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.

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.

The rat corpulent (cp) mutation maps to the same interval on (Pgm1-Glut1) rat chromosome 5 as the fatty (fa) mutation.

The autosomal recessive obesity mutations fatty (fa) and corpulent (cp) arose in separate rat strains, 13M and Koletsky, respectively. By complementation analysis, the two mutations appear to be in the same gene. The somewhat different phenotypes of fa/fa and cp/cp animals probably reflect the fact that the mutations are segregating on different rat strains. The fa mutation has been mapped to the interval between Pgm1 and Glut1 on rat Chr 5, but cp has not been mapped genetically. We mapped cp in 30 obese progeny of a LA/N-BN cp/+ intercross using microsatellite markers for these flanking genes. Cp maps to the same genetic interval as rat fa and mouse db. Cp is flanked by Glut1 and Pgm1: Pgm1-------- cp -------- Glut1 map distance (cM) 1.67 6.67 Thus, cp and fa map to the same approximately 8 cm interval of the rat genome. In conjunction with the complementation studies alluded to above, these findings indicate that cp and fa are mutations in the same gene (Lepr).

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)

Diabetic glomerulopathy in the SHR/N-corpulent rat: role of dietary carbohydrate in a model of NIDDM.

We evaluated the course of diabetes and nephropathy in the SHR/N-cp (corpulent) rat characterized by genetic obesity, non-insulin-dependent diabetes (NIDDM), and hypertension, and examined whether the nephropathy in this model is influenced by the type of carbohydrate intake. Two groups of obese and lean SHR/N-cp rats were fed diets containing 54% carbohydrate, as either sucrose or starch for 3 months (group I) and 9 months (group II). After 3 months on either diet, group I obese rats had higher 2-h response serum glucose levels and urinary glucose excretion than lean rats. Sucrose feeding was associated with greater proteinuria and a higher percentage of abnormal glomeruli in obese rats. Morphometric evaluation of glomeruli (by computerized image analysis) showed greater mean renal corpuscular volume and mesangial fraction in obese than in lean rats fed similar diets. Mean renal corpuscular volume and mesangial fraction were also greater in sucrose-fed obese rats than in starch-fed obese rats. After 9 months, group II obese rats had substantial reductions in serum and urine glucose levels but they were still hyperinsulinaemic and showed more proteinuria than lean rats and a higher percentage of sclerotic glomeruli compared with group I obese rats. At this time, mean mesangial fraction but not renal corpuscular volume was still higher in obese than in lean rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Glucose turnover in lean and obese rats of the SHR/N-cp and LA/N-cp strains.

1. The relationship between hypertension, obesity, non-insulin-dependent diabetes mellitus and various parameters of glucose metabolism was studied. Lean and obese rats of the SHR/N-cp and LA/N-cp congenic strains were studied at four months of age. 2. Tritium and 14C-labeled glucoses were infused in one set of rats while tritiated water and 14C-labeled alanine were infused in a second group. 3. Glucose oxidation, turnover, conversion to glycogen, fatty acid synthesis, and alanine conversion to glucose were determined, as were blood pressure, pulse pressure and heart rate. 4. The presence of obesity influenced body weight, body fat, de novo fatty acid synthesis, organ weights, glucose mass, glucose oxidation, glucose synthesis, glucose carbon turnover and pulse pressure. 5. It had no effect on glycogen synthesis, tissue glycogen levels, blood glucose, glucose space, or blood pressure. 6. Strain differences were observed in final body weight, organ weights, blood pressure, pulse pressure, hepatic fatty acid synthesis, glucose mass, glucose space, glucose synthesis, liver glycogen levels and glucose conversion to muscle glycogen. 7. Strain-phenotype interaction effects were observed on glucose incorporation into hepatic glycogen, Cori cycle activity, hepatic de novo fatty acid synthesis, final body weight, fat pad weight, heart weight, and mean arterial pressure. 8. These results suggest that although obesity and hypertension are genetic traits in these rats, these traits are independent in their influence on the metabolism of glucose and the development of non-insulin-dependent diabetes mellitus.

Effect of dietary carbohydrate and phenotype on sucrase, maltase, lactase, and alkaline phosphatase specific activity in SHR/N-cp rat.

The obese spontaneous hypertensive rat/NIH-corpulent (SHR/N-cp) rat exhibits some of the metabolic and pathologic alterations associated with non-insulin-dependent diabetes mellitus and hypertension. The current study was conducted to investigate the influence of phenotype (ob versus In) and source of dietary carbohydrate (sucrose versus starch) on intestinal sucrase, maltase, lactase, and alkaline phosphatase activity in SHR/N-cp rats. For 3 months, lean and obese male SHR/N-cp rats were fed isocaloric diets containing as the sole source of carbohydrate either 54% cooked corn starch or sucrose. Serum and urine markers for diabetes were observed in obese rats. Wet weight and length of intestines were significantly increased in obese rats compared with lean littermates. Among the intestinal enzymes measured, statistical tests confirmed that sucrase activity was significantly increased (P < 0.01) by both phenotype (ob > In) and feeding a sucrose diet. Diet alone (sucrose > starch) significantly increased (P < 0.05) maltase activity in obese rats, but had no effect on lean rats. Lactase activity was significantly higher (P < 0.05) in obese sucrose-fed rats compared with obese starch-fed and/or lean littermates. Statistical tests revealed that intestinal alkaline phosphatase activity was significantly altered (P < 0.05) by both phenotype and diet. Intestinal alkaline phosphatase was higher in starch-fed lean rats compared with lean littermates fed sucrose and to starch or sucrose-fed obese rats. These results are not indicative of a simple, nonspecific increase in intestinal enzyme activity, since the effects observed in intestinal alkaline phosphatase contrast the effects observed in intestinal sucrase, maltase, and lactase activity. These results indicate that both phenotype and diet alter structural and enzymatic intestinal activities of SHR/N-cp rats. Distinct variations in the observed intestinal enzymatic activities suggest that these enzymes are under the control of genetic, hormonal, and dietary factors. Rationale for these differences are discussed.

The effects of the intestinal glucosidase inhibitory BAY M 1099 (miglitol) on glycemic status of obese-diabetic rats.

1. Groups of lean and obese-diabetic (NIDDM) congenic male SHR/Nutl parallel-cp rats were fed a nutritionally adequate, high carbohydrate diet ad libitum with or without the alpha-glucosidase inhibitor miglitol (150 mg/kg diet) from 8 until 15 weeks of age, and key glycemic parameters were monitored throughout the study. 2. Miglitol treatment resulted in clinical improvement toward normal in percent glycosylated hemoglobin, glycemic and insulinogenic responses to an oral glucose tolerance, and in liver glucokinase activity, in concert with modest decreases in weight gain in obese rats. 3. These observations are consistent with improved insulin sensitivity in peripheral tissues following miglitol treatment, and indicate that this drug may be a useful adjunct to diet in the treatment of obesity, NIDDM, and possibly other disorders of carbohydrate metabolism.

Adaptation in enzyme (metabolic) pathways to obesity, carbohydrate diet and to the occurrence of NIDDM in male and female SHR/N-cp rats.

Twenty-four male (12 obese and 12 lean) and 21 female (11 obese and 10 lean) SHR/N-cp rats were fed a diet containing either 54% sucrose or starch for periods of 3-4 months. Rats were killed after a 14-16 h fast and liver enzyme activities were determined in both sex groups. Liver glucose-6-phosphatase (G6Pase), fructose 1,6-bisphosphatase (FBPase), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), malic enzyme (ME), phosphofructokinase (PFK), glucokinase (GK), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (per total liver capacity) were significantly affected by phenotype (obese > lean). Arginase and ornithine transcarbamylase levels were analysed only in male rats and were found to be elevated in obese rats as compared to lean littermates. Some of the above changes in enzyme levels were exaggerated by sucrose feeding but not the changes in FBPase, PEPCK, ME and GK (in both sexes) plus AST, arginase and arginine synthase activities in male rats and ALT levels in female rats. Results from SHR/N-cp rats published in this paper were compared to results obtained from LA/N-cp rats published previously. Comparison of the non-diabetic obese LA/N-cp with the diabetic obese SHR/N-cp male shows a greater excess in lipogenic capacity of the liver in the LA/N-cp male rat. The SHR/N-cp obese female also shows a greater liver lipogenic capacity as compared with the obese male SHR/N-cp rat. The results suggest that an adaptation of excessive lipogenesis in the liver of obese rats may be an anti-diabetogenic adaptation resulting in increased glucose conversion to lipids, thus reducing blood glucose levels.

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.

Effects of dietary carbohydrate and phenotype on adipose cellularity in female SHR/N-cp rats.

1. Adipose mass and cellularity were studied in congenic female SHR/N-cp rats fed iosenergetic diets containing 54% carbohydrate as sucrose (SU) or cooked cornstarch (CS), 20% protein, 16% mixed dietary fat plus vitamins, minerals, and non-nutritive fiber ad libitum from 5 weeks until 8.5 months of age. Measures of adipocyte lipid content, cell number per depot, and mass of principal white (WAT) and interscapular brown (IBAT) adipoe tissue depots were determined at the end of the study. 2. Final body weights (BW) of corpulent rats were more than twice those for their lean littermates, and were greater when fed the SU than the CS diet in both phenotypes. Phenotype effects (corpulent greater than lean) were present for fat pad weight, adipocyte number, and adipocyte lipid content in the dorsal (DOR) and retroperitoneal (RP) WAT depots. Diet effects were present for depot weight, adipocyte number, and adipocyte lipid content in both WAT depots, and were of qualitatively similar magnitude in both phenotypes. 3. IBAT weights, IBAT:BW ratios, and IBAT cell number of corpulent greater than lean, and were greater than with SU than CS diet in both phenotypes. 4. These results indicate that obesity in the corpulent phenotype of the SHR/N-cp rat occurs as the result of hypertrophy and hyperplasia of white adipose tissue, and that isoenergetic substitution of simple for complex carbohydrate resulted in greater fat accretion in both phenotypes. The greater diet and phenotype-associated adiposity occurred despite greater mass and cellularity of BAT. The results also indicate that sexual dimorphism occurs regarding effects of diet and phenotype on expression of adipose tissue development in this strain.

The effects of low-dose Bay-m-1099 (Miglitol) on serum lipids and liver enzyme activity of obese and obese-diabetic corpulent rats.

1. Groups of lean, obese, and obese-non-insulin-dependent diabetic LA/N-cp and SHR/N-cp rats were administered the a-glucosidase inhibitor Miglitol (150 mg/kg diet, ad libitum) from 8 until 15 weeks of age. 2. Phenotype effects (obese greater than lean) were present for weight gain, adiposity, serum glycemic and lipid parameters, and for liver glucokinase, glucose-6-phosphate dehydrogenase, and malic enzyme activity. Miglitol treatment was associated with improvements in glucokinase and malic enzyme in both strains, and in improvements in glycemic parameters in obese rats. 3. These results are consistent with variable improvements in glycemic control and insulin action following low dose Miglitol treatment, and indicate that indirect effects of the drug on insulin sensitivity in peripheral tissues and on glucoregulatory enzymes may contribute to the glycemic improvements observed with this drug, while greater dosages or longer treatment may be required to observe comparable improvements in adiposity or plasma lipid profiles.

Effects of diet and phenotype on adipose cellularity and 5'-deiodinase activity of liver and brown adipose tissue of diabetic SHR/N-cp rats.

1. Groups of lean and obese male SHR/N-cp rats were fed isoenergetic diets containing 54% carbohydrate as cornstarch (CS) or sucrose (SU) plus other nutrients from 5 weeks of age, and measures of adiposity, thyroxine 5' deiodinase (T4-5'DI) activity, and tissue and plasma triiodothyronine (T3) content determined at 9.5 months of age. 2. Body weights (BW) of obese greater than lean, and were greater when fed the SU than CS diet in both phenotypes. Phenotype effects (obese greater than lean) were present for fat pad weights and adipose cellularity in most primary adipose tissue depots, and diet effects (SU greater than CS) were present for epididymal and retroperitoneal depots in both phenotypes. 3. Interscapular brown adipose tissue (IBAT) and IBAT:BW ratios of obese greater than lean, and diet effects (SU greater than CS) were present for lean but not obese rats. Liver T4-5'DI activity and plasma and tissue T3 of lean greater than obese, while IBAT 5'DI activity of obese greater than lean in the CS diet. 4. These results indicate that obesity occurs in the SHR/N-cp rat as the result of hypertrophy and hyperplasia of adipose tissue, and that isoenergetic substitution of simple for complex carbohydrate exaggerates fat accretion in lean but not obese rats. Moreover, the obesity occurs in spite of greater mass, cellularity, and T4-5'DI activity of IBAT, consistent with a thermogenic defect in the obese phenotype of this strain.

Influence of genetic obesity, dietary carbohydrate and age on parameters of glucose tolerance and kidney and adrenal gland histology in female SHR/N-corpulent rats.

Young female obese (cp/cp) and lean littermates (?/+) of the recently developed congenic strain, SHR/NIH-corpulent (SHR/N-cp), were fed for 6.5 months isocaloric diets containing 54 percent carbohydrate as either sucrose or starch. Glycemic, lipidemic and renal parameters were determined after 1, 3 and 6 months. Systolic blood pressure and plasma corticosterone levels were determined after 3 months. After 6.5 months rats were killed for histological examination. Obese rats were hyperglycemic following an oral glucose challenge (1 hour response greater than 11.1 mmol/l) (200 mg/dl), hyperinsulinemic, hypertriglyceridemic, and developed proteinuria and mild hypertension. Feeding sucrose, as compared to starch, further increased serum glucose, insulin and triglyceride levels and urinary protein excretion in obese rats and serum triglyceride levels in lean rats. An amelioration of glucose intolerance was observed in sucrose-fed obese rats by 6 months. In contrast to serum insulin levels, serum triglyceride levels increased with age in obese rats. Obese rats exhibited hypertrophy of the kidney and adrenal cortex with abnormal histology. The study demonstrates that obese female SHR/N-cp rats exhibit some of the metabolic and histopathological changes associated with NIDDM in humans and that feeding sucrose, as the source of dietary carbohydrate, further magnifies the expression of diabetes in this model.

Animal models of spontaneous diabetic kidney disease.

Kidney disease, characterized by proteinuria and glomerular lesions, is a common complication of spontaneous diabetes mellitus in many animal species. It occurs in animals with hypoinsulinemia, hyperinsulinemia, or impaired glucose tolerance. The renal functional and structural abnormalities in spontaneously diabetic animals resemble human diabetic nephropathy in many respects. Mesangial expansion and glomerular basement membrane thickening, two structural hallmarks of diabetic glomerulopathy in humans, are the most frequently encountered lesions in animals. In addition, a nodular form of mesangial expansion that resembles but is not identical with human nodular glomerulosclerosis or the Kimmelstiel-Wilson lesion has been observed in some animal models. Other abnormalities, such as exudative hyaline lesions and arteriolar hyalinosis, have also been noted occasionally in other models. Although diabetic animals may develop kidney disease that resembles human diabetic nephropathy, no single animal model develops renal changes identical to those seen in humans. Nonetheless, animal models with spontaneous diabetic kidney disease may be useful for investigating the mechanisms of development of diabetic nephropathy and the effects of various treatment modalities on the progression of renal disease.

Enzyme-specific activities and mineral concentrations of the exocrine pancreas from female SHR/N-corpulent (cp) rats.

A new rodent model, SHR/N-cp, for study of non-insulin-dependent diabetes mellitus (NIDDM) has recently been developed. The present study reports exocrine pancreatic enzyme activities and mineral concentrations in female corpulent (cp/cp) and lean (+/?) rats fed a diet containing carbohydrate as cooked corn starch or sucrose for 7 months to determine the potential of the model for studies of diet and pancreatic function in NIDDM. Although corpulent female rats weighed 2.5 times more than their lean littermates, they consumed less calories when expressed per 100 g body weight than lean rats. Corpulent rats had a significantly smaller relative pancreatic weight than lean rats (p less than 0.0001), but had greater total pancreatic DNA content and concentration (p less than 0.003) and higher pancreatic amylase (p less than 0.0001), lipase (p less than 0.0011), and chymotrypsinogen (p less than 0.0208) specific activities. Corpulent rats had a significantly lower pancreatic copper concentration than their lean littermates (p less than 0.0193). Corpulent rats consuming starch had a higher pancreatic iron concentration than all other experimental groups (p less than 0.05). The corpulent female rats were only mildly diabetic based upon serum and urine indices. The data suggest that the female SHR/N-corpulent rat may be a useful model for studying exocrine pancreatic function of mild cases of non-insulin-dependent diabetes.

Effect of dietary carbohydrates on insulin and glucagon receptors in a new model of noninsulin-dependent diabetes-SHR/N-corpulent rat.

A new congenic strain of rat, the SHR/N-corpulent, provides a good model for noninsulin-dependent diabetes and was used in the present study. Corpulent rats as compared to their lean littermates are obese, hyperlipidemic, and severely hyperinsulinemic, and show an age-dependent loss of glucose tolerance. Mild fasting hyperglycemia is seen only in corpulent rats fed sucrose. Since dietary sucrose is more lipogenic than starch and since insulin and glucagon are involved in lipid and carbohydrate metabolism, we studied the effect of the type of dietary carbohydrate on insulin and glucagon levels and their receptors in lean and corpulent SHR/N rats. A significant phenotypic effect was observed (corpulent greater than lean) on plasma levels of triglyceride, cholesterol, and insulin. Dietary sucrose increased these parameters in corpulent rats but not in lean rats. Insulin and glucagon binding to liver plasma membranes was lower in corpulent rats than in lean; decreases were due to fewer receptors without a significant change in affinity. Thus, in corpulent rats, in addition to hyperinsulinemia, fewer glucagon receptors and their failure to be regulated by plasma glucagon levels appear to contribute to the hyperlipidemia. Furthermore, the hyperglycemia observed in sucrose-fed corpulent rats may be due to extreme resistance to insulin despite lower plasma glucagon and fewer glucagon receptors.