A model of beta-cell response to GLP-1 to quantify incretin effect in healthy and prediabetic subjects

Autor: Micheletto, Francesco
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Popis: Glucose regulation, in healthy subjects, relies on a complex control system that keeps blood glucose level within a narrow range around its basal value. Impairment of the glucose regulatory system is the cause of several metabolic derangements, including diabetes, which is characterized by chronic hyperglycemia which leads to severe micro and macro-vascular complications. Diabetes is generally classified into two categories, type 1 and type 2 diabetes. Both arise from complex interactions between genes and the environment, and are characterized by an absolute deficiency of insulin production (type 1) or a relative deficiency of the pancreas to produce insulin in amounts sufficient to meet the body needs (type 2). The prevalence of diabetes is increasing dramatically in populations of the world, and its global incidence has been increasing steadily in the past several years. Traditional medications for type 2 diabetes, including insulin, sulfonylureas, glitinides, acarbose, metformin, and thiazolidinediones, lower blood glucose through diverse mechanisms of action. However, many of the oral hypoglycemic agents lose their efficacy over time, resulting in progressive deterioration in β-cell function and loss of glycemic control due to progressive loss of β-cell mass. Consequently, there is an increasing interest in developing therapeutic agents that preserve or restore functional β-cells mass such as the incretin hormone Glucagon-Like Peptide-1 (GLP-1). It not only acutely lowers blood glucose by promoting insulin secretion and inhibiting glucagon release, but also engages signaling pathways in the islet β-cells that leads to stimulation of β-cells proliferation and neo-genesis and inhibition of β-cell apoptosis. Impairment of insulin secretion and glucagon suppression suggests that decreased β-cells responsiveness to GLP-1 is part of the pathogenesis of type 2 diabetes. Thus the ability to measure the effect of GLP-1 on insulin secretion can be useful to understand the pathogenesis of type 2 diabetes. Moreover it can be employed to optimized GLP-1 based therapy by determining those individuals who may benefit more from such therapy. However, a mechanistic model enabling direct quantitation of pancreatic response to GLP-1 has never been developed. In this contribution a mathematical model which describes the mechanism of GLP-1 action on insulin secretion is proposed. It provides a direct measure of the β-cells responsivity indexes to glucose and GLP-1. Three databases were used to develop, test and validate the model. Data of 88 healthy individuals, who underwent a hyperglycemic clamp with a concomitant GLP-1 intravenous infusion, were used for model formulation. A set of models of increasing complexity describing GLP-1 action on insulin secretion were tested. All models share the common assumption that insulin secretion is made up of two components, one proportional to glucose rate of change through dynamic responsivity, Φd, and one proportional to glucose through static responsivity, Φs, but differ in the modality of GLP-1 control on β-cells. For each model potentiation index П was derived representing the percent increase in secretion due to 1 pmol/l of circulating GLP-1. All the models fit the data well, as confirmed by the run test, which supported randomness of residuals in 70% of the subjects and provide precise estimate of model parameters. Model selection was tackled using standard criteria (e.g. ability to describe the data, precision of parameter estimates, model parsimony, residual independence). The most parsimonious model in most subjects assumes that above-basal insulin secretion depends linearly on GLP-1 concentration and its rate of change. However, the hyperglycemic clamp with concomitant intravenous infusion of GLP-1, is not physiological and easy to perfume in large scale studies. Thus data of 22 impairing fasting glucose (IFG) subjects, studied twice with a mixed meal, were used to test the model performance in a more physiological condition. We found that during an oral test, a simpler model is sufficient to describe the data. Validation of the model was performed using both simulations and real data of 10 healthy subjects studied with an OGTT and matched intravenous glucose challenge (I-IVG). The protocol allows to calculate a model-independent index (PI) from the comparison of insulin secretion rate estimated in these two occasions. The comparison between model-derived Π and incretin potentiation index PI shows that they are very similar (П = 6.55, CV = 65%; PI = 6.15 % per pmol/l). In addition in silico validation proved the ability of the model to single out the effect of GLP-1 on insulin secretion since it correctly estimated П in the 93 ± 1% of the simulations.
Databáze: OpenAIRE
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