Residual Insulin Secretion Research Articles

Efficacy and safety of alogliptin in a pediatric patient with maturity-onset diabetes of the young type 1.

.The first-line pharmacological treatment for patients with maturity-onset diabetes of the young type 1 (MODY1) and maturity-onset diabetes of the young type 3 (MODY3) are sulfonylureas (SUs) or insulin. However, several reports have suggested the possibility of using incretin-associated drugs, including dipeptidyl-peptidase-4 (DPP-4) inhibitors, for the treatment of patients with these types of MODY. Here we report a case of a pediatric patient with MODY1 who was successfully treated with a DPP-4 inhibitor, alogliptin. A 13-yr-old Japanese girl with diabetes was initially treated with insulin for 5 mo. After diagnosis of MODY1, confirmed via a genetic analysis, treatment was changed from insulin to alogliptin. SUs were prescribed temporarily, but monotherapy with alogliptin finally resulted in good glycemic control. After changing to alogliptin, the patient maintained optimal glycemic control with glycated hemoglobin levels of 6.3–7.0% while maintaining substantial β-cell function. No adverse events associated with alogliptin were observed. These results suggest that DPP-4 inhibitors may be a potential treatment for patients with MODY1 at the early stage of the disease when residual insulin secretion is still being sustained.

Clinical outcomes in youth beyond the first year of type 1 diabetes: Results of the Pediatric Diabetes Consortium (PDC) type 1 diabetes new onset (NeOn) study.

Current data are limited on the course of type 1 diabetes (T1D) in children and adolescents through the first few years of diabetes. The Pediatric Diabetes Consortium T1D new onset (NeOn) Study was undertaken to prospectively assess natural history and clinical outcomes in children treated at 7 US diabetes centers from the time of diagnosis. This paper describes clinical outcomes in the T1D NeOn cohort during the first 3 years postdiagnosis. A total of 1048 participants (mean age 9.2 years, 49% female, 65% non-Hispanic White) were enrolled between July 2009 and April 2011. Mean glycated hemoglobin (HbA1c) (±SD) was 7.2% (55 mmol/mol) at 3 months, followed by a progressive rise to 8.4% (68 mmol/mol) at 36 months postdiagnosis, with only 30% of participants achieving target HbA1c<7.5% (58 mmol/mol). The percentage of participants in partial remission estimated by insulin dose adjusted HbA1c [HbA1c % + (4×insulin dose unit/kg/24 h)] ≤9 sharply declined from 23% at 12 months to 7% at 36 months. The percentage of participants developing diabetic ketoacidosis (DKA) was 1% in the first year after diagnosis, increasing to 6% in years 2 and 3. These results demonstrate the gradual decline in glycemic control due to waning residual endogenous insulin secretion with increasing duration of T1D in children and adolescents. These data indicate the need to translate recent advances in automated insulin delivery, new insulin analogs, and adjunctive pharmacologic agents into novel treatment strategies to maintain optimal glycemic control even early in the course of T1D.

Liraglutide add-on to insulin improved glycaemia but exhibited short durability after cessation in type 1 diabetes with residual insulin secretion

Liraglutide add-on to insulin improved glycaemia but exhibited short durability after cessation in type 1 diabetes with residual insulin secretion

The impact of oxidative stress on state of insulin secretion and insulin-binding activity of blood cells under diabetes mellitus and its complications in children

The study of condition of carbohydrate and lipid metabolism in 137 children and adolescents suffering of diabetes mellitus type I demonstrated progressing decrease of residual insulin secretion and insulin-binding activity of lymphocytes and erythrocytes against the background of metabolic disorders. This is the risk factor for severe course of disease with fast development of diabetic complications. The persistent disorder of carbohydrate and lipid metabolism, higher level of overoxidation of lipids with disorder of activity of enzymes of antioxidant defense and reliable decreasing of insulin-binding activity of blood cells testify presence of oxidative stress in children. The metabolic disorders, presence of residual insulin secretion and oxidative stress are to be taking into account for prevention of deterioration of condition of patient with progressing course of disease. These processes determine application of adequate dosages of insulin and necessity of application of effective remedies with antioxidant activity.

The clinical potential of low-level C-peptide secretion

ABSTRACTIntroduction: In all forms of diabetes, especially so in Type 1 diabetes (T1D), beta cell function is crucial for the course. The interest for residual beta cell function has been meagre, but increased in recent years with interventions to preserve function.Areas covered: Importance and clinical use of C-peptide in Type 1 diabetes. Data for this review were identified by searches of PubMed, and references from relevant articles using the search terms: “type 1 diabetes”, “C-peptide”, “beta cell function”, “HbA1c”, quality of life”, “complications”. s and reports from meetings were not included.Expert commentary: C-peptide may help to get a correct diagnosis, and it is of practical clinical value to know degree of residual insulin secretion to diminish the risk of severe hypoglycaemia and ketoacidosis. Evidence shows that even a quite reduced beta cell function may play an important role for quality of life, for metabolic balance/control, possibility to avoid complications and even for long-term survival. Furthermore, the evidence is increasing for C-peptide being a hormone per se.

Fall in C-Peptide During First 4 Years From Diagnosis of Type 1 Diabetes: Variable Relation to Age, HbA1c, and Insulin Dose.

OBJECTIVEWe aimed to describe the natural history of residual insulin secretion in Type 1 Diabetes TrialNet participants over 4 years from diagnosis and relate this to previously reported alternative clinical measures reflecting β-cell secretory function.RESEARCH DESIGN AND METHODSData from 407 subjects from 5 TrialNet intervention studies were analyzed. All subjects had baseline stimulated C-peptide values of ≥0.2 nmol/L from mixed-meal tolerance tests (MMTTs). During semiannual visits, C-peptide values from MMTTs, HbA1c, and insulin doses were obtained.RESULTSThe percentage of individuals with stimulated C-peptide of ≥0.2 nmol/L or detectable C-peptide of ≥0.017 nmol/L continued to diminish over 4 years; this was markedly influenced by age. At 4 years, only 5% maintained their baseline C-peptide secretion. The expected inverse relationships between C-peptide and HbA1c or insulin doses varied over time and with age. Combined clinical variables, such as insulin-dose adjusted HbA1c (IDAA1C) and the relationship of IDAA1C to C-peptide, also were influenced by age and time from diagnosis. Models using these clinical measures did not fully predict C-peptide responses. IDAA1C ≤9 underestimated the number of individuals with stimulated C-peptide ≥0.2 nmol/L, especially in children.CONCLUSIONSCurrent trials of disease-modifying therapy for type 1 diabetes should continue to use C-peptide as a primary end point of β-cell secretory function. Longer duration of follow-up is likely to provide stronger evidence of the effect of disease-modifying therapy on preservation of β-cell function.

The Mystery of Good Metabolic Control in Type 1 Diabetes – Evidence Based Lessons from a Pediatric Clinic

Too few patients with ‘Type 1 diabetes have enough good metabolic control to prevent complications. Residual insulin secretion is important, but also other physiological differences between patients contribute to the degree of blood glucose balance. Still, the treatment plays an important role and the way how the diabetes team work with the patient is absolutely crucial. It is proven that HbA1c can be influenced by intensity of treatment, and also that patients at certain clinics have lower HbA1c than at other clinics. Psychological approach and treatment policy explains some of this difference. Although it is difficult to study such factors in randomized, controlled double-blind studies, we have performed studies giving evidence of the importance of attitudes, goals, how the diabetes team works and what message it conveys. Thus some parts of treatment which could be called “art of medicine”, based on skill, experience, empathy and similar “soft” values should not be neglected.

Therapies to Preserve β-Cell Function in Type 1 Diabetes.

In spite of modern techniques, the burden for patients with type 1 diabetes mellitus will not disappear, and type 1 diabetes will remain a life-threatening disease causing severe complications and increased mortality. We have to learn of ways to stop the destructive process, preserve residual insulin secretion or even improve the disease via β-cell regeneration. This will give a milder disease, a more stable metabolism, simpler treatment and perhaps even cure. Therapies based on single drugs have not shown sufficient efficacy; however, there are several treatments with encouraging efficacy and no apparent, or rather mild, adverse events. As the disease process is heterogeneous, treatments have to be chosen to fit relevant subgroups of patients, and step by step efficacy can possibly be improved by the use of combination therapies. Thus immunosuppressive therapies like anti-CD3 and anti-CD20 monoclonal antibodies might be combined with fusion proteins such as etanercept [tumor necrosis factor (TNF)-α inhibitor] and/or abatacept (CTLA4-Ig) early after onset to stop the destructive process, supported by β-cell protective agents. The effect may be prolonged by using autoantigen therapy [glutamate decarboxylase (GAD) proinsulin], and by adding agents facilitating β-cell regeneration [e.g. glucagon-like peptide-1 (GLP-1)] there should be a good chance to make the disease milder, perhaps leading to cure in some patients.

How to transform a metabolic syndrome score into an insulin sensitivity value?

The metabolic syndrome (MetS) predicts cardiovascular risk and incident type 2 diabetes mellitus. The presence of a MetS is defined by the clustering of ≥3 out of 5 cardiometabolic criteria (hyperglycemia; hypertension; enlarged waist; low high-density lipoprotein-cholesterol; and hypertriglyceridemia), each of which is connected with insulin resistance. It is not known whether the severity of MetS, ranked from the sextet of scores range [0/5 to 5/5], is linearly related to reduced insulin sensitivity (IS) and/or lesser hyperbolic product across the glycemic spectrum. A total of 839 adults (54 normoglycemic; 785 with abnormal glucose homeostasis, among whom 711 type 2 diabetes mellitus) had insulin sensitivity assessed together with their cardiometabolic phenotype. There was a significant gradient according to interval-scale MetS score in insulinemia; body mass index; (visceral) fat; hepatic steatosis; and macroangiopathy. There was an inverse linear relationship between increasing MetS scores and decreased insulin sensitivity, allowing to define an insulin resistance-predicting linear equation: IS (%) = [-15.1 × MetS score] + 109.4 (R(2) = 0.221). For each MetS category, mean IS values did not significantly differ between groups of patients across the glycemic spectrum. The hyperbolic product (β-cell function × IS) and/or its loss rate were inversely related to MetS severity. Insulin sensitivity is linearly and inversely related to MetS severity across the 6 scores. This novel way to exploit information intrinsic to the MetS criteria provides an easy and low cost means to quantify insulin sensitivity across the glycemic spectrum. Moreover, a higher MetS score is associated with lesser residual insulin secretion, and faster B-cell function loss. Copyright © 2015 John Wiley & Sons, Ltd.

Evidence for Residual and Partly Reparable Insulin Secretory Function and Maintained β-Cell Gene Expression in Islets From Patients With Type 1 Diabetes.

It is commonly accepted that type 1 diabetes (T1D) is an autoimmune and inflammatory disease that results from the wholesale yet surprisingly selective killing of the insulin-secreting β-cells of pancreatic islets (1–4). While the relative importance of reduced β-cell function versus reduced β-cell mass is currently debated in type 2 diabetes (5), T1D has been considered the classic example where diabetes results from reduced β-cell mass secondary to autoimmune attack (1,3,4,6). However, this view has recently been challenged (2,6–9). In this issue of Diabetes , Krogvold et al. (10) compare residual glucose-dependent insulin secretion and whole-genome RNA sequencing of islet tissue from donors with and without diabetes. Islets were obtained from adult T1D subjects soon after the onset of the disease. Recent studies have shown that residual plasma C-peptide levels are present long after the onset of diabetes in patients with T1D (1,6,11–14). However, it is unknown whether this low level of insulin production represents secretion from β-cells that have somehow survived autoimmune attack, perhaps because the autoimmune process was halted or because not all of the β-cells were equivalently affected, or whether they represent a newly regenerated β-cell subpopulation (2). A third possibility is that the surviving β-cells, being in the minority, may simply represent the tail end of the normal distribution of islets originally residing in the pancreas (15). Finding residual C-peptide secretion is …

Remission in Type 1 Diabetes - What's New?

Type 1 diabetes is an autoimmune disease, in which there is a destruction of pancreatic islets βcells. In the natural course of the disease we deal with a gradual progress during the few years of reduction of cell mass. The symptoms of diabetes appear when the mass of insulin-secreting β cells will be reduced by about 80-90%. In this state, the amount of insulin is insufficient to ensure normoglycemia. Many patients shortly after diagnosis of diabetes type 1 and initiation of insulin therapy come to partial cell β renewal and consequently to reduce the need for exogenous insulin. This phenomenon is called the remission of the disease. This period is also called honeymoon. The glucose concentration decreases so the insulin dose should be also reduced, however complete cessation of insulin is not recommended. Accuracy to determine and compare the prevalence of type 1 diabetes remission is difficult because of ambiguous criteria for its diagnosis: most remission criteria take into account the following parameters:glycated hemoglobin (HbA1c), daily need for exogenous insulin, and the concentration C-peptide in the blood. In all definitions of remission, although different criteria are used, residual insulin secretion is underlined, as well as demonstrated measurement of C-peptide and low demand on exogenous insulin.

Prevalence of detectable C-Peptide according to age at diagnosis and duration of type 1 diabetes.

It is generally accepted that complete β-cell destruction eventually occurs in individuals with type 1 diabetes, which has implications for treatment approaches and insurance coverage. The frequency of residual insulin secretion in a large cohort of individuals at varying ages of diagnosis and type 1 diabetes duration is unknown. The frequency of residual insulin secretion was determined by measurement of nonfasting serum C-peptide concentration in 919 individuals with type 1 diabetes according to prespecified groups based on age at diagnosis and duration of disease (from 3 to 81 years' duration). Stimulated C-peptide was measured in those with detectable nonfasting values and a group of those with undetectable values as control. The overall frequency of detectable nonfasting C-peptide was 29%, decreasing with time from diagnosis regardless of age at diagnosis. In all duration groups, the frequency of C-peptide was higher with diagnosis age >18 years compared with ≤18 years. Nineteen percent of those with undetectable nonfasting C-peptide were C-peptide positive upon stimulation testing. The American Diabetes Association's definition of type 1 diabetes as "usually leading to absolute insulin deficiency" results in clinicians often considering the presence of residual insulin secretion as unexpected in this population. However, our data suggest that residual secretion is present in almost one out of three individuals 3 or more years from type 1 diabetes diagnosis. The frequency of residual C-peptide decreases with time from diagnosis regardless of age at diagnosis, yet at all durations of disease, diagnosis during adulthood is associated with greater frequency and higher values of C-peptide.

Association of fasting insulin and C peptide with diabetic retinopathy in Latinos with type 2 diabetes

ObjectiveResidual insulin secretion provides important protection against the development of diabetic retinopathy in type 1 diabetes. The data to support this in type 2 diabetes are unclear. We therefore tested...

GAD‐treatment of children and adolescents with recent‐onset type 1 diabetes preserves residual insulin secretion after 30 months

This study aimed to analyse data from two different studies (phase II and phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum) at 30 months after administration to children and adolescents with type 1 diabetes. The phase II trial was a double-blind, randomised placebo-controlled study, including 70 children and adolescents who were followed for 30 months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and 1 month later. During a subsequent larger European phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9 months. The phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up, and 45 patients completed the trial at 30 months. Both studies included GAD65 auto-antibodies-positive patients with fasting C-peptide ≥ 0.10 nmol/l. We have now combined the results of these two trials. There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide area under the curve had decreased significantly less (9 m: p < 0.037; 15 m: p < 0.032; 21 m: p < 0.003 and 30 m: p < 0.004), and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide > 0.2 nmol/L (p < 0.05), as compared with placebo. Treatment with two doses of GAD-alum in children and adolescents with recent-onset type 1 diabetes shows no adverse events and preserves residual insulin secretion.

Residual C-peptide in type 1 diabetes: what do we really know?

Connecting peptide, or C-peptide, is a protein that joins insulin's α and B chains in the proinsulin molecule. During insulin synthesis, C-peptide is cleaved from proinsulin and secreted in an equimolar concentration to insulin from the β cells. Because C-peptide experiences little first-pass clearance by the liver, and because levels are not affected by exogenous insulin administration, it may be used as a marker of endogenous insulin production and a reflection of β-cell function. Residual β-cell function, as measured by C-peptide in those with type 1 diabetes (T1D), has repeatedly been demonstrated to be clinically important. The Eisenbarth model of type 1 diabetes postulated immune-mediated linear loss of β cells, with clinical diagnosis occurring when there was insufficient insulin secretion to meet glycemic demand. Moreover, the model also implied that all individuals with T1D rapidly and inevitably progressed to absolute insulin deficiency. Correspondingly, it was assumed that most people with longstanding T1D would show little to no residual C-peptide secretion. While more than a quarter century of data confirms that this model remains largely true and appropriately serves as the basis for prevention studies, accumulating evidence suggests that the natural history of β-cell function before, during and after diagnosis is more complex. In this review, we discuss the clinical benefits of residual insulin secretion and present recent data about the natural history of insulin secretion in those with, or at risk for T1D.

Clinical factors associated with absolute and relative measures of glycemic variability determined by continuous glucose monitoring: An analysis of 480 subjects

AimFactors associated with absolute and relative measures of glycemic variability have not been determined by continuous glucose monitoring (CGM) and concurrent measurement of fasting C-peptide levels. MethodsWe analyzed CGM data for subjects with type 1 diabetes (T1D; n=81) and type 2 diabetes (T2D; insulin-treated, n=168; not insulin-treated, n=231) who underwent CGM between October 2009 and September 2011 at Samsung Medical Center. Correlations between clinical factors and both standard deviation (SD) and coefficient of variance (CV) in CGM were analyzed by multiple regression. ResultsRegardless of the type of diabetes and insulin therapy, higher CV, but not SD, was significantly associated with a minimum glucose level of <70mg/dL (3.9mmol/l) in CGM (p<0.001). In T1D, fasting C-peptide levels inversely correlated with SD while BMI inversely correlated with CV, and duration of diabetes, and HDL levels positively correlated with CV. Use of pre-mixed insulin increased both SD and CV. In insulin-treated T2D, fasting C-peptide levels inversely correlated with both SD and CV while HbA1c correlated with SD, and duration of diabetes positively correlated with CV. In T2D without insulin therapy, age, BMI, HbA1c, HDL, triglyceride levels and use of sulfonylurea positively correlated with SD while HDL levels and use of sulfonylurea positively correlated with CV, and LDL levels inversely correlated with CV. ConclusionsRelative glycemic variability (CV) was determined by factors different from those that affect absolute glycemic variability (SD). Some of these factors were indicators of higher insulin sensitivity and residual insulin secretion.

Immune Intervention for Type 1 Diabetes, 2012–2013

Immune Intervention for Type 1 Diabetes, 2012–2013

Following the Fate of the Failing β-Cell: New Insights From First-Phase Insulin Responses

The benefits of residual endogenous insulin secretion in improving metabolic control and reducing complications in patients with type 1 diabetes (T1D) (1) have highlighted the need for early intervention to preserve β-cell mass. However, the time course of β-cell destruction in T1D is still poorly understood (2). Islet autoantibodies indicative of ongoing autoimmunity often appear in early infancy and may be present for many years before diabetes develops (3). Thus, autoantibodies are very useful for identifying individuals at high risk of progression but do not provide precise estimates of time to diabetes onset. Current tests of T-cell activity are poor guides to the rate of progression. Imaging methods for tracking β-cell loss are in development, but are unlikely to be available for several years (4). Metabolic testing is therefore the best approach for monitoring the decline in β-cell capacity (5,6) (Fig. 1). FIG. 1. Schematic showing potentially informative tests for tracking the loss of β-cell mass and function. Deterioration of FPIR in the IVGTT and of OGTT responses are currently the best indicators of impending diabetes. Imaging methods for monitoring β-cell mass are still in development. Little is known about the pattern of insulitis and decline in β-cell mass in humans during the prediabetic prodrome. PI/C-peptide, proinsulin-to-C-peptide ratio; Teff, effector T cells. Several tests have been used to assess β-cell function. These vary in complexity and differ in what …

Cellular and Humoral Immune Responses in Type 1 Diabetic Patients Participating in a Phase III GAD-alum Intervention Trial

OBJECTIVEGAD formulated in aluminum hydroxide (GAD-alum) has previously been shown to induce preservation of residual insulin secretion in recent-onset type 1 diabetes, but recent phase II and III GAD-alum trials failed to reach primary outcomes. The European phase III study was therefore closed after 15 months, and only a minority of patients completed the 30 months of follow-up.RESEARCH DESIGN AND METHODSThis study aimed to characterize cellular and humoral responses in the Swedish patients (n = 148) participating in the phase III trial, receiving four (4D) or two (2D) GAD-alum doses or placebo. Serum GAD65 antibody (GADA) levels, GADA IgG1–4 subclass distribution, cytokine secretion, and proliferative responses in peripheral blood mononuclear cells (PBMCs) were analyzed.RESULTSThe GAD65-induced cytokine profile tended to switch toward a predominant Th2-associated profile over time both in the 2D and 4D group. The groups also displayed increased GADA levels and PBMC proliferation compared with placebo, whereas GADA IgG subclass distribution changed in 4D patients.CONCLUSIONSBoth 2D and 4D patients displayed GAD65-specifc cellular and humoral effects after GAD-alum treatment, but at different time points and magnitudes. No specific immune markers could be associated with treatment efficacy.

Persistent C-peptide

The assumption that patients with an extended duration of type 1 diabetes mellitus (T1D) do not retain residual functional β cells and endogenous insulin production has recently been challenged. The purpose to this review is to highlight some of the key emerging evidence supporting residual insulin and C-peptide secretion in long-standing T1D. Recent investigations conducted in a group of type 1 diabetics of long-term duration, characterized clinically and histologically, provided solid evidence to suggest that pancreatic β cells are still present even after 50 years in a majority of these individuals. These residual β cells can secrete insulin in a physiologically regulated manner. Several published reports showed promising effects of glucagon-like peptide 1 (GLP-1) agonists on the glycemic control and residual C-peptide production in long-term T1D, although prospective studies are needed to rule out the potential long-term adverse effects of these drugs. C-peptide is no longer considered an irrelevant by-product of insulin biosynthesis. In-depth basic and translational investigations aimed at understanding the molecular immunology and the pathophysiology are needed to elucidate the mechanisms underlying the residual insulin and C-peptide production in long-term T1D. This may shed light on to the regenerative capacity of β cells, the genetic susceptibility of the mechanisms of resistance to β-cell destruction, and possibly identifying new therapeutic strategies for T1D. Studies evaluating the long-term effects of insulin secretogogue agents along with immune intervention hold promise for their use in future clinical trials for long-term T1D.