Title: Fatty Acids and Insulin Secretion
1Fatty 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
2Diabetes
- 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
3Insulin 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
4Insulin Signaling Pathway
Glucose
Insulin
AKT
Glycogen Synthesis
5Free 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
6Terms
- 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
7Fatty 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
8Objective
- To look at the long term effects of non-esterfied
free fatty acids on insulin stimulation
secretion.
9Methods
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
11Effects 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
12Glucose 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
13Etoximer 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
14Inhibitory 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
15Effects of Fatty Acids on Insulin Secretion
16Time-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
17Time and Palmitate play an integral role in
insulin secretion
18Role 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
19Fasting 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
20Effects 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
21Effects of Palmitate on Proinsulin Ratio
22Triglyceride 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
23Why 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
24Effects 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
25Do 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
26Which 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
27Long 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
28Conclusions
- 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
29Further Studies
- Other FFAs with similar composition of Palmitic
Acid (160) - Other factors that may have a negative influence
on B-cell function
30Questions?