Chapter 7. Omega-3 Fish Oils and Lipoprotein Metabolism

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lipoproteins are hydrolyzed by lipoprotein lipase (LpL) and converted into smaller lipoproteins

called remnants and IDL, respectively. The remnants and IDL are cleared from the circulation by

the liver through mechanisms involving LDL-receptor-related protein (LRP), which binds to apoE

and hepatic lipase (HL). Although all the chylomicron remnants are cleared by the hepatic uptake,

some of the IDL are further catabolized to LDL. During this process, the TG core is replaced by

cholesterol ester; all of the apoproteins except apo B100 are removed.

Catabolism of LDL depends primarily on the receptor-mediated uptake. The LDL receptor

binds the apo B100. The LDL and the LDL receptor are internalized and catabolized in the

lysosomes, releasing free cholesterol. Free cholesterol inhibits the key enzyme of cholesterol

synthesis (3-hydroxy 3-methyl glutaryl-CoA reductase), creating a feedback mechanism to prevent

excessive cholesterol production. Simultaneously, LDL-receptor synthesis is decreased, and cholesterol esterification is stimulated. These feedback mechanisms tightly regulate the intracellular

free cholesterol levels.

Metabolism of HDL is complicated. Nascent HDL containing only a bilayer of phospholipid

and apoproteins is formed in the liver and the intestine.1 These lipid-poor particles acquire cholesterol and phospholipids from peripheral tissues via ATP binding cassette transporter A1 (ABCA1)

generating cholesterol-enriched particles. The enzyme lecithin cholesterol acyl transferase (LCAT),

carried on HDL particles, esterifies the free cholesterol to form cholesteryl ester which migrates

to the core of the HDL. These HDL particles change further through intravascular modeling by

lipases and lipid transfer proteins. Cholesteryl ester transfer protein (CETP) facilitates the exchange

of cholesteryl ester (CE) in HDL for the triglyceride in chylomicrons and VLDL. Phospholipid

transfer protein (PLTP) mediates phospholipid transfer from chylomicrons and VLDL to HDL.

These lipids are then delivered to the liver with the assistance of the hepatic lipase, which hydrolyzes

the triglyceride in HDL and releases lipid-poor apoA-I HDL and the scavenger receptor (SR)-B1,

which removes cholesterol.



III. EFFECTS OF N-3 FISH OILS ON LIPOPROTEINS

A. HEPATIC PRODUCTION



OF



VLDL



At the fasting state, elevated plasma triglyceride levels reflect the presence of excess amounts of

VLDL in the circulation. Fish oils consistently decrease plasma concentration of triglycerides by

decreasing VLDL-TG, VLDL-cholesterol, and VLDL-apoB (Figure 7.1). Kinetic studies in

humans, nonhuman primates, and small animal models consistently demonstrate decreased VLDLTG and VLDL apoB secretion rates.2–5 The degree of suppression in TG relative to apoB influences

the VLDL particle size. Although in general, fish oils decrease the secretion of TG more than

apoB and lead to the production of smaller, lipid-poor particles, this response is modified by the

genetic background.4

Fish oils regulate hepatic production of VLDL by inhibiting fatty-acid synthesis, increasing

oxidation, decreasing triglyceride and cholesteryl ester production, and increasing the degradation

of apoB. Recent research demonstrated that the effects of fish oils are mediated through the actions

of several nuclear receptors such as peroxisome proliferator-activated receptor (PPAR), liver X

receptors (LXR) and hepatic nuclear factor-4 (HNF4), and sterol regulatory element-binding proteins (SREBP).6

Fatty acid production: The major lipogenic enzyme in the liver is fatty acid synthase (FAS).

The promoter of FAS has a SREBP response element. Thus, SREBP stimulates transcription of

FAS. In turn, SREBP gene expression is regulated by the nuclear receptor LXR. Fish oils interfere

with the binding of the ligand oxysteroids to LXR, decrease SREBP availability, and consequently

downregulate the transcription of FAS. Over-expression of the nuclear form of SREBP-1c overrides the suppressive effect of PUFA on lipogenic gene expression.6–9 Thus, down-regulation of



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Omega-3 Fish Oils and Lipoprotein Metabolism



147



VLDL

TG

ApoB

TG/ApoB



(-)

RXRα



(+)

Peroxisomal

β-Oxidation



LXR



(-)



LpL ?

LRP ?



(+)



? (+)



SREBP



(-)

Lipogenesis



LDL-receptor



Apo B



IDL



Scavengerreceptor B1



(+)



LDL



(+)



HDL-C

HDL-Apo Al



FIGURE 7.1 Effects of fish oil supplementation on lipoprotein metabolism.



the nuclear form of SREBP may account for many of the suppressive effects of fish oils on hepatic

lipogenesis.

Fatty acid oxidation: Fish oils increase catabolism fatty acids by stimulating the hepatic

enzymes to facilitate β-oxidation in the peroxisomes (acyl-CoA oxidase, AOX) and in the mitochondria (carnitine palmitoyltransferase, CPT). Fish oils mediate transcription of AOX through the

nuclear receptor PPARα. The PPARα-deficient (PPARα –/–) mice do not increase liver AOX mRNA

in response to fish oil.10 Regulation of the rate-limiting enzyme of mitochondrial β-oxidation, the

carnitine palmitoyltransferase 1 (L-CPT 1) gene, is not dependent on PPARα.11

Triglyceride and cholesteryl ester production: Fish oils are poor substrates for diacylglycerol

acyltransferase, the last step in triglyceride synthesis.12,13 They are also poor substrates for

cholesterol esterification. Instead, they get preferentially incorporated into phospholipids.14 In

vivo studies show that fish oil feeding causes a 25% decrease in glycerol production from acyl

CoA, a 15% decrease in the incorporation of DAG into the TG pool, and a 20% decrease in

hepatic TG secretion.15

ApoB degradation: ApoB is the obligatory protein for VLDL assembly, which occurs in two

steps16: During the first step, a small quantity of triglyceride becomes associated with apoB in the

rough endoplasmic reticulum, forming a small, dense, VLDL precursor. This process is facilitated by

the microsomal triacylglycerol transfer protein (MTP). During the second step, the VLDL-precursor

joins with a triglyceride droplet and forms a large VLDL. A small GTP-binding protein that activates

phospholipase D, ADP-ribosylation factor 1 (ARF-1), appears to facilitate the second step.

The apoB that cannot be lipidated during the first step is destroyed through endoplasmic

reticulum-associated degradation and reuptake.17 The apoB in the larger, lipid-enriched VLDL are

degraded by a newly described pathway called post-ER presecretory proteolysis.18 Fish oils reduce

hepatic VLDL secretion primarily by increasing post-ER presecretory proteolysis of apoB.18



B. INTESTINAL PRODUCTION



OF



CHYLOMICRONS



After a meal, the increase in plasma triglyceride levels reflects the amount of chylomicrons produced

in the intestine. Effects of fish oils on chylomicron production have been addressed in humans and



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animal models by studying both the absorption characteristics of fish oils and the effects of longterm fish oil supplementation on chylomicron production from other fats. These studies show that

in humans, fish oil-rich test meals increase plasma chylomicrons and triglycerides as much as olive

oil-rich test meals. Fish oils given either as ethyl esters or triglycerides are equally well absorbed.

The individual fatty acids in fish oils, EPA vs. DHA, have similar absorption rates.19 All these

findings suggest that a single load of fish oil does not affect chylomicron production in the human

intestine. However, long-term fish oil supplementation can cause adaptive changes and blunt the

increase in chylomicrons after oral fat loading. Furthermore, fish oil supplementation decreases the

chylomicron remnants during the late postprandial phase.20 These findings are in contrast with the

results of animal studies that showed long-term fish oil feeding stimulated the enzymes that

synthesize chylomicron lipids, acyl-CoA:cholesterol acyltransferase (ACAT and acyl-CoA:1,2diacylglycerol acyltransferase (DGAT) and therefore increased chylomicron synthesis.21



C. LIPOLYSIS



OF



TRIGLYCERIDE-RICH LIPOPROTEINS



Both the VLDL-TG produced in the liver and the chylomicron-TG from the intestine are hydrolyzed

in the peripheral tissues.

VLDL: A recent kinetic study demonstrated that fish oils increased the conversion rates of

VLDL-apoB to IDL-apoB by 71% and to LDL-apoB by 93%.2 One explanation for the accelerated

conversion may be that the relatively TG-poor VLDL particles, produced during fish oil supplementation, can be lipolyzed more efficiently. However, the experimental evidence does not support

this hypothesis. In vitro, when fish oil-enriched VLDL were hydrolyzed by using purified LpL and

HL, both EPA-and DHA-enriched particles had lower rates of hydrolysis as compared with soy

oil. Release of fatty acids from EPA-enriched particles was even slower than those of the DHA.22

Fish-oil-enriched chylomicrons, treated with LpL, lipolyzed at a higher rate than the palm oil-rich

particles, but at a comparable rate with olive oil-rich or corn oil-rich particles.23 When accelerated

lipolysis is induced in vivo by intravenous heparin infusion, there was no increase in the lipolysis

of VLDL-TG during fish oil treatment as compared to the olive oil placebo.24 Another explanation

may be that although fish oils do not increase the susceptibility of the TG-rich lipoproteins to

lipolysis in vitro, they can stimulate the activities of the lipolyzing enzymes LpL and HL in vivo.

This hypothesis is supported by the findings that fish oils increased the heparin releasable LpL and

HL in healthy subjects, and the post-heparin LpL in patients with hyperlipidemia.24,25

Chylomicron remnants and IDL: In humans, there is conflicting evidence about the effects of

fish oils on the clearance of chylomicron remnants and IDL; both increased and unchanged rates

have been observed. In patients with diabetes or hypertriglyceridemia, supplementation of fish

oils or EPA-ethyl ester decreased the endogenous remnant-like particles in the circulation.20,26

However, when remnant-like particles were injected intravenously in men treated with fish oils,

their clearance rate was unchanged.2 In rats, clearance of chylomicron remnants appears to be

accelerated. Fish oil-rich remnants are taken up more efficiently by the isolated hepatocytes.27,28

The biliary excretion of cholesterol from fish oil-rich chylomicrons is increased.29 This may be

partly due to the induction of 7α-hydroxylase, the rate-limiting enzyme of bile acid synthesis and

cholesterol excretion, by fish oil.30

The hepatic uptake of chylomicron remnants can be facilitated by LDL receptor, LDL receptorrelated protein (LRP), and hepatic lipase. ApoE is a ligand for the LRP. The current evidence

suggests that the fatty acid composition of the chylomicron remnants influence their hepatic uptake.

In addition, fish oil supplementation causes long-term adaptive changes in liver tissue. The response

to the fatty acid composition is mediated primarily by the LDL receptor, whereas the long-term

adaptation involves both the LDL receptor and the LRP.27 Fish oils can modulate the LRP-mediated

uptake also by increasing apoE levels.31 However, the significance of this increase is not clear

because in apoE*3-leiden transgenic mice model, which has decreased clearance of chylomicron

and VLDL remnants, fish oils can still increase VLDL clearance.32 Similarly, in apoE knockout



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(Apoetm1Unc) mice, fish oil and n-3 fatty acid ethyl esters decrease triglyceride, cholesterol, and

phospholipid levels and regulate the activity and mRNA levels of the hepatic enzymes involved in

fatty acid oxidation and synthesis.33 Finally, although hepatic lipase plays a role in chylomicron

remnant clearance, the available evidence indicates that hepatic lipase does not mediate the effects

of fish oils.34



D. METABOLISM



OF



LDL



Despite having beneficial effects on coronary artery disease,35 fish oils do not decrease, and can

even increase, the most atherogenic lipoproteins in the circulation: LDL. To explain this discrepancy,

it was proposed that fish oils may increase the less atherogenic, large, buoyant LDL particles but

not the more atherogenic, small, dense LDL particles. Recent research verified this in patients with

combined hyperlipidemia36 but not in patients with type 2 diabetes.37 The increase in LDL is mostly

due to increased conversion of VLDL apoB to LDL apoB,2,38 but oversecretion of apoB into the

IDL fraction also occurs.38 Studies in animal models and cell cultures consistently demonstrate that

n-3 fish oils decrease the number of LDL receptors.39 However, kinetic studies in humans do not

show a decreased fractional catabolic rate of LDL.2,3



E. METABOLISM



OF



HDL



Omega-3 fatty-acid supplementation has been associated with variable HDL cholesterol response.

Recent research indicates that fish oils may preferentially increase the smaller, cholesterol-poor

HDL particles, which may be more efficient in cholesterol uptake.37 Fish oils may also increase

the delivery of cholesterol from the HDL to the liver, the reverse cholesterol transport, by increasing

scavenger receptor B-1 gene expression.40 Plasma HDL is constantly remodeled by incorporation

of cholesterol ester by LCAT, transfer of neutral lipids between lipoproteins by lipid transfer proteins

and CETP, incorporation of surface lipids and apoproteins during the LpL-mediated lipolysis of

TG-rich lipoproteins, removal of cholesterol ester and phospholipids by HL, and removal of

cholesterol by scavenger receptor. Decreased LCAT,41–43 increased as well as decreased CETP,44,45

decreased lipid transfer protein,41 and increased or unchanged LpL and HL activities25,46 all have

been reported.



IV. SPECIFIC EFFECTS OF INDIVIDUAL N-3 FATTY ACIDS

The recent availability of purified ethyl esters of EPA and DHA provided the opportunity to identify

their specific actions on the lipid metabolism. Although earlier research showed a more potent

triglyceride lowering effect of EPA47 as compared to DHA, recent research disputes this finding.31

Effects of fish oils have also been compared with those of flaxseed oil, which is rich in α-linolenic

acid (18:3 n–3), the precursor of EPA and DHA. Flaxseed oil, unless given in very large amounts,

does not lower plasma TG.48,49



V. POTENTIAL ADVERSE EFFECTS OF FISH OILS:

LIPID PEROXIDATION

Oxidative modification of lipoproteins in the arterial wall is a significant step in atherosclerosis.

The susceptibility of individual fatty acids to oxidation directly depends on their degree of unsaturation. Thus fish oils, with their five or six unsaturated double bonds, can be easily oxidized.50

Recent research suggests that n-3 fatty acids are less susceptible to oxidation than the n-6 fatty

acids that contain a similar number of double bonds;51 fish oils may increase the HDL-bound

antioxidant enzyme paraoxonase;52 thus fish oils may not increase oxidation in vivo.53 As an

additional precaution, most fish oil supplements contain vitamin E.54



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VI. FISH OILS AS COMBINATION THERAPY

FOR HYPERLIPIDEMIA

Statins are the most effective therapeutic agents for LDL-cholesterol lowering while fibrates have

potent triglyceride-lowering effects. Although these two classes of medicines can be used in

combination, this increases the risk of myopathy. Therefore, fish oils have been combined with

statins as an alternative to fibrates and provided additional triglyceride lowering.55,56 Recently, a

different class of LDL-lowering medicine that inhibits intestinal cholesterol absorption, ezetimibe,

became available. To my knowledge, the effects of fish oil and ezetimibe in combination have not

yet been tested.



VII. CONCLUSION

The potent triglyceride-lowering effects of fish oils have been known for a long time. In searching

for the mechanisms, recent research highlighted the importance of fish oils in the regulation of

nuclear receptors. It became evident that fish oils decreased lipogenesis by decreasing SREBP

production by the LXR, and increased peroxisomal β-oxidation of the fatty acids by regulating

PPARα. Currently, several studies are investigating the structural and functional properties of fish

oils and their metabolic products as ligands for nuclear receptors. In addition, the gene-array

technique is providing enormous information about the effects of fish oils on the mRNA abundance.

These efforts are establishing the importance of fish oils, a readily available nutrient, as a significant

modulator of important biochemical pathways.



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43. Parks, J.S., Thuren, T.Y., and Schmitt, J.D. Inhibition of lecithin: cholesterol acyltransferase activity

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45. de Silva, P.P., Agarwal-Mawal, A., Davis, P.J., and Cheema, S.K. The levels of plasma low density

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very low density lipoproteins in humans. Metabolism 44: 1223–1230, 1995.

47. Rambjor, G.S., Walen, A.I., Windsor, S.L., and Harris, W.S. Eicosapentaenoic acid is primarily

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48. Layne, K.S., Goh, Y.K., Jumpsen, J.A., Ryan, E.A., Chow, P., and Clandinin, M.T. Normal subjects

consuming physiological levels of 18: 3(n-3) and 20: 5(n-3) from flaxseed or fish oils have characteristic differences in plasma lipid and lipoprotein fatty acid levels. J Nutr 126: 2130–2140, 1996.

49. Lucas, E.A., Wild, R.D., Hammond, L.J., Khalil, D.A., Juma, S., Daggy, B.P., Stoecker, B.J., and

Arjmandi, B.H. Flaxseed improves lipid profile without altering biomarkers of bone metabolism in

postmenopausal women. J Clin Endocrinol Metab 87: 1527–1532, 2002.

50. Pedersen, H., Petersen, M., Major-Pedersen, A., Jensen, T., Nielsen, N.S., Lauridsen, S.T., and

Marckmann, P. Influence of fish oil supplementation on in vivo and in vitro oxidation resistance of

low-density lipoprotein in type 2 diabetes. Eur J Clin Nutr 57: 713–720, 2003.

51. Napolitano, M., Bravo, E., Avella, M., Chico, Y., Ochoa, B., Botham, K.M., and Rivabene, R. The

fatty acid composition of chylomicron remnants influences their propensity to oxidate. Nutr Metab

Cardiovasc Dis 14: 241–247, 2004.

52. Calabresi, L., Villa, B., Canavesi, M., Sirtori, C.R., James, R.W., Bernini, F., and Franceschini, G.

An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia. Metabolism 53:

153–158, 2004.

53. Tholstrup, T., Hellgren, L.I., Petersen, M., Basu, S., Straarup, E.M., Schnohr, P., and Sandstrom, B.

A solid dietary fat containing fish oil redistributes lipoprotein subclasses without increasing oxidative

stress in men. J Nutr 134: 1051–1057, 2004.

54. Suarez, A., Ramirez-Tortosa, M., Gil, A., and Faus, M.J. Addition of vitamin E to long-chain polyunsaturated fatty acid-enriched diets protects neonatal tissue lipids against peroxidation in rats. Eur

J Nutr 38: 169–176, 1999.

55. Chan, D.C., Watts, G.F., Mori, T.A., Barrett, P.H., Beilin, L.J., and Redgrave, T.G. Factorial study of

the effects of atorvastatin and fish oil on dyslipidaemia in visceral obesity. Eur J Clin Invest 32:

429–436, 2002.

56. Durrington, P.N., Bhatnagar, D., Mackness, M.I., Morgan, J., Julier, K., Khan, M.A., and France, M.

An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides

in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart

85: 544–548, 2001.



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Fish Oils and

8 Omega-3

Insulin Resistance

Sidika E. Kasim-Karakas

CONTENTS

I. Clinical Indications for n-3 Fish Oils in Diabetes ............................................................155

II. Maintenance of Glucose Homeostasis...............................................................................156

III. Effects of n-3 Fish Oils on Glycemic Control ..................................................................156

IV. Effects of n-3 Fish Oils on Pancreatic Insulin Secretion..................................................158

V. Effects of n-3 Fish Oils on Hepatic Glucose Production..................................................158

VI. Effects of n-3 Fish Oils on Peripheral Insulin Action ......................................................158

VII. Effects of n-3 Fish Oils on Adipokines.............................................................................159

VIII. Conclusion..........................................................................................................................159

References ......................................................................................................................................160



I. CLINICAL INDICATIONS FOR N-3 FISH OILS IN DIABETES

It is important to note that fish oils do not lower blood glucose or exert any beneficial effects of

glycemic control. The primary indication for fish oils in diabetes has been the treatment of coronary

artery disease (CAD) risk factors. Diabetes increases the risk of coronary artery disease by 2.4 to

5.1 times. Although women develop CAD at a later age than men, diabetic women lose this relative

protection. Recent research emphasizes the role of fish oils in the prevention and treatment of CAD,

especially in diabetic women.1 In a prospective study, Hu and colleagues2 examined the association

between intake of fish oils and risk of CAD mortality among 5103 female nurses with type 2

diabetes. The relative risk of CAD decreased from 1.0 to 0.36 as the fish intake increased from

less than 1 serving per month to 5 or more servings per week. This inverse relationship was

confirmed in another prospective cohort study of 229 postmenopausal women who participated in

the Estrogen Replacement and Atherosclerosis trial.3 This study used quantitative coronary angiography and showed that diabetic women who consumed more than 2 servings of fish per week had

approximately 3 to 5% less increase in coronary artery stenosis than those women who rarely ate

fish. Higher fish consumption was associated with smaller decreases in coronary artery diameter

and also fewer new lesions.

It has been known for a long time that fish oils have potent triglyceride lowering effects.4–7 As

the CAD risk research expanded from the traditional risk factors such as hyperlipidemias and

hypertension to the newer risk factors such as inflammation, lipid peroxidation, and arterial wall

biology, effects of fish oils on these emerging risk factors were examined. Unfortunately, the

research specific to diabetes is somewhat limited. Mori and colleagues8 reported that both EPA and

DHA reduced in vivo oxidant stress without changing inflammatory markers in hypertensive type

2 diabetic subjects. The same group also investigated changes in platelet aggregation, collagenstimulated thromboxane release, tissue-type plasminogen activator, plasminogen activator inhibitor1, von Willebrand factor and p-selectin levels, and flow-mediated and glyceryl-trinitrate-mediated



155



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dilatation of the brachial artery.9 Relative to placebo, DHA but not EPA significantly reduced

collagen aggregation and thromboxane release, whereas platelet aggregation, fibrinolysis, or vascular function did not change. It appeared that highly purified DHA might be a more effective

antithrombotic agent than EPA. A report from Nomura and colleagues10 indicated that EPA supplementation reduced monocyte activation markers, platelet activation markers, soluble adhesion

molecule E-selectin and the autoantibodies directed against oxidized LDL. These findings suggest

that fish oils reduce CAD risk through multiple mechanisms, above and beyond their beneficial

effects on the plasma lipids. Unfortunately, it is not yet known whether these beneficial outcomes

also occur in diabetic patients.

Another use for fish oils may be in the prevention of diabetes.11 Suresh and Das12 tested the

effects of individual fatty acids on the development of alloxan induced diabetes in rats. Eicosapentanoic acid and DHA, administered either for 5 d prior to alloxan or along with alloxan, protected

against diabetes. In vitro studies in a rat insulinoma cell line suggested that EPA and DHA rendered

this protective effect by preventing alloxan-induced cytotoxicity. In humans, use of cod liver oil,

but not other vitamin D supplements, during the first year of life was associated with a significantly

lower risk of type-1 diabetes, suggesting possible protective effects of fish oils.13

Thus, patients who have diabetes or who are insulin resistant may be asked to supplement their

diet with either fish or fish oils for several reasons. Because earlier studies indicated that fish oils

may have adverse effects on glycemic control,6,14 it is important to review the current information

about the effects of fish oils on various aspects of diabetes.



II. MAINTENANCE OF GLUCOSE HOMEOSTASIS

Normal glucose homeostasis is achieved by a delicate balance among pancreatic insulin secretion,

hepatic glucose production, and peripheral glucose utilization. A change in any one of these can

be compensated for by an alteration in another. For example, impaired insulin action in the peripheral

tissues or increased hepatic glucose output can be compensated for by increased pancreatic insulin

secretion and hyperinsulinemia. In contrast, improvement in peripheral insulin action may result

in decreased pancreatic insulin secretion.

Effects of fish oils on glucose homeostasis have been studied at various levels. Their overall

effect on glycemic control is assessed by measuring blood glucose, glycosylated hemoglobin (Hgb

A1C), and urine glucose excretion. Secretion of insulin from the pancreas is determined by

measuring insulin and C-peptide responses to administration of oral or intravenous glucose, by

mixed meal, and by hyperglycemic insulin clamp technique. Hepatic glucose production and

peripheral insulin action are assessed by the euglycemic clamp technique and by simultaneous use

of radioisotopes. All these assays and techniques have been adapted to animal models. Furthermore,

in vitro studies were carried out to identify the cellular and molecular mechanisms of the effects

of fish oils. In this chapter, the recent research about the effects of fish oils has been reviewed. The

studies included in the earlier publication of this chapter15 have been mentioned briefly.



III. EFFECTS OF N-3 FISH OILS ON GLYCEMIC CONTROL

Earlier clinical studies showed that fish oil supplementation caused either no change16–19 or deterioration of glycemic control.6,14 Two recent meta analyses20,21 concluded that although fish oil

supplementation increased fasting glucose by 5 to 7 mg/dl and HgBA1 by 0.15 to 0.2%, these

changes were not statistically significant. An evidence-based review of the health effects of the fish

oils also found similar elevations in blood glucose and HgBA1 levels, and agreed with the conclusion

of the meta analyses that these changes were not significant (Figure 8.1 and Figure 8.2).22 The

studies included in these analyses showed a wide range of changes in fasting blood glucose levels,

indicating that individual response to fish oil supplementation can be quite variable. All of the

effects of fish oils were reversible after the discontinuation of the therapy.