Role Fatty Acids in the Control of Insulin Secretion

In the fasting state, plasma FFA (not glucose) is the primary energy substrate for sustaining insulin secretion (378). Following a meal, pancreatic P-cells switch from using FFA to glucose as the preferred energy source. This occurs as glucose enters the P-cell by high-capacity, low-affinity GLUT2

transporters and is rapidly phosphorylated to glucose-6-phosphate (G-6-P) by glucokinase that acts as the glucose sensor or "pacemaker" for insulin secretion (379). Glucokinase is the rate-limiting step for insulin secretion as the capacity of GLUT2 to transport glucose inside the P-cell is much greater than the capacity of glucokinase to phosphorylate it. Most of the glucose is then converted through glycolysis to pyruvate (P-cells have limited capacity to generate glycogen or lactic acid from glucose), entering the mitochondria and generating ATP through the Krebs cycle as acetyl-CoA. This promotes the formation of citrate, which is transported to the cytoplasm inhibiting CPT-1, which is the transporter of fatty acids (as long-chain fatty acyl-CoA) into the mitochondria. This way, malonylCoA acts as the metabolic "switch" for insulin secretion from the fasting to the fed state: FFA goes from being oxidized as a fuel for basal insulin secretion in the fasting state, to being stored within the P -cell during the fed state for use in the next period of fasting. This rapid fuel switch requires intact mitochon-drial function capable to adapt immediately to the changing metabolic state. It also seems that the composition of circulating fatty acids has a significant impact on the ability of fatty acids to promote glucose-stimulated insulin secretion, such that exposure to saturated fatty acids stimulates much more insulin secretion compared to unsaturated fats, although this remains to be confirmed in humans (380-382). Therefore, it is important to recognize the importance of FFA (either exogenous or endogenous from lipolysis) to support normal insulin secretion and that a rapid increase of FFA may acutely potentiate glucose-stimulated secretion by increasing fatty acyl-CoA or complex lipids within the P-cell that act distally by modulating insulin exocytosis upon demand. Long chain acyl-CoA controls multiple functions within the P-cell, including function of ion channels, activation of PKC, nitric oxide-mediated apoptosis, protein acylation, transcription activity, and ceramide formation. The ability of the P-cell to switch between endogenous fatty acid synthesis and oxidation is critical to optimal function and molecular defects secondary to plasma FFA oversupply lead to the accumulation of reactive "toxic" lipids (i.e., ceramide and DAG) (148, 276, 372-376). Therefore, a chronic increase of plasma FFA, meant to enhance basal and glucose-stimulated insulin secretion in obesity and in other insulin-resistant states, may lead in a minority of FH+ subjects to P-cell lipotoxicity and tip them over to diabetes, as they appear to have genetically-determined diminished P-cell adaptation to excess FFA supply, as discussed below.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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