Evidence for mechanistic alterations of Ca2+ homeostasis in Type 2 diabetes mellitus.

Balasubramanyam, M and Balaji, R A and Subashini, B and Mohan, V (2001) Evidence for mechanistic alterations of Ca2+ homeostasis in Type 2 diabetes mellitus. International journal of experimental diabetes research, 1 (4). pp. 275-87. ISSN 1560-4284



Altered cytosolic Ca2+ is implicated in the aetiology of many diseases including diabetes but there are few studies on the mechanism(s) of the altered Ca2+ regulation. Using human lymphocytes, we studied cytosolic calcium (Cai) and various Ca2+ transport mechanisms in subjects with Type 2 diabetes mellitus and control subjects. Ca2+-specific fluorescent probes (Fura-2 and Fluo-3) were used to monitor the Ca2+ signals. Thapsigargin, a potent and specific inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), was used to study Ca2+-store dependent Ca2+ fluxes. Significant (P<0.05) elevation of basal Ca, levels was observed in lymphocytes from diabetic subjects. Cai levels were positively correlated with fasting plasma glucose and HbA1c. There was also a significant (P<0.05) reduction in plasma membrane calcium (PMCA) ATPase activity in diabetic subjects compared to controls. Cells from Type 2 diabetics exhibited an increased Ca2+ influx (as measured both by Fluo-3 fluorescence and 45Ca assays) as a consequence of thapsigargin-mediated Ca2+ store depletion. Upon addition of Mn2+ (a surrogate of Ca2+), the fura-2 fluorescence decayed in an exponential fashion and the rate and extent of this decline was steeper and greater in cells from type 2 diabetic patients. There was also a significant (P<0.05) difference in the Na+/Ca2+ exchange activity in Type 2 diabetic patients, both under resting conditions and after challenging the cells with thapsigargin, when the internal store Ca2+ sequestration was circumvented. Pharmacological activation of protein kinase C (PKC) in cells from patients resulted in only partial inhibition of Ca2+ entry. We conclude that cellular Ca2+ accumulation in cells from Type 2 diabetes results from (a) reduction in PMCA ATPase activity, (b) modulation of Na+/Ca2+ exchange and (3) increased Ca2+ influx across the plasma membrane.

Item Type:Article
Official URL/DOI:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC247774...
Uncontrolled Keywords:Ca2+ homeostasis;Diabetes; type 2 diabetes
Subjects:Biochemistry,Cell and Molecular Signalling > Genomics in Diabetes
Diabetology > Diabetes Mellitus Type 2
Divisions:Department of Cell and Molecular Biology
Department of Diabetology
ID Code:238
Deposited On:04 Dec 2009 12:23
Last Modified:04 Dec 2009 12:23
Related URLs:

Repository Staff Only: item control page