Calpains and Their Multiple Roles in Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) can lead to death without treatment and it has been predicted that the condition will affect 215 million people worldwide by 2010. T2DM is a multifactorial disorder whose precise genetic causes and biochemical defects have not been fully elucidated, but at both levels, calpains appear to play a role. Positional cloning studies mapped T2DM susceptibility to CAPN10, the gene encoding the intracellular cysteine protease, calpain 10. Further studies have shown a number of noncoding polymorphisms in CAPN10 to be functionally associated with T2DM while the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease. Here we review recent studies, which in addition to the latter enzyme, have linked calpain 5, calpain 3, and its splice variants, calpain 2 and calpain 1 to T2DM-related metabolic pathways along with T2DM-associated phenotypes, such as obesity and impaired insulin secretion, and T2DM-related complications, such as epithelial dysfunction and diabetic cataract.

Variante en CAPN10 y factores ambientales muestran evidencia de asociación con exceso de peso en jóvenes de Medellín, Colombia

“…This strongly suggests that it corresponds to a neutral variant. The particular associations that have been observed are the result of LD with one or more variants that increase or decrease the CAPN10 gene expression, whereby this allele can be a risk factor in one population and a protector factor in another (18,25,54,56). It has been proposed that LD can occur with variants in the CAPN10 gene promoter, which may involve changes in gene expression caused by environmental factors.…”

“…In this gene, SNPs 19, 43 and 63 have been implicated in decreased energy expenditure in several populations (25,26). Among the mechanisms in the CAPN10 variants that lead to decreased energy expenditure are mitochondria-dependent negative regulation of glucose metabolism, decreased insulin secretion, and β 3 -adrenoceptor lipolytic sensitivity (27).…”

OGG1 is degraded by calpain following oxidative stress and cisplatin exposure

“…Alzheimer's disease, type 2 diabetes, ischemia/reperfusion injury, and cancer are all associated with increased oxidative stress, elevated intracellular calcium and calpain hyperactivation (10)(11)(12)(13)(14)(15). In affected tissues in these conditions, elevated 8-oxoguanine in DNA, decreased levels of OGG1 enzyme, and decreased 8-oxoguanine excision activity have been observed (16)(17)(18)(19)(20)(21).…”

Synthesis of Novel Sulfonamide-Based Calpain Inhibitors and Their Potential as Anti-Tumor Agents

“…60 It has been predicted that T2DM will affect 215 million people worldwide by 2010. 73,77 For both TIDM and T2DM, in most cases, the precise biochemical defects, genetic causes and other contributing factors of these diseases are not fully elucidated. 73 However, it is becoming increasingly clear that members of the calpain family are involved in T2DM.…”

“…[73][74][75][76] T1DM accounts for approximately 5-10% of all cases of diabetes with the major susceptibility gene mapping to the HLA region of chromosome 6. 73,77 Type 2 diabetes mellitus (T2DM), or non-insulin-dependent diabetes mellitus (NIDDM), which is characterized by defects in hepatic glucose production, insulin action and insulin secretion, 60,73 is the most common form of diabetes. T2DM accounts for approximately 90% of cases and affecting 10-20% of those over 45 years of age in many developed countries.…”