. Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes. Am J Physiol Endocrinol Metab 286: E116-E122, 2004. First published October 7, 2003 10.1152/ajpendo.00331.2003.-Thiazolidinediones may slow the progression of type 2 diabetes by preserving pancreatic ␤-cells. The effects of pioglitazone (PIO) on structure and function of ␤-cells in KKA(y), C57BL/6J ob/ob, and C57BL/KsJ db/db mice (genetic models of type 2 diabetes) were examined. ob/ob (n ϭ 7) and db/db (n ϭ 9) mice were randomly assigned to 50-125 mg⅐kg body wt Ϫ1 ⅐day Ϫ1 of PIO in chow beginning at 6-10 wk of age. Control ob/ob (n ϭ 7) and db/db mice (n ϭ 9) were fed chow without PIO. KKA(y) mice (n ϭ 15) were fed PIO daily at doses of 62-144 mg⅐kg body wt Ϫ1 ⅐day Ϫ1

Summary. The mutant mouse, C 57 BL/KsJ.db, develops spontaneous diabetes with many symptoms similar to those observed in the diabetic human. Food intake, body weight, and plasma insulin in the db mouse were increased by 4 weeks of age and blood sugar by 7 weeks. The blood sugar continued to increase with age but by 3 months plasma insulin, pancreatic insulin, and body weight decreased despite continued elevated food intake. Blood sugar and plasma insulin could be stabilized and pancreatic insulin increased of young diabetics were kept on a limited diet. Baseline glucose oxidation by adipose tissue in vitro was elevated in weanling db mice but depressed in older diabetics. The response to insulin of adipose tissue from older db mice was markedly reduced and gluconeogenic enzymes were increased. These observations suggested that diabetes in the db mouse results from the eventual inability of the pancreas to control a continual, abnormally increased supply of glucose. In the very young diabetics, elevated plasma insulin and increased glucose oxidation by the tissues (adipose tissue) maintained the glucose concentration at a normal level. In the older db's, elevated food intake, depressed glucose utilization, and continuous output of glucose by the liver produced a constant, severe stress on the beta cells, resulting eventually in beta cell exhaustion and in the development of lethal diabetes. Influence de t'dge et des conditions alimentaires sur le diab~te de la souris db~gsumd. La souris du mutant C57BL/KsJ-db ddveloppe un diab~te spontan@ dent beaucoup de symptSmes ressemblent ~ ceux du diab@te humain. La prise de nourriture, le poids corporel et l'insulingmie de la souris db sent augraentds d~s la 4e semaine, celle du glucose sanguin d~s l'&ge de 7 semaines. Le sucre sanguln continue augmenter avec l'&ge mais, d@s le 3 roofs, l'insulin6mie, le contenu du pancr@as en insulin et le poids corporel diminuent en d@pit d'une prise alimentaire 4lev@e. Le taux de glucose sanguin et l'insulln@mie peuvent @tre stabilisds, le contenu pancr@atique en insuline augmente si les jeunes animaux diab6tiques sent soumis ~ une restriction alimentaire. --L'oxidation basale du glucose pax le tissue adipeux in vitro est dlev@e chez la souris db apr@s le sevrage, mais abaissde ehez los animaux diabdtiques plus &ggs. La rdponsc du tissu adipeux a Finsuline chez les souris db &gdes est consid@rablement diminu@e et l'activit6 des enzymes de la glucon@ogdn&se est augment6e. Ceci suggSre que le diab&te de la souris db serait d~ au fair qu'a la longue, le pancr@as ne peut contrSler une production de glucose continuellement et anormalement augmentde. Chez les trSs jeunes anirnaux diab6tiques, l'insulin6mie @levee et l'oxidation accrue du glucose par les tissus. (tissu adipeux) contribuent a maintenir le taux de glucose ~ niveau normal. Chez les souris db plus &gdes, uue prise alimentaire augment6e, une utillsation abaiss6e du glucose et la production continue de glucose par le foie provoquent un stress constant et s@v~re sur les cellules fl, ...

No abstract

Evidence is presented that the early hyperglycemia (two to four hours after injection) following streptozotocin administration is not a result of an interference with insulin action, since streptozotocin did not block insulin action on skeletal muscle in vitro. Compounds with known metabolic effects were tested for their ability to block streptozotocin-induced diabetes. Mannoheptulose, glucosamine, diazoxide, NAD, glucose, epinephrine, 3,5-dimethylpyrazole, 3-carboxy-5-methylpyrazole, glutamic acid, glycine, asparagine, cysteine, sodium tolbutamide, guanidoacetic acid, glutathione, p-aminobenzoic acid, and ethyl alcohol were ineffective as blocking agents. Pretreatment with pyrazinamid blocked streptozotocin diabetes,but was ineffective following streptozotocin treatment. 2-carboxypyrazine (the metabolite of pyrazinamide) did not block streptozotocin diabetogenic activity. Administration of 2-deoxyglucose blocked streptozotocin-induced diabetes; this is postulated to be the result of an interference with streptozotocin transport into the β cell. Pretreatment with nicotinamide, or treatment as long as two hours after streptozotocin, blocked the diabetogenic effect of streptozotocin. Nicotinic acid was ineffective. It is postulated that streptozotocin interferes with NAD formation in the β cell, and that nicotinamide treatment abolishes the streptozotocin effect by its ability to maintain ah adequate concentration of NAD in the β cell.

Glucose tolerance was abnormal in many male KK mice studied although fasting blood sugars were generally normal Glucosuria of KK mice was intermittent and nonfasting blood sugar was elevated in some. Plasma insulin of nonfasted KK mice was 10-100 times that of nondiabetic mice and pancreatic insulin was 50% higher than that of control mice. The diaphragm and fat pads of KK mice were insensitive to insulin in vitro. The baseline glucose uptake by diaphragm muscles of KK mice was normal, whereas baseline glucose oxidation by adipose tissue was significantly lower in tissue from KK mice. Limited diet lowers plasma insulin and body weight and restores the adipose tissue sensitivity to insulin. It is postulated that diabetes in the KK mouse is due to decreased sensitivity of fat and muscle to endogenous insulin and to increased food intake which results in an increased demand for insulin. The pancreas responds to this demand by increased insulin secretion and elevated plasma insulin, and as this condition continues, islet hypertrophy results. Continued inbreeding of KK mice produced animals with fewer abnormalities. Fourth to seventh generation animals derived from inbreeding offspring from I~:K • C57 BL/6J mice exhibited relatively large numbers of abnormal animals. M~usen vermindert die H~uiigkeit yon Stoffweehselano-mMien, dagegen wurde sie durch Kreuzung yon KK-M~usen mit einem Stature yon normalen Tieren ab der 4. Generation deutlieh gesteigert.

Ciglitazone, 5-[4-(1-methylcyclohexylmethoxy) benzyl]-thiazolidine-2,4-dione, is a new hypoglycemic agent orally active in the obese-hyperglycemic animal models. In C57BL/6J-ob/ob mice, treatment with 100 mg/kg ciglitazone for 2 days elicited a drastic fall in blood glucose. It also decreased plasma insulin, triglycerides, and free fatty acids and food intake without affecting the body weight. Its hypoglycemic activity was independent of its effect on food intake. Regranulation of islet beta-cells and increased pancreatic insulin content were observed in ob/ob mice treated for 41-44 days with 100 mg/kg/day ciglitazone. Ciglitazone showed no effect on food intake, blood glucose, or pancreatic islet beta-cells in a group of lean C57BL/6J-+/? mice concomitantly treated at a dose of 150 mg/kg/day. In C57BL/KsJ-db/db mice, ciglitazone decreased blood glucose and food intake. The untreated db/db mice lost weight despite hyperphagia, whereas the ciglitazone-treated db/db mice gained weight. In the spontaneously diabetic Chinese hamsters, ciglitazone showed no significant effect on food intake, body weight, blood glucose, or insulin content in either plasma or pancreas, but it lowered plasma lipids. In normal rats, ciglitazone failed to affect fasting blood glucose but improved glucose tolerance without increasing insulin secretory response to glucose. In streptozotocin-diabetic rats, it showed no effect on blood glucose or glycemic response to exogenous insulin. The hypoglycemic activity of ciglitazone was specific for obese-hyperglycemic and insulin-resistant animals.

No abstract

The renal tissue of 12-, 29-, 90- and 165-day-old genetically obese, hyperphagic, diabetic KKA^y and age-matched nondiabetic C57BL/6 mice was morphometrically analyzed to characterize the development of peripheral glomerular capillary basement membrane thickening in the kidney of this animal model. Peripheral glomerular basement membrane (GBM) thickness was unremarkable in KKA^y mice at 12 days of age (prior to onset of hyperinsulinemia) or at 29 days of age (after development of hyperinsulinemia). By 90 days of age, when the KKA^y mice became severely hyperinsulinemic and hyperglycemic, the peripheral GBM thickness was greater (13%, p < 0.002) in the diabetic compared with the nondiabetic mice. Furthermore, the peripheral GBM thickness was exacerbated (20%, p < 0.001) by 165 days of age in the KKA^y mice. The results of the present study suggest that peripheral glomerular capillary basement membrane thickening has an early onset and develops rapidly in the KKA^y mouse in comparison with other diabetic animal models. Therefore, the KKA^y mouse seems to be an appropriate model for further investigation of early structural and functional defects in the glomerular filtration barrier.