The Kinetics of Insulin Release

Grodsky, Gerold M.

doi:10.1007/978-3-642-66002-3_1

Cited by 10 publications

(9 citation statements)

References 80 publications

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“…It is possible that the different storage compartments within the b-cell are differently affected by the progression of diabetes and possibly by the interventional treatment (10,17).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Long-Term Treatment Effect in a Type 1 Diabetes Intervention Trial: Differences After Stimulation With Glucagon or a Mixed Meal

Pozzilli

Peled²,

Elias³

et al. 2014

Diabetes Care

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OBJECTIVEEndogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes. RESEARCH DESIGN AND METHODSA recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST-and MMTT-derived C-peptide AUC. Pearson's correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (ΔAUC). RESULTSThe absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74-0.9). However, the correlations between the ΔAUC were much weaker (r = 0.39-0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4-11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose. CONCLUSIONSMeasurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.

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“…It is possible that the different storage compartments within the b-cell are differently affected by the progression of diabetes and possibly by the interventional treatment (10,17).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Long-Term Treatment Effect in a Type 1 Diabetes Intervention Trial: Differences After Stimulation With Glucagon or a Mixed Meal

Pozzilli

Peled²,

Elias³

et al. 2014

Diabetes Care

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“…A detailed review of insulin secretory processes is beyond the scope of this article and is reported elsewhere [4,7].…”

Section: Physiology Of Normal Insulin Secretionmentioning

confidence: 99%

“…Exposure of isolated pancreatic beta cells to glucose results in a phasic pattern of insulin secretion [7]. The initial response to glucose is characterized by a rapid increase in insulin secretion followed by a decline to near basal rates.…”

Section: Physiology Of Normal Insulin Secretionmentioning

confidence: 99%

The role of impaired early insulin secretion in the pathogenesis of Type II diabetes mellitus

2001

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Normal glucose tolerance is maintained by a precise balance between insulin secretion from pancreatic beta cells and insulin action on sensitive tissues, principally muscle, adipose tissue and liver [1,2]. Patients with Type II (non-insulin-dependent) diabetes mellitus manifest impairments in insulin secretion and insulin action and an increased rate of endogenous glucose production [1±3]. The relative importance of these abnormalities in the pathogenesis of the disease has been debated for many years. It is now generally accepted that abnormalities in insulin secretion and insulin action contribute to the development of Type II diabetes, whereas the increase in endogenous glucose production is a later phenomenon. Insulin secretory dysfunction in Type II diabetes is both quantitative and qualitative [3±4]. In addition to a relative impairment in the amount of insulin released, the pattern of insulin secretion is abnormal. In this review, we focus on the critical role of impaired early insulin secretion in the pathogenesis of Type II diabetes.Current understanding of the pathophysiology of Type II diabetes is based on the contributions of many laboratories working with different populations around the world. Since 1982, the National Institutes of Health has conducted a longitudinal study of the metabolic predictors of Type II diabetes in the Pima Indians of Arizona [5], a population uniquely suited for such studies because of their extraordinarily high Diabetologia (2001) AbstractPatients with Type II (non-insulin-dependent) diabetes mellitus manifest abnormalities in insulin action and insulin secretion. It is widely accepted that insulin resistance is an early finding, evident before the onset of hyperglycaemia and predictive of the subsequent development of diabetes. Whether abnormalities in insulin secretion also precede and predict diabetes has been debated. However, recent studies clearly indicate that early insulin secretion plays a critical role in maintaining normal glucose homeostasis. Crosssectional analyses show that acute insulin secretory responses (AIR) to intravenous glucose are lower in subjects with impaired glucose tolerance and those at high risk for developing diabetes. Prospectively, a low AIR predicts the development of diabetes in several populations. In longitudinal studies, AIR declines dramatically as patients progress from normal to impaired glucose tolerance and ultimately to diabetes. Early insulin secretion is important for the rapid and efficient suppression of endogenous glucose production after a meal. Thus, loss of early insulin secretion initially leads to post-prandial hyperglycaemia which, as the disease progresses, worsens to clinical hyperglycaemia. Strategies that enhance early insulin secretion improve glucose tolerance and represent a novel and more physiologic approach to improving glycaemic control in patients with Type II diabetes mellitus. [Diabetologia (2001) 44: 929±945]

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“…Insulin secretion at the organ level was extensively studied by Grodsky and colleagues (an overview of their findings can be found in Ref. 50). They used the isolated rat pancreas perfused with a buffer containing glucose to study insulin secretion dynamics in response to a variety of glucose stimuli, such as stepwise and staircase increments as well as short pulses (30,48,51,52).…”

Section: Biphasic Nature Of the Insulin Response: In Vitro And In Vivmentioning

confidence: 99%

First-phase insulin secretion: does it exist in real life? Considerations on shape and function

Caumo¹,

Luzi²

2004

American Journal of Physiology-Endocrinology and Metabolism

151

120

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To fulfill its preeminent function of regulating glucose metabolism, insulin secretion must not only be quantitatively appropriate but also have qualitative, dynamic properties that optimize insulin action on target tissues. This review focuses on the importance of the first-phase insulin secretion to glucose metabolism and attempts to illustrate the relationships between the first-phase insulin response to an intravenous glucose challenge and the early insulin response following glucose ingestion. A clear-cut first phase occurs only when the ␤-cell is exposed to a rapidly changing glucose stimulus, like the one induced by a brisk intravenous glucose administration. In contrast, peripheral insulin concentration following glucose ingestion does not bear any clear sign of biphasic shape. Coupling data from the literature with the results of a ␤-cell model simulation, a close relationship between the first-phase insulin response to intravenous glucose and the early insulin response to glucose ingestion emerges. It appears that the same ability of the ␤-cell to produce a pronounced first phase in response to an intravenous glucose challenge can generate a rapidly increasing early phase in response to the blood glucose profile following glucose ingestion. This early insulin response to glucose is enhanced by the concomitant action of incretins and neural responses to nutrient ingestion. Thus, under physiological circumstances, the key feature of the early insulin response seems to be the ability to generate a rapidly increasing insulin profile. This notion is corroborated by recent experimental evidence that the early insulin response, when assessed at the portal level with a frequent sampling, displays a pulsatile nature. Thus, even though the classical first phase does not exist under physiological conditions, the oscillatory behavior identified at the portal level does serve the purpose of rapidly exposing the liver to elevated insulin levels that, also in virtue of their up-and-down pattern, are particularly effective in restraining hepatic glucose production. insulin pulsatile secretion; mathematical models; early-phase insulin secretion IN THE PAST THREE DECADES, the relevance of insulin secretion abnormalities in the pathogenesis of type 2 diabetes mellitus have been extensively debated (32,43,86,93,97), and a consensus has been reached that, to fulfill its pivotal role in regulating glucose metabolism, insulin secretion must not only be quantitatively appropriate, but also possess qualitative, dynamic features that optimize insulin action on target tissues. In particular, increasing emphasis has been placed on the importance of the so-called first-phase insulin secretion to glucose homeostasis (27,35,55). The aim of this review is to address the following questions. Does a first-phase insulin secretion really exist in in vivo physiology? What is the relationship between the first-phase insulin response to a brisk intravenous glucose challenge and the early insulin response following glucose ingestion? What ar...

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The Kinetics of Insulin Release

Cited by 10 publications

References 80 publications

Evaluation of Long-Term Treatment Effect in a Type 1 Diabetes Intervention Trial: Differences After Stimulation With Glucagon or a Mixed Meal

Evaluation of Long-Term Treatment Effect in a Type 1 Diabetes Intervention Trial: Differences After Stimulation With Glucagon or a Mixed Meal

The role of impaired early insulin secretion in the pathogenesis of Type II diabetes mellitus

First-phase insulin secretion: does it exist in real life? Considerations on shape and function

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