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

By Ralph DeFronzo. Diabetologia, 2010

888 citations recorded by the source corpus.

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.

Subfields: Endocrinology, Diabetes and Metabolism, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d3f7be38c2390a664d6497142a816a330d9581c7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Endocrinology, Diabetes and Metabolism

1. I. Tabas
2. K. Bornfeldt
3. A. Lichtman

In Epidemiology

1. K. Bornfeldt
2. I. Tabas
3. A. Lichtman

In Molecular Biology

1. K. Bornfeldt
2. I. Tabas
3. A. Lichtman
4. J. Malhotra
5. R. Kaufman
6. K. Moore

Citations in the corpus

• Insulin Resistance, Hyperglycemia, and Atherosclerosis (2011, positive): “There is ample clinical evidence that insulin resistance increases the risk for coronary artery disease (CAD) even in the absence of hyperglycemia (DeFronzo, 2010).”
• Homeostasis, Inflammation, and Disease Susceptibility (2015, neutral): “Similarly, the abnormal accumulation of harmful lipid mediators (lipotoxicity) in adipocytes, liver, and muscle in obesity leads to cellular stress and tissue dysfunction, and consequently to inflammation (DeFronzo, 2010; Samuel and Shulman, 2012; Summers, 2006).”