Evidence for Mechanistic Alterations of Ca²⁺Homeostasis in Type 2 Diabetes Mellitus

Abstract

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 Cai levels was observed in lymphocytes from diabetic subjects. Cai levels were positively correlated with fasting, plasma glucose and HbAlc. 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 fliorescence and C45a assays) as a consequence of 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.

Alteration of Ca2+‐ATPase activity in the homogenate, plasma membrane and microsomes of the salivary glands of streptozotocin‐induced diabetic rats

“…5,6,8,10,11,[35][36][37][38] The concentration of calcium is of importance for the functioning of exocrine gland where the salivary glands are included. 12,13,39 In this aspect microsomal and plasma membrane Ca 2þ -ATPase, play a crucial role. The difference we may find between submandibular and parotid salivary gland is understandable, once they are histologically and functionally different.…”

Augmented Contractile Response of Vascular Smooth Muscle in a Diabetic Mouse Model

“…Thus additional factors could be involved in the enhanced contractile mechanism in diabetic mouse aortae. Some of these could be related to abnormal Ca 2+ metabolism, which is associated with the diabetic state [42, 43]; for example, inactivation of Na + ,K + -ATPase [43, 44]or potassium channels [45, 46], which control Ca 2+ influx via the membrane potential, or modulation of Ca 2+ -ATPase [47]. Alternatively, sensitization to Ca 2+ through a Rho-kinase pathway could contribute to enhanced vasoconstriction in diabetes [5, 6].…”

Adverse effect of obesity on red cell membrane arachidonic and docosahexaenoic acids in gestational diabetes

“…If the membrane protein structure changes by extracellular forces such as peroxidation and glycosylation, its folding property will alter, thereby its lipid composition may have to change to match. Abnormal glucose transporters [41], decreased insulin receptor binding protein [42], Ca ++ transmembrane movement [43], alteration of uncoupling and remodelling of actin [44,45] are examples of altered membrane protein function depressed in diabetes and obesity. The red cell membrane is essentially an example of plasma membrane.…”