A modified high-fat diet induces insulin resistance in rat skeletal
muscle but not adipocytes.

Wilkes JJ, Bonen A, Bell RC.
Department of Kinesiology, University of Waterloo, Waterloo, Ontario,
Canada N2L 3G1.

We hypothesized that variation in dietary fatty acid composition in
rats fed a high-fat diet had tissue-specific effects on glucose uptake
sufficient to maintain normal glucose tolerance. Rats were fed one of
three diets for 3 wk. The isocaloric high-fat-mixed oil (HF-mixed)
diet and the high-fat-safflower oil (HF-saff) diet both provided 60%
kcal fat, but fat composition differed [HF-mixed = saturated,
polyunsaturated (n-3 and n-6), and monounsaturated fatty acids; HF-
saff = polyunsaturated fatty acids (mainly n-6)]. The control diet was
high carbohydrate (HCHO, 10% kcal fat). Insulin-stimulated 3-O-
methylglucose uptake into perfused hindlimb muscles was reduced in
rats fed HF-saff and HF-mixed diets compared with those fed HCHO diet
(P < 0.02). Basal uptake increased in HF-saff- and HF-mixed-fed rats
vs. HCHO-fed rats (P < 0.04). In adipocytes, HF-saff feeding decreased
2-deoxyglucose uptake vs. HF-mixed feeding and HCHO feeding (P <
0.05), but 2-deoxyglucose uptake in HF-mixed-fed rats did not differ
from that in HCHO-fed rats (P > 0.05). Glucose tolerance was
significantly reduced in HF-saff-fed rats but was unaffected by the HF-
mixed diet. Therefore, in skeletal muscle of rats, 1) feeding a diet
high in fat induces a reduction in insulin-stimulated glucose uptake
but 2) provides an increase in basal glucose uptake. In contrast, 3)
in adipocytes, insulin-stimulated glucose transport is reduced only
when the high-fat diet is high in n-6 polyunsaturated fatty acids but
not when fat comes from these mixed sources. Glucose intolerance
becomes evident when insulin resistance is seen in multiple tissues.
PMID: 9755088

Diabetes. 1991 Feb;40(2):280-9.

Influence of dietary fat composition on development of insulin
resistance in rats. Relationship to muscle triglyceride and omega-3
fatty acids in muscle phospholipid.

Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW.
Garvan Institute of Medical Research, St. Vincent's Hospital,
Darlinghurst, New South Wales, Australia.

High levels of some but not all dietary fats lead to insulin
resistance in rats. The aim of this study was to investigate the
important determinants underlying this observation. Insulin action was
assessed with the euglycemic clamp. Diets high in saturated,
monounsaturated (omega-9), or polyunsaturated (omega-6) fatty acids
led to severe insulin resistance; glucose infusion rates [GIR] to
maintain euglycemia at approximately 1000 pM insulin were 6.2 +/- 0.9,
8.9 +/- 0.9, and 9.7 +/- 0.4 mg.kg-1. min-1, respectively, versus 16.1
+/- 1.0 mg.kg-1.min-1 in chow-fed controls. Substituting 11% of fatty
acids in the polyunsaturated fat diet with long-chain omega-3 fatty
acids from fish oils normalized insulin action (GIR 15.0 +/- 1.3
mg.kg-1.min-1). Similar replacement with short-chain omega-3 (alpha-
linolenic acid, 18:3 omega 3) was ineffective in the polyunsaturated
diet (GIR 9.9 +/- 0.5 mg.kg-1.min-1) but completely prevented the
insulin resistance induced by a saturated-fat diet (GIR 16.0 +/- 1.5
mg.kg-1.min-1) and did so in both the liver and peripheral tissues.
Insulin sensitivity in skeletal muscle was inversely correlated with
mean muscle triglyceride accumulation (r = 0.95 and 0.86 for soleus
and red quadriceps, respectively; both P less than 0.01). Furthermore,
percentage of long-chain omega-3 fatty acid in phospholipid measured
in red quadriceps correlated highly with insulin action in that muscle
(r = 0.97). We conclude that 1) the particular fatty acids and the
lipid environment in which they are presented in high-fat diets
determine insulin sensitivity in rats; 2) impaired insulin action in
skeletal muscle relates to triglyceride accumulation, suggesting
intracellular glucose-fatty acid cycle involvement; and 3) long-chain
omega-3 fatty acids in phospholipid of skeletal muscle may be
important for efficient insulin action.

J Clin Endocrinol Metab. 2004 Apr;89(4):1641-5.

Differential metabolic effects of saturated versus polyunsaturated
fats in ketogenic diets.

Fuehrlein BS, Rutenberg MS, Silver JN, Warren MW, Theriaque DW, Duncan
GE, Stacpoole PW, Brantly ML.
Department of Medicine, College of Medicine, University of Florida,
Gainesville, Florida 32610, USA.

Ketogenic diets (KDs) are used for treatment of refractory epilepsy
and metabolic disorders. The classic saturated fatty acid-enriched
(SAT) KD has a fat:carbohydrate plus protein ratio of 4:1, in which
the predominant fats are saturated. We hypothesized that a
polyunsaturated fat-enriched (POLY) KD would induce a similar degree
of ketosis with less detrimental effects on carbohydrate and lipid
metabolism. Twenty healthy adults were randomized to two different
weight-maintaining KDs for 5 d. Diets were 70% fat, 15% carbohydrate,
and 15% protein. The fat contents were 60 or 15% saturated, 15 or 60%
polyunsaturated, and 25% monounsaturated for SAT and POLY,
respectively. Changes in serum beta-hydroxybutyrate, insulin
sensitivity (S(I)), and lipid profiles were measured. Mean circulating
beta-hydroxybutyrate levels increased 8.4 mg/dl in the POLY group (P =
0.0004), compared with 3.1 mg/dl in the SAT group (P = 0.07). S(I)
increased significantly in the POLY group (P = 0.02), whereas total
and low-density lipoprotein cholesterol increased significantly in the
SAT group (both P = 0.002). These data demonstrate that a short-term
POLY KD induces a greater level of ketosis and improves S(I), without
adversely affecting total and low-density lipoprotein cholesterol,
compared with a traditional SAT KD. Thus, a POLY KD may be superior to
a classical SAT KD for chronic administration.
http://jcem.endojournals.org/cgi/content/full/89/4/1641