Insulin Resistance presentations about Insulin Resistance EB with interest for Insulin Resistance Validating Insulin Resistance content Free registration form / enregistrement gratuit
  Franšais - August 16, 2011
Welcome to the #1 online source of information for Diabetes Specialists! An international online community of more than 10,000 Diabetes Specialists.

CME on Diabetes is a website built to transmit top-level CME conferences given by international experts in endocrinology, insulin resistance, prediabetes, metabolic syndrome and type 2 diabetes. More than 2.6 million slides have been viewed since the website launch. Thank you for your continued support and commitment!

"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.

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


  Username :
  Password :
  Lost your password?

  Search our website
  Would you like to know more about insulin resistance? Are you looking for information pertaining to Type 2 Diabetes? You can find what you are looking for in over 2000 references available on CMEonDiabetes.

  Let others know about this presentation.


Copyright © 2002-2015 MULTILEARNING Group INC.. All rights reserved.  Disclaimer
Powered by Multiwebcast - webcast services

insulin resistanceC-Reactive Protein (CRP)CRP, C-Reactive ProteinADHD ADDdiabetes insulin