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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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Insulin-stimulated glucose disposal (40 mU m−2 min−1, euglycaemic–hyperinsulaemic clamp) in lean healthy control (CON) participants, obese normal-glucose-tolerant participants (NGT), lean drug-naive type 2 diabetic participants (T2DM), lean normal-glucose-tolerant hypertensive participants (HTN), NGT hypertriacylglycerolaemic (Hypertriacyl) participants and non-diabetic participants with coronary artery disease (CAD). White sections, non-oxidative glucose disposal (glycogen synthesis); black sections, glucose oxidation. **p < 0.01 vs CON; ***p < 0.001 vs CON. Figure adapted with permission from Kashyap et al. [19] and DeFronzo et al. [20]. To change glucose uptake into SI units, divide by 180
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Fig1: Insulin-stimulated glucose disposal (40 mU m−2 min−1, euglycaemic–hyperinsulaemic clamp) in lean healthy control (CON) participants, obese normal-glucose-tolerant participants (NGT), lean drug-naive type 2 diabetic participants (T2DM), lean normal-glucose-tolerant hypertensive participants (HTN), NGT hypertriacylglycerolaemic (Hypertriacyl) participants and non-diabetic participants with coronary artery disease (CAD). White sections, non-oxidative glucose disposal (glycogen synthesis); black sections, glucose oxidation. **p < 0.01 vs CON; ***p < 0.001 vs CON. Figure adapted with permission from Kashyap et al. [19] and DeFronzo et al. [20]. To change glucose uptake into SI units, divide by 180

Mentions: Much evidence indicates that insulin resistance per se and associated components of the insulin resistance (metabolic) syndrome (see textbox: Syndrome of insulin resistance) [38–40] contribute to development of CVD. Studies from our laboratory (Fig. 1) [1, 9, 41–44] and others [45, 46] have demonstrated that lean type 2 diabetic and obese normal glucose tolerant participants are resistant to insulin and that their insulin resistance primarily affects the glycogen synthetic pathway. Type 2 diabetes [4, 5] and obesity [15, 16] are major cardiovascular risk factors. A common thread linking all components of the insulin resistance (metabolic) syndrome is the basic cellular/molecular cause of insulin resistance [44], which not only promotes inflammation and atherogenesis, but leads to and/or aggravates other components of the syndrome, which themselves are major CVD risk factors.Fig. 1


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

DeFronzo RA - Diabetologia (2010)

Insulin-stimulated glucose disposal (40 mU m−2 min−1, euglycaemic–hyperinsulaemic clamp) in lean healthy control (CON) participants, obese normal-glucose-tolerant participants (NGT), lean drug-naive type 2 diabetic participants (T2DM), lean normal-glucose-tolerant hypertensive participants (HTN), NGT hypertriacylglycerolaemic (Hypertriacyl) participants and non-diabetic participants with coronary artery disease (CAD). White sections, non-oxidative glucose disposal (glycogen synthesis); black sections, glucose oxidation. **p < 0.01 vs CON; ***p < 0.001 vs CON. Figure adapted with permission from Kashyap et al. [19] and DeFronzo et al. [20]. To change glucose uptake into SI units, divide by 180
© Copyright Policy
Related In: Results  -  Collection

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

Fig1: Insulin-stimulated glucose disposal (40 mU m−2 min−1, euglycaemic–hyperinsulaemic clamp) in lean healthy control (CON) participants, obese normal-glucose-tolerant participants (NGT), lean drug-naive type 2 diabetic participants (T2DM), lean normal-glucose-tolerant hypertensive participants (HTN), NGT hypertriacylglycerolaemic (Hypertriacyl) participants and non-diabetic participants with coronary artery disease (CAD). White sections, non-oxidative glucose disposal (glycogen synthesis); black sections, glucose oxidation. **p < 0.01 vs CON; ***p < 0.001 vs CON. Figure adapted with permission from Kashyap et al. [19] and DeFronzo et al. [20]. To change glucose uptake into SI units, divide by 180
Mentions: Much evidence indicates that insulin resistance per se and associated components of the insulin resistance (metabolic) syndrome (see textbox: Syndrome of insulin resistance) [38–40] contribute to development of CVD. Studies from our laboratory (Fig. 1) [1, 9, 41–44] and others [45, 46] have demonstrated that lean type 2 diabetic and obese normal glucose tolerant participants are resistant to insulin and that their insulin resistance primarily affects the glycogen synthetic pathway. Type 2 diabetes [4, 5] and obesity [15, 16] are major cardiovascular risk factors. A common thread linking all components of the insulin resistance (metabolic) syndrome is the basic cellular/molecular cause of insulin resistance [44], which not only promotes inflammation and atherogenesis, but leads to and/or aggravates other components of the syndrome, which themselves are major CVD risk factors.Fig. 1

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