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Fatty Acids and Insulin Secretion

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Islets obtained from rats were exposed to palmitate, oleate, and octanoate ... Palmitate and oleate had inhibitory effects on glucose stimulated insulin-resistance ... – PowerPoint PPT presentation

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Title: Fatty Acids and Insulin Secretion


1
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

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 Krebs cycle

7

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
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 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

11
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

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 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

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
Effects of Fatty Acids on Insulin Secretion
16
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

17
Time and Palmitate play an integral role in
insulin secretion
18
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

19
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

20
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

21
Effects of Palmitate on Proinsulin Ratio
22
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

23
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

24
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

25
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

26
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

27
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

28
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

29
Further Studies
  • Other FFAs with similar composition of Palmitic
    Acid (160)
  • Other factors that may have a negative influence
    on B-cell function

30
Questions?
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