Islet transplantation to the renal subcapsular space in streptozotocin-diabetic rats: short-term effects on glucose-stimulated insulin secretion

The immediate and short-term effects of transplantation of freshly isolated islets on glucose-stimulated insulin secretion were studied in streptozotocin-diabetic rats. At 2 days after the intravenous injection of streptozotocin (70 mg/kg), either 400 or 1000 freshly isolated, hand-picked islets were transplanted to the left renal subcapsular space. Intravenous glucose infusion (10 mg/min) performed 1, 3, 6, and 10 days after transplantation revealed that already at day 3, rats transplanted with 1000 islets had a significant plasma insulin response to glucose, though the response was lower than in healthy controls. At 6 and 10 days after transplantation, the 1000 islet-transplanted group of rats had a near-normal plasma insulin response to glucose. Basal plasma glucose levels were, however, still slightly elevated. Rats transplanted with 400 islets had a significant plasma insulin response at 10 days after transplantation, though the response was lower than in those transplanted with 1000 islets. It is concluded that a near-normal in vivo insulin secretory response to glucose is already obtained 6 days after transplantation with 1000 freshly isolated islets to the left renal subcapsular space in streptozotocin-diabetic rats. However, a slight hyperglycemia persists.     

The increase in lipid peroxidation in diabetic rat lens can be reversed by oral sorbinil

Malondialdehyde (MDA), a product of lipid peroxidation, was measured in the lens of rats in which diabetes had been induced by treatment with streptozotocin (85 mg/kg). The MDA level increases nearly 100% in lenses from diabetic rats, compared with lenses from age-matched control rats. Treating rats with insulin decreases the MDA content of the diabetic rat lens to normal levels. This suggests that the increase in MDA of diabetic rats lens is not due to a toxic effect of streptozotocin, but instead is the result of diabetes mellitus or insulin deficiency. Administration of the aldose reductase inhibitor, sorbinil, decreases lens MDA levels in diabetic rats in a dose-dependent manner with a median effective dose (ED50) of 7.5 mg/kg. This study demonstrates that sorbinil can prevent lipid peroxidation of rat lens resulting from insulin deficiency, which can aid in helping the lens to cope with the oxidative stress of diabetes.     

Effects of the angiotensin converting enzyme inhibitor, lisinopril, on normal and diabetic rats

The comparative effects of lisinopril, a third generation angiotensin converting enzyme (ACE) inhibitor, on components of the renin-angiotensin system were assessed in normal and in an animal model of diabetes-related hypertension, the streptozotocin-diabetic rat. Two weeks after injection of streptozotocin the mean systolic blood pressure of diabetic rats was elevated 11% above that of normal rats. This effect was prevented by daily injection of insulin. The mean serum ACE activity was elevated 71% above that of normal rats. Lisinopril reduced systolic blood pressure and inhibited serum ACE activity in both normal and diabetic rats in a dose-response fashion. In normal rats maximum inhibition of blood pressure occurred at a mean dose of 1.0 mg/kg and in the diabetic rat at a mean dose of 5.0 mg/kg. At a mean dose of 5 mg/kg, ACE was inhibited by 100 and 92% in normal and diabetic rats, respectively. Plasma renin activity (PRA) increased sharply in both groups of rats treated with the lower doses of lisinopril, only to decrease at the 5 mg/kg level. At 20 mg/kg, PRA continued to decline in normal animals, but not in diabetic rats. Formation of angiotensin II (Ang II) in both normal and diabetic rats was maximally inhibited at doses of 1.0 and 0.1 mg/kg of lisinopril, respectively without a significantly greater effect at the higher doses of the drug. In separate experiments the effects of chronic treatment with lisinopril at two dosage levels on various physiological parameters of streptozotocin-diabetic rats were compared with the effects of another hypotensive agent, hydralazine, an arteriolar vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of maternal diabetes on fetal rat development: alteration of insulin receptors in fetal liver and lung

The influence of maternal diabetes on fetal development was studied in rats made diabetic by administration of streptozotocin on day 2 of gestation as well as in genetically diabetic BB Wistar rats. A dose of 65 mg streptozotocin/kg produced severe diabetes with plasma glucose levels of approximately 36 mmol/l, this was associated with fetal growth retardation but not fetal hyperinsulinaemia. In contrast, a smaller dose of streptozotocin (45 mg/kg) produced moderate diabetes with plasma glucose levels of approximately 20 mmol/l and was associated with fetal hyperinsulinaemia but only a marginal effect on fetal size. In both groups of diabetic animals, maternal body weight gain was decreased, maternal plasma insulin levels were low and fetal glucose levels were similar. In a small group of genetically diabetic BB rats on insulin therapy the fetuses were macrosomic and hyperinsulinaemic. The specific binding of 125I-labelled insulin to partially purified liver and lung membranes of fetuses of both groups of streptozotocin-induced diabetic rats was significantly lower than the binding to membranes from fetuses of control animals. The specific binding of 125I-labelled insulin to fetal liver and lung membranes from the diabetic BB Wistar rats also appeared to be reduced when compared to tissues from controls. Decreased insulin receptors in fetal lung and liver of diabetic rats suggest a role for insulin in the development of these organs during the fetal and neonatal period.     

Moderate insulinopenia can cause insulin antagonism

Profound insulin deficiency can cause insulin antagonism. To assess whether more modest insulinopenia can also cause insulin antagonism, male Sprague-Dawley and female obese (fa/fa) Zucker rats received streptozotocin injections (20, 30 or 40 mg/kg) or citrate buffer alone. After 1 and 2 weeks, the animals underwent glucose (0.5 g/kg) and insulin (0.2 U/kg)-glucose (0.7 mg/kg) tolerance tests, respectively, after an overnight fast. In the Sprague-Dawley rats: (a) basal glucose concentrations were significantly increased in the 40 mg/kg group; (b) glucose-induced insulin responses were significantly decreased in the 30 and 40 mg/kg groups; (c) glucose disappearance rates after glucose alone were significantly decreased in the 40 mg/kg group; and (d) glucose disappearance rates after insulin and glucose were significantly decreased in both the 30 and 40 mg/kg group. All obese Zucker rats injected with 30 and 40 mg/kg died within the first week with marked hyperglycemia. In the 20 mg/kg groups: (a) basal glucose levels were significantly elevated; (b) glucose disappearance rates and insulin responses were significantly decreased; (c) glucose disappearance rates after insulin and glucose were 20% lower than in the control rats but the difference did not reach statistical significance. In conclusion, Zucker rats are much more sensitive to streptozotocin than Sprague-Dawley rats. In the Sprague-Dawley strain, a modest insulin deficiency is associated with insulin antagonism. Since these rats treated with low doses of streptozotocin are characterized by decreased glucose-induced insulin secretion and insulin antagonism, they may serve as an appropriate model for type 2 diabetes mellitus.     

Streptozotocin-induced diabetes decreases mammary gland lipoprotein lipase activity and messenger ribonucleic acid in pregnant and nonpregnant rats

Diabetes mellitus is associated with a reduction of lipoprotein lipase (LPL) activity in adipose tissue and development of hypertriglyceridemia. To determine how a condition of severe insulin deficiency affects mammary gland LPL activity and mRNA expression during late pregnancy, streptozotocin (STZ) treated (40 mg/kg) and non-treated (control) virgin and 20 day pregnant rats were studied. In control rats, both LPL activity and mRNA were higher in pregnant than in virgin rats. When compared to control rats, STZ-treated rats, either pregnant or virgin, showed decreased LPL activity and mRNA content. Furthermore, mammary gland LPL activity was linearly correlated with mRNA content, and either variable was linearly correlated with plasma insulin levels. Thus, insulin deficiency impairs the expression of LPL in mammary glands, revealing the role of insulin as a modulator of the enzyme at the mRNA expression level.     

Glycine N-methyltransferase deficiency: A new patient with a novel mutation

We report studies of a Greek boy of gypsy origin that show that he has severe deficiency of glycine N -methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine. At age 2 years he was found to have mildly elevated serum liver transaminases that have persisted to his present age of 5 years. At age 4 years, hypermethioninaemia was discovered. Plasma methionine concentrations have ranged from 508 to 1049 micro mol/L. Several known causes of hypermethioninaemia were ruled out by studies of plasma metabolites: tyrosinaemia type I by a normal plasma tyrosine and urine succinylacetone; cystathionine beta-synthase deficiency by total homocysteine of 9.4-12.1 micro mol/L; methionine adenosyltransferase I/III deficiency by S -adenosylmethionine (AdoMet) levels elevated to 1643-2222 nmol/L; and S -adenosylhomocysteine (AdoHcy) hydrolase deficiency by normal AdoHcy levels. A normal plasma N -methylglycine concentration in spite of elevated AdoMet strongly suggested GNMT deficiency. Molecular genetic studies identified a missense mutation in the coding region of the boy's GNMT gene, which, upon expression, retained only barely detectable catalytic activity. The mild hepatitis-like manifestations in this boy are similar to those in the only two previously reported children with GNMT deficiency, strengthening the likelihood of a causative association. Although his deficiency of GNMT activity may well be more extreme, his metabolic abnormalities are not strikingly greater. Also discussed is the metabolic role of GNMT; several additional metabolite abnormalities found in these patients; and remaining questions about human GNMT deficiency, such as the long-term prognosis, whether other individuals with this defect are currently going undetected, and means to search for such persons.     

A new model of Type 2 (non-insulin-dependent) diabetes mellitus in spontaneously hypertensive rats: diabetes induced by neonatal streptozotocin treatment

Summary This study was designed to develop an animal model of Type 2 (non-insulin-dependent) diabetes with persistent hypertension. Male spontaneously hypertensive rats were treated with 25.0, 37.5, 50.0, 62.5 or 75.0 mg/kg of streptozotocin given intraperitoneally at 2 days of age and maintained for 12 weeks. In the rats which received 50.0 mg/kg or more streptozotocin, overt hyperglycaemia gradually and consistently developed following incomplete recovery from an initial hyperglycaemia. Compared to vehicle-treated controls, body weight gain in these animals did not differ for the first 8 weeks; thereafter, it was slightly but significantly (p < 0.05) reduced. The animals treated with 25.0 or 37.5 mg/kg streptozotocin developed mild to moderate hyperglycaemia, but their body weight gain was similar to controls. The relationships between streptozotocin dose and metabolic responses (plasma glucose, glycosylated haemoglobin, urinary glucose, food intake, etc.) were clearly demonstrated. Systolic blood pressure rose with progressing age in both controls and streptozotocin-treated rats, irrespective of dosage or metabolic response. This new rat model of Type 2 diabetes associated with persistent hypertension may be useful in studying these combined effects on small and large vessels.     

Methionine adenosyltransferase I/III deficiency: two Korean compound heterozygous siblings with a novel mutation

Two Korean sisters, one detected during neonatal screening, the other ascertained at age 3 years during family screening, have persistent hypermethioninaemia without elevation of plasma tyrosine or severe liver disease. Plasma total homocysteine (tHcy) is mildly elevated, but not so markedly as to establish a diagnosis of homocystinuria due to cystathionine beta-synthase (CBS) deficiency. CBS deficiency was ruled out by the presence of slightly elevated concentrations of plasma cystathionine. Although the plasma concentrations of methionine were markedly elevated, plasma S-adenosylmethionine (AdoMet) was not. This pattern of metabolic abnormalities suggested that the patients have deficient activity of methionine adenosyltransferase (MAT) in their livers (MAT I/III deficiency). Molecular genetic studies demonstrate that each patient is a compound heterozygote for two mutations in MAT1A, the gene that encodes the catalytic subunit that composes MAT I and MAT III: a previously known inactivating G378S point mutation, and a novel W387X truncating mutation. W387X mutant protein, expressed in E. coli and purified, has about 75% of wild-type activity. Negative subunit interaction between the mutant subunits is suggested to explain the hypermethioninaemia of these sisters. They have had normal growth and development and have no mental retardation, neurological abnormalities, or other clinical problems. They are the first individuals of Korean descent proven to have MAT I/III deficiency.     

Plasma eicosanoid levels in rats with nonketotic diabetes mellitus: effect of severity

Nonketotic diabetes mellitus (DM) is associated with increased platelet production of thromboxane (TX) A2 and decreased endothelial production of prostacyclin (prostaglandin [PG]I2), but measurements of stable derivatives of these substances in the circulation have yielded discordant results. We studied the relationship between the severity of nonketotic DM and the plasma levels of 13,14-dihydro-15-keto-PGE2, 6-keto-PGF1 alpha, and TXB2 (stable derivatives of PGE2, PGI2, and TXA2, respectively) in rats, using three commonly employed doses of streptozotocin (40, 50, and 60 mg/kg body weight) to induce nonketotic DM of varying severity. Small differences in the severity of DM were associated with considerable differences in the plasma levels of 13,14-dihydro-15-keto-PGE2 and 6-keto-PGF1 alpha but not TXB2. Each eicosanoid responded differently to variations in the severity of DM. The plasma 13,14-dihydro-15-keto-PGE2 level was significantly lower than normal in the rats given 40 mg/kg streptozotocin, was unchanged from normal in the rats given 50 mg/kg and was significantly higher than normal in the rats given 60 mg/kg. The plasma 6-keto-PGF1 alpha level was significantly increased in rats given 40 mg/kg and 60 mg/kg, but was unchanged in those given 50 mg/kg. The plasma TXB2 level was not significantly different from normal in any one of the three groups of rats with nonketotic DM. The effect of severity on the plasma levels of the PGE2 and PGI2 derivatives is unexplained, but may reflect the origin of these derivatives from diverse organs and tissues, and the differing effects of abnormal metabolic factors (eg, fatty acids, glucose, insulin, pH) on the synthesis of these derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of long-term insulin deficiency and insulin treatment on the composition of triglyceride-rich lipoproteins and triglyceride turnover in rats.

The effect of long-term (4 months) insulin deficiency on triglyceride turnover was examined using Triton WR1339 in rats. Triglyceride secretion rate was estimated in rats 2 weeks and 4 months after induction of diabetes with 40 mg/kg of streptozotocin. By the second week diabetic rats showed prominent hyperglycemia and the plasma insulin level was very low. In spite of a lower triglyceride secretion rate compared to non-diabetic control rats, diabetic rats showed normotriglyceridemia. Thus, the estimated fractional catabolic rate for plasma triglyceride was decreased in the diabetic rats of 2 weeks duration. By the fourth month diabetic rats still showed a suppressed triglyceride secretion rate but plasma triglyceride was markedly higher than in the non-diabetic control rats. Therefore, their estimated fractional catabolic rate for plasma triglyceride was severely suppressed. They also showed hyperglycemia and hypercholesterolemia. The triglyceride-rich lipoprotein particles obtained after Triton injection in long-term diabetic rats were significantly cholesterol-enriched and triglyceride-depleted compared to control rats. These changes were already present in 2-week diabetic rats but the magnitude was significantly smaller that those in long-term diabetic rats. All of these abnormalities (including triglyceride turnover and the particle composition) were almost normalized by 2 weeks of insulin treatment (6 units/day). Thus, it was concluded from the present data that duration of insulin deficiency is an important determinant of triglyceride removal rate from the circulation in rats. Further modification of lipid composition of triglyceride-rich lipoprotein particles by long-term insulin-deficiency could be one of the reasons for this removal defect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Control of blood glucose levels in the streptozotocin diabetic rat using a long-acting heat-treated insulin

Summary Diurnal plasma glucose levels have been studied two hourly in streptozotocin diabetic rats during insulin treatment. Protamine Zinc Insulin induced a very steep fall in plasma glucose level from 359±100 (SD) mg/100 ml to 91± 49 mg/100 ml within two hours. Plasma glucose was then low (13–60 mg/100 ml) until after 18 hours when an equally steep rise in glucose concentration ocurred. Six other insulin preparations and several insulin treatment regimens were tested with the aim of normalising the 24 hour plasma glucose profile of streptozotocin diabetic rats. One preparation, a non-commercial, very long acting Ultralente NOVO (Mc, ox pH 5.5) yielded a diurnal plasma glucose profile reasonably close to normal when it was administered once a day and when the dose was based on daily blood glucose measurements. Mean plasma glucose was 122±55 mg/100 ml with a nadir of 55±15 and a maximal of 187±99 mg/100 ml.     

Hypermethioninaemia due to methionine adenosyltransferase I/III (MAT I/III) deficiency: diagnosis in an expanded neonatal screening programme

The Expanded Newborn Screening Program (MS/MS) in the region of Galicia (NW Spain) was initiated in 2000 and includes the measurement of methionine levels in dried blood spots. Between June 2000 and June 2007, 140 818 newborns were analysed, and six cases of persistent hypermethioninaemia were detected: one homocystinuria due to cystathionine β-synthase (CβS) deficiency, and five methionine adenosyltransferase I/III (MAT I/III) deficiencies. The five cases of MAT I/III deficiency represent an incidence of 1/28 163 newborns. In these five patients, methionine levels in dried blood spots ranged from 50 to 147 μmol/L. At confirmation of the persistence of the hypermethioninaemia in a subsequent plasma sample, plasma methionine concentrations were moderately elevated in 4 of the 5 patients (mean 256 μmol/L), while total homocysteine (tHcy) was normal; the remaining patient showed plasma methionine of 573 μmol/L and tHcy of 22.8 μmol/L. All five patients were heterozygous for the same dominant mutation, R264H in the MAT1A gene. With a diet not exceeding recommended protein requirements for their age, all patients maintained methionine levels below 300 μmol/L. Currently, with a mean of 2.5 years since diagnosis, the patients are asymptomatic and show developmental quotients within the normal range. Our results show a rather high frequency of hypermethioninaemia due to MAT I/III deficiency in the Galician neonatal population, indicating a need for further studies to evaluate the impact of persistent isolated hypermethioninaemia in neonatal screening programmes.     

Effects of streptozotocin-induced diabetes on circulating levels of vitamin D metabolites

In order to investigate vitamin D metabolism in insulin-deficient diabetic rats, plasma vitamin D metabolites were measured at various periods after induction of diabetes by iv administration of 60 mg/kg streptozotocin (STZ). After STZ injection, plasma insulin was significantly decreased and plasma urea nitrogen increased with the duration of diabetes, while plasma creatinine remained unchanged. Plasma calcium, 25-dihydroxyvitamin D (25(OH)D), and 24,25-dihydroxyvitamin D (24,25(OH)2D) progressively decreased. On the other hand, plasma 1,25-dihydroxyvitamin D (1,25(OH)2D) did not change at any period, but the ratio of 1,25(OH)2D to 25(OH)D became high in proportion to the severity of hypocalcaemia. Since significantly lower 25(OH)D and 24,25(OH)2D levels were observed at the later stage of diabetes, it is suggested that the altered vitamin D metabolism in diabetes is secondary to the disturbances in metabolic homeostasis derived form the insulin deficiency.     

Protection by nicotinamide against streptozotocin-induced reduction in pancreatic TRH

The concentration of thyrotrophin-releasing hormone (TRH) immunoreactivity was determined in pancreatic islets and acini in the rat. In addition, time-course changes in TRH in response to an iv injection of streptozotocin (65 mg/kg body weight) with or without nicotinamide (500 mg/kg body weight) were examined in the whole pancreas. Furthermore, pancreatic TRH was measured in diabetic rats treated with insulin for 3 weeks. The TRH concentration in rat islets was 42-fold higher than in exocrine glands, indicating that the majority of pancreatic TRH is of islet origin. The mean concentration of pancreatic TRH decreased to 60 and 65% of the respective control values at 4 and 7 h after administration of streptozotocin, respectively. AT 24 h, it fell to 10% of control values without significant changes in TRH levels in the hypothalamus and gastrointestinal tract. In contrast, no significant change in pancreatic TRH was noted in rats given combined treatment with streptozotocin and nicotinamide. The injection of streptozotocin alone resulted in severe hypoglycaemia at 7 h and hyperglycaemia at 24 h, whereas neither resulted from the combined treatment. Insulin therapy had no influence on the decreased TRH concentrations in the diabetic pancreas. These results suggest that TRH may be localized to the B cells of pancreatic islets, and that the marked reduction in TRH in diabetic pancreases is not a metabolic consequence of insulin deficiency.     

Streptozotocin-induced diabetes in the spontaneously hypertensive rat.

Spontaneously hypertensive rats (SHR) were more sensitive to the diabetogenic effects of streptozotocin than normotensive Wistar-Kyoto (WKY) rats. Thus, 10 days after intravenous administration of 25 mg/kg streptozotocin in SHR, mean pancreatic insulin content was decreased by 42% (p less than 0.05), and mean plasma glucose concentration was increased from 85 to 215 mg/dl (p less than 0.001), whereas between 37.5 and 50 mg/kg of streptozotocin was required to produce similar effects in normotensive WKY rats. Also, there was a progressive decrease in blood pressure in SHR injected with 25, 35.7, or 50 mg/kg of streptozotocin, whereas blood pressure was progressively increased after streptozotocin in normotensive WKY rats. The opposite effects of streptozotocin-induced diabetes on blood pressure in SHR and WKY rats could be observed at similar degrees of hyperglycemia and are presently unexplained.     

薏苡仁多糖对实验性2型糖尿病大鼠胰岛素抵抗的影响

目的 观察薏苡仁多糖对实验性2型糖尿病大鼠胰岛素抵抗的影响。方法 用小剂量链脲佐菌素（25mg/kg,iv)加高热量饲料（热卡：20.083J/g)建立实验性2型糖尿病大鼠模型，然后用薏苡仁多糖分三个剂量组（25、50、100mg/kg，ip)给药治疗2周，并测定葡萄糖耐量，血浆胰岛素以及肝糖原、肌糖原、肝细胞膜胰岛素受体结合率和肝葡萄糖激酶活性。结果 薏苡仁多糖能改善实验性2型糖尿病大鼠糖耐量异常，增加肝糖原量和肝葡萄糖激酶活性，且呈现一定的量效关系。但对血浆胰岛素水平及胰岛素受体最大结合率和受体最大结合容量均无影响。结论 薏苡仁多糖能够改善实验性2型糖尿病大鼠胰岛素抵抗，这可能与其调节糖代谢酶的活性有关。     

Reduced insulin binding to hepatic plasma membranes in D-galactosamine-treated rats

Six to 12 hr after IP injection of 400 mg/kg of D-galactosamine in rats a 5-fold increase in plasma insulin was observed. In addition, impaired glucose assimilation was present after an IV Load in spite of unchanged fasting glucose levels. In streptozotocin-diabetic rats (100 mg/kg IV) plasma insulin remained diminished 12 h after induction of D-galactosamine hepatitis. Under identical conditions of preparation and incubation, the liver plasma membranes of D-galactosamine-treated rats, in both normal and diabetic states, bound only 40--60% as much insulin per mg of membrane protein as those of the control rats. Scatchard analysis suggested that this was due to a decrease in the number of receptor sites in the membranes of the D-galactosamine-injected rats. No difference in the insulin degrading capacity and in insulin-receptor dissociation of the plasma membranes between control and D-galactosamine-treated groups was found. These data suggest that a reduction in the number of hepatic insulin receptors in galactosamine hepatitis can lead to insulin resistance and hyperinsulinaemia.     

Studies on the mechanism of the diabetogenic activity of streptozotocin and on the ability of compounds to block the diabetogenic activity of streptozotocin (author's transl)]

The present study was undertaken to clarify the mechanism of the diabetogenic activity of streptozotocin. Experiments were conducted to determine the resistance of animals to the diabetogenic action of streptozotocin; to follow the time course of irreversible beta-cell damage, and to determine the influence on streptozotocin action of certain compounds. Streptozotocin, a broad spectrum antibiotic, with antitumoral properties, was shown to be diabetogenic in rats and mice, but not in cats, rabbits, or guinea pigs. Intravenous or intraperitoneal administration of 65 mg/kg body weight of streptozotocin to male Wistar rats evoked a tri-phasic blood sugar response. It induced an initial hyperglycemic peak with no apparent change in plasma insulin concentrations, followed by profound hypoglycemia caused by liberation of large amounts of insulin from the pancreas. Forty-eight hours after injection, the animals were completely diabetic. Light- and electron-microscopic exadminations during the first forty-eight hours after the injection of streptozotocin showed pyknosis, degranulation and marked degeneration of the beta-cells. 1egenerative and necrotic changes were also seen in a few alpha-cells. These streptozotocin-induced diabetic rats revealed polydipsia, polyuria, polyphagia and glucosuria, and decreased body weight. Blood sugar, plasma FFA and insulin concentrations were examined after oral administration of glucose (OGTT: 3g/kg). Blood sugar and plasma FFA were significantly elevated but plasma insulin concentrations were markedly decreased, so insulin treatments were most effective in these animals. It has been reported that nicotinamide prevents the diabetogenic activity of streptozotocin and the deformity action of 6-aminonicotinamide and 3-acetylpridine. Pre-treatment with picolinamide, methyl-nicotinamide, and nicotinohydroxamic acid also blocked its diabetogenic action, but nicotinic acid, mannoheptulose and glucose were ineffective. N-nitrosodimethylamin and ethyl-N-nitrosomethylcarbamate were devoid of diabetogenicity. It seems that streptozotocin interfers with NAD formation in the beta-cell. Functioning pancreatic islets cell tumors were observed on the rats both at 407 days after streptozotocin administration and at 473 days after streptozotocin administration with nicotinamide (500 mg/kg, i.p.).     

Effects of chronic sodium salicylate feeding on the impaired glucagon and epinephrine responses to insulin-induced hypoglycaemia in streptozotocin diabetic rats

Summary The potential role of endogenous prostaglandins in glucagon and epinephrine responses to insulin-induced hypoglycaemia was studied in streptozotocin-diabetic and age-matched control adult male rats. Rats made diabetic with a single intravenous injection of streptozotocin (65 mg/kg) developed impaired glucagon and epinephrine responses to insulin-induced hypoglycaemia by 80–100 days. Plasma glucagon levels in response to insulin-induced hypoglycaemia in streptozotocin-diabetic rats (167+67 pg/ml) were significantly lower (p<0.01) than those in control rats (929±272 pg/ml). Similarly, plasma epinephrine levels in hypoglycaemic state in streptozotocin-diabetic rats (l1±8 pmol/ml) were also significantly lower (p<0.01) compared to control rats (37±13 pmol/ml). Steptozotocin-diabetic rats provided with sodium salicylate (25 mg/100 ml) in their drinking water from day one of diabetes exhibited prevention of the blunted glucagon and epinephrine responses to insulin-induced hypoglycaemia. About 80–100 days after the chronic sodium salicylate treatment in streptozotocin-diabetic rats, both plasma glucagon levels (1080±169 pg/ml) and plasma epinephrine levels (39±8 pmol/ml) were essentially identical to plasma glucagon levels (1074±134 pg/ml) and plasma epinephrine levels (37±5 pmol/ml) in control rats in hypoglycaemic state. These animals also exhibited an improvement in the diabetic state in that they had less severe hyperglycaemia and lack of weight gain. These results suggest that the blunted glucagon and epinephrine responses to insulin-induced hypoglycaemia may be related to altered prostaglandin levels in streptozotocin-diabetes.