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 less than .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 less than .05), glucose excretion (+63%, P less than .02), and protein excretion (+242%, P less than .005). In obese rats, protein excretion correlated with glucose excretion (r = .71, P less than .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.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of insulin secretory patterns in obese nondiabetic LA/N-cp and obese diabetic SHR/N-cp rats. Role of hyperglycemia.

Obese diabetic SHR/N-(cp/cp) rats are a genetic model for non-insulin-dependent diabetes mellitus. When SHR/N-cp rats are overtly diabetic, they are hyperinsulinemic and hyperglycemic in the fed state when consuming commercial chow or semipurified high-carbohydrate diets. Obese SHR/N-cp rats were hyperinsulinemic by 4 wk of age, although hyperglycemia did not appear until 3-4 wk later and was exacerbated by a high-sucrose diet (mean +/- SE 1488 +/- 238 microU/ml insulin and 425 +/- 51 mg/dl glucose). The control SHR/N-cp rats (+/?) on the sucrose diet remained lean and normoglycemic. The obese diabetic SHR/N-cp rats showed three alterations in pancreas perfusion data (not present in control rats): 1) paradoxically high insulin secretion at low glucose levels (2.5 mM), 2) secretion of insulin in response to arginine (10 mM) in the absence of glucose, and 3) impaired response of insulin secretion to high glucose (16.7 mM). To determine whether hyperglycemia was responsible for the abnormalities of insulin secretion, perfusion studies were conducted in obese nondiabetic LA/N-cp rats and compared with the SHR/N-cp rats. The obese LA/N-cp rats resembled the corpulent SHR/N-cp rats in every way, except that they were normoglycemic on the sucrose diet. The obese LA/N-cp rats had two of the three alterations in insulin secretion shown by obese SHR/N-cp rats, lacking only the impaired response to high glucose, suggesting that hyperglycemia was required for that defect to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversible impairment of glucose-induced insulin secretion in SHR/N-cp rats. Genetic model of type II diabetes.

The SHR/N-cp rat is a new genetically obese model for non-insulin-dependent diabetes mellitus. Expression of the diabetes is enhanced by a high-sucrose (54%) diet. After 4 wk on the diet, the cp/cp rats weigh significantly more than their +/? controls, have postprandial hyperglycemia (greater than 400 mg/dl), and are hyperinsulinemic, with immunoreactive insulin (IRI) levels 10- to 20-fold greater than controls. Total pancreatic IRI tends to be increased 1.6-fold in the cp/cp rats (although not significantly). There is no increase in pancreatic proinsulin content as a percent of total IRI. Studies of in vitro pancreatic function were carried out with the isolated nonrecirculating perfused pancreas method. The cp/cp rats (n = 10) showed impaired or absent IRI responses to 16.5 mM glucose, whereas +/? rats (n = 9) responded with classic biphasic curves. Comparison of insulin secreted in 20 min revealed a greater than 53% decrease in IRI secretion in cp/cp rats (P less than .05). A paradoxical hypersecretion of IRI at glucose concentrations of 0-2.7 mM was noted in cp/cp but not lean rats, i.e., 1.8 +/- 0.2 mU/min IRI in cp/cp rats vs. 0.04 +/- 0.007 mU/min in +/? rats. Perfusion of pancreases for 45 min with buffers containing no glucose resulted in restoration of a normal biphasic IRI response to 16.5 mM glucose in the cp/cp rats, whereas response in the lean rats was markedly reduced. Brisk IRI responses to 10 mM arginine in buffers with no glucose also occurred in cp/cp but not +/? rats. Glucagon secretion was relatively suppressed in the cp/cp rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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 isocaloric exchange of dietary starch and sucrose in humans on the gastric inhibitory polypeptide response to a sucrose load.

Ten men and nine women aged 35 to 55 consumed two diets for 6 weeks each in a cross-over design. The diets were composed of identical natural foods and 30% of the calories as either sucrose or wheat starch. Carbohydrate, fat and protein supplied 43, 42, and 15% of the calories, respectively. The dietary pattern consisted of two meals divided so as to provide 10% of the calories at breakfast (7:00 to 8:30 AM) and 90% of the calories at dinner (4:30 to 6:30 PM). Initial body weights were essentially maintained. The gastric inhibitory polypeptide response after a sucrose load (2 g/kg body weight) was significantly greater (P < 0.01) after th subjects consumed the sucrose rather than the starch diet. The gastric inhibitory polypeptide response was significantly greater (P < 0.01) after 6 weeks on diet than during pretest. These results suggest that the increases in insulin levels observed after sucrose feeding may be mediated by an effect on the enteric hormone gastric inhibitory polypeptide.

Effect of dietary sucrose on the SHR/N-corpulent rat: a new model for insulin-independent diabetes.

A new congenic strain of genetically obese rat, SHR/N-corpulent (cp), was studied. Young male corpulent (cp/cp) and lean (cp/+ or +/+) rats approximately 5 wk of age were fed a diet containing 54% carbohydrate as either sucrose or cooked cornstarch for 9 wk. A phenotype effect was observed with body weight, fasting levels of serum insulin, triglyceride and total cholesterol, levels of serum insulin and glucose after an oral glucose load, and level of urine glucose (corpulent greater than lean), and with systolic blood pressure (corpulent less than lean). Only lean rats were hypertensive. Corpulent rats were hyperinsulinemic, hyperlipidemic, exhibited glycosuria, and were hyperglycemic after an oral glucose load. Lean rats were hyperinsulinemic, but normoglycemic. A diet effect (sucrose greater than starch) was observed with body weight, level of serum glucose after an oral glucose load, and urine volume in both corpulent and lean rats, and with levels of serum insulin and total urine glucose in corpulent rats. Corpulent rats fed sucrose had 20 to 40% higher levels of serum glucose and insulin after an oral glucose load, and twice the amount of total urine glucose, than did corpulent rats fed starch. The data demonstrate that corpulent rats have metabolic characteristics associated with insulin-independent diabetes in humans and that sucrose is more diabetogenic than starch. Manifestation of hyperglycemia in this model may be the result of superimposing obesity on an insulin-resistant genetic background.

Serum insulin and glucose in hyperinsulinemic subjects fed three different levels of sucrose.

Twenty-four adult men and women, classified as carbohydrate-sensitive on the basis of an exaggerated insulin response to a sucrose load, consumed diets containing 5, 18, and 33% of calories as sucrose for 6 wk each in a cross-over design. The diets contained identical natural and processed foods except for a patty containing 2, 15, or 30% of the calories as sucrose at the expense of wheat starch. Carbohydrate, fat, and protein provided 44, 42, and 14% of the calories, respectively. Of total calories, 25% were consumed at breakfast and 75% at dinner. Initial body weights of the subjects were essentially maintained. Fasting serum insulin levels increased with the sucrose content of the diet and were significantly higher in men than in women. Mean fasting glucose was significantly higher on either 18 or 33% sucrose than on 5% sucrose. The sucrose content of the diet did not affect fasting serum glucagon. When compared to the insulin response to a sucrose load (2 g/kg body weight) after consuming the 5% sucrose diet, serum insulin was significantly higher at 1 h after the 18% sucrose diet and at 0.5, 1, 2, and 3 h after the 33% sucrose diet. Except after 2 h, the glucose response was significantly greater after the 18 and 33% sucrose diets than after the 5% sucrose diet. These results indicate that sucrose intake by carbohydrate-sensitive individuals, even at levels approximating the average United States intake, can produce undesirable changes in several parameters associated with glucose tolerance.

Isocaloric exchange of dietary starch and sucrose in humans. I. Effects on levels of fasting blood lipids.

For 6 weeks, 10 men and nine women aged 35 to 55 consumed each of two diets in a cross-over design. The diets were comprised of identical natural foods with 30% of the calories as either sucrose or cooked wheat starch. Carbohydrate, fat and protein supplied 43, 42, and 15% of the calories, respectively. Of the calories 10% were eaten at breakfast (7:00 to 8:30 AM) and 90% at dinner (4:30 to 6:30 PM). Initial body weights were essentially maintained. Total serum lipids, triglycerides, and total cholesterol levels were significantly higher when the subjects consumed the sucrose diet than when they consumed the starch diet. Increases associated with the sucrose diet were greatest for triglycerides (33.0%). In a subgroup of nine subjects with triglyceride levels above the normal range, sucrose feeding increased triglyceride levels 45.2%. Triglycerides and pre-beta lipoproteins were significantly higher in males than in females. Pre-beta lipoproteins were 32% higher when the subjects consumed sucrose than when they consumed starch. For alpha and beta lipoproteins, small, nonsignificant increases were associated with sucrose feeding. Serum free fatty acids were not affected by diet. These results indicate that the consumption of sucrose can increase blood lipids that are considered to be risk factors in heart disease and that males and carbohydrate-sensitive individuals may be more susceptible than others to the effects of sucrose.

Isocaloric exchange of dietary starch and sucrose in humans. II. Effect on fasting blood insulin, glucose, and glucagon and on insulin and glucose response to a sucrose load.

Ten men and nine women ages 35 to 55 consumed two diets for 6 weeks each in a cross-over design. The diets were composed of identical natural foods and 30% of the calories as either sucrose or wheat starch. Carbohydrate, fat, and protein supplied 43, 42, and 15% of the calories, respectively. Of the calories 10% was eaten at breakfast (7:00 to 8:30 AM) and 90% at dinner (4:30 to 6:30 PM). Inital body weights were essentially maintained. Fasting serum insulin and glucose levels were significantly higher with the sucrose than with the starch diet. The insulin response and the insulin:glucose ratios after a sucrose load (2 g/kg body weight) were greater after the subjects consumed the sucrose diet. Sucrose feeding produced increases in fasting serum insulin, the insulin:glucose ratio and the insulin response to a sucrose load that were of greater magnitude in a subgroup of nine subjects classified as potentially carbohydrate-sensitive than in normal subjects. Glucose response to a sucrose load and fasting serum glucagon did not differ significantly with diet. Fasting insulin and glucose showed significant increases as a function of time on diet. These results indicate that sucrose feeding produces undersirable changes in several of the parameters associated with glucose tolerance.

Development and characteristics of a new strain of obese hyperinsulinemic and hyperlipidemic Dahl salt-sensitive rat. The Dahl salt-sensitive/NIH-corpulent rat.

A new congenic rat strain, the Dahl salt-sensitive/NIH-corpulent (DSS/N-cp) rat, has been developed to study the role of obesity and type of dietary carbohydrate in the development of hypertension and its complications. Three groups (n = 6) of young male obese and lean DSS/N-cp rats were fed diets containing either 54% sucrose, 18% sucrose plus 36% starch, or 54% starch, with 0.1% dietary sodium for 12 weeks. Regardless of the diet, obese and lean rats showed mildly elevated systolic blood pressure (SBP), being significantly higher in obese than in lean rats (SBP 156 +/- 5 mm Hg v 141 +/- 3 mm Hg, P < .05). However, SBP was not different between the three diet groups. Levels of serum insulin, triglyceride, and cholesterol as well as urinary protein excretion were significantly higher in obese than in lean rats. Obese rats fed the sucrose diets as compared to the starch diet, had higher serum insulin and lipid levels, but had lower body weights and higher serum creatinine levels. Histopathologic examination of tissues from different organs revealed a vasculopathy seen almost exclusively in obese rats fed the sucrose diets. Vascular lesions were characterized by subintimal fibrin deposition, fibrinoid necrosis, and cell proliferation with "onion skinning" in small arteries and arterioles of kidneys, intestine, pancreas, and testes.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of perindopril on metabolic parameters and the heart in the spontaneously hypertensive/NIH-corpulent rat with non-insulin-dependent diabetes mellitus and hypertension.

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic model that exhibits both non-insulin-dependent diabetes mellitus (NIDDM) and hypertension. To determine the impact of long-term treatment with the long-acting angiotensin-converting enzyme (ACE) inhibitor perindopril (PE) on the glucose metabolism, lipid levels, and heart in this model, studies were performed in three groups of SHR/N-cp rats maintained on a diet containing 54% carbohydrate with 18% sucrose and 36% starch. One group of obese rats received PE (0.5 to 1.0 mg/kg body weight/d) for 3 to 4 months, a second group of obese rats received no treatment, and a third group of lean rats were used as controls. The mean systolic blood pressure (SBP) increased gradually in both untreated obese and lean rats, with lean animals showing slightly higher levels compared with untreated obese rats. By contrast, SBP was reduced to normal levels in PE-treated obese rats throughout the treatment period. Compared with lean rats, obese rats showed significantly higher body weight and fasting serum levels of glucose, insulin, total cholesterol (TC), and triglyceride (TG). However, no significant differences were observed in these metabolic parameters between PE-treated and untreated obese rats. Plasma renin activity measured at the end of the treatment period was significantly higher in PE-treated rats compared with untreated obese and untreated lean rats. The mean heart weight and left ventricular weight, expressed in absolute terms or indexed to body weight, were significantly lower in PE-treated versus untreated obese and untreated lean rats. To further determine whether glucose metabolism is directly affected by PE treatment, in vitro glycogen synthesis was evaluated in isolated soleus muscles obtained from three additional groups of animals. The basal rate of muscle glycogen synthesis was significantly lower in obese compared with lean rats (P < .05), but did not differ between PE-treated and untreated obese rats. Maximal insulin-stimulated glycogen synthesis increased threefold in PE-treated obese rats, but this increase did not differ from the increases observed in untreated obese and lean rats. In conclusion, the present study shows that long-term PE treatment in obese SHR/N-cp rats with NIDDM and hypertension effectively controlled systemic arterial pressure and resulted in a significant reduction in left ventricular weight. However, these favorable effects of PE were not associated with significant improvement in glucose tolerance, hyperinsulinemia, and hyperlipidemia in this model. PE also had no direct stimulatory effects on either basal or insulin-mediated glycogen synthesis in the isolated soleus muscle of obese rats, perhaps because of the severe insulin-resistant state of the animals. Our results support the clinical observations that antihypertensive therapy with ACE inhibitors has neutral effects on glucose metabolism and insulin sensitivity in patients with combined hypertension and NIDDM.

Specificity of the disaccharide effect in the rat.

Male rats were starved and refed diets containing 40% disaccharides (maltose, trehalose, sucrose, turanose), trisaccharide (melezitose), starch, or the monosaccharide equivalents. Responses of hepatic glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), fatty acid synthetase (FAS), and total liver lipid (TLL) or changes in concentration of portal blood total carbohydrate and fructose were determined following refeeding of the different carbohydrate diets. Maltose, trehalose, sucrose, and turanose refeeding resulted in G6PD and ME responses which were higher than the responses to their component monosaccharides (disaccharide effect). Starch refeeding decreased the responses of G6PD, ME, and FAS when compared to refeeding of glucose. Refeeding diets containing fructose (sucrose, turanose, melezitose, and monosaccharide equivalents containing fructose) increased the responses of G6PD, ME, FAS, and TLL. No correlation between portal blood carbohydrate concentration and hepatic enzyme levels could be demonstrated. It is concluded that readily digestible disaccharides produce an effect which is greater than the effect produced by their monosaccharide equivalents. If these disaccharide configurations are fed as part of a trisaccharide or polysaccharide, the disaccharide effect is no longer discernible.

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.

Effect of dietary sucrose in humans on blood uric acid, phosphorus, fructose, and lactic acid responses to a sucrose load.

10 men and 9 women consumed diets that were identical, except for the 30% of the calories derived from either starch or sucrose, for 6 weeks in a crossover design. Of the total calories, 10% were given at breakfast and 90% at dinner. A sucrose load of 2 g/kg body weight was administered 1 week before and during the last week of both dietary periods. Blood was drawn before (fasting) and 0.5, 1, 2 and 3 h after the sucrose load. Serum uric acid was significantly higher (p < 0.01) and blood fructose significantly lower (p < 0.05) before and at all times after the sucrose load when subjects consumed the sucrose versus the starch diet. Levels of serum inorganic phosphorus and blood lactic acid were not affected by kind of carbohydrate in the diet.

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.

The role of obesity, hypertension and diet in diabetes and its complications in the Spontaneous Hypertensive/NIH-corpulent rat.

The Spontaneous Hypertensive/NIH-corpulent rat is a recently developed genetic model of obesity and diabetes. The strain exhibits both metabolic and histopathological characteristics associated with non-insulin dependent diabetes mellitus in humans. This rodent model is unique in that glucose intolerance is expressed in both sexes and in both phenotypes.

Inner ear damage secondary to diabetes mellitus. II. Changes in aging SHR/N-cp rats.

The congenic spontaneous hypertensive/National Institutes of Health (Bethesda, Md)-corpulent rat (SHR/N-cp) is a model for non-insulin-dependent diabetes mellitus. A previous study in our laboratory found significant loss of outer hair cells (OHC) in diabetic rats at 5.0 months of age. Our present study was designed to further evaluate the effects of the diabetic state on the inner ear in 10.5-month-old rats. The following comparisons were made: diabetic vs euglycemic control animals; obese vs lean phenotypes; and sucrose vs starch as the source of dietary carbohydrate. Cochleas were removed, fixed, stained, mounted on slides, and analyzed for OHC loss. We found a significant OHC loss in the cochleas of all diabetic animals. No statistical difference was found when comparing obese and lean phenotypes. Increased OHC loss was observed in all sucrose-fed vs starch-fed diabetic animals, although this increase was not statistically significant. Compared with an earlier study, an increase in OHC loss was also noted in the 10.5-month-old lean SHR/N-cp animals. Our results indicate that there is a relationship between non-insulin-dependent diabetes mellitus and inner ear damage and suggest that OHC loss is related to hyperglycemia and a genetic predisposition for glucose intolerance.

Inner ear damage secondary to diabetes mellitus. I. Changes in adolescent SHR/N-cp rats.

The association between diabetes mellitus and hearing impairment has been debated in many previous studies. The spontaneous hypertensive/NIH-corpulent (SHR/N-cp) rat has been shown to be a unique genetic model for non-insulin-dependent diabetes mellitus. Seventeen diabetic and 17 control young male rats were divided into groups according to diet and phenotype. The rats were fed either 54% of sucrose or 54% starch diets for 3.5 months and killed at 5 months. The cochleas were fixed, decalcified, dissected, and stained for hair cell counting. A significant loss of outer hair cells was noted in the diabetic obese (SHR/N-cp) animals when compared with the control obese (LA/N-cp) animals in every group. Although no significant difference was noted between the diabetic obese (SHR/N-cp) animals receiving the starch and sugar diets, the diabetic obese (SHR/N-cp) animals were more severely affected than the nondiabetic lean (SHR/N-cp) rats.

Degenerated intramural pericytes ('ghost cells') in the retinal capillaries of diabetic rats.

One of the earliest histopathological signs of diabetic retinopathy is a selective loss of intramural pericytes from retinal capillaries. In the present study, the retinal vessels of rats with streptozotocin-induced diabetes (STZ Wistar) and rats with genetically-induced insulin dependent diabetes mellitus (BB Wistar) and non-insulin dependent diabetes mellitus (SHR/N-corpulent) were examined after 6 to 8 months duration for diabetes-related retinal microangiopathies. The SHR/N-corpulent (cp) rats were fed a 54% sucrose diet, whereas the STZ Wistar and BB Wistar rats were fed laboratory chow for 32 to 36 weeks. In all the diabetic rats, the retinal capillaries in enzyme-digested flat mounts exhibited an increase in periodic-acid-Schiff (PAS) staining and loss of pericytes compared to their respective euglycemic controls. Pericyte "ghosts", like those defined in human diabetes as intramural pockets lacking normal cell contents, were documented by high resolution micrographs in all the diabetic rats. Endothelial cell proliferation, capillary dilation, and varicose loop formation were noted in some of the diabetic rats. Hence, similar capillary lesions were found in very different groups of diabetic rats. The findings suggest that a chronic high tissue concentration of glucose is the underlying factor which triggers pathogenesis in the pericyte. Hyperglycemia-induced activation of endogenous aldose reductase of the polyol pathway is probably the initial insult, but other factors such as advanced glycosylation products may affect the final outcome.

Gender differences in adrenal cortex steroid production in SHR/N-corpulent rats.

Gender differences in adrenal steroid hormone production and serum steroid hormone levels were compared in the spontaneous hypertensive/NIH-corpulent (cp) rat, which exhibits characteristics of both obesity and non-insulin-dependent diabetes mellitus. The study demonstrated that adrenal gland size correlated with adrenal production and serum levels of steroid hormones. Obese female SHR/N-cp rats were more steroidogenic than male SHR/N-cp rats; the size of their adrenal glands was twice that of the males (70 vs 33 mg). Body weights averaged 666 g for females and 829 g for males. Obese female rats had significantly higher serum concentrations of both corticosterone (827 vs 536 ng/ml) and aldosterone (675 vs 482 pg/ml) than obese male rats. As determined by in vitro assay, adrenal cortex production of corticosterone (2157 vs 1435 ng/30 min) and aldosterone (13.3 vs 9.5 ng/30 min) was significantly higher in obese female than in obese male rats. Adrenal production of testosterone in the in vitro assay was also significantly higher for obese female than male rats; however, adrenal estrogen production in obese rats did not differ significantly. The type of carbohydrate consumed (sucrose > starch) significantly affected serum levels of corticosterone, but not aldosterone, testosterone, or estrogen. Gender differences in adrenal steroid production and serum steroid levels suggest that hyperglycemia in obese SHR/N-cp rats may be, in part, the result of excess adrenal production of steroid hormones.