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© 2005 American Society for Nutrition J. Nutr. 135:2634-2638, November 2005

Nutrient Interactions and Toxicity

Dietary (n-3) Long Chain Polyunsaturated Fatty Acids Prevent Sucrose-Induced Insulin Resistance in Rats1

Ghafoorunissa2, Ahamed Ibrahim, Laxmi Rajkumar and Vani Acharya

National Institute of Nutrition, Indian Council of Medical Research, Hyderabad-500 007 A.P. India

2To whom correspondence should be addressed. E-mail: ghafoorunissanin@rediffmail.com; ghafoorunissanin{at}yahoo.com.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
This study was designed to determine the effect of substituting (n-3) long-chain PUFAs (LCPUFAs) for linoleic acid and hence decreasing the (n-6):(n-3) fatty acid ratio on sucrose-induced insulin resistance in rats. Weanling male Wistar rats were fed casein-based diets containing 100 g/kg fat for 12 wk. Insulin resistance was induced by replacing starch (ST) with sucrose (SU). The dietary fats were formulated with groundnut oil, palmolein, and fish oil to provide the following ratios of (n-6):(n-3) fatty acids: 210 (ST-210, SU-210), 50 (SU-50), 10 (SU-10), and 5 (SU-5). Compared with starch (ST-210), sucrose feeding (SU-210) significantly increased the plasma insulin and triglyceride concentrations and the plasma insulin area under the curve (AUC) in response to an oral glucose load. Adipocytes isolated from rats fed SU-210 had greater lipolytic rate, lower insulin stimulated glucose transport, and lower insulin-mediated antilipolysis than those from rats fed ST-210. Decreasing the dietary (n-6):(n-3) ratio in sucrose-fed rats (SU-10 and SU-5) normalized the plasma insulin concentration and the AUC of insulin after a glucose load. The sucrose-induced increase in plasma triglyceride concentration was normalized in rats fed SU-50, SU-10 and SU-5. Further, sucrose-induced alterations in adipocyte lipolysis and antilipolysis were partially reversed and glucose transport improved in rats fed diets SU-5 and SU-10. In diaphragm phospholipids, decreasing the (n-6):(n-3) ratio in the diet increased the concentration of (n-3) LCPUFAs with concomitant decreases in the concentration of (n-6) LCPUFAs. These results suggest that (n-3) LCPUFAs at a level of 2.6 g/kg diet [0.56% energy (n-3) LCPUFAs, (n-6):(n-3) ratio = 10] may prevent sucrose-induced insulin resistance by improving peripheral insulin sensitivity.

KEY WORDS: • insulin resistance • dietary sucrose • adipose tissue • (n-3) long-chain polyunsaturated fatty acids • rats

Insulin resistance is a major metabolic abnormality associated with several diet-related chronic diseases such as type 2 diabetes, obesity, hypertension, and coronary heart disease (1). Studies have demonstrated that the amount and the type of specific dietary fatty acids are important environmental determinants of insulin resistance (2). High intakes of SFAs lead to insulin resistance, whereas (n-3) PUFAs prevent the development of insulin resistance. Several lines of evidence documented that the (n-3) long-chain PUFAs (LCPUFAs),3 eicosapentaenoic acid [20:5(n-3)] and docosahexaenoic acid [22:6(n-3)], present in fish oil have potential antiatherothrombogenic effects (3). More recent studies in rats showed that fish oil prevented insulin resistance induced by diets containing high fat (4,5) or high sucrose (6–9). Storlien et al. (5) demonstrated that substitution of SFA with fish oil protected against insulin resistance. Further, in sucrose-induced insulin-resistant rats, we reported that substitution of dietary {alpha}-linolenic acid [18:3(n-3)] for linoleic acid [18:2(n-6)] improved peripheral insulin sensitivity (10).

In type 2 diabetics, fish oil supplementation was shown both to improve (11) and to worsen (12) glycemic control. The conflicting results could be due to differences in the dose of (n-3) LCPUFAs, the background diets, or differences in the intake of other fatty acids. To our knowledge, there is no information about the level of (n-3) LCPUFAs [particularly in relation to (n-6) PUFAs] needed to prevent insulin resistance. In the present study, mixtures of groundnut oil, palmolein, and fish oil were used to create a series of diets with differing levels of (n-3) LCPUFAs and ratios of (n-6) to (n-3) fatty acids. The effects of feeding these diets to sucrose-fed rats on plasma indices of insulin sensitivity including glucose and insulin concentrations and the insulin response to an oral glucose load were investigated. To investigate insulin sensitivity in target tissues of insulin action, adipocyte lipolysis and adipocyte glucose transport and phospholipid fatty acid composition of the diaphragm were studied.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Materials. Insulin, HEPES, phloretin, norepinephrine, and fatty acid–free bovine serum albumin were purchased from Sigma Chemical. [1,2-3H]-2-deoxy glucose was purchased from Perkin Elmer. Collagenase was obtained from Gibco (Invitrogen). Fatty acid standards were obtained from Nu-Chek-Prep.

    Rats and diets. All procedures involved in animal experiments were approved by the institutional animal ethical committee, National Institute of Nutrition, Hyderabad, India. Male Wistar rats (n = 80, National Institute of Nutrition), 3 wk old, were housed individually in polypropylene cages at 21 ± 1°C with a 12-h light:dark cycle. Rats were initially fed a standard rat diet (National Centre of Laboratory Animal Sciences, Hyderabad, India). After a 1-wk acclimation period, they were assigned randomly to 5 groups and fed experimental diets (Table 1) for 12 wk. Insulin resistance was induced by replacing starch (ST) with sucrose (SU). The dietary fats were formulated with groundnut oil, palmolein, and fish oil (Max EPA, Merck) to provide different ratios of (n-6) and (n-3) fatty acids. The fatty acid compositions of dietary fats were determined by GC as described earlier (13). The fatty acid composition of the diet (Table 1) was designed to maintain constant proportions of SFAs, monounsaturated fatty acids (MUFAs), and PUFAs [18:2(n-6) + (n-3) LCPUFAs] and differ only in the ratios of (n-6):(n-3) fatty acids. In the starch group (ST-210), the (n-6):(n-3) ratio was 210. The (n-6):(n-3) ratios in sucrose-fed rats were 210 (SU-210), 50 (SU-50), 10 (SU-10), and 5 (SU-5). The concentration of (n-3) LCPUFAs (g/kg diet) in the various groups were: 0.14 (ST-210, SU-210), 0.55 (SU-50), 2.6 (SU-10), and 4.6 (SU-5). Diets were prepared once weekly by adding the oils to the base mixture containing other nutrients and stored at 4°C before use. The oils and base mixtures were stored at 4°C until preparation of the diet. Fish oil was kept under an atmosphere of nitrogen and stored at –20°C. All of the diets were supplemented with {alpha}-tocopherol (0.015 g/kg diet) to prevent oxidation. Rats were given fresh diet every day and had free access to food and water. The food intake of individual rats was recorded daily and the body weight was recorded once each week.


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  		TABLE 1 Fatty acid and ingredient composition of the experimental diets1, 2

 
The oral glucose tolerance test was done after 11 wk of feeding the experimental diets to the rats. Rats were given D-glucose (3 g glucose/kg body weight) through gastric gavage after being deprived of food for 18 h. Blood was collected from the retro-orbital sinus of unanesthetized rats into in EDTA tubes at 0, 30, 60, and 120 min. Plasma was separated and stored at –70°C until analysis. Areas under the curves (AUCs) for glucose and insulin were calculated by the trapezoidal rule.

At the end of the experimental period (12 wk), rats were deprived of food for 18 h, blood was collected in EDTA tubes, and plasma was separated (1500 x g for 20 min) and stored at –70°C until analysis. The rats were killed by CO2 asphyxiation. Liver, diaphragm, and epididymal and retroperitoneal fat pads were removed. A portion of the epididymal adipose tissue was put immediately into Bouin’s fixative and the cell size was measured using the procedure of Ashwell and Priest (15).

    Adipocyte isolation. Adipocytes were isolated from the epididymal fat pad by collagenase digestion according to Rodbell (16). Briefly, minced epididymal fat pads were incubated with collagenase (1 mg/g tissue, type II, GIBCO, Invitrogen) at 37°C for 1 h in Krebs Ringer HEPES buffer (KRH, pH 7.4, 130 mmol/L NaCl, 1.4 mmol/L MgSO4, 5.2 mmol/L KCl, 1.4 mmol/L CaCl2, 1 mmol/L KH2PO4, 10 mmol/L HEPES containing 10 g/L bovine serum albumin and 2 mmol/L pyruvate). Adipocytes were washed 3 times with collagenase-free buffer and suspended in KRH buffer.

    Adipocyte lipolysis and antilipolysis. Lipolysis was assayed by measuring glycerol release into the incubation medium (17). Adipocytes (~2 x 108 cells/L) were incubated at 37°C in polyethylene tubes for 2 h in KRH buffer (pH 7.4) in a final volume of 0.5 mL. The antilipolytic effect of insulin was assessed by incubating adipocytes with 1 µmol/L norepinephrine (maximum stimulating concentration) and various concentrations of insulin (18). After 2 h of incubation, the tubes were placed in an ice bath and cells were separated from the medium by a brief centrifugation (500 x g for 1 min). The infranatant below the cell layer was removed and the glycerol content was estimated.

    Adipocyte glucose transport. Basal and insulin-stimulated glucose transport were measured as described (19). Adipocytes (~2 x 108 cells/L) were preincubated with and without various concentrations of porcine insulin at 37°C for 45 min. The cells were incubated with 2-[1,2-3H] deoxyglucose at a concentration of 0.1 mmol/L in KRH buffer (pH 7.4). The assay was terminated at the end of 3 min by transferring the assay mixture to a microcentrifuge tube containing silicone oil. The tubes were centrifuged at 3000 x g for 3 min. The top layer containing adipocytes was transferred to a liquid scintillation vial and radioactivity associated with adipocytes was measured in a liquid scintillation counter. All data were corrected for nonspecific transport by measuring glucose transport in the presence of 0.3 mmol/L phloretin.

    Diaphragm lipid analysis. Diaphragm total lipids were extracted using the method of Folch (20). Neutral lipids were separated from phospholipids by TLC on silica gel G with hexane:diethyl ether:acetic acid (80:20:1 by vol) and the fatty acid methyl esters were analyzed by GC using a SP-2330 capillary column (30 m x 0.25 mm i.d., Supelco) as described earlier (13). Diaphragm triglycerides were quantitated using an enzymatic assay kit (glycerol phosphate oxidase/peroxidase kit) from Biosystems. Protein was estimated by Lowry’s method (21).

    Plasma analysis. Plasma glucose (glucose oxidase/peroxidase kit), triglycerides (glycerol phosphate oxidase/peroxidase kit), and cholesterol (cholesterol oxidase/peroxidase kit) were estimated using enzymatic methods (Biosystems) and insulin by RIA using a kit (RIAK-1) from BRIT.

    Statistical analysis. Statistical analysis was done using the SPSS statistical program. All of the values are presented as means ± SEM. Data were evaluated by one-way ANOVA followed by least square difference (LSD) post hoc tests. Differences of P < 0.05 were considered significant.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    Energy intake, body weight gain, and adipose tissue relative weights. Rats fed SU-210 consumed more energy than controls fed ST-210 (Table 2). Body weight gain and adipose tissue relative weights were higher in rats fed SU-210 than in those fed ST-210. Increasing dietary (n-3) LCPUFAs and decreasing the (n-6):(n-3) ratio in sucrose-fed rats did not prevent the increase in body weight gain and adipose tissue weight. Neither dietary sucrose nor (n-3) LCPUFAs altered adipocyte number or size (Table 2).


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  		TABLE 2 Energy intake, body weight gain, and adipose tissue relative weights in rats fed a starch diet or sucrose diets with different (n-6):(n-3) fatty acid ratios1

 
    Plasma chemistry. Rats fed SU-210 had significantly higher plasma insulin and triglyceride concentrations than those fed ST-210 (Table 3). In sucrose-fed rats, decreasing the (n-6):(n-3) ratio to 50 (SU-50) normalized plasma triglycerides and decreased (SU-50) or normalized (SU-5 and SU-10) plasma insulin concentrations. The SU-10 and SU-5 groups had lower plasma total cholesterol concentrations than the SU-210 group. After a glucose load, the SU-210 and SU-50 groups had greater plasma insulin AUCs than rats fed ST-210 (Fig. 1). Increasing (n-3) LCPUFAs in the sucrose diet (SU-10 and SU-5) significantly lowered the plasma insulin response to a glucose load.


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  		TABLE 3 Plasma concentrations of glucose, insulin, and lipids in rats fed a starch diet or sucrose diets with different (n-6):(n-3) fatty acid ratios1

 


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  		FIGURE 1 Plasma insulin responses to an oral glucose load in rats fed a starch diet or sucrose diets with different (n-6):(n-3) fatty acid ratios. Values are means ± SEM, n = 14. Means at a time or AUC means (pmol/L · min) without a common letter differ, P < 0.05.

 
    Adipocyte lipolysis, insulin-mediated antilipolysis, and glucose transport. Rats fed SU-210 and SU-50 had higher basal and norepinephrine-stimulated lipolysis (Fig. 2A) and insulin-mediated antilipolysis (Fig. 2B) than those fed ST-210. Increasing (n-3) LCPUFAs in the diet (SU-10 and SU-5) generally decreased norepinephrine-mediated lipolysis. Adipocyte sensitivity to the antilipolytic effect of insulin was greater in both the SU-10 and SU-5 groups than in the SU-210 and SU-50 groups. The dose response curve for insulin-stimulated glucose transport showed increased glucose transport in the SU-5 group compared with the SU-210 and SU-50 groups (Fig. 3).



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  		FIGURE 2 Dose-response curves of norepinephrine-stimulated lipolysis (A) and the antilipolytic effect of insulin (B) in isolated epididymal adipocytes from rats fed a starch diet or sucrose diets with different (n-6):(n-3) fatty acid ratios. Glycerol release by adipocytes into the incubated medium was used as an index of lipolysis. Values are means ± SEM, n = 16. Means at a concentration without a common letter differ, P < 0.05.

 


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  		FIGURE 3 Dose-response curves of insulin-stimulated glucose in isolated epididymal adipocytes from rats fed a starch diet or sucrose diets with different (n-6):(n-3) fatty acid ratios. Values are means ± SEM, n = 16. Means at a concentration without a common letter differ, P < 0.05.

 
    Diaphragm lipid composition. The groups did not differ in diaphragm triglyceride content (Table 4). Total SFA and MUFA in phospholipids did not differ among the groups (Table 4). As the (n-6):(n-3) fatty acid ratio of the diet decreased, the proportion of (n-6) LCPUFAs in diaphragm phospholipids decreased progressively. This was paralleled by a progressive increase in the proportion of (n-3) LCPUFAs.


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  		TABLE 4 Diaphragm triglyceride content and phospholipid fatty acid composition in rats fed a starch diet or sucrose diets with different (n-6):(n-3) fatty acid ratios1

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
Several animal studies indicated that the (n-3) LCPUFAs present in fish oil have a preventive effect against high-fat (4,5) and high-sucrose (6–9) diet-induced insulin resistance. Further, (n-3) LCPUFAs were shown to increase insulin sensitivity in normal rats (22). Although there are several studies on the beneficial effects of (n-3) LCPUFAs, the minimum amount of (n-3) LCPUFAs and the optimal (n-6):(n-3) fatty acid ratio needed for the prevention of insulin resistance are not known. High-sucrose diets were shown to impair peripheral (23) and hepatic (24) insulin sensitivity in rats. Our earlier study showed that {alpha}-linolenic acid [18:3(n-3)] at 11 g/kg diet [(n-6):(n-3) ratio = 2] improved insulin sensitivity in sucrose-fed rats (10). The present study demonstrated that substitution of (n-3) LCPUFAs for linoleic acid without changing the total PUFA, SFA, and MUFA prevented the sucrose-induced insulin resistance. The minimum amount of (n-3) LCPUFAs required for prevention of hyperinsulinemic response to a glucose challenge was 2.6 g/kg diet [(n-6):(n-3) ratio = 10]. The observed decrease in compensatory insulin response in (n-3) LCPUFA-fed rats suggests an increase in insulin sensitivity.

Fish oils were shown to decrease visceral adiposity (25). In the present study, sucrose feeding was associated with an increase in adipose tissue weight and body weight, which could be due to increased energy intake. The lack of effect of (n-3) LCPUFAs in reducing the visceral adiposity in sucrose-fed rats suggests that >4.6 g/kg diet of (n-3) LCPUFAs may be needed to reduce visceral adiposity. Several animal and human studies showed that (n-3) LCPUFAs decrease plasma triglyceride levels dose dependently (26,27). In the present study 0.5 g/kg diet of (n-3) LCPUFAs [(n-6):(n-3) ratio of 50] normalized the sucrose-induced increase in plasma triglycerides. It therefore appears that the dose of (n-3) LCPUFAs required for the hypotriglyceridemic effect may be lower than the level needed for the prevention of hyperinsulinemia.

The mechanism by which dietary (n-3) LCPUFAs prevent insulin resistance remains unclear. Adipose tissue releases FFA and adipocytokines into the circulation, and its metabolic activity is the main contributor to the development of insulin resistance (28). The present study suggests that a decrease in adipocyte lipolysis by (n-3) LCPUFAs could play an important role in increasing insulin sensitivity by reducing the fatty acid availability and increasing glucose utilization as reported by Randle et al. (29). The fatty acid composition of membrane phospholipids of insulin target tissues is an important factor influencing insulin sensitivity through their effect on insulin receptor and the glucose transporter (GLUT4). Studies showed that the (n-3) LCPUFA content in adipose tissue and skeletal muscle phospholipids contributes to efficient insulin action (5,6). We reported earlier (10) that the increase in (n-3) LCPUFAs in adipocyte plasma membrane and diaphragm in rats fed high levels of 18:3 (n-3) in sucrose-based diets was associated with an improvement in insulin sensitivity. Girion et al. (30) demonstrated that dietary fish oil supplementation increased the expression of GLUT4 mRNA in skeletal muscle of diabetic rats. The observed increase of (n-3) LCPUFAs in diaphragm phospholipids and therefore possibly in all skeletal muscle and adipocyte plasma membrane could have contributed to the reversal of insulin resistance in sucrose-fed rats. Another mechanism by which (n-3) LCPUFAs may improve insulin action could be through correction of hyperinsulinemia. Del Parto et al. (31) showed that hyperinsulinemia caused by either exogenous insulin infusion or endogenous insulin secretion induced insulin resistance. In this context, a recent study indicated that sucrose feeding increased fat storage and decreased pyruvate dehydrogenase complex activity in the ß cell of the pancreas, resulting in abnormal secretion of insulin and peripheral insulin resistance (32). Supplementation of fish oil reversed these alterations. Thus, correction of hyperinsulinemia could be one mechanism by which (n-3) LCPUFAs prevent sucrose-induced insulin resistance. Alternatively, (n-3) LCPUFAs could prevent insulin resistance by a direct membrane independent effect on gene expression. The (n-3) LCPUFAs regulate the transcription of several genes involved in glucose and lipid metabolism (33,34). It is also possible that (n-3) LCPUFAs may improve insulin sensitivity through upregulation of the intracellular insulin signaling pathway (35). Recent studies indicated that adipose tissues produce and release a number of proteins collectively known as adipocytokines, which may play a major role in the prevention of insulin resistance. Leptin and adiponectin were shown to prevent insulin resistance, whereas resistin and tumor necrosis factor {alpha} induced insulin resistance (36). Indeed, cell culture (37) and animal studies (38) reported that (n-3) LCPUFAs upregulate leptin mRNA expression and secretion. Further, (n-3) LCPUFAs were shown to ameliorate conjugated linoleic acid–induced insulin resistance by upregulating the expression of leptin and adiponectin (39). These studies suggest that the beneficial effects of (n-3) LCPUFAs in preventing insulin resistance may be exerted indirectly through adipocytokines.

In conclusion, the results of the present study demonstrate that in diets providing 28 g of 18:2 (n-6)/kg diet, substitution of ~10% of (n-3) LCPUFAs [(n-6):(n-3) ratio = 10] prevented sucrose-induced insulin resistance in rats, and these effects may be mediated through incorporation of (n-3) LCPUFAs in membrane lipids. Thus, inclusion of fish in the diets or use of fish oil supplements may be beneficial for alleviation and prevention of insulin resistance and for reducing the risk of associated chronic diseases.


   FOOTNOTES
 
1 Supported by a grant from the Department of Science and Technology, Government of India. Back

3 Abbreviations used: GLUT, glucose transporter; KRH, Krebs Ringer HEPES buffer; LCPUFA, long-chain PUFA; MUFA, monounsaturated fatty acid; ST, starch; SU, sucrose; ST-210, SU-210, SU-50, SU-10, SU-5, starch and sucrose diets with (n-6):(n-3) fatty acid ratios of 210, 50, 10, and 5. Back

Manuscript received 13 February 2005. Initial review completed 18 April 2005. Revision accepted 2 August 2005.


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