Diabetes mellitus is recognized as a clinical syndrome that is characterized by hyperglycemia due to deficiency of insulin. The global prevalence of diabetes has been estimated to increase from 4% (1995) to 5.4% by the year 2025. Insulin dependent diabetes mellitus (IDDM/Type-1) in human, generating hyperglycemia due to insulin deficiency as a consequence of destructing beta cells in the pancreatic islets. Non-insulin dependent diabetes mellitus (NIDDM/Type-II), is a multifactorial, exact biochemical and genetic defect which has not yet been elucidated completely. Calpains seem to play a role in NIDDM and IDDM. Positional cloning experiments revealed that there is a NIDDM susceptibility to calpain 10 (CAPN10). Increased calpain activity and leukocyte trafficking were noticed in the microcirculation in ZDF (Zuker diabetic fatty) rats. Exercise and low body weight play a significant role in reducing calpains expression or elevating the calpains degradation in the skeletal muscle of NIDDM rats. Numerous investigations have been reported that non-coding polymorphisms in CAPN10 proteins might be involved in the NIDDM. Calpain and its mRNA presence had been reported in tissues from many mammalian species. CAPN10 and other calpains seem to be linked to glucose metabolism, insulin secretion and action pathways. This review will give an overview of the role of calpain in NIDDM and IDDM.