Diabetes in Chinese hamster was initially detected by qualitative tests for urine ~lucose. The disease was ct~aracterized by quantitating urine glucose, glucose tolerance tests and measurement of fasting and nonfasting blood sugar, blood ketones, plasma free fatty acids (FFA), plasma insulin, pancreatic insulin and fasting levels of liver glycogen. In addition, basal levels of glucose utilization by diaphragms and epididymal adipose tissue and the response of these tissues to insulin was measured. Those animals requiring insulin received their last injection 24 hours prior to study. Glucosuria varied from 51 to 1600 mg/24 hours. Diabetics had significantly decreased tolerance to a 250 mg/kg glucose load. The response varied considerably in diabetics but was uniform in the nondiabetics. Diabetics had mean fasting liver glycogen levels of 3.1 :~ 1.0 compared with 0.4 --0.7 percent of fresh liver weight for nondiabetics. Severely ketotic, diabetic Chinese hamsters had significantly elevated FFA and ketone levels and significantly lower plasma and pancreatic insulin levels but mild diabetics did not differ from controls with respect to these parameters. Alt Chinese hamsters had high plasma FFA levels (nondiabeties 1800 teE/l, severe diabetics 2800 teE/l). Fasting and nonfasting FFA levels did not differ in mild diabetic and nondiabetie animals. Muscle and adipose tissues from diabetic hamsters had basal rates similar to nondiabetics and had similar responses to insulin. Hamsters maintained on insulin had greatly elevated immunoreaetive insulin levels in their plasma, which persisted for 26 days. --The data suggest that severely diabetic hamsters may have a decreased ability of the pancreas to secrete insulin in response to a glucose stimulus. The observations that plasma insulin levels are normal in mild diabetics but that these animals have glucosuria, hyperglycemia and abnormal glucose tolerance suggest that mild diabetes in the Chinese hamster may involve interference with insulin action and/or increased hepatic glucose output.Caract~risation du diab~te du hamster chino@. Vol. 3, No. 2, 1967 G.C. GERaITS]~ and W.E. DuLI~<: Diabetes in the Chinese Hamster 75 ist noch 26 Tage nach der letzten Injektion nachweisbar. --Diese Ergebnisse lessen vermuten, dal~ dcr Pankreas des diabetischen Hamsters nur schwerlich in der Late ist, naeh ether Glucosestimulierung Insulin auszuschiitten. Die Beobachtung, dal~ der Plasma-Insulinspiegel im leithten Diabetes normal ist, diese Tiere jedoch Glucosurie, Hyperglyk~mie and abnormale Glucosetoleranz aufweisen, fiihrt zu der Annahme, dal3 ein leichter Diabetes beim chinesisehen Hamster eine Beeintr~ichtigung der Insulinwirkung mit sich bringen, und Ursache einer vermehrten Glucoseproduktion durch die Leber sein kalm.

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, ...

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.

D-glucose in the pyranose (ring) form exists as two anomers. The alpha-anomer is more effective than the beta-anomer in promoting insulin secretion, suppressing that of glucagon, and protecting beta-cells against alloxan toxicity. Streptozotocin (SZ), a beta cell toxin, is composed of a cytotoxic moiety, 1-methyl 1-nitrosourea, attached to carbon-2 of glucose and exists as either of two anomers in the pyranose form. In 24-hour-fasted male rats, predominantly alpha- or predominantly beta-SZ was injected intravenously and plasma glucose levels were obtained 48 hours later. The alpha-anomer produced significantly greater beta-cell necrosis at doses of 30, 35, and 40 mg./kg. body weight. At higher doses, no differences between the alpha and beta anomers were observed. 3-O-Methyl glucose (3-OMG) protected against both SZ anomers; however, the alpha-SZ remained more toxic. Larger doses of glucose protected against the lower doses of SZ and, under such conditions, the individual glucose anomers appeared equally potent. Finally, mannitol at comparable molar concentrations was ineffective in protecting against the SZ toxicity. This study suggests that streptozotocin's beta cell toxicity is mediated through recognition by the beta cell. In addition, 3-OMG and, to a lesser but significant extent, glucose were shown to protect against the streptozotocin toxicity, whereas mannitol did not.

No abstract

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.

As a hypoglycemic agent, 3,5-dimethylpyrazole (U-6245) was found to be fifty-four times more potent orally than tolbutamide in glucose-injected, fasted intact rats. U-6245 increased glucose oxidation by intact rats. It lowered plasma free fatty acids but not blood sugar of eviscerate rats and was effective in decreasing the fasting bloodsugar levels of alloxan-diabetic rats which were unresponsive to tolbutamide. U-6245 markedly depressed plasma FFA fifteen minutes to three hours after its administration. The mechanism of hypoglycemic activity of 3,5-dimethylpyrazole is not the same as insulin, sulfonylureas or biguanides in that: (1) It is ineffective in lowering the blood sugar of eviscerates while insulin is. (2) U-6245 is active in alloxan diabetic rats which are unresponsive to tolbutamide. (3) The pyrazole increases glucose oxidation and biguanides do not. Although the mechanism of action of 3,5-dimethylpyrazole is not understood, data are presented which support the hypothesis that its action may depend on its effect on plasma FFA and also on the presence of the liver and/or intestinal tract. Since the pyrazole increases glucose oxidation in intact rats, it appears that at least part of its action may be due to the stimulation of glucose oxidation by the intestinal tract and/or liver.

No abstract