Otho E. Michaelis

Serum uric acid, inorganic phosphorus, and glutamic-oxalacetic transaminase and blood pressure in carbohydrate-sensitive adults consuming three different levels of sucrose.

12 men and 12 women, classified as carbohydrate-sensitive on the basis of an exaggerated insulin response to a sucrose load, consumed diets containing either 5, 18, or 33% sucrose in a crossover design. The diets simulated the average American diet and consisted of identical natural and processed foods with the exception of a patty. The patty provided the experimental levels of sucrose; the difference was made up by starch. Each level of sucrose was consumed for a 6-week period. Subject body weights were maintained. Fasting serum uric acid and inorganic phosphorus increased as the level of dietary sucrose increased. Diastolic blood pressure was significantly higher when subjects were on the 33% sucrose diet as compared to the 5 and 18% diets. Serum glutamic-oxalacetic transaminase was not affected by diet. In tolerance tests after a sucrose load (2 g/kg body weight), the uric acid response was higher after the 18 and 33% sucrose diets than after the 5% sucrose diet. Serum inorganic phosphorus, which increased significantly with each level of dietary sucrose, decreased following the sucrose load. These results indicate that carbohydrate-sensitive individuals may be affected adversely by the level of sucrose commonly found in the Westernized diet. Since elevated serum uric acid and blood pressure have been identified as risk factors in degenerative diseases, this study suggests that carbohydrate-sensitive individuals should limit their sucrose consumption.

Effect of dietary sucrose and genotype on metabolic parameters of a new strain of genetically obese rat: LA/N-corpulent

Abstract A new strain of genetically obese rat, LA/N-corpulent ( cp ) was studied. Homozygous ( cp/cp ) corpulent and heterozygous ( cp/+ ) and homozygous ( +/+ ) lean young male rats were fed for 4 weeks diets containing 54% carbohydrate as either sucrose or starch. A genotype effect between corpulent and lean rats (corpulent > lean) was observed with food intake, weight gain, total fat pad weight and size, liver weight and size, activities of liver lipogenic enzymes, fasting levels of serum triglyceride, free fatty acid, total cholesterol and insulin, and response levels of serum insulin and glucose. Levels of insulin and triglyceride were 6 to 8 times greater in corpulent than lean rats. The magnitude of metabolic responses in lean rats was similar except for total fat pad weight and size which was greater in cp/+ than +/+ rats. A sucrose effect (sucrose > starch) was observed with weight gain, total fat pad weight and size, liver weight and size, activities of liver lipogenic enzymes, fasting level of serum triglyceride and response levels of serum insulin and glucose. The data demonstrate that corpulent ( cp/cp ) rats have metabolic characteristics similar to type IV hyperlipoproteinemia in humans and that these characteristics are magnified by feeding of sucrose.

Effects of dietary carbohydrate and phenotype on thyroid hormones and brown adipose tissue locularity in adult LA/N-cp rats

1. Groups of lean and corpulent LA/N-cp rats were fed isoenergetic diets containing, 54% carbohydrate as maize starch (MS) or sucrose (SU), 20% protein, 16% mixed fats, plus other essential nutrients and fiber from 1.5-9 months of age. Final body weights of corpulent rats were 2-3 times those of their lean littermates, and were greater with SU than MS diet in both phenotypes. 2. Interscapular brown adipose tissue (IBAT) mass was greater in corpulent than lean and was greater with SU than MS diet in lean but not corpulent rats. IBAT cell diameters and adipocyte volumes were generally similar in both phenotypes, and were not markedly affected by dietary carbohydrate type. 3. Brown adipocyte locularity profiles were qualitatively similar in both phenotypes, and were morphologically indicative of thermogenic activity in both phenotypes. Locule profiles of corpulent animals contained a greater proportion of thermogenically less active types IV and V brown adipocytes than similarly fed lean animals, however, and locule distribution profiles were not influenced by diet. 4. Serum T3 concentrations were similar in both phenotypes, were greater in SU than MS lean rats and were not influenced by diet in the corpulent phenotype. In contrast, serum thyroxine concentrations and percent thyroxine uptake were not influenced by diet or phenotype. 5. These results are consistent with a partial impairment in BAT-mediated thermogenic activity in the corpulent phenotype and suggest that obesity in this strain may be due to factors other than biochemically defective brown adipose tissue thermogenesis.

Perindopril ameliorates glomerular and renal tubulointerstitial injury in the SHR/N-corpulent rat.

We compared the effects of long-term treatment with the angiotensin-converting enzyme inhibitor perindopril and triple therapy (hydrochlorothiazide, reserpine, and hydralazine) on the metabolic and renal features in the SHR/N-corpulent (cp) rat, a genetic model of non-insulin-dependent diabetes mellitus and hypertension. Obese male SHR/N-cp rats (4 to 6 weeks old) were fed a 54% carbohydrate diet containing 18% sucrose and 36% starch. After 2 months on the diet, rats were assigned to one of three groups: one group (n=8) received perindopril (PE); the second group (n=8) received triple therapy (TT); and the third group (n=8) did not receive therapy. Treatment was maintained for 3 to 4 months. Body weight, food intake, and fasting levels of serum glucose and insulin did not differ among the three groups. Control rats exhibited progressive proteinuria in parallel with the rise in systolic blood pressure (SBP). Both PE and TT equally lowered SBP to normal levels and reduced proteinuria in treated rats. However, the reduction of proteinuria was greater and more sustained with PE than with TT (P<.05), whereas the effect of TT on proteinuria was delayed. Plasma renin activity was increased in PE and TT rats compared with control rats (P<.02). Semiquantitative analysis of renal lesions showed that the percentage of glomeruli with mesangial expansion and sclerosis and the tubulointerstitial score (an index of severity of tubulointerstitial lesions, namely tubular atrophy, inflammatory cellular infiltrates, and interstitial fibrosis) was reduced in both PE and TT rats. However, the reduction of glomerulosclerosis and tubulointerstitial lesions was greater in PE than in TT rats (P<.01). The percentage of glomerular sclerosis was positively correlated with the severity score of tubulointerstitial lesions (r=.60, P<.01). We conclude that PE is more effective than TT in halting the progression of proteinuria in the SHR/N-cp rat with non-insulin-dependent diabetes mellitus and hypertension. The antiproteinuric effect of PE is associated with significant reduction in glomerulosclerosis and tubulointerstitial lesions, independent of the effect of treating hypertension.

Effect of feeding sucrose or starch diets on parameters of glucose tolerance in the LA/N-corpulent rat

Abstract A study was conducted to determine the long-term effects of consuming diets containing sucrose or starch, as the source of dietary carbohydrate, on characteristics of glucose tolerance in a new strain of genetically obese rat, LA/N-corpulent ( cp ). Body weight and glycemic indices were measured in male corpulent ( cp / cp ) and lean ( cp / + or + / + ) littermates fed 54% carbohydrate diets for 1 and 10.5 months. A phenotype effect (corpulent>lean) and a diet effect (sucrose>starch) was observed with body weight, fasting level of serum insulin, and levels of serum insulin and glucose following an oral glucose load. A reduction with age in levels of serum insulin was observed in corpulent rats and in lean rats fed starch. Both corpulent and lean littermates were normoglycemic in the fasting and response states at 10.5 months.

Long-Term Effects of Starvation-Refeeding in the Rat

The effects of one vs. two episodes of starvation-refeeding were studied in young male rats as a function of elapsed time between the two episodes of starvation-refeeding. Starved-refed rats ate more and gained weight faster than ad libitum-fed rats. The difference in weight gains could be attributed to the greater amount of body fat in the starved-refed rats. The responses of four NADP-linked liver dehydrogenases:isocitrate dehydrogenase (ICD)/LS-isocitrate:NADP oxidoreductase (decarboxylating) (EC 1.1.1.42), glucose-6-phosphate dehydrogenase (G6PD)/D-glucose-6-phosphate:NADP oxidoreductase (EC 1.1.1.49); 6-phosphogluconate dehydrogenase (6PGD/6-phospho-D-gluconate:NADP oxidoreductase (decarboxylating) (EC 1.1.1.44); and malic enzyme (ME)/L-malate:NADP oxidoreductase (decarboxylating) (EC 1.1.1.40) were studied. Starvation-refeeding caused an overshoot of G6PD, 6PGD, and ME, but not of ICD. A second episode of starvation caused an even greater enzyme overshoot; this difference persisted for 3 weeks with G6PD and for 2 weeks with 6PGD and ME. No significant differences in blood cholesterol were detected.

Nonshivering thermogenesis in the diabetic SHR/N-cp (corpulent) rat

The effects of isoenergetic sucrose and starch-based diets on thermogenesis were investigated in young adult, male, lean and corpulent SHR/N-cp rats. Corpulent rats gained weight 1.5 times more rapidly than lean, and sucrose diets resulted in more rapid weight gains in both phenotypes. Rates of resting and of norepinephrine-stimulated oxygen consumption were similar in both groups of lean rats and in sucrose-fed corpulent rats, but were decreased in starch-fed corpulent rats. The thermic response to injected norepinephrine occurred normally in all groups. Colonic and rectal temperatures were greater in lean than in corpulent rats. Acute cold exposure (5 degrees C) resulted in decreases in rectal but not colonic temperature in lean rats fed both diets, but resulted in lower temperatures at both sites in corpulent rats, with the greatest decreases being observed in the starch fed corpulent rats. Fifty percent of the corpulent but none of the lean rats succumbed within 24-48 hours following cold exposure. Urinary vanilmandelic acid (VMA) excretion was greater in lean than in corpulent rats, and the sucrose diet induced a greater increment in urinary VMA excretion in lean rats than in corpulent rats. These results are consistent with an impaired activation of sympathetically-mediated thermogenesis via nutritional or environmental stimuli in the corpulent genotype of the SHR/N-cp rat in concert with an economy in energy expenditure which may be contributing factors in the causation of their obese state.

Effect of Carbohydrate Intake on Kidney Function and Structure in SHR/N-cp Rats: A New Model of NIDDM

The SHR/N corpulent (cp) rat is a genetically obese rat that develops hyperglycemia, hyperinsulinemia, and proteinuria. This study was designed to evaluate the effects of high carbohydrate (CHO) intake on renal function and structure in this animal model and to determine whether the renal effects are related to the type of CHO ingested. Two groups of 5-wk-old obese male SHR/N-cp rats and lean male littermates were fed diets containing 54% CHO in the form of sucrose or starch. After 12 wk, renal function parameters, including creatinine clearance, urinary glucose excretion, and urinary protein excretion, were measured. Renal morphology was evaluated by semiquantitative light and electron microscopy. On either diet, obese rats had significantly higher urinary glucose and protein excretions than their lean littermates. Mean creatinine clearance (ml/min) in obese rats did not differ significantly from values observed in lean rats. When corrected for body weight, creatinine clearance (ml · min−1 · kg−1) tended to be lower in obese than in lean rats, but the difference was significant (P < .02) only for obese and lean sucrose-fed animals. Obese rats fed sucrose compared with their obese counterparts fed starch had higher body weight (+ 8%, P < .05), glucose excretion (+ 63%, P < .02), and protein excretion (+ 242%, P < .005). In obese rats, protein excretion correlated with glucose excretion (r = .71, P < .01). Glomerular lesions consisting of mesangial expansion and intercapillary nodules were found in obese but not in lean rats.Moreover, obese rats fed sucrose had a significantly greater number of involved glomeruli than obese rats fed starch. There was no evidence of glomerular basement membrane thickening in any of the animals studied. We conclude that the SHR/N-cp rat is sensitive to a high-CHO diet and develops glucosuria, proteinuria, renal insufficiency, and glomerular lesions resembling human diabetic nephropathy and that these characteristics are accentuated by high sucrose intake.

Hormonal and Lipogenic and Gluconeogenic Enzymatic Responses in LA/N-Corpulent Rats

Abstract Genetically obese normotensive rats, LA/N-corpulent (cp), were fed ad libitum diets containing either 54% sucrose or cooked corn starch for 12 weeks. Twenty-four rats were used for the study; half were corpulent (cp/cp) and half were lean (cp/+ or +/+). Fasting levels of plasma insulin, glucose, corticosterone, glucagon and growth hormone, and activities of liver and epididymal fat pad glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), and liver and kidney glucose-6-phosphatase (G6Pase), fructose 1,6-diphosphatase (FDPase), and phosphoenolpyruvate carboxykinase (PEPCK) were measured. A significant phenotype effect was observed in insulin, corticosterone, growth hormone, and liver G6PD, ME, FDPase, and kidney PEPCK, G6Pase, FDPase, and epididymal fat pad G6PD and ME (corpulent > lean), and glucagon (lean > corpulent). Diet effect (sucrose > starch) was significant for plasma glucose, liver ME, and kidney G6Pase. Although not significant at the P < 0.05 level, insulin, corticosterone, liver G6PD and FDPase and kidney FDPase tended to be higher in sucrose-fed rats. This study suggests that the corpulent rat is more lipogenic and gluconeogenic than the lean, and that the hormones responsible are effective in keeping both the lipogenic and gluconeogenic enzyme activity elevated.

Tissue somatostatin levels in three models of genetic obesity in rats.

Abstract A potential role for somatostatin (SRIF) in the pathogenesis of the hyperinsulinemia of obese rats was considered. SRIF like immunoreactivity (ng/mg protein) was therefore measured in hot 2 N acetic acid extracts of pancreas, stomach, pituitary, and hypothalamus in tissues obtained from three models of genetic obesity in rats. These models included the obese and lean controls of LA/N-cp, SHR/N-cp, and Zucker rats. To assess the effects of diet on SRIF levels, mixed diets were provided ad lib which contained a carbohydrate as either sucrose or starch. Some groups were fed chow diets. No significant dietary effects on tissue levels of SRIF were obtained. However, two of the three models (Zucker and SHR/N-cp) showed phenotypic effects on SRIF levels in pancreas; namely, obese rats showed a significantly greater concentration of SRIF (P < 0.0005 and < 0.0002, respectively) than did the lean littermates. These findings were confirmed by measurement of total pancreas SRIF content. Gastric levels were significantly altered only in the obese Zucker rats (P < 0.005) where obese tissues had lower concentrations than those of lean animals. However similar directional changes in pancreas and stomach were observed in all models. It is concluded that the hyperinsulinemia of the obese animals studied is not due to absolute deficiency in pancreatic SRIF content. It is postulated however that decreased pancreatic SRIF secretion (paracrine or otherwise) relative to pancreatic insulin content could still play a role.