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 Presentation

"Insulin Resistance and Islet Apoptosis"

Prof. Daniel J. Drucker (biography)
English - 2002-04-26 - 29 minutes
(2 slides)

Summary :
Type 2 diabetes is characterized by a combination of insufficient insulin
secretion and/or defective insulin action culminating in the development of
hyperglycemia and the metabolic syndrome associated with suboptimal control
of nutrient assimilation and disposal. Although hyperinsulinemia and
beta-cell hyperplasia are frequently seen early in the course of diabetes,
these compensatory alterations are not sustainable, leading to a progressive
decline in beta-cell mass and insulin deficiency. Evidence from experimental
models of rodent diabetes suggests that beta-cell apoptosis, a normal
feature of the developmental remodeling of the islet, contributes in part to
the steady decline in functioning beta-cell mass associated with progressive
deterioration in insulin secretion over prolonged time periods. Given the
limitations in imaging the in situ proliferation and apoptosis of the human
beta-cell, it is assumed, but not yet proven, that the biology of the
failing human islet mirrors in part the pathophysiology observed in studies
of rodent diabetes.

Given the therapeutic importance of preserving beta-cell mass in diabetes,
understanding the pathophysiology of beta-cell failure, and delineating the
pro-apoptotic signals associated with diabetes, is of major clinical
relevance. Hyperglycemia may represent a significant risk factor for islet
apoptosis, as supported by somewhat conflicting evidence from studies of
islet and beta-cells in vitro, and normal and transplanted islets in vivo.
Hyperglycemia induces the expression of both pro- and anti-apoptotic genes
in the rodent beta-cell; hence the influence of glucose on beta-cell
survival appears context-specific. Activation of the sulfonylurea receptor
in the setting of high glucose may also enhance experimental apoptosis in
islet beta-cells in vitro. Lipotoxicity associated with intraislet lipid
accumulation leads to ceramide formation and activation of the apoptotic
machinery leading to beta-cell death. Treatment of rodents that exhibit
genetic susceptibility to lipotoxicity and beta-cell failure with
thiazolidinediones reverses many of the biochemical and morphological
features of lipotoxicity, reduces intraislet lipid and ceramide
accumulation, and preserves or enhances beta-cell mass. Experiments using
enzyme inhibitors and murine models of gene inactivation support potential
roles for poly (ADP-ribose) polymerase and protein kinase C gamma as
downstream mediators of beta-cell apoptosis. Mice with an inactivating
mutation in the MODY gene HNF-1 alpha exhibit inappropriately reduced
beta-cell mass and antagonism of HNF-1 alpha in islet cells enhances
sensitivity to ceramide-induced apoptosis. The level of beta-cell cAMP may
be an important determinant of both islet cell proliferation and apoptosis,
and insulinotropic peptides that enhance beta-cell cAMP, such as PACAP, VIP,
GIP, and GLP-1, may indirectly promote beta-cell survival via reduction of
the susceptibility to apoptosis. Similarly, unraveling the pathways linking
ER translational stress to apoptosis provides a mechanism for linking
prolonged up-regulation of insulin biosynthesis to beta-cell death. Taken
together, the recent increase in our understanding of the factors that
promote both
beta-cell proliferation and cell death provides opportunities for
development of therapeutic strategies targeted at preservation of
beta-cell mass in subjects with diabetes.

Learning objectives :
- To understand the experimental models for studying beta cell death.
- To review the data contrasting apoptosis in rodent vs human beta cells/ animalmodels vs in vitro studies.
- To discuss the evidence supporting therapeutic intervention for restoration of beta cell mass and prevention of apoptosis.


Bibliographic references :
Biological actions and therapeutic potential of the glucagon-like peptides.

Drucker DJ.

The Banting and Best Diabetes Centre, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. d.drucker@utoronto.ca

The glucagon-like peptides (GLP-1 and GLP-2) are proglucagon-derived peptides cosecreted from gut endocrine cells in response to nutrient ingestion. GLP-1 acts as an incretin to lower blood glucose via stimulation of insulin secretion from islet beta cells. GLP-1 also exerts actions independent of insulin secretion, including inhibition of gastric emptying and acid secretion, reduction in food ingestion and glucagon secretion, and stimulation of beta-cell proliferation. Administration of GLP-1 lowers blood glucose and reduces food intake in human subjects with type 2 diabetes. GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal motility. Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis. GLP-2 also attenuates chemotherapy-induced mucositis via inhibition of drug-induced apoptosis in the small and large bowel. GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome. The actions of GLP-2 are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine. The beneficial actions of GLP-1 and GLP-2 in preclinical and clinical studies of diabetes and intestinal disease, respectively, has fostered interest in the potential therapeutic use of these gut peptides. Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV). Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases.

Gastroenterology 2002 Feb;122(2):531-44




   


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