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Article

High Glycemic Index Starch Promotes Hypersecretion of Insulin and Higher Body Fat in Rats without Affecting Insulin Sensitivity¹

Human Nutrition Unit, Department of Biochemistry, The University of Sydney, NSW 2006, Australia

²To whom correspondence should be addressed. E-mail: j.brandmiller{at}biochem.usyd.edu.au.

	ABSTRACT

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In rats, prolonged feeding of high glycemic index (GI) starch results in basal hyperinsulinemia and an elevated insulin response to an intravenous glucose tolerance test (IVGTT). The aim of this study was to assess hepatic and peripheral insulin resistance (IR) using euglycemic hyperinsulinemic clamps. Insulin sensitivity, epididymal fat deposition and fasting leptin concentrations were compared in rats fed isocalorically a low or high GI diet for 7 wk (45% carbohydrate, 35% fat and 20% protein as energy) or a high fat diet (20% carbohydrate, 59% fat and 21% protein as energy) for 4 wk so that final body weights were similar. At the end of the study, high GI rats had higher basal leptin concentration and epididymal fat mass than the low GI group, despite comparable body weights. High GI and high fat feeding both resulted in the higher insulin response during IVGTT, but impaired glucose tolerance was seen only in rats fed high fat. The GI of the diet did not affect basal and clamp glucose uptake or hepatic glucose output, but high fat feeding induced both peripheral and hepatic IR. The findings suggest that hypersecretion of insulin without IR may be one mechanism for increased fat deposition in rats fed high GI diets.

KEY WORDS: • glycemic index • insulin hypersecretion • insulin sensitivity • adipose tissue • rats

	INTRODUCTION

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The macronutrient composition of the diet has been shown to affect the development of insulin resistance (IR).³ In particular, high fat feeding induces peripheral and hepatic IR via multiple mechanisms involving muscle triglyceride (TG) accumulation (1) , elevated muscle lipid oxidation and overstimulation of hepatic gluconeogenesis (2) . The type of fat is of crucial importance because saturated and polyunsaturated (n-6) fatty acids are implicated specifically in the promotion of severe IR (3) . In contrast, polyunsaturated (n-3) fatty acids exert a protective effect, which may involve the modification of phospholipid components in the skeletal muscle membranes (4) . For these reasons, diets that are low in saturated fat or high in carbohydrate are recommended for the prevention of IR and diabetes.

It is less clear how different types of carbohydrate influence insulin sensitivity. Animal and human intervention studies often compare the effects of a "simple" carbohydrate (mostly sucrose) with a "complex" one (unspecified starch). Such a classification of carbohydrates, however, gives little insight into their actual postprandial metabolic effects. Differences in the glycemic index (GI) of the carbohydrates used in those studies may contribute to variable and conflicting results. The GI classifies the carbohydrates in foods on the basis of their immediate postprandial glycemic effect and offers a more physiologic and standardized approach toward metabolic studies of dietary carbohydrates.

Recent epidemiologic studies have shown a positive association between dietary GI and the risk of Type II diabetes (5) and myocardial infarction in women (6 ,7) and a negative association with HDL cholesterol (8) . Similarly, increased consumption of (low GI) whole grains has been found to have a protective effect on the development of cardiovascular disease (9) as well as cancer (10) . Together, these findings suggest that the GI influences insulin sensitivity.

The metabolic pathways by which dietary carbohydrates may contribute directly to the pathogenesis of IR are poorly understood, and few studies have focused on the type of starch and insulin sensitivity. High GI diets have been shown to cause increases in muscle TG concentration in humans, with little change in insulin sensitivity (11) . This finding, however, contrasts with the reported improvement in insulin sensitivity and glucose tolerance among patients with coronary heart disease who consumed a low GI diet (12 ,13) .

Our group showed that long-term feeding of a high GI starch (amylopectin) in rodents resulted in high postprandial glucose and insulin profiles compared with a low GI starch (amylose) (14) . The high GI diet promoted a high insulin response during an intravenous glucose tolerance test (IVGTT) (14) , which increased with the duration of feeding (15) and eventually led to fasting hyperinsulinemia. The glucose response, however, was not affected, implying a lack of impairment in insulin sensitivity.

The primary aim of this study was to investigate the effects of long-term feeding with starches of differing GI on insulin sensitivity, assessed by both hyperinsulinemic clamp and IVGTT. Our second aim was to determine whether high GI diets led to differences in fat mass and fasting metabolites in the blood. We investigated the effect of high vs. low GI starches incorporated into a diet that was similar in its macronutrient composition to an average human diet [35% energy (E) as fat, 20% E protein and 45% E as carbohydrate (CHO)]. A third group was fed a high fat diet for comparison.

	MATERIALS AND METHODS

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Animals.

Australian Albino Wistar rats (6–7 wk of age), weighing 215 ± 6 g, were purchased from Biological Resources Center, University of NSW, Australia and maintained in a normal light cycle (0600–1800 h, light; 1800–0600 h, dark). The rats were allowed to acclimate for a week before the commencement of the study. Ethics approval was obtained from The Sydney University Animal Ethics Committee.

Feeding protocol.

Rats were allocated randomly to three groups and fed a diet containing either high GI starch (amylopectin) or low GI starch (amylose) with 35% E as fat. The third group was fed a high fat (60% E as fat) diet to induce hepatic and peripheral IR (Table 1). All rats were approximately the same weight at the beginning of the study. They were fed two meals per day; however, to maximize the metabolic effect of the CHO, one meal was higher in CHO than the other (morning, 20% CHO as energy; evening, 70% CHO) (Fig. 1 ). Rats were fed the high and low GI diets for 7 wk and the high fat diet for 4 wk so that final body weights were similar. In this way, differences in body fatness or insulin sensitivity were attributable to diet rather than body weight. At the end of the dietary intervention, basal blood was collected by tail bleeding using sodium citrate as anticoagulant. Plasma samples were stored at -70°C and used to determine plasma TG, nonesterified fatty acids (NEFA), insulin and glucose.

View larger version (31K): [in this window] [in a new window]   Figure 1. A schematic representation of macronutrient composition of the meals in each dietary group. All rats in this study received the same morning meal [7.8 g of the 59% fat as energy (E) diet]. To intensify the effect of glycemic index (GI) and to maintain the diets isocaloric, the evening meals were different for each group. Rats in high fat group (High fat) were given 7.8 g of the 59% E fat diet, in high GI group (High GI), 12.5g of the 11% E fat high GI diet and in low GI group (Low GI), 15g of 11% E low GI diet per meal. Abbreviation: CHO, carbohydrate.

This procedure was modified from Kraegen et al. (16) and Horton et al. (17) . At the end of the feeding trial, rats were anesthetized with an intraperitoneal injection of ketamine hydrochloride (50 mg/kg) and xylazine (10 mg/kg). Cannulae were implanted in the left carotid artery and right jugular vein and exteriorized through the back of the neck. During the postsurgical period, rats consumed their respective diets and were at 95% of their presurgical body weight at the time of the study. Studies were conducted 6–7 d after surgery in unrestrained and conscious rats. The carotid artery catheter was used for blood sampling and the jugular vein catheter was used for infusions of human insulin, glucose and tracer. A blood sample was taken from food-deprived rats, and a primed (222 kBq), continuous (4.5 kBq/min) infusion of [3-H³]glucose (Amersham Life Science, Little Chalfont, UK) was started. A steady state of plasma glucose specific activity was established after 90 min and blood samples (250 µL) were taken at 100, 110 and 120 min. After a final basal blood sample, insulin infusion [0.25 U/(kg · h)] and variable glucose infusion (30% glucose) were started. Glucose infusate was spiked with [3-H³]glucose to prevent reduction in blood glucose specific activity during the clamp. Approximately 7–8 blood samples (25 µL) were taken every 10 min to clamp blood glucose at 5.5 mmol/L. The clamp steady state was established after 90 min of euglycemia and three blood samples were taken every 10 min. Peripheral glucose disposal (R_d) and hepatic glucose production (R_a) were calculated as follows:

(1)

(2)

where R^*_a is the tracer infusion rate (dpm/min); SA_g is glucose specific activity at the steady state; and R_I is the glucose infusion rate.

Intravenous glucose tolerance test (IVGTT).

After the clamp, rats were allowed to recover for 7 d. A blood sample (250 µL) was taken from food-deprived rats before infusion of the glucose solution (500 g/L) as a bolus (1 g/kg body) via jugular vein and flushed with 300 µL of saline. Blood samples (150 µL) were collected in sodium citrate–containing tubes from the vein at the 2-, 4-, 6-, 8-, 10-, 15-, 30-, 45- and 60-min time points. All blood samples were immediately centrifuged, (30 s, 12,000 g) and the plasma was stored at -70°C for glucose and insulin measurements. RBC were resuspended in saline/heparin solution and reinfused into the rats during IVGTT.

Analytic techniques.

Blood glucose concentration during the clamp was determined using a glucose analyzer (2300 Stat Plus; Yellow Springs Instrument, Yellow Spring, OH). Plasma glucose was determined by the glucose oxidase/peroxidase method. Plasma fatty acids and TG were assayed using colorimetric tests (Wako Chemicals, Osaka, Japan and Boehringer Mannheim, Mannheim, Germany, respectively). Insulin was measured by RIA (Linco Research, St. Charles, MO). Clamp plasma samples (150 µL) for the determination of tracer concentration were deproteinized with 0.3 mmol/L ZnSO₄ and saturated Ba(OH)₂ and centrifuged (30 s, 12,000 g). Aliquots of the supernatant were used to determine glucose concentration. Other aliquots were evaporated to dryness at 60°C to remove ³H₂O, reconstituted and counted in a liquid scintillation counter using Ultima Gold scintillant (Packard Bioscience, Groningen, The Netherlands).

Data analysis.

Data are presented as means ± SEM. Repeated-measures ANOVA with Fisher’s post-hoc test was used to analyze the effect of time and diet on glucose and insulin response during IVGTT. All other variables were compared using factorial ANOVA with Fisher’s post-hoc test. Significant difference was accepted at P < 0.05.

	RESULTS

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Body weight, epididymal fat pads.

Rats in all three groups (high GI, low GI and high fat) consumed both meals without spilling. There were no differences in body weight among the three dietary groups at the end of the study periods (Table 2). The relative mass of epididymal fat pads in the low GI group (g/100 g body) was 22% lower than the high GI group and 41% lower than high fat–fed rats (Table 2) . Both high GI and high fat feeding resulted in greater weight of epididymal fat pads in the absence of any difference in body weight.

Basal leptin levels were significantly higher but TG lower after high GI feeding compared with low GI (Table 2) . High GI rats had plasma leptin concentrations not different from those of the high fat diet group but higher levels of NEFA and lower TG. There was no difference in insulin levels among the groups, but basal plasma glucose was greater in rats fed high fat than in the other two groups.

Intravenous glucose tolerance test.

There were no differences in basal insulin and glucose concentration at the beginning of the IVGTT. High fat–fed rats showed reduced ability to clear the glucose load as indicated by significantly greater plasma glucose level at all time points measured (Fig. 2 ). In contrast, both the incremental area over the first 60 min of the glucose response curve (AUC) and the peak plasma glucose levels during IVGTT were not different in high and low GI rats [AUC: 253 ± 32 and 315 ± 30 mmol/(L · 60min), peak glucose: 28.7 ± 1.3 and 29.2 ± 1.4 mmol/L, respectively].

View larger version (27K): [in this window] [in a new window]   Figure 2. The effect of consumption by rats of a high fat (High fat) diet for a period of 4 wk and a low or high glycemic index (Low GI or High GI, respectively) diet for 7 wk on plasma glucose during an intravenous glucose tolerance test (IVGTT). All rats received a 1 g/kg intravenous bolus of glucose. (A) Glucose response curve to a bolus of glucose. *P < 0.05 comparing High GI to High fat over 60 min (ANOVA repeated measures). (B) Incremental area under 60-min glucose response curve; *P < 0.05 comparing High GI diet to High fat diet (ANOVA); #P < 0.05 comparing Low GI diet to High fat diet. Data are expressed as means ± SEM, n = 10.

View larger version (28K): [in this window] [in a new window]   Figure 3. The effect of consumption by rats of a high fat (High fat) diet for a period of 4 wk and a low or high glycemic index (Low GI or High GI, respectively) diet for 7 wk on plasma insulin during an intravenous glucose tolerance test (IVGTT). All rats received a 1 g/kg intravenous bolus of glucose. (A) Insulin curve in response to the glucose bolus; *P < 0.05 comparing Low and High GI diets (ANOVA repeated measures). (B) Incremental area under the first 30 min of insulin response curve; *P < 0.05 comparing Low GI with High GI (ANOVA). Data are expressed as means ± SEM, n = 10.

Basal and insulin-stimulated glucose metabolism variables are summarized in Table 3 . The type of starch in the diet had no effect on the liver and peripheral glucose sensitivity under either basal or clamp conditions. Exogenous glucose infusion rate (GIR) and insulin effectiveness in suppression of hepatic glucose production during the clamp were significantly lower in the high fat group compared with high GI rats. There were no differences in the whole-body glucose utilization rate as indicated by similar insulin-stimulated glucose turnover in the high fat, high and low GI groups.

	DISCUSSION

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In contrast to our previous studies (14 ,15) (with 11% E as fat), the fat content of the low and high GI diets was relatively high (35% E as fat), to match the level of fat commonly consumed in the Western diet. Nevertheless, the elevated insulin response during an IVGTT was still observed in the rats fed a high GI diet. We speculate that this hypersecretion of insulin in response to a glucose challenge after only 7 wk of feeding may alter fuel utilization and patterns of energy disposition, irrespective of changes in insulin sensitivity.

The potential mechanisms involved in hypersecretion of insulin in high GI rats are not readily apparent. An acute increase in circulating NEFA stimulates insulin secretion in normal subjects and those predisposed to Type II diabetes (18) , and in mice (19) and rats (20) . However, it is questionable that this mechanism is involved here because NEFA after food deprivation in the high GI group were only slightly and not significantly (P = 0.1) elevated compared with rats fed low GI. There was also no difference between the groups in the NEFA concentration during IVGTT (data not shown). Elevated NEFA have no effect on the first phase (first 10 min) of glucose-stimulated insulin secretion in human subjects (18) . In this study, in fact, the most pronounced differences in insulin secretion were observed in the first 10 min of IVGTT. In studies of perfused pancreas, insulin production increased in parallel with the increase in pancreatic TG concentration in normal Wistar and prediabetic Zucker rats (21) . Similarly, pancreatic islets, which were isolated from rats fed a high GI diet, contained more TG and secreted more insulin (fourfold) in a response to basal (5 mmol/L) glucose stimulation than islets from rats fed the low GI diet (22) . These differences suggest that other factors such as local TG accumulation in islets rather than circulating NEFA and TG may be involved.

The high GI starch used in this study increased postprandial glycemia in response to a single meal, which persisted over a 120-min period after consumption (14) . Extended periods of hyperglycemia induced by chronic glucose infusion have been shown to produce muscle IR in animal studies (23 24 25) . In humans, hyperglycemia of 12.6 mmol/L was associated with decreased GIR and glucose uptake (26) . However, with glycemia below 9 mmol/L, no changes in insulin sensitivity were observed (26 ,27) . Byrnes et al. (14) studied the effects of the evening meal on the postprandial glycemic profile; a high GI CHO meal was found to produce a peak glycemia of a maximum of 10 mmol/L. The degree of resulting glycemia may not be high and prolonged enough to lead to IR, at least in the short term.

Rats fed the high GI diet had significantly lower basal plasma TG concentrations than rats fed the low GI diet in the presence of similar basal glucose and insulin profiles, which disagrees with published studies (28) . Triglyceride secretion has been shown to correlate positively with plasma leptin in normal rats and those with ventromedial lesions (29) , suggesting an increase in TG release with increasing adiposity. Triglycerides increased with chronic hyperinsulinemia in insulin-resistant fructose-fed rats but not in insulin-sensitive glucose-fed rats (30) . In contrast, acute administration of insulin results in decreased secretion of VLDL-TG (31) . The activity of lipoprotein lipase, which hydrolyzes the TG component of circulating lipoproteins, is not affected by the GI of diets (32) . The mechanism of lower plasma TG in high GI–fed animals remains to be investigated. It may be associated with enhanced shunting of TG into adipose tissue in young and still growing rats.

Plasma leptin is usually positively correlated with a general adiposity, irrespective of distribution of fat (33 ,34) . We found higher leptin concentrations and larger epididymal fat pads in both the high fat and high GI groups. Rats fed a high fat diet have recently been reported to have lower plasma leptin concentration per unit abdominal fat mass than controls (35) . Consistent with this finding, in this study, the plasma leptin (µg/L)/epididymal fat (g) ratio tended to be higher (P = 0.10) in the high GI group compared with the high fat group.

Compared with low GI starch feeding, consumption of the high GI starch resulted in significantly greater epididymal fat pad weight despite the similar body weight gain and isocaloric feeding regimen. Support for this finding comes from a study that showed higher adipocyte volume in rats fed a high GI wheat starch vs. a low GI mung bean starch (36) . However, in that study, both food intake and weight gain were higher in the high GI group. It has been reported that the mRNA expression and activity of fatty acid synthase, a key lipogenic enzyme, increase in adipose tissue after only 3 wk of wheat starch feeding (32) . In this study, however, rats consumed the same amount of energy, which suggests that differences in nutrient partitioning stimulated by altered postprandial hormonal responses may be involved.

Clamp GIR in high fat–fed rats was significantly decreased, implying decreased glucose uptake and lower insulin sensitivity. The reduced rate of GIR in the high fat–fed group resulted from the reduced ability of insulin to suppress hepatic glucose production because glucose turnover during the clamp was not different between the groups. The absolute value of the glucose turnover in all groups was similar to a high fat–fed rat model (16 , 36) , suggesting a degree of peripheral IR in all three groups of rats, possibly associated with the relatively high fat content of the diets used. Most of the studies using high fat–fed animals to study dietary-induced IR compared it with a diet much lower in fat (7–20% E as fat) (16 , 37) . However, the hepatic IR that often precedes muscle IR was present only among rats fed the high fat (60%) diet, who also had significantly greater epididymal fat accumulation than the high GI–fed rats. It has been shown that visceral fat reduction, achieved either by surgery (38) , food restriction or infusion of ß₃-adrenoreceptor agonist or leptin (39) , improves hepatic IR.

In a well-controlled multicenter population-based cohort of nearly 3000 young healthy adults, fiber intake was strongly associated with risk factors for cardiovascular disease including high fasting and 2-h postglucose insulin levels, TG, low HDL and high LDL cholesterol, and fibrinogen (9) . Greater weight gain over the period of 10 y of follow-up occurred among subjects who consumed high CHO diets that were also low in fiber. Those diets generally have inherently high GI and lead to relatively high postprandial insulin secretion. Similarly, in a prospective study of normal glucose-tolerant offspring of two parents with Type II diabetes, first-phase insulin hypersecretion during IVGTT was identified as an independent risk factor for rapid weight gain, particularly among insulin-sensitive individuals (40) . Results from the European Group for the Study of Insulin Resistance suggest that hyperinsulinemia of obesity can originate either from compensatory hypersecretion of insulin (which is characteristic of the insulin resistant state) or from primary hypersecretion (41) . In fact, after correction for lean body mass, IR was found to be less frequent than insulin hypersecretion in obese subjects. Therefore, primary insulin hypersecretion is likely a factor contributing to obesity, ß-cell exhaustion and the development of diabetes.

In conclusion, we found that 7 wk of high GI starch consumption by rats led to increased first-phase insulin secretion during an IVGTT and increased epididymal fat pad weight. Nonetheless, rats remained glucose tolerant and neither peripheral nor hepatic insulin sensitivity was affected by the type of starch in the diet. The composition of the diet used in this study is physiologically realistic and relevant to the modern Western diet. Our findings, therefore, implicate the high GI nature of modern starchy foods in the pathogenesis of obesity. More research is required to determine the mechanisms involved in insulin hypersecretion and fat accumulation and possible links between the two.

	FOOTNOTES

 
¹ Supported by grants from National Health and Medical Research Council (NHMRC) and Sydney University Nutrition Research Foundation (SUNRF).

³ Abbreviations used: AUC, area under the curve; CHO, carbohydrate; E, energy; GI, glycemic index; GIR, glucose infusion rate; IR, insulin resistance; IVGTT, intravenous glucose tolerance test; NEFA, nonesterified fatty acids; TG, triglyceride.

Manuscript received May 30, 2000. Initial review completed August 7, 2000. Revision accepted October 17, 2000.

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