The powerful relation between atherosclerosis and diabetes may have a common genetic basis. However, few genes predisposing to both have been identified. Calpain-10 (CAPN10) was the first gene for type 2 diabetes identified by positional cloning, wherein a combination of haplotypes conferred increased risk of diabetes. We sought to determine whether CAPN10 influences subclinical atherosclerosis. Among nondiabetic subjects from 85 Mexican-American families with a history of coronary artery disease, subclinical atherosclerosis was assessed by common carotid artery intima-media thickness (IMT), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and insulin secretion was estimated by the oral glucose tolerance test. These phenotypes were tested for association with CAPN10 haplotypes. Haplotype 1112 (of single nucleotide polymorphisms [SNPs] 44, 43, 56, and 63) was associated with increased IMT, while haplotype 1221 was associated with decreased IMT. The 112/121 haplotype combination (of SNPs 43, 56, and 63), originally found to confer increased risk for diabetes, was associated with the largest IMT in our study population. CAPN10 was also associated with both insulin sensitivity and insulin secretion. Covariate analysis suggested that CAPN10 affects IMT independently of these diabetes-related phenotypes. The fact that the diabetes gene CAPN10 also influences the risk for atherosclerosis shows that inherited factors may underlie the frequent co-occurrence of these two conditions.
[Show abstract][Hide abstract] ABSTRACT: Variation in the calpain-10 gene has been linked to a three-fold increased risk for type 2 diabetes in Pima Indian and some European populations. Furthermore, reduced skeletal muscle expression of calpain-10 is associated with reduced insulin mediated glucose disposal and carbohydrate oxidation. The skeletal muscle specific calpain-3 plays a key role in skeletal muscle integrity and has also been linked to insulin resistance in humans and rodents.
The major aims of this thesis were to 1) investigate the hypothesis that alterations in insulin sensitivity in healthy humans would lead to significant changes in the mRNA and protein expression of calpain-10 and -3, 2) investigate the effect of hyperinsulinaemia and lipid availability on calpain-10 and -3 expression, 3) further address the role of genetic variation in the calpain-10 gene on glucose utilisation in humans and finally 4) investigate the expression of calpain-10 in skeletal muscle of type 2 diabetic patients.
The studies in this thesis show for the first time that insulin resistance as a result of short term fasting or high fat availability is not associated with changes in calpain-10 and -3 mRNA and protein expression, providing evidence against an adaptive role for these genes in the development of fasting- and lipid-induced insulin resistance.
[Show abstract][Hide abstract] ABSTRACT: Diabetes mellitus is one of the major risk factors for cardiovascular disease which is the leading cause of death in the U.S. Increasing prevalence of diabetes and diabetic atherosclerosis makes identification of molecular mechanisms by which diabetes promotes atherogenesis an important task. Targeting common pathways may ameliorate both diseases. This review focuses on well known as well as newly discovered mechanisms which may represent promising therapeutic targets.
Drug Discovery Today Disease Mechanisms 02/2007; 4(3):131-140. DOI:10.1016/j.ddmec.2007.12.005
[Show abstract][Hide abstract] ABSTRACT: It is becoming increasingly clear that suboptimal blood glucose control results in adverse effects on large blood vessels, thereby accelerating atherosclerosis and cardiovascular disease, manifested as myocardial infarction, stroke, and peripheral vascular disease. Cardiovascular disease is accelerated by both type 1 and type 2 diabetes. In type 1 diabetes, hyperglycemia generally occurs in the absence of elevated blood lipid levels, whereas type 2 diabetes is frequently associated with dyslipidemia. In this review article, we discuss hyperglycemia versus hyperlipidemia as culprits in diabetes-accelerated atherosclerosis and cardiovascular disease, with emphasis on studies in mouse models and isolated vascular cells. Recent studies on LDL receptor-deficient mice that are hyperglycemic, but exhibit no marked dyslipidemia compared with nondiabetic controls, show that diabetes in the absence of diabetes-induced hyperlipidemia is associated with an accelerated formation of atherosclerotic lesions, similar to what is seen in fat-fed nondiabetic mice. These effects of diabetes are masked in severely dyslipidemic mice, suggesting that the effects of glucose and lipids on lesion initiation might be mediated by similar mechanisms. Recent evidence from isolated endothelial cells demonstrates that glucose and lipids can induce endothelial dysfunction through similar intracellular mechanisms. Analogous effects of glucose and lipids are also seen in macrophages. Furthermore, glucose exerts many of its cellular effects through lipid mediators. We propose that diabetes without associated dyslipidemia accelerates atherosclerosis by mechanisms that can also be activated by hyperlipidemia.
Circulation Research 03/2007; 100(6):769-81. DOI:10.1161/01.RES.0000259589.34348.74 · 11.02 Impact Factor
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