Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

Abstract

Aim/hypothesis Hyperinsulinaemia maintains euglycaemia in insulin-resistant states. The precise cellular mechanisms by which the beta cells adapt are still unresolved. A peripherally derived cue, such as increased circulating fatty acids, may instruct the beta cell to initiate an adaptive programme to maintain glucose homeostasis. When this fails, type 2 diabetes ensues. Because mitochondria play a key role in beta cell pathophysiology, we tested the hypothesis that mitochondrial metabolism is critical for beta cell adaptation to insulin resistance. Methods C57BL/6J mice were given high-fat (HF) diet for 12 weeks. We then analysed islet hormone secretion, metabolism in vivo and in vitro, and beta cell morphology.Results HF diet resulted in insulin resistance and glucose intolerance but not frank diabetes. Basal insulin secretion was elevated in isolated islets from HF mice with almost no additional response provoked by high glucose. In contrast, a strong secretory response was seen when islets from HF mice were stimulated with fuels that require mitochondrial metabolism, such as glutamate, glutamine, alpha-ketoisocaproic acid and succinate. Moreover, while glucose oxidation was impaired in islets from HF mice, oxidation of glutamine and palmitate was enhanced. Ultrastructural analysis of islets in HF mice revealed an accumulation of lipid droplets in beta cells and a twofold increase in mitochondrial area. Conclusions/interpretation We propose that beta cells exposed to increased lipid flux in insulin resistance respond by increasing mitochondrial volume. This expansion is associated with enhanced mitochondrial metabolism as a means of beta cell compensation.

Transamination Is Required for α-Ketoisocaproate but Not Leucine to Stimulate Insulin Secretion*

“…Leucine thus could augment its insulinotropic effect through this paracrine control of exocrine pancreas over ␤-cell function. Further supporting relevance is the observation that KIC causes hypersecretion of insulin in diabetes-susceptible BTBR mice and high fat diet-fed mice (20,48). It has also been reported that the prevalence of insulin hypersecretion is higher than that of insulin resistance in obese subjects (49) and in some instances may represent a primary metabolic defect (50).…”

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

“…Whether such translocation occurs in beta cells is unknown. In fact, while very little is known about the structure of triacylglycerol stores in beta cells, studies have demonstrated lipid droplet formation within beta cells, either upon exposure to NEFA or in animals fed a high-fat diet [16,35].…”

“…Sections (10 μm) from frozen pancreas were cut in a cryostat, thawed, air-dried and fixed [35]. As an index of neutral lipid content that would reflect triacylglycerol content, optical density was measured in four randomly chosen slides from the KO mice and three slides from controls.…”

“…Immunocytochemistry and measurement of beta cell mass Immunocytochemistry and measurement of beta cell mass were performed as described [35]. Digitised images of all islets in three sections per animal were analysed.…”

Excess Lipid Availability Increases Mitochondrial Fatty Acid Oxidative Capacity in Muscle

“…Mice with muscle-specific overexpression of lipoprotein lipase, which increases fatty acid influx into skeletal muscle, display extensive mitochondrial proliferation (32). Fatty acids have also been shown to increase PGC-1␣ expression in muscle cells (33) and ␤-cells (34), and this is associated with increased mitochondrial metabolism (33,35). The fatty acid subtype appears to be important (33), as palmitate alone reduces PGC-1␣ expression (36); however, this may be related to its activation of inflammatory pathways that are known to impact on PGC-1␣ expression (37).…”