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Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009.

DeFronzo RA - Diabetologia (2010)

Bottom Line: Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD).Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis.Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive-MSC 7886, San Antonio, TX, 78229, USA. Albarado@uthscsa.edu

ABSTRACT
Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients.

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Related in: MedlinePlus

Fat topography in type 2 diabetes and effect of thiazolidine-diones (TZD) (see text for a detailed discussion)
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Fig8: Fat topography in type 2 diabetes and effect of thiazolidine-diones (TZD) (see text for a detailed discussion)

Mentions: Accumulation of fat within the intraabdominal cavity, i.e. visceral fat (Fig. 8), is associated with insulin resistance and CVD [131, 168, 169]. Although the mechanism(s) for this association remain(s) unclear, visceral obesity is part of the insulin resistance (metabolic) syndrome [38–40]; however, the individual components of the insulin resistance syndrome, not the increase in visceral fat, may account for the increased incidence of CVD.Fig. 8


Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009.

DeFronzo RA - Diabetologia (2010)

Fat topography in type 2 diabetes and effect of thiazolidine-diones (TZD) (see text for a detailed discussion)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2877338&req=5

Fig8: Fat topography in type 2 diabetes and effect of thiazolidine-diones (TZD) (see text for a detailed discussion)
Mentions: Accumulation of fat within the intraabdominal cavity, i.e. visceral fat (Fig. 8), is associated with insulin resistance and CVD [131, 168, 169]. Although the mechanism(s) for this association remain(s) unclear, visceral obesity is part of the insulin resistance (metabolic) syndrome [38–40]; however, the individual components of the insulin resistance syndrome, not the increase in visceral fat, may account for the increased incidence of CVD.Fig. 8

Bottom Line: Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD).Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis.Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive-MSC 7886, San Antonio, TX, 78229, USA. Albarado@uthscsa.edu

ABSTRACT
Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients.

Show MeSH
Related in: MedlinePlus