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We addressed the hypothesis that hypercaloric diets induce hyperkinetic hypertension irrespective of day-night cycle and locomotor activity that is associated with altered cardiac myosin isozymes. Normotensive rats with implanted radiotelemetry pressure transducers were fed increasing amounts of coconut fat (8, 16, and 24%, each for 2 wk) corresponding to 20-47% of total calories from fat. Thereafter, increasing amounts of sucrose (16, 32, and 50%) and fructose (50%) were added to the 24% fat diet corresponding to 13-40% of total calories from sugar. In contrast to the fat diets, the 32% and 50% sucrose diets as well as the 50% fructose diets increased (P < 0.05) blood pressure (systolic maximum +13 mmHg, diastolic maximum +4 mmHg, mean maximum +7 mmHg) and heart rate (maximum +50 beats/min) irrespective of the day-night cycle and the unaltered locomotor activity. Furthermore, body weight increased (P < 0.05) during the 32% and 50% sucrose feedings. The increased blood pressure and heart rate normalized after rats were fed a regular chow. We concluded that an excessive caloric intake results in hyperkinetic hypertension that increases the myosin V(1) proportion.

The involvement of glucocorticoids (GC) in the development of diet-induced obesity and in the concomitant adaptations of triglyceride (TG)-rich lipoprotein metabolism were examined. Rats were fed either rodent chow, which maintains a low lipid flux, or a diet high in sucrose and fat (HSF) that increases lipid flux, leading to metabolic perturbations similar to those that define the plurimetabolic syndrome in humans. The GC status was manipulated through adrenalectomy (ADX) and corticosterone (Cort) replacement. Compared with chow, the HSF diet increased energy intake (17%) and whole body (8%) and adipose tissue (80%) weights. The HSF diet also increased the acute postprandial rise in plasma insulin (4-fold) and TG (3-fold), fasting liver TG content (3-fold), triglyceridemia (54%), and adipose tissue lipoprotein lipase (LPL) activity (2-fold). ADX decreased energy intake and whole body and adipose tissue weights in both dietary cohorts, but more so in HSF-fed than in chow-fed animals. These ADX-induced effects were totally prevented by Cort replacement in rats fed chow, but only partially so in those fed the HSF diet in proportion to the degree of restoration of energy intake. In the chow-fed cohort, the above indexes of TG metabolism remained unaffected by the Cort status, whereas in the HSF-fed cohort, these variables were decreased by ADX to levels of chow-fed animals. Cort replacement in the HSF-fed animals restored indexes of TG metabolism to intact levels and reestablished the diet-related differences observed in intact animals. These findings indicate that GC modulate fasting TG metabolism only minimally when a diet that maintains a low lipid flux is fed. In contrast, their presence is a necessary condition for the development of diet-induced obesity and the concomitant alterations in insulin sensitivity and TG-rich lipoprotein metabolism.

It has been reported that, unlike high-fat diets, high-sucrose diets cause insulin resistance in the absence of an increase in visceral fat and that the insulin resistance develops only in male rats. This study was done to 1) determine if isolated muscles of rats fed a high-sucrose diet are resistant to stimulation of glucose transport when studied in vitro and 2) obtain information regarding how the effects of high-sucrose and high-fat diets on muscle insulin resistance differ. We found that, compared with rat chow, semipurified high-sucrose and high-starch diets both caused increased visceral fat accumulation and insulin resistance of skeletal muscle glucose transport. Insulin responsiveness of 2-deoxyglucose (2-DG) transport measured in epitrochlearis and soleus muscles in vitro was decreased approximately 40% (P < 0.01) in both male and female rats fed a high-sucrose compared with a chow diet. The high-sucrose diet also caused resistance of muscle glucose transport to stimulation by contractions. There was a highly significant negative correlation between stimulated muscle 2-DG transport and visceral fat mass. In view of these results, the differences in insulin action in vivo observed by others in rats fed isocaloric high-sucrose and high-starch diets must be due to additional, specific effects of sucrose that do not carry over in muscles studied in vitro. We conclude that, compared with rat chow, semipurified high-sucrose and high-cornstarch diets, like high-fat diets, cause increased visceral fat accumulation and severe resistance of skeletal muscle glucose transport to stimulation by insulin and contractions.

Insulin-stimulated glucose uptake is defective in patients with type 2 diabetes. To determine whether transgenic glucose transporter overexpression in muscle can prevent diabetes induced by a high-fat, high-sugar diet, singly (GLUT-1, GLUT-4) and doubly (GLUT-1 and -4) transgenic mice were placed on a high-fat, high-sugar diet or a standard chow diet. On the high-fat, high-sugar diet, wild-type but not transgenic mice developed fasting hyperglycemia and glucose intolerance (peak glucose of 337 +/- 19 vs. 185-209 mg/dl in the same groups on the high-fat, high-sugar diet and 293 +/- 13 vs. 166-194 mg/dl on standard chow). Hyperinsulinemic clamps showed that transporter overexpression elevated insulin-stimulated glucose utilization on standard chow (49 +/- 4 mg. kg-1. min-1 in wild-type vs. 61 +/- 4, 67 +/- 5, and 63 +/- 6 mg. kg-1. min-1 in GLUT-1, GLUT-4, and GLUT-1 and -4 transgenic mice given 20 mU. kg-1. min-1 insulin, and 54 +/- 7, 85 +/- 4, and 98 +/- 11 in wild-type, GLUT-1, and GLUT-4 mice given 60-80 mU. kg-1. min-1 insulin). On the high-fat, high-sugar diet, wild-type and GLUT-1 mice developed marked insulin resistance, but GLUT-4 and GLUT-1 and -4 mice were somewhat protected (glucose utilization during hyperinsulinemic clamp of 28.5 +/- 3.4 vs. 42.4 +/- 5.9, 51.2 +/- 8.1, and 55.9 +/- 4. 9 mg. kg-1. min-1 in wild type, GLUT-1, GLUT-4, GLUT-1 and -4 mice). These data demonstrate that overexpression of GLUT-1 and/or GLUT-4 enhances whole body glucose utilization and prevents the development of fasting hyperglycemia and glucose intolerance induced by a high-fat, high-sugar diet. GLUT-4 overexpression improves the insulin resistance induced by the diet. We conclude that upregulation of glucose transporters in skeletal muscle may be an effective therapeutic approach to the treatment of human type 2 diabetes.

To investigate the role of increased polyol pathway activity and hemodynamic deficits in the pathogenesis of diabetic retinopathy in non-insulin-dependent diabetes mellitus (NIDDM), Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human NIDDM, were given water with or without 30% sucrose and some of them were fed laboratory chow containing 0.03% cilostazol, an anticoagulant, or 0.05% [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate (TAT), an aldose reductase inhibitor, for 8 wk. Long-Evans Tokushima Otsuka (LETO) rats were used as nondiabetic controls. The peak latencies of oscillatory potentials of the electroretinogram in sucrose-fed OLETF rats were significantly prolonged compared with those in OLETF rats without sucrose feeding and LETO rats. There was a marked increase in platelet aggregability and a significant decrease in erythrocyte 2,3-diphosphoglycerate in sucrose-fed OLETF rats. Cilostazol significantly improved these parameters without changes in retinal levels of sorbitol and fructose. TAT, however, ameliorated all of these parameters. These findings confirm that the sucrose-fed OLETF rat is a useful animal model of retinopathy in human NIDDM and suggest that cilostazol improved diabetic retinopathy by modifying vascular factors, not by altering polyol pathway activity.

To understand the mechanism of hepatic glycogen depletion found in uremia and under sucrose feeding, we examined net hepatic glycogenolysis-associated active enzymes and metabolites during fasting. Liver was taken 2, 7, and 18 h after food removal in uremic and pair-fed control rats fed either a sucrose or cornstarch diet for 21 days. Other uremic and control rats fasted for 18 h were refed a sucrose meal to measure glycogen increment. Glycogen storage in uremia was normal, suggesting effective glycogen synthesis. During a short fast, sucrose feeding and uremia enhanced net glycogenolysis through different but additive mechanisms. Under sucrose feeding, there were high phosphorylase alpha levels associated with hepatic insulin resistance. In uremia, phosphorylase alpha levels were low, but the enzyme was probably activated in vivo by a fall of inhibitors (ATP, alpha-glycerophosphate, fructose-1,6-diphosphate, and glucose) and a rise of Pi, as verified in vitro. Enhanced gluconeogenesis was also suggested, but excessive hepatic glucose production was unlikely in uremia. During fasting, hypoglycemia occurred in uremia due to reduced glycogenolysis, inefficient hepatic gluconeogenesis, and impaired renal gluconeogenesis. This may be relevant to poor fasting tolerance in uremia, which could be aggravated under excessive sucrose intake.

A high-sucrose diet reduces the ability of insulin to suppress hepatic glucose production (hepatic insulin resistance) in rats. The purpose of the present study was to investigate the contribution of hepatic gluconeogenesis to sucrose-induced hepatic insulin resistance. Single-pass liver perfusions were performed on 24-h food-deprived male Wistar rats after 8 wk on either a high-corn starch (ST; 68% of energy) or high-sucrose (SU; 68% of energy) diet. Hepatic glucose output (HGO, micromol of glucose x min(-1) x g(-1)) in the presence of lactate, alanine, or dihydroxyacetone (DHA) was used as an estimate of gluconeogenic capacity, because liver glycogen levels after the 24-h fast were negligible (<1.2 mg/g). HGO was significantly (P < 0.05) greater in SU vs. ST at all concentrations of lactate, alanine, and DHA. Maximal rates of HGO were 1.9 +/- 0.4 and 2.8 +/- 0.3 at 10 mM lactate, 0.6 +/- 0.2 and 1.4 +/- 0.3 at 10 mM alanine, and 1.7 +/- 0.3 and 2.6 +/- 0.2 at 20 mM DHA in ST and SU, respectively. When HGO was matched between SU and ST with the use of different precursor concentrations, there was a significant (P < 0.05) reduction in the ability of insulin (175 microU/ml) to suppress HGO in SU vs. ST. These data suggest that sucrose feeding increases gluconeogenesis from lactate, alanine, and DHA and that this route of glucose production is resistant to insulin suppression.

In the present study, the time course of change in sucrose-induced insulin resistance, triglyceride (TG) concentration, and liver fatty acid composition was examined. Male rats (n = 8-10/group per time point) was fed a high-starch (ST) diet for 2 wk and were then equicalorically fed ST or a high-sucrose (SU) diet for 1, 2, 5, or 8 wk. Body weight and percent body fat were similar between ST and SU diets at all time points. Glucose infusion rate (GIR) was significantly (P < 0.05) lower in the SU diet (9.2 +/- 0.9, 7.4 +/- 0.5, 6.2 +/- 1.0, and 6.0 +/- 0.9 mg.kg-1.min-1) vs. the ST diet (15.1 +/- 1.7, 15.7 +/- 0.7, 14.7 +/- 1.9, and 14.2 +/- 0.9 mg.kg-1.min-1) at 1, 2, 5, and 8 wk, respectively. Reduced suppression of glucose appearance accounted for 85, 50, 45, and 40% of the reduction in GIR at these same time points. Muscle glycogen synthesis was reduced (P < 0.05 vs. ST diet) in the SU diet at 2, 5, and 8 wk. Fasting plasma TG concentration was inversely related (r = -0.79, P < 0.001) to muscle glycogen synthesis, and liver TG concentration was positively related (r = 0.59, P < 0.01) to glucose appearance. Liver fatty acid composition was similar between diet groups. In summary, the SU diet produced insulin resistance in liver before muscle. TG concentration appears to be related to sucrose-induced insulin resistance in liver and muscle.