1,721,516 research outputs found
Apoptosis in the beta cells. cause or consequence of insulin secretion defect in diabetes?
No full textPancreatic beta-cell dysfunction and insulin resistance are two interrelated defects in the pathophysiology of type 2 diabetes. Defects in peripheral insulin action precede the development of glucose intolerance, as the pancreas compensates for insulin resistance by increasing insulin production and secretion. This may be achieved by enhancing cellular secretory capacity or by increasing beta-cell mass. Over time, the pancreatic secretion of insulin becomes inadequate for the extent of insulin resistance, and the levels of fasting and postprandial glucose rise leading to the onset of frank hyperglycemia, which leads to reduction in beta-cell function and survival through a process referred to as glucose toxicity. There is increasing evidence that apoptosis is the main mode of pancreatic beta-cell death not only in type 1 but also in type 2 diabetes. Recently, studies in knockout mice, human and rat islets, and pancreatic beta-cell lines demonstrated that defective insulin signaling in beta-cells might play an important pathophysiological role by affecting both secretory function and cell survival. The purpose of this review is to present recent advances in understanding of the interrelationship between molecular mechanisms underlying defects in insulin secretion and beta-cell survival in type 2 diabetes caused by impaired activation of insulin signaling pathways
Role of the insulin receptor variant forms in human metabolic disorders
No full textThe pathophysiology of type 2 diabetes includes two apparently distinct defects i.e. impaired insulin
action at the level of muscle, fat and liver, and failure in b-cells secretory capacity. Insulin action is mediated by the
insulin receptor, (IR) a member of the receptor tyrosine kinase family also including the type 1 Insulin-like Growth
Factor I (IGF-I) receptor (IGF-IR) and the orphan receptor Insulin Receptor-Related Receptor (IRR). IR exists in two
functionally distinct isoforms differing by the absence (Ex11-) or presence (Ex11+) of a 12 amino acid sequence in
the COOH-terminus of the a-subunit due to alternative splicing of exon 11. In addition to forming homodimers, IR,
IGF-IR and IRR can form hybrid receptors. IR/IGF-IR hybrids bind IGF-I, but not insulin, with high affinity, and
function as IGF-IR homoreceptors rather than IR homoreceptors. The function of IRR is unknown and it does not
transduce signals through IR/IRR hybrids. The generation of genetically engineered knockout mice with total or
tissue –specific lack of IR has been instrumental in dissecting the pathophysiological role of IR not only in
classical target tissues, such as muscle and liver, but also in non-classical target tissues, such as brain and
pancreatic b-cells. Some, but not all, studies have reported that expression of the low-affinity Ex11+ isoform is
increased in target tissues from type 2 diabetics, thus contributing to insulin resistance. There is evidence that
abundance of IR/IGF-IR hybrid receptors is increased in insulin target tissues, where they might affect insulin
sensitivity by sequestering IR in a less insulin-responsive form. This review will focus on the structural and
functional heterogeneity of IR and related receptors, and will discuss the studies in knockout mice lacking IR.
Finally, studies addressing the potential role of IR variant forms in the development of conditions of insulin
resistance, such as obesity and type 2 diabetes mellitus will be reviewed
Effects of glucagon-like peptide-1 on appetite and weight. Preclinical data and clinical studies [Effetti del glucagon-like peptide-1 sull'appetito e sul peso. Dati preclinici e studi clinici]
No full textObesity is associated with an increased risk of developing type 2 diabetes and cardiovascular disease. Pharmacological treatments of diabetes are mostly associated with weight gain, an undesirable event due to the fact that an increase in adiposity, especially visceral, is associated with reduced insulin sensitivity, worse cardiovascular risk profile and decreased adherence to treatment. Analogues of glucagon-like peptide-1 (GLP-1) represent a new therapeutic option for type 2 diabetes, which offer the advantage of combining beneficial effects on metabolic control with a significant reduction in body weight
Insulin receptor substrates (IRSs) polymorphisms and type 2 diabetes mellitus
No full textInsulin receptor substrate (IRS) molecules are key mediators in insulin signalling and play a central role in maintaining basic cellular functions, such as growth, survival and metabolism. They act as docking proteins for the insulin receptor and a complex network of intracellular signalling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3 and IRS-4) of this family have been identified that differ in tissue distribution, subcellular localisation, developmental expression, binding to the insulin receptor and interaction with SH2 domain-containing proteins. Results from targeted disruption of the IRS genes in mice have provided important clues as to the functional differences among these related molecules and suggest that they play very different roles in vivo. The available data are consistent with the notion that both IRS-1 and IRS-2 are important for insulin action and glucose homeostasis in vivo, whereas IRS-and IRS-4 appear to play a redundant role in the IRS signalling system. Considering their key role in both insulin action and insulin secretion, IRS-1 and IRS-2 molecules have been considered plausible candidate genes involved in the pathogenesis of Type 2 diabetes. Several polymorphisms in the IRS genes have been identified, but only the Gly → Arg972 substitution
of IRS-1, acting with environmental factors, seems to have a pathogenic role in the development of Type 2 diabetes. In contrast, polymorphisms of the other IRS genes do not appear to contribute to Type 2 diabetes
Pathophysiology of insulin resistance
No full textInsulin resistance is a feature of a number of clinical disorders, including type 2 diabetes/glucose
intolerance, obesity, dyslipidaemia and hypertension clustering in the so-called metabolic syndrome.
Insulin resistance in skeletal muscle manifests itself primarily as a reduction in insulinstimulated
glycogen synthesis due to reduced glucose transport. Ectopic lipid accumulation plays
an important role in inducing insulin resistance. Multiple defects in insulin signalling are responsible
for impaired glucose metabolism in target tissues of subjects with features of insulin resistance.
Inflammatory molecules and lipid metabolites inhibit insulin signalling by stimulating
a number of different serine kinases which are responsible for serine phosphorylation of Insulin
Receptor Substrate-1 (IRS-1)
Harnessing the weight-regulating properties of glucagon-like peptide-1 in the treatment of type 2 diabetes
No full textThe prevalence and incidence of type 2 diabetes are progressively increasing because of a concomitant rise in the prevalence of obesity. Intentional weight loss in patients with type 2 diabetes has been associated with a 25% reduction in total mortality and a 28% reduction in cardiovascular disease and diabetes mortality (1). Weight gain is not only a risk factor
for development of type 2 diabetes, but it is also the undesirable feature of several current antidiabetic treatments such as
thiazolidinediones, sulfonylureas, and insulin, with an estimated 2-kg weight gain for every 1% decrease inHbA1c). Reasons for this include defensive snacking to treat or prevent hypoglycemia, decreased glucosuria, decreased basal metabolic rate, and expansion in adipose tissue and fluid retention.Recently, novel therapeutic agents were developed for the treatment of type 2 diabetes. Among these are the incretin based therapies, which include glucagon like peptide (GLP)-1 receptor agonists and inhibitors of the protease dipeptidyl peptidase (DPP)-4. Both classes of drugs
use the antidiabetic properties of GLP-1, an incretin hormone that potentiates insulin secretion in a glucose-dependent
manner
Searching for type 2 diabetes genes. prospects in pharmacotherapy
No full textType 2 diabetes is a complex, heterogeneous group of metabolic disorders that has reached epidemic proportions, affecting over 5% of the population in western countries. The pathophysiology of type 2 diabetes includes two apparently distinct defects, ie impairments in insulin action at the level of skeletal muscle, fat and liver, and a failure in insulin secretory capacity of pancreatic beta-cells. There is strong evidence that genetic factors play an important role in both of these components given the familial nature, the high concordance rate between monozygotic twins, and the high prevalence in certain ethnic groups
Reduce the risk of hypoglycemia in the treatment of the diabetic patient: What has changed from the '90s to today in clinical approach?
No full textNew therapies for type 2 diabetes: Glucagon-Like Peptide 1 (GLP-1) analogs and Dipeptidyl Peptidase-4 inhibitors
No full textEffects of anti-diabetic therapy on overweight/obesity and dyslipidemia: traditional hypoglycemic agents (metformin, sulfonylureas, thiazolidinediones) versus glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors
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