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Fatty Acids and Insulin Secretion

Fatty Acids and Insulin Secretion. Grill V, and E. Qvigstad E. 2000. Fatty acids and insulin secretion. British Journal of Nutrition 83:79-84. Empress Hughes Bio 475 Dr. Peter Lin. Diabetes. Is defined as a state in which carbohydrate is improperly regulated by insulin.

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Fatty Acids and Insulin Secretion

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  1. Fatty Acids and Insulin Secretion Grill V, and E. Qvigstad E. 2000. Fatty acids and insulin secretion. British Journal of Nutrition 83:79-84. Empress Hughes Bio 475 Dr. Peter Lin

  2. Diabetes • Is defined as a state in which carbohydrate is improperly regulated by insulin. • 143 million people worldwide with diabetes • 16 million people in the United States • Common among African Americans, Mexican and Native Americans • Blindness • Limb amputation • Types: • Type 1-Lack of insulin • Type 2 –Insulin resistance

  3. Insulin Resistance • When a normal dose of insulin does not increase glucose uptake and storage in the cell • Major characteristic of non-insulin dependant Type 2 diabetes • Associated with obesity and cardiovascular disease • Previous studies have shown that there is a relationship between lipid availability and insulin resistance

  4. Insulin Signaling Pathway Glucose Insulin AKT Glycogen Synthesis

  5. Free Fatty Acids • Major link between obesity, insulin resistance and type II diabetes • Release by enlarged adipose tissue of one or more messenger that interfere with insulin action (FFA, leptin, TNFa, resistin) • Plasma FFA levels are elevated (1.5 mM) in most non-insulin dependant obese patients • Physiological elevations of plasma FFA by lipid infusion inhibit insulin-stimulatation • Previous studies only looked at short term effects

  6. Terms • NEFA- non-esterified free fatty acids • GLUT4- is a transporter protein • Db/Db mouse- diabetic mouse (II) • Insulin-a peptide hormone that stimulates glucose uptake • AKT- protein that is phosphorylated by insulin • Proinsulin- the insulin ratio of secretion • CPT-I- carnithine-palmitoyl tranferase I, a enzyme that is necessary for transport of fatty acids in the mitochondria for oxidation • PDH- pyruvate dehdrogenase enzyme, a regulator of glucose in the Kreb’s cycle

  7. Fatty Acids Used in Study Name Structure Abbreviation Saturated Palmitic Acid CH3(CH2)4CO2H 16:0 Unsaturated Oleic Acid CH3(CH2)7HC=CH(CH2)7CO2H 18:1D9 Octanoic Acid C15H17Br2NO2

  8. Objective To look at the long term effects of non-esterfied free fatty acids on insulin stimulation secretion.

  9. Methods

  10. Long Term Effects of NEFA’s • Study done in normal rats • Rats were given intralipid, fat emulsion for 3, 6 or 48 hours • This tripled the levels of NEFA’s • It’s response to insulin was measured in the pancreas

  11. Effects of NEFA’s • After addition of intrapilid after 3 hours insulin’s response to glucose was increased • Insulin’s response to glucose seemed to be completely lost after 6 hours • Insulin secretion was inhibited 50% after 48 hours • Also effected the islets in the pancreas

  12. Glucose Oxidation • Glucose oxidation was measured in isolates islets from the rats infused with intraplipid for 48 hours (previous study) • Having a high glucose concentration in the cells increased glucose oxidation

  13. Etoximer Improves glucose oxidation • Etoximir, Sodium 2[6(40chlorophenoxy)-hexyl] oxirane-2-carboxylateoxirane-2-carboxylate was tested for oxidation • It inhibits the CPT-I enzyme, necessary for fatty acid transport into the mitochondria for oxidation • Added in vitro • Upon application of Etomoxir to islets of rats glucose oxidation and insulin secretion greatly improved

  14. Inhibitory Effects of Fatty Acids • Tissue culture was used to show how fatty acids induce and inhibit B cell function • Islets obtained from rats were exposed to palmitate, oleate, and octanoate • They were added to the cells and incubated for 6, 24, and 48 hours

  15. Time-Dependency important for inhibition • At least 24hours was needed to see inhibition insulin secretion • The effects were able to be reversed within a day • It was also found that protein biosynthesis and glucose regulation of B-cell function was also inhibited, which was previously unknown

  16. Role of PDH and PDH kinase • Can be deactivated by phoshorylation • The study found that after being incubated 48hours led to a decrease in the amount of PDH being in the active form • Long term exposure increased PDH kinase activity in islet mitochondria

  17. Fasting and NEFA’s • Starvation and fasting lead to elevated fatty acids, FA oxidation and insulin resistance • Tested fatty acids during fasting for insulin’s response to glucose • Had a decreased insulin response to glucose • Reduced oxidation • When looking at the ratio of oxidation versus utilization it was found that it decreased • Thus, concluded that only aerobic metabolism was effected, not anaerobic • Supported the original hypothesis that fatty acids during fasting would affect B cell secretion and metabolism

  18. Triglyceride Stores • NEFA’s lead to increased amount of triglycerides • Thought to be toxic to B cells • Shimbukaroet al found that it causes cellular depletion and fibrosis • More studies need to be done in this area

  19. Why this Animal model? • Db/db mouse gets diabetes early in life due to a defect in the hypothalamic leptin receptor • Insulin secretion diminishes after 3-6 moths after adiposity • The mice resemble diabetic human patients

  20. Effects of NEFA in animal models • 3 month old db/db mice were hyperglycemic and hyperinsulinaemic • Levels of NEFA were high • Insulin's response to glucose was reduced • Oxidation was also reduced • PDH was decreased • Exposure to Etomoxir like before, reversed these reactions

  21. Do animal models compare with humans? • Studied human islets in vitro • Obtained from Beta Cell transplants • Fatty acids introduced to islets • Fatty acids still continued to inhibit insulin secretion • PDH activity was inhibited as well • The same results as in rat model • Enhanced proinsulin noted after 48hours

  22. Which fatty acids played the leading role? • Palmitate and oleate had inhibitory effects on glucose stimulated insulin-resistance • Long chain fatty acids seem to stimulate insulin release more that short-chain fatty acids • Saturated had a greater effect than unsaturated • Unable at this time to correlate a specific faty acid with the greatest potential for inhibiting insulin secretion

  23. Long term Effects • Tested the effects of nicotinic acid, Acipmox in 22 diabetic subjects • Aciipimox was administered 60 min before the hyperglycaemic clamp enhanched insulin secretion • Proves that insulin secretion is supressed by elevated NEFA’s in type 2 diabetes patients

  24. Conclusions • The results indicate that glucose transport can be modulated by fatty acids • Etoximer improved glucose oxidation and insulin secretion, which indicated that • the inhibition of glucose metabolism by long term exposure is linked to fatty acid oxidation

  25. Further Studies • Other FFA’s with similar composition of Palmitic Acid (16:0) • Other factors that may have a negative influence on B-cell function

  26. Questions?

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