulin therapy to oral hypoglycemic agents (OHAs) among patients with type 2 diabetes (T2D). Materials and Methods We recruited 275 patients with T2D who had been registered in 3 cohorts of initiated insulin therapy and followed up for 33 months. The participants were divided into 2 groups according to whether they switched from insulin to OHAs (Group I) or not (Group II), and Group I was further classified into 2 sub-groups: maintenance on OHAs (Group IA) or resumption of insulin (Group IB). Results Of 275 patients with insulin initiation, 63% switched to OHAs (Group I) and 37% continued insulin (Group II). Of these, 44% were in Group IA and 19% in Group IB. The lowest tertile of baseline postprandial C-peptide-to-glucose ratio (PCGR), higher insulin dose at switching to OHAs, and higher HbA1c level at 6 months after switching to OHAs were all associated with OHA failure (Group IB; p=0.001, 0.046, and 0.014, respectively). The lowest tertile of PCGR was associated with ultimate use of insulin (Group IB and Group II; p=0.029). Conclusion Higher baseline level of PCGR and lower HbA1c levels at 6 months after switching to OHAs may be strong predictors for the successful maintenance of OHAs after switching from insulin therapy in Korean patients with T2D. PMID:27593867

Longest delayed hemothorax reported after blunt chest injury.

PubMed

Yap, Darren; Ng, Miane; Chaudhury, Madhu; Mbakada, Nik

2018-01-01

Blunt chest injury is a common presentation to the emergency department. However, a delayed hemothorax after blunt trauma is rare; current literature reports a delay of up to 30days. We present a case of 44-day delay in hemothorax which has not been previously reported in current literature. A 52-year-old Caucasian male first presented to the emergency department complaining of persistent right sided chest pain 2weeks after having slipped on a wet surface at home. His initial chest X-ray showed fractures of the right 7th and 8th ribs without a hemothorax or pneumothorax. He returned 30days after the initial consultation (44days post-trauma) having increasing shortness of breath. A chest X-ray this time revealed a large right hemothorax and 1850ml of blood drained from his chest. There was a complete resolution of the hemothorax within 48h and the patient was discharged after a 6-week follow-up with the chest physicians. Delayed hemothorax after blunt trauma is a rare clinical occurrence but associated with significant morbidity and mortality. The management of delayed hemothorax includes draining the hemothorax and controlling the bleeding. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be vigilant and weary that hemothorax could be a possibility after a chest injury despite a delay in presentation. A knowledge of delayed hemothorax will prompt physicians in providing important advice, warning signs and information to patients after a chest injury to avoid a delay in seeking medical attention. Copyright © 2017 Elsevier Inc. All rights reserved.

Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant

PubMed Central

Piston, David W.

2015-01-01

Traditional therapies for type 1 diabetes (T1D) involve insulin replacement or islet/pancreas transplantation and have numerous limitations. Our previous work demonstrated the ability of embryonic brown adipose tissue (BAT) transplants to establish normoglycemia without insulin in chemically induced models of insulin-deficient diabetes. The current study sought to extend the technique to an autoimmune-mediated T1D model and document the underlying mechanisms. In nonobese diabetic (NOD) mice, BAT transplants result in complete reversal of T1D associated with rapid and long-lasting euglycemia. In addition, BAT transplants placed prior to the onset of diabetes on NOD mice can prevent or significantly delay the onset of diabetes. As with streptozotocin (STZ)-diabetic models, euglycemia is independent of insulin and strongly correlates with decrease of inflammation and increase of adipokines. Plasma insulin-like growth factor-I (IGF-I) is the first hormone to increase following BAT transplants. Adipose tissue of transplant recipients consistently express IGF-I compared with little or no expression in controls, and plasma IGF-I levels show a direct negative correlation with glucose, glucagon, and inflammatory cytokines. Adipogenic and anti-inflammatory properties of IGF-I may stimulate regeneration of new healthy white adipose tissue, which in turn secretes hypoglycemic adipokines that substitute for insulin. IGF-I can also directly decrease blood glucose through activating insulin receptor. These data demonstrate the potential for insulin-independent reversal of autoimmune-induced T1D with BAT transplants and implicate IGF-I as a likely mediator in the resulting equilibrium. PMID:25898954

The design and development of a computer game on insulin injection.

PubMed

Ebrahimpour, Fatemeh; Najafi, Mostafa; Sadeghi, Narges

2014-01-01

Insulin therapy is of high importance in glycemic control and prevention of complications in type 1 diabetes in children. However, this treatment is unpleasant and stressful for many children, and it is difficult for them to accept. The purpose of the study was to design and develop an educational computer game for diabetic children to familiarize them with insulin injections. After a review of the literature and the collection of basic information, we discussed the purpose of this research with some diabetic children, their parents, and nurses. The findings that we acquired from the discussion were considered in designing and developing the game. Then, following the principles associated with the development of computer games, we developed seven different games that related to insulin injections, and the games were evaluated in a pilot study. The games developed through the design and programming environment of Adobe Flash Player and stored on a computer disk (CD). The seven games were a pairs game, a puzzle game, a question and answer game, an insulin kit game, a drawing room game, a story game, and an insulin injection-room game). The idea was that diabetic children could become acquainted with insulin injections and the injection toolkit by playing a variety of entertaining and fun games. They also learned about some of the issues associated with insulin and experienced insulin injection in a simulated environment. It seems that the use of new technologies, such as computer games, can influence diabetic children's acquaintance with the correct method of insulin injection, psychological readiness to initiate insulin therapy, reduction in stress, anxiety, and fear of insulin injection.

The Design and Development of a Computer Game on Insulin Injection

PubMed Central

Ebrahimpour, Fatemeh; Najafi, Mostafa; Sadeghi, Narges

2014-01-01

Background: Insulin therapy is of high importance in glycemic control and prevention of complications in type 1 diabetes in children. However, this treatment is unpleasant and stressful for many children, and it is difficult for them to accept. The purpose of the study was to design and develop an educational computer game for diabetic children to familiarize them with insulin injections. Methods: After a review of the literature and the collection of basic information, we discussed the purpose of this research with some diabetic children, their parents, and nurses. The findings that we acquired from the discussion were considered in designing and developing the game. Then, following the principles associated with the development of computer games, we developed seven different games that related to insulin injections, and the games were evaluated in a pilot study. Results: The games developed through the design and programming environment of Adobe Flash Player and stored on a computer disk (CD). The seven games were a pairs game, a puzzle game, a question and answer game, an insulin kit game, a drawing room game, a story game, and an insulin injection-room game). The idea was that diabetic children could become acquainted with insulin injections and the injection toolkit by playing a variety of entertaining and fun games. They also learned about some of the issues associated with insulin and experienced insulin injection in a simulated environment. Conclusions: It seems that the use of new technologies, such as computer games, can influence diabetic children’s acquaintance with the correct method of insulin injection, psychological readiness to initiate insulin therapy, reduction in stress, anxiety, and fear of insulin injection. PMID:25763157

Symplocos cochinchinensis enhances insulin sensitivity via the down regulation of lipogenesis and insulin resistance in high energy diet rat model.

PubMed

Antu, Kalathookunnel Antony; Riya, Mariam Philip; Nair, Anupama; Mishra, Arvind; Srivastava, Arvind K; Raghu, Kozhiparambil Gopalan

2016-12-04

This plant has been utilized in Indian system of medicine for treatment of diabetes. This is clearly evident from the composition of Ayurvedic preparation for diabetes 'Nisakathakadi Kashayam' where this is one of the main ingredients of this preparation AIM OF THE STUDY: The study aims in elucidating the molecular mechanisms underlying the insulin sensitizing effects of Symplocos cochinchinensis ethanol extract (SCE) using a high fructose and saturated fat (HFS) fed insulin resistant rat model. Experimental groups consisted of normal diet (ND), ND+SCE 500mg/kg bwd, HFS+vehicle, HFS+metformin 100mg/kg bwd, HFS+SCE 250/500mg/kg bwd. Initially the animals were kept under HFS diet for 8 weeks, and at the end of 8 week period, animals were found to develop insulin resistance and dyslipidemia. Post-administration of SCE, metformin or vehicle were carried out for 3 weeks. Gene and protein expressions relevant to insulin signalling pathway were analysed. HFS significantly altered the normal physiology of animals via proteins and genes relevant to metabolism like stearoyl-CoA desaturase (SCD1), sterol regulatory element binding protein 1 (SREBP-1c), fatty acid synthase (FAS), glucose 6 phosphatase (G6Pase), phosphoenol pyruvate carboxykinase (PEPCK), glucose transporter 2 (GLUT2), protein tyrosine phosphatse 1B (PTP1B), peroxisome proliferator activated receptor alpha (PPAR alpha), sirtuin 1 (SIRT1) and glucokinase. SCE administration attenuates the insulin resistance in HFS rat by the down regulation of SCD1 gene expression that modulates SREBP-1c dependent and independent hepatic lipid accumulation. SCE enhances insulin sensitivity via the down regulation of lipogenesis and insulin resistance in HFS rat model. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cross-reactivity of insulin analogues with three insulin assays.

PubMed

Dayaldasani, A; Rodríguez Espinosa, M; Ocón Sánchez, P; Pérez Valero, V

2015-05-01

Immunometric assays have recently shown higher specificity in the detection of human insulin than radioimmunoassays with almost no cross-reaction with proinsulin or C peptide. The introduction of the new insulin analogues on the market, however, has raised the need to define their cross-reactivity in these assays. Several studies have been published in this regard with different results. The analogues studied were insulins lispro, aspart, glargine, detemir, and glulisine. Insulin concentrations were measured in Immulite(®) 2000 and Advia Centaur(®) XP (Siemens Healthcare Diagnostics), and Elecsys(®) Modular Analytics E170 (Roche). All samples were processed 15 times in the same analytical run following a random sequence. Those samples which showed statistically and clinically significant changes in insulin concentration were reprocessed using increasing concentrations of analogue, and this was done twice, using two different serum pools, one with a low concentration of insulin and one with a high concentration of insulin. In the Elecsys(®) E170 analyser, glargine showed statistical changes (comparison of mean concentrations with p < 0.05) and clinically significant changes in measured insulin (percentage difference 986.2% > reference change value: 59.8%), and the interference increased with increasing concentrations of analogue; the differences were not significant in the case of the other analogues. In the Advia Centaur(®) and Immulite(®) 2000 only the results for glulisine did not present significance (percentage difference 44.7% < reference change value 103.5%). Increasing concentrations of aspart, glargine, and lispro showed increased interference in Immulite(®) 2000. In the Elecsys(®) E170 assay, relevant cross-reactivity was only detected with insulin glargine, whereas in the other analysers all analogues except glulisine showed significant interference. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Pathogenesis of NOD Diabetes is Initiated by Reactivity to the Insulin B Chain 9–23 Epitope and Involves Functional Epitope Spreading1

PubMed Central

Prasad, Suchitra; Kohm, Adam P.; McMahon, Jeffrey S.; Luo, Xunrong; Miller, Stephen D.

2012-01-01

Type 1 diabetes (T1D) is mediated by destruction of pancreatic β cells by CD4 and CD8 T cells specific for epitopes on numerous diabetogenic autoantigens resulting in loss of glucose homeostasis. Employing antigen-specific tolerance induced by i.v. administration of syngeneic splenocytes ECDI cross-linked to various diabetogenic antigens/epitopes (Ag-SP), we show that epitope spreading plays a functional role in the pathogenesis of T1D in NOD mice. Specifically, Ag-SP coupled with intact insulin, Ins B9–23 or Ins B15–23, but not GAD65509–528, GAD65524–543 or IGRP206–214, protected 4–6 week-old NOD mice from the eventual development of clinical disease; infiltration of immune cells to the pancreatic islets; and blocked the induction of DTH responses in a Treg-dependent, antigen-specific manner. However, tolerance induction in 19–21 week-old NOD mice was effectively accomplished only by Ins-SP, suggesting Ins B9–23 is a dominant initiating epitope, but autoimmune responses to insulin epitope(s) distinct from Ins B9–23 emerge during disease progression. PMID:22647732

Evidence for the lack of spare high-affinity insulin receptors in skeletal muscle.

PubMed Central

Camps, M; Gumà, A; Viñals, F; Testar, X; Palacín, M; Zorzano, A

1992-01-01

In this study, the relationship between the concentration of extracellular insulin, insulin binding and insulin action was evaluated in skeletal muscle. Initially we investigated the dose-response relationship of insulin action using three different experimental models that are responsive to insulin, i.e. the isolated perfused rat hindquarter, incubated strips of soleus muscle, and insulin receptors partially affinity-purified from skeletal muscle. We selected as insulin-sensitive parameters glucose uptake in the perfused hindquarter, lactate production in the incubated muscle preparation, and tyrosine receptor kinase activity in the purified receptor preparation. Our results showed that the dose-response curves obtained in the perfused hindquarter and in the incubated muscle were superimposable. In contrast, the dose-response curve for insulin-stimulated receptor tyrosine kinase activity in partially purified receptors was displaced to the left compared with the curves obtained in the perfused hindquarter and in the incubated muscle. The differences between the dose-response curve for receptor tyrosine kinase and those for glucose uptake and lactate production were not explained by a substantial insulin concentration gradient between medium and interstitial space. Thus the medium/interstitial insulin concentration ratio, when assayed in the incubated intact muscle at 5 degrees C, was close to 1. We also compared the dose-response curve of insulin-stimulated receptor tyrosine kinase with the pattern of insulin-binding-site occupancy. The curve of insulin-stimulated receptor kinase activity fitted closely with the occupancy of high-affinity binding sites. In summary, assuming that the estimation of the medium/interstitial insulin concentration ratio obtained at 5 degrees C reflects the actual ratio under more physiological conditions, our results suggest that maximal insulin action is obtained in skeletal muscle at insulin concentrations which do allow full

Evidence for the lack of spare high-affinity insulin receptors in skeletal muscle.

PubMed

Camps, M; Gumà, A; Viñals, F; Testar, X; Palacín, M; Zorzano, A

1992-08-01

In this study, the relationship between the concentration of extracellular insulin, insulin binding and insulin action was evaluated in skeletal muscle. Initially we investigated the dose-response relationship of insulin action using three different experimental models that are responsive to insulin, i.e. the isolated perfused rat hindquarter, incubated strips of soleus muscle, and insulin receptors partially affinity-purified from skeletal muscle. We selected as insulin-sensitive parameters glucose uptake in the perfused hindquarter, lactate production in the incubated muscle preparation, and tyrosine receptor kinase activity in the purified receptor preparation. Our results showed that the dose-response curves obtained in the perfused hindquarter and in the incubated muscle were superimposable. In contrast, the dose-response curve for insulin-stimulated receptor tyrosine kinase activity in partially purified receptors was displaced to the left compared with the curves obtained in the perfused hindquarter and in the incubated muscle. The differences between the dose-response curve for receptor tyrosine kinase and those for glucose uptake and lactate production were not explained by a substantial insulin concentration gradient between medium and interstitial space. Thus the medium/interstitial insulin concentration ratio, when assayed in the incubated intact muscle at 5 degrees C, was close to 1. We also compared the dose-response curve of insulin-stimulated receptor tyrosine kinase with the pattern of insulin-binding-site occupancy. The curve of insulin-stimulated receptor kinase activity fitted closely with the occupancy of high-affinity binding sites. In summary, assuming that the estimation of the medium/interstitial insulin concentration ratio obtained at 5 degrees C reflects the actual ratio under more physiological conditions, our results suggest that maximal insulin action is obtained in skeletal muscle at insulin concentrations which do allow full

Molecular Mechanisms of Insulin Secretion and Insulin Action.

ERIC Educational Resources Information Center

Flatt, Peter R.; Bailey, Clifford J.

1991-01-01

Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection

NASA Astrophysics Data System (ADS)

Park, Eun-Joo; Dodds, Jeff; Barrie Smith, Nadine

2010-03-01

Prior studies have demonstrated the effectiveness of noninvasive transdermal insulin delivery using a cymbal transducer array. In this study the physiologic response to ultrasound mediated transdermal insulin delivery is compared to that of subcutaneously administered insulin. Anesthetized rats (350-550 g) were divided into four groups of four animals; one group representing ultrasound mediated insulin delivery and three representing subcutaneously administered insulin (0.15, 0.20, and 0.25 U/kg). The cymbal array was operated for 60 minutes at 20 kHz with 100 mW/cm2 spatial-peak temporal-peak intensity and a 20% duty cycle. The blood glucose level was determined at the beginning of the experiment and, following insulin administration, every 15 minutes for 90 minutes for both the ultrasound and injection groups. The change in blood glucose from baseline was compared between groups. When administered by subcutaneous injection at insulin doses of 0.15 and 0.20 U/kg, there was little change in the blood glucose levels over the 90 minute experiment. Following subcutaneous administration of insulin at a dose of 0.25 U/kg, blood glucose decreased by 190±96 mg/dl (mean±SD) at 90 minutes. The change in blood glucose following ultrasound mediated insulin delivery was -262±40 mg/dl at 90 minutes. As expected, the magnitude of change in blood glucose between the three injection groups was dependant on the dose of insulin administered. The change in blood glucose in the ultrasound group was greater than that observed in the injection groups suggesting that a higher effective dose of insulin was delivered.

Importance of hepatitis C virus-associated insulin resistance: Therapeutic strategies for insulin sensitization

PubMed Central

Kawaguchi, Takumi; Sata, Michio

2010-01-01

Insulin resistance is one of the pathological features in patients with hepatitis C virus (HCV) infection. Generally, persistence of insulin resistance leads to an increase in the risk of life-threatening complications such as cardiovascular diseases. However, these complications are not major causes of death in patients with HCV-associated insulin resistance. Indeed, insulin resistance plays a crucial role in the development of various complications and events associated with HCV infection. Mounting evidence indicates that HCV-associated insulin resistance may cause (1) hepatic steatosis; (2) resistance to anti-viral treatment; (3) hepatic fibrosis and esophageal varices; (4) hepatocarcinogenesis and proliferation of hepatocellular carcinoma; and (5) extrahepatic manifestations. Thus, HCV-associated insulin resistance is a therapeutic target at any stage of HCV infection. Although the risk of insulin resistance in HCV-infected patients has been documented, therapeutic guidelines for preventing the distinctive complications of HCV-associated insulin resistance have not yet been established. In addition, mechanisms for the development of HCV-associated insulin resistance differ from lifestyle-associated insulin resistance. In order to ameliorate HCV-associated insulin resistance and its complications, the efficacy of the following interventions is discussed: a late evening snack, coffee consumption, dietary iron restriction, phlebotomy, and zinc supplements. Little is known regarding the effect of anti-diabetic agents on HCV infection, however, a possible association between use of exogenous insulin or a sulfonylurea agent and the development of HCC has recently been reported. On the other hand, insulin-sensitizing agents are reported to improve sustained virologic response rates. In this review, we summarize distinctive complications of, and therapeutic strategies for, HCV-associated insulin resistance. Furthermore, we discuss supplementation with branched

Pancreatic β-Cell Electrical Activity and Insulin Secretion: of Mice and Men

PubMed Central

Rorsman, Patrik; Ashcroft, Frances M

2018-01-01

The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration. Impaired insulin secretion results in the chronic hyperglycaemia that characterizes type 2 diabetes (T2DM), which currently afflicts >450 million people worldwide. The healthy β-cell acts as a glucose sensor matching its output to the circulating glucose concentration. It does so via metabolically induced changes in electrical activity, which culminate in an increase in the cytoplasmic Ca2+ concentration and initiation of Ca2+-dependent exocytosis of insulin-containing secretory granules. Here, we review recent advances in our understanding of the β-cell transcriptome, electrical activity and insulin exocytosis. We highlight salient differences between mouse and human β-cells, provide models of how the different ion channels contribute to their electrical activity and insulin secretion, and conclude by discussing how these processes become perturbed in T2DM. PMID:29212789

Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients.

PubMed

Hu, Xiaolei; Chen, Fengling

2018-01-01

Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs). IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS). The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS. © 2018 The authors.

Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients