Palmitate-induced impairment of glucose-stimulated insulin secretion precedes mitochondrial dysfunction in mouse pancreatic islets

Abstract

It has been well established that excessive levels of glucose and palmitate lower glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells. This β-cell 'glucolipotoxicity' is possibly mediated by mitochondrial dysfunction, but involvement of bioenergetic failure in the pathological mechanism is the subject of ongoing debate. We show in the present study that increased palmitate levels impair GSIS before altering mitochondrial function. We demonstrate that GSIS defects arise from increased insulin release under basal conditions in addition to decreased insulin secretion under glucose-stimulatory conditions. Real-time respiratory analysis of intact mouse pancreatic islets reveals that mitochondrial ATP synthesis is not involved in the mechanism by which basal insulin is elevated. Equally, mitochondrial lipid oxidation and production of reactive oxygen species (ROS) do not contribute to increased basal insulin secretion. Palmitate does not affect KCl-induced insulin release at a basal or stimulatory glucose level, but elevated basal insulin release is attenuated by palmitoleate and associates with increased intracellular calcium. These findings deepen our understanding of β-cell glucolipotoxicity and reveal that palmitate-induced GSIS impairment is disconnected from mitochondrial dysfunction, a notion that is important when targeting β-cells for the treatment of diabetes and when assessing islet function in human transplants.

Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies

“…We did not assess other fatty acid biomarkers, which should be the subject of future investigations—particularly saturated fatty acids such as palmitic acid, which has shown pro-diabetogenic effects in experimental studies. 30–32 In addition, the re liability of type 2 diabetes ascertainment was likely to have differed across the cohorts, which might have caused some outcome misclassification and underestimation of true associations. Our findings are relevant for the incidence of type 2 diabetes, but not type 1 diabetes.…”

Into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases

“…Firstly, no standard method has been putted forward about isolation, purification and specific marker molecules for the identification of BM-MSCs. Secondly, the efficiency of BM-MSCs differentiation is not ideal, which is currently one of the research focus on how to induce BM-MSCs to differentiate to the single specific tissue and cells (46)(47)(48)(49). Thirdly, the signal transduction mechanism and the molecular basis of BM-MSCs' differentiation such as which transcription factors or gene were activated to make it for some specific differentiation is still not clear though it is generally considered to be related to reprogramming of BM-MSCs.…”

The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 β-Cells

“…Palmitate reportedly causes cellular dysfunction in pancreatic β-cells [24,25], and MCP-1 and VEGF have been confirmed to promote chronic inflammation by recruiting macrophages into hypertrophic adipose tissue. Furthermore, in our previous study, we have demonstrated that 3T3-L1 adipocytes stimulated with palmitate increase the secretion of MCP-1 and VEGF 120 [20].…”