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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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a Association between insulin resistance (HOMA-IR) and 8-year incidence of CVD in non-diabetic participants in the San Antonio Heart Study before (black bars) and after (white bars) adjustment for age, sex, blood pressure, plasma lipids, smoking, exercise and waist circumference. Events, n = 187, participants, n = 2,569. Panel adapted with permission from Hanley et al. [67]. b Bar graph of 6.9 year risk of CVD in 3,606 participants with the metabolic syndrome (MS) and with individual components of the metabolic syndrome, i.e. dyslipidaemia (Dyslip), hypertension (HTN), obesity (OB) and insulin resistance (IR, highest HOMA quartile) in the Botnia Study. Panel adapted with permission from Isomaa et al. [68]
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Fig2: a Association between insulin resistance (HOMA-IR) and 8-year incidence of CVD in non-diabetic participants in the San Antonio Heart Study before (black bars) and after (white bars) adjustment for age, sex, blood pressure, plasma lipids, smoking, exercise and waist circumference. Events, n = 187, participants, n = 2,569. Panel adapted with permission from Hanley et al. [67]. b Bar graph of 6.9 year risk of CVD in 3,606 participants with the metabolic syndrome (MS) and with individual components of the metabolic syndrome, i.e. dyslipidaemia (Dyslip), hypertension (HTN), obesity (OB) and insulin resistance (IR, highest HOMA quartile) in the Botnia Study. Panel adapted with permission from Isomaa et al. [68]

Mentions: Multiple prospective studies have demonstrated that insulin resistance predicts future CVD. In the San Antonio Heart Study [67], insulin resistance was quantitated by HOMA of insulin resistance (HOMA-IR) in 2,564 non-diabetic participants who were followed for 8 years. Individuals in the highest quintile of insulin resistance had an approximately 2.5-fold increased incidence of CVD (Fig. 2a). After adjustment for multiple cardiovascular risk factors, individuals in the highest quintile of insulin resistance still had a twofold increased incidence of CVD. In 3,606 non-diabetic participants followed for 6.9 years in the Botnia Study [68] (Fig. 2b), the metabolic syndrome was associated with a threefold increased risk of CVD. Each component of the metabolic syndrome, as well as insulin resistance (HOMA-IR) itself, was associated with a 1.5- to 2-fold increased incidence of CVD (Fig. 2b). Similar observations have been made in the Bruneck [69], Verona Diabetes [70] and Insulin Resistance Atherosclerosis studies [71]. A strong relationship between HOMA-IR and carotid intimal media thickness has also been demonstrated [72], as has an association between insulin resistance and greater cardiovascular risk factor load [73].Fig. 2


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

DeFronzo RA - Diabetologia (2010)

a Association between insulin resistance (HOMA-IR) and 8-year incidence of CVD in non-diabetic participants in the San Antonio Heart Study before (black bars) and after (white bars) adjustment for age, sex, blood pressure, plasma lipids, smoking, exercise and waist circumference. Events, n = 187, participants, n = 2,569. Panel adapted with permission from Hanley et al. [67]. b Bar graph of 6.9 year risk of CVD in 3,606 participants with the metabolic syndrome (MS) and with individual components of the metabolic syndrome, i.e. dyslipidaemia (Dyslip), hypertension (HTN), obesity (OB) and insulin resistance (IR, highest HOMA quartile) in the Botnia Study. Panel adapted with permission from Isomaa et al. [68]
© Copyright Policy
Related In: Results  -  Collection

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Fig2: a Association between insulin resistance (HOMA-IR) and 8-year incidence of CVD in non-diabetic participants in the San Antonio Heart Study before (black bars) and after (white bars) adjustment for age, sex, blood pressure, plasma lipids, smoking, exercise and waist circumference. Events, n = 187, participants, n = 2,569. Panel adapted with permission from Hanley et al. [67]. b Bar graph of 6.9 year risk of CVD in 3,606 participants with the metabolic syndrome (MS) and with individual components of the metabolic syndrome, i.e. dyslipidaemia (Dyslip), hypertension (HTN), obesity (OB) and insulin resistance (IR, highest HOMA quartile) in the Botnia Study. Panel adapted with permission from Isomaa et al. [68]
Mentions: Multiple prospective studies have demonstrated that insulin resistance predicts future CVD. In the San Antonio Heart Study [67], insulin resistance was quantitated by HOMA of insulin resistance (HOMA-IR) in 2,564 non-diabetic participants who were followed for 8 years. Individuals in the highest quintile of insulin resistance had an approximately 2.5-fold increased incidence of CVD (Fig. 2a). After adjustment for multiple cardiovascular risk factors, individuals in the highest quintile of insulin resistance still had a twofold increased incidence of CVD. In 3,606 non-diabetic participants followed for 6.9 years in the Botnia Study [68] (Fig. 2b), the metabolic syndrome was associated with a threefold increased risk of CVD. Each component of the metabolic syndrome, as well as insulin resistance (HOMA-IR) itself, was associated with a 1.5- to 2-fold increased incidence of CVD (Fig. 2b). Similar observations have been made in the Bruneck [69], Verona Diabetes [70] and Insulin Resistance Atherosclerosis studies [71]. A strong relationship between HOMA-IR and carotid intimal media thickness has also been demonstrated [72], as has an association between insulin resistance and greater cardiovascular risk factor load [73].Fig. 2

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