Chronic Palmitate Exposure Inhibits Insulin Secretion by Dissociation of Ca2+ Channels from Secretory Granules

Abstract

SummaryLong-term (72 hr) exposure of pancreatic islets to palmitate inhibited glucose-induced insulin secretion by >50% with first- and second-phase secretion being equally suppressed. This inhibition correlated with the selective impairment of exocytosis evoked by brief (action potential-like) depolarizations, whereas that evoked by long (∼250 ms) stimuli was unaffected. Under normal conditions, Ca2+ influx elicited by brief membrane depolarizations increases [Ca2+]i to high levels within discrete microdomains and triggers the exocytosis of closely associated insulin granules. We found that these domains of localized Ca2+ entry become dispersed by long-term (72 hr), but not by acute (2 hr), exposure to palmitate. Importantly, the release competence of the granules was not affected by palmitate. Thus, the location rather than the magnitude of the Ca2+ increase determines its capacity to evoke exocytosis. In both mouse and human islets, the palmitate-induced secretion defect was reversed when the β cell action potential was pharmacologically prolonged.

Calcium signaling in pancreatic β-cells in health and in Type 2 diabetes

“…1) is unevenly distributed over the plasma membrane so that Ca 2+ microdomains with high [Ca 2+ ] have been detected in ␤-cells [50][51][52][53][54]. Interestingly, the density of voltage-dependent Ca 2+ channels in ␤-cells is 5-10% of that in adrenal chromaffin cells.…”

“…Moreover, distinct domains of exocytotic proteins might inhibit and stimulate L-type current [59,60]. Although L-type channels play a prominent role in the glucoseinduced [Ca 2+ ] c rise, it has been suggested that, in human ␤-cells, P/Q-type channels are more tightly coupled to exocytosis than Ltype channels [16,17,53]. It is unclear whether this reflects distinct voltage-dependencies or different associations to exocytotic proteins for both types of channels.…”

Metabolism–Secretion Coupling and Mitochondrial Calcium Activities in Clonal Pancreatic β-Cells

“…Under resting conditions, [Ca 2þ ] cyto is kept around 90 nM, and even during stimulation, overall cytosolic Ca 2þ hardly exceeds concentrations of 400 nM (Rojas et al, 1994). Intracellular application of 10 mM of the Ca 2þ -chelating agent EDTA does not prevent granule exocytosis (Hoppa et al, 2009), indicating that the b-cell has apparently developed a very efficient system of cellular Ca 2þ handling to secure both insulin secretion and the transfer of Ca 2þ signals from subplasmalemmal microdomains to cellular compartments such as the mitochondria (Rutter, Tsuboi, & Ravier, 2006).…”

Vascular endothelial growth factor-B: Impact on physiology and pathology

“…41 The lipids in the islets are also concerned. Free fatty acids (FFAs) promote insulin production in the short term 42 yet repressing by interfering the co-localization of calcium channels and the secretory granules 43 , 44 in the long term. Obesity and high fatty diet (HFD) duplicated the effects of long-term incubation of islets with FFAs on the Ca 2+ channel distribution and insulin output.…”