Fatty Acids and Insulin Secretion

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Fatty Acids and Insulin Secretion
Grill V, and E. Qvigstad E. 2000. Fatty acids and
insulin secretion. British Journal of Nutrition
8379-84.

• Empress Hughes
• Bio 475
• Dr. Peter Lin

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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

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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

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Insulin Signaling Pathway
Glucose
Insulin
AKT
Glycogen Synthesis
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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

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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 Krebs cycle

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Fatty Acids Used in Study
Name Structure Abbreviation
Saturated
Palmitic Acid CH3(CH2)4CO2H 160
Unsaturated
Oleic Acid CH3(CH2)7HCCH(CH2)7CO2H 181D9
Octanoic Acid C15H17Br2NO2
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Objective

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

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Methods
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Long Term Effects of NEFAs

• Study done in normal rats
• Rats were given intralipid, fat emulsion for 3, 6
  or 48 hours
• This tripled the levels of NEFAs
• Its response to insulin was measured in the
  pancreas

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Effects of Non-esterfied Fatty Acids

• After addition of intrapilid after 3 hours
  insulins response to glucose was increased
• Insulins 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

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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

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Etoximer Improves glucose oxidation

• Etoximir, Sodium 26(40chlorophenoxy)-hexyl
  oxirane-2-carboxylateoxirane-2-carboxylate was
  tested for oxidation
• Inhibits the CPT-I enzyme,
• Added in vitro
• Upon application of Etomoxir to islets of rats
  glucose oxidation and insulin secretion greatly
  improved

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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

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Effects of Fatty Acids on Insulin Secretion
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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

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Time and Palmitate play an integral role in
insulin secretion
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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

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Fasting and Non-esterfied fatty acids

• Starvation and fasting lead to elevated fatty
  acids, FA oxidation and insulin resistance
• Tested fatty acids during fasting for insulins
  response to glucose
• Had a decreased insulin response to glucose
• Reduced oxidation

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Effects of Fasting contd

• 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

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Effects of Palmitate on Proinsulin Ratio
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Triglyceride Stores

• NEFAs lead to increased amount of triglycerides
• Thought to be toxic to B cells
• Shimbukaro et al found that it causes cellular
  depletion and fibrosis
• More studies need to be done in this area

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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

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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

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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

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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

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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 NEFAs in type 2 diabetes patients

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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

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Further Studies

• Other FFAs with similar composition of Palmitic
  Acid (160)
• Other factors that may have a negative influence
  on B-cell function

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Questions?