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

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.

Contrasting associations of insulin resistance with diabetes, cardiovascular disease and all-cause mortality in the elderly: PROSPER long-term follow-up

“…The possibility that hyperinsulinaemia promotes atherosclerosis is tempered by observations that insulin can be protective in some animal models [6], although insulin resistance itself is usually considered an adverse CVD phenotype. For instance, insulin resistance may act through inflammatory or endothelial dysfunction pathways to promote atherosclerosis [7]. Recent meta-analyses suggest the association of HOMA-IR and fasting insulin with CVD is likely to be modest, although many individual studies had limited power [8,9]; for example, the most powerful study relating HOMA-IR to CVD had only 318 events during a 30 year follow-up [9].…”

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

“…Insulin resistance or the compensating hyperinsulinaemia leads to the manifestation of a cluster of risk factors, including hyperglycaemia, hypertriacylglycerolaemia, low plasma levels of HDL-cholesterol and arterial hypertension, that has been termed the metabolic syndrome. Although much progress [5] has been made in the understanding of the mutual relationships between obesity, insulin resistance, type 2 diabetes and atherosclerosis, the complete picture remains elusive. In the last years the carbohydrate-centred view of the pathogenesis of diabetes has widened to include different classes of lipids [5][6][7] and inflammatory factors [8].…”

“…Although much progress [5] has been made in the understanding of the mutual relationships between obesity, insulin resistance, type 2 diabetes and atherosclerosis, the complete picture remains elusive. In the last years the carbohydrate-centred view of the pathogenesis of diabetes has widened to include different classes of lipids [5][6][7] and inflammatory factors [8]. Mounting evidence suggests that sphingolipids play a role in the pathogenesis of insulin resistance and diabetes [9][10][11].…”

Physical exercise improves low cardiorespiratory fitness associated with intramyocellular lipids in patients with metabolic syndrome

“…4 Insulin-resistant individuals have a reduced rate of fat oxidation, compared with normal, insulin-sensitive individuals, and thus, the decreased mitochondrial fat oxidative capacity could lead to an increase in the intracellular fat content. 5 It has also been reported that IHL accumulation is associated with impaired hepatic glucose metabolism. The suppressive effect of insulin on hepatic glucose production was shown to be negatively correlated with the IHL content in both healthy subjects and patients with type 2 diabetes.…”