Thyroxine effects on parameters of glucose turnover in BHE rats fed menhaden oil

The effect of hyperthyroidism on glucose turnover in BHE rats fed menhaden oil was studied. Thyroxine-treated rats had a greater glucose mass, a greater absolute glucose synthesis rate, less hepatic and muscle glycogen levels, and greater hepatic and peripheral fat cell lipogenic rates than nontreated rats. No differences in body weight gain were observed, nor were there differences in blood glucose levels, glucose space, or fractional reversible or irreversible glucose use. These observations suggest that thyroxine and menhaden oil were additive in their effects on glucose metabolism in BHE rats, which are genetically programmed to develop non-insulin-dependent diabetes mellitus.     

In vivo modulation of N-myristoyltransferase activity by orthovanadate

N-Myristoyltransferase (NMT) catalyses the transfer of myristate from myristoyl-CoA to the NH₂-terminal glycine residue of several proteins and are important in signal transduction. STZ-induced diabetes (an animal model for insulin-dependent diabetes mellitus, IDDM) resulted in a 2-fold increase in rat liver NMT activity as compared with control animals. In obese Zucker (fa/fa) rats (an animal model for non-insulin dependent diabetes mellitus, NIDDM) there was a4.7-fold lower liver particulate NMT activity as compared with the control lean rat livers. Administration of sodium orthovanadate to the diabetic rats normalised liver NMT activity. These results would indicate that the rat liver particulate N-myristoyltransferase activity appears to be inversely proportional to the level of plasma insulin, implicating insulin in the control of N-myristoylation.Abbreviations NMT N-myristoyl-CoA:protein N-myristoyltransferase - IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - NIP₇₁ 71 kDa N-myristoyltransferase inhibitor protein - NAF₄₅ 45 kDa N-myristoyltransferase activating factor     

Glucose-induced insulin mRNA accumulation is impaired in islets from neonatal streptozotocin-treated rats.

According to the glucose toxicity hypothesis, hyperglycemia contributes to defective beta-cell function in type 2, non-insulin-dependent diabetes mellitus. This concept is supported by substantial data in rodent models of diabetes. However, the ability of glucose to stimulate the accumulation of insulin mRNA, a critical feature of normal beta-cell physiology, has not been investigated in in vivo models of chronic hyperglycemia. The aim of this study was to determine whether glucose-induced insulin mRNA accumulation is impaired in the neonatal streptozotocin-treated rat (n0-STZ rat), a model of non-obese, non-insulin-dependent diabetes mellitus. Islets of Langerhans isolated from n0-STZ and control rats were cultured for 24 h in the presence of 2.8 or 16.7 mmol/L glucose, and insulin mRNA levels were measured by Northern analysis. Insulin mRNA levels were increased more than twofold by glucose in control islets. In contrast, no significant effect of glucose was found on insulin mRNA levels in n0-STZ islets. We conclude that insulin gene regulation by glucose is impaired in n0-STZ rat islets.     

Glucose-induced insulin mRNA accumulation is impaired in islets from neonatal streptozotocin-treated rats.

According to the "glucose toxicity" hypothesis, hyperglycemia contributes to defective beta-cell function in type 2, non-insulin-dependent diabetes mellitus. This concept is supported by substantial data in rodent models of diabetes. However, the ability of glucose to stimulate the accumulation of insulin mRNA, a critical feature of normal beta-cell physiology, has not been investigated in in vivo models with chronic hyperglycemia. The aim of this study was to determine whether glucose-induced insulin mRNA accumulation is impaired in the neonatal streptozotocin-treated rat (n0-STZ rat), a model of non-obese, non-insulin-dependent diabetes mellitus. Islets of Langerhans isolated from n0-STZ and control rats were cultured for 24 h in the presence of 2.8 or 16.7 mmol/l glucose, and insulin mRNA levels were measured by Northern analysis. Insulin mRNA levels were increased more than twofold by glucose in control islets. In contrast, no significant effect of glucose was found on insulin mRNA levels in n0-STZ islets. We conclude that insulin gene regulation by glucose is impaired in n0-STZ rat islets.     

Potential role of N-myristoyltransferase in pathogenic conditions

N-Myristoyltransferase (NMT) is the enzyme that catalyzes the covalent transfer of myristic acid to the N-terminal glycine residue of a protein substrate. In this review article, I summarize that NMT may have a potential role in cardiac muscle in the experimentally induced ischemia-reperfusion rat model and also in the streptozotoein-induced diabetic rat. Both the expression and activity of NMT were increased by ischemia-reperfusion. Immunohistochemical studies showed cytosolic localization of NMT in normal rat heart and predominant nuclear localization after ischemia followed by reperfusion. However, the localization of NMT is reversed by treatment with a calpain inhibitor (ALLM N-Ac-Leu-Leu-methioninal). During ischemia-reperfusion, the degradation of c-Src, which is a substrate of NMT, was observed. These findings suggested that the Src signaling may be impaired in ischemia-reperfusion owing to the altered localization of NMT from cytoplasm to nucleus. Streptozotocin-induced diabetes (an animal model for insulin-dependent diabetes mellitus) resulted in a 2.0-fold increase in rat liver NMT activity as compared with control animals. In obese (fa/fa) Zucker rats (an animal model for non-insulin-dependent diabetes mellitus), there was an approximately 4.7-fold lower liver particulate NMT activity as compared with control lean rat livers. Administration of sodium orthovanadate to the diabetic rats normalized liver NMT activity. These results would indicate that rat liver particulate NMT activity appears to be inversely proportional to the level of plasma insulin, implicating insulin in the control of N-myristoylation. These are the first studies demonstrating the role of NMT in the pathogenesis of ischemia-reperfusion and diabetes mellitus. These conditions remain an important area of investigation.     

Characterization of a novel congenic strain of diabetic fatty (WBN/Kob-Lepr(fa)) rat

The WBN/Kob-Lepr^fa rat is a new congenic strain for the fa allele of the leptin receptor gene (Lepr). Homozygous (fa/fa) WBN/Kob-Lepr^fa rats provide a model of non-insulin-dependent diabetes with obesity. Here, we describe the characteristics of this new animal model in detail. At 7 weeks of age, both male and female obese WBN/Kob rats showed inflammatory cell infiltration of the pancreas that suggested pan-pancreatitis and an abnormal OGTT. At 3 months of age, both male and female obese WBN/Kob rats developed overt diabetes mellitus associated with severe chronic pancreatitis. In contrast, lean female WBN/Kob rats do not develop pancreatitis or diabetes. In WBN/Kob rats, this mutation might promote the onset of severe pancreatitis, leading to the rapid development of diabetes mellitus.     

Comparative studies on lipogenesis and cholesterogenesis in lipemic BHE rats and normal Wistar rats.

The BHE strain of rat is characterized by early hyperinsulinemia and maturity onset hyperlipemia and hyperglycemia. Since we have previously shown that insulin is required for the coordinate regulation of a number of lipogenic enzymes in rat liver, a comparative study of the hepatic activities of the rate-limiting enzymes of lipid synthesis and the in vivo rates of fatty acid and cholesterol synthesis in the liver and the adipose tissue has been conducted in BHE and Wistar rats. In the liver, BHE rats had 25–28% higher acetyl-CoA carboxylase and fatty acid synthetase activities as measured in vitro but a 100% greater rate of fatty acid synthesis in vivo as compared to Wistar animals. These results strongly suggest that factors other than the amount of acetyl-CoA carboxylase, such as allosteric effectors, must be operating in vivo, thereby facilitating the carboxylase to function at its maximal capacity in BHE rats. Such a regulation of fatty acid biosynthesis by allosteric modifiers of acetyl-CoA carboxylase is already known, although the mechanism of this regulation is not fully understood. BHE rats also exhibited a twofold greater rate of fatty acid synthesis in the adipose tissue compared to the Wistar rats. Thus, increased lipogenic capacity and increased lipogenesis in BHE rats are consistent with early hyperinsulinemia in this strain. Furthermore, BHE rats had 71% more 3-hydroxy-3-methylglutaryl CoA reductase activity with a 97% greater rate of cholesterol synthesis as compared to Wistar rats. In contrast, cholesterol 7α-hydroxylase activity was only 20% greater in BHE rats compared to Wistar rats, suggesting that the BHE rat does not have the capacity to degrade cholesterol to bile acids at a rate commensurate with the increased rate of cholesterol synthesis. This difference in synthesis versus degradation might account for the hypercholesterolemia which occurs in BHE rats, but not in Wistar rats.     

Genetic dissection of "OLETF," a rat model for non-insulin-dependent diabetes mellitus: quantitative trait locus analysis of (OLETF x BN) x OLETF.

To identify genetic determinants relevant to non-insulin-dependent diabetes mellitus (NIDDM), we performed a genome-wide analysis for quantitative trait loci (QTLs) using 359 backcross progeny of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF strain is a well-studied animal model of obese NIDDM, with features of hyperinsulinemia, hyperglycemia, insulin resistance, and abundant abdominal fat. Our extensive genomic scanning with 218 markers revealed nine significant QTLs, including a strong determinant of obesity on chromosome 1 (Dmo1: LOD = 13.99, for body weight). Two highly significant QTLs for glucose homeostasis were found, one on chromosome 1 (Dmo4 LOD = 7.16, for postprandial glucose level) and the other on chromosome X (Dmo11/Odb1: LOD = 7.81, for postprandial glucose level). These data are comparable to results of our previous studies of the OLETF rat.     

Diabetes mellitus in Mohawks of Kahnawake,PQ: a clinical and epidemiologic description.

The authors report the rates of obesity, hypertension, hypercholesterolemia, smoking, and macrovascular and microvascular complications among Mohawks of Kahnawake, PQ, who have non-insulin-dependent diabetes mellitus. The data were derived from a study comparing rates of macrovascular and microvascular complications among the diabetic subjects and a nondiabetic group matched for age and sex. The data for both groups were collected by means of chart review, interview and body measurement. There were no important differences between the male and female diabetic subjects. Both sexes had high levels of obesity, hypertension, hypercholesterolemia and diabetic complications. A total of 86% of the diabetic subjects were obese; the rate was also very high (74%) among the nondiabetic subjects. The mean age at onset of diabetes, 59 years, was 10 years higher than that observed in Oneida Iroquois of Ontario. The rates of macrovascular disease among the diabetic subjects were higher than those found among Cree/Ojibwa in Ontario and Manitoba. Our findings add to the knowledge of non-insulin-dependent diabetes in North American Indians in Canada and show that there are differences between our Mohawk subjects and diabetic people of other native communities.     

Type 2 diabetes mellitus in obese mouse model induced by monosodium glutamate.

The number of diabetic patients is increasing every year, and new model animals are required to study the diverse aspects of this disease. An experimental obese animal model has reportedly been obtained by injecting monosodium glutamate (MSG) to a mouse. We found that ICR-MSG mice on which the same method was used developed glycosuria. Both female and male mice were observed to be obese but had no polyphagia, and were glycosuric by 29 weeks of age, with males having an especially high rate of incidence (70.0%). Their blood concentrations of glucose, insulin, total cholesterol, and triglycerides were higher than in the control mice at 29 weeks. These high concentrations appeared in younger males more often than in females, and were severe in adult males. Also, the mice at 54 weeks of age showed obvious obesity and increased concentrations of glucose, insulin, and total cholesterol in the blood. The pathological study of ICR-MSG female and male mice at 29 weeks of age showed hypertrophy of the pancreatic islet. This was also observed in most of these mice at 54 weeks. It was recognized as a continuation of the condition of diabetes mellitus. From the above results, these mice are considered to be useful as new experimental model animals developing a high rate of obese type 2 (non-insulin dependent) diabetes mellitus without polyphagia.     

Spontaneous diabetes mellitus in captive Mandrillus sphinx monkeys: a case report

Case history The two obese mandrills (Mandrillus sphinx) showed clinical signs of depression, anorexia, hyperglycemia, hypertriglyceridemia, glucosuria, proteinuria and ketonuria. Septic bed sore wounds were noted on both fore and hind limbs. Results Histopathological study revealed severe islet amyloidosis in both mandrills. Immunohistochemical study using polyclonal anti-cat amylin antibody confirmed derivation of the islet amyloid from islet amyloid polypeptide (IAPP). Cardiomyopathy and myocardial fibrosis were also evident. Conclusions The present study documents diabetes mellitus in two obese mandrills. Diabetes in these animals had features very similar type 2 diabetes mellitus of humans, including the development of severe, IAPP-derived islet amyloidosis. The mandrill may, therefore, serve as an animal model of human type 2 diabetes mellitus.     

Hepatic glycogen synthase phosphatase and phosphorylase phosphatase activities are increased in obese (fa/fa) hyperinsulinemic Zucker rats: effects of glyburide administration

The chronically hyperinsulinemic Zucker fatty rat, with peripheral insulin resistance and glucose intolerance, represents a model of noninsulin dependent diabetes mellitus (NIDDM). These animals have elevated hepatic glycogen levels. Hepatic levels of synthase phosphatase and phosphorylase phosphatase, which are diminished in the IDDM rat, were markedly increased in the obese rats. Glyburide, a sulfonylurea used in treatment of NIDDM, resulted in reduced levels of glycemia and increased insulin levels in Zucker rats. Hepatic glycogen levels were increased, as was the activation of glycogen synthase, although there were no effects of drug administration on synthase phosphatase or phosphorylase phosphatase activities. G6P levels were increased by glyburide in lean rats but not in obese animals. These effects of glyburide on liver glycogen metabolism are accounted for via potentiation of the glycogenic effects of insulin.     

Examination of OLETF-derived non-insulin-dependent diabetes mellitus QTL by construction of a series of congenic rats

The Otuska Long-Evans Tokushima Fatty (OLETF) rat is one of the well-characterized animal models for the study of type 2 diabetes. Our previous QTL mapping identified 11 loci responsible for non-insulin-dependent diabetes mellitus (NIDDM) susceptibility in the OLETF rat. Here we generated a series of congenic animals by individually introgressing all 11 OLETF-derived NIDDM loci into a normoglycemic F344 background. Subsequent oral glucose tolerance test revealed that the congenic strains for Nidd1/of, Nidd2/of, Nidd3/of Nidd4/of, Nidd7/of, and Nidd10/of showed significantly higher levels of blood glucose in comparison with parental host strain F344. Furthermore, simultaneously made heterozygote animals for Nidd1/of and Nidd2/of did not increase blood glucose levels, indicating that these loci are recessively inherited as predicted by the QTL analysis. Congenic strains for the other five loci—Nidd5/of, Nidd6/of, Nidd8/of, Nidd9/of, and Nidd11/of—were apparently normoglycemic, presumably owing to heterosis or because the effect of these loci may not be detected unless interactions with other OLETF genes exist. We believe that these congenic strains should provide useful agents for decomposing complex diabetic traits and for positional cloning.     

Hypoglycaemic effect of metformin in genetically obese (fa/fa) rats results from an increased utilization of blood glucose by intestine.

The insulin-resistant obese fa/fa rat is a convenient model in which to study a potential effect of metformin, a biguanide used in the treatment of non-insulin-dependent diabetes, on insulin-mediated glucose utilization. Female fa/fa rats were given metformin orally for 8 days. Studies were performed on anaesthetized post-absorptive rats 5 h after the last dose of metformin. Glucose production and utilization were enhanced 1.5-fold in metformin-treated rats. The enhanced glucose production was almost entirely due to increased glucose recycling. The digestive tract was the only tissue responsible for the enhanced glucose utilization.     

Nutrient-gene interactions in mitochondrial function: vitamin A needs are increased in BHE/Cdb rats

The BHE/Cdb rat has a maternally inherited mutation in the ATPase 6 mitochondrial gene that associates with impaired oxidative phosphorylation (OXPHOS) and glucose intolerance. A longevity study revealed that feeding an egg-rich (vitamin A-rich) diet delayed the onset of impaired glucose tolerance. Two experiments were conducted to test the hypothesis that BHE/Cdb rats require more dietary vitamin A than normal rats. Experiment 1 was a dose-response study examining OXPHOS in BHE/Cdb rats fed one of six levels of vitamin A. In experiment 2 BHE/Cdb and Sprague-Dawley rats were used. The rats were depleted of retinol stores, then repleted with 4 or 12 IU vitamin A/g diet. Vitamin A status was assessed in depleted, never depleted, and depleted/repleted rats. OXPHOS was optimized at 4 IU/g diet for the Sprague-Dawley rats and 12 IU/g diet for the BHE/Cdb rats. These results suggested that the criteria for vitamin intake adequacy in the BHE/Cdb rats is the optimization of mitochondrial OXPHOS. Using this criteria, we conclude that diabetes-prone BHE/Cdb rats require more dietary vitamin A than normal rats.     

Genetic Dissection of “OLETF,” a Rat Model for Non-Insulin-Dependent Diabetes Mellitus: Quantitative Trait Locus Analysis of (OLETF × BN) × OLETF

To identify genetic determinants relevant to non-insulin-dependent diabetes mellitus (NIDDM), we performed a genome-wide analysis for quantitative trait loci (QTLs) using 359 backcross progeny of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF strain is a well-studied animal model of obese NIDDM, with features of hyperinsulinemia, hyperglycemia, insulin resistance, and abundant abdominal fat. Our extensive genomic scanning with 218 markers revealed nine significant QTLs, including a strong determinant of obesity on chromosome 1 (Dmo1: LOD = 13.99, for body weight). Two highly significant QTLs for glucose homeostasis were found, one on chromosome 1 (Dmo4 LOD = 7.16, for postprandial glucose level) and the other on chromosome X (Dmo11/Odb1: LOD = 7.81, for postprandial glucose level). These data are comparable to results of our previous studies of the OLETF rat.     

IAPP与SS在大鼠和家兔背根神经节细胞内分布与共存的免疫组织化学研究

应用免疫组织化学ABC法,观察到在大鼠和家兔背根神经节内存在胰岛淀粉样多肽免疫阳性反应细胞.用相邻镜像邻片免疫双标记技术,证实胰岛淀粉样多肽存在于背根神经节内那些生长抑素免疫反应阳性的细胞中,说明胰岛淀粉样多肽在大鼠和家兔背根神经节内与生长抑素共存.实验结果为胰岛淀粉样多肽的胰腺外研究提供了新的资料,为进一步研究背根神经节内生物活性物质间的关系及生理作用提供了形态学证据.     

Changes in the content and structure of the coenzyme A moiety in the liver of diabetic mice (db/db) administered a regimen of nicotinamide

Alterations in the content and structure of CoA moiety typical of hyperlipogenesis (a rise in total and free CoA levels, a drop in short-chained fatty acyl-CoA/CoA and long-chained fatty acyl-CoA/CoA ratios) were found in the liver of obese mice with non-insulin-dependent diabetes (db/db). The treatment of diabetic mice with nicotinamide, an antilipemic drug, was accompanied by a decrease in total and free CoA levels and a rise in short-chained fatty acyl-CoA content and short-chained fatty acyl-CoA/CoA and long-chained fatty acyl-CoA/CoA ratios, probably leading to the inhibition of the enzymes of primary lipogenesis steps. It is suggested that CoA moiety structure is essential as an integral index regulating the rate of fatty acid biosynthesis in diabetes mellitus.     

New insights into body composition assessment in obese women.

During treatment of patients with non-insulin-dependent diabetes mellitus, there may be marked body weight loss. Therefore, body composition should be monitored to check for a decrease in fat mass alone, without an excessive decrease of both fat-free mass and total body water. Accordingly, it is useful to monitor the hydration of these patients. One method that allows us to check the status of body hydration is the multifrequency bioelectric impedance analysis (MFBIA). It makes use of formulas that estimate total body water on the basis of the concept that the human body may be approximated to a cylinder of length equal to body height. In normal subjects body water estimates are sufficiently accurate, but in obese subjects the true hydration status may be overestimated. In this report, we describe the accuracy of mathematical models previously described in the literature, and correct for the overestimation of total body water in obese subjects by means of a new equation based on a new model. The coefficients for each model have been recalculated by the weighing of our sample in order to test the accuracy of estimates obtained with the equations. This new model includes both body volume and two impedances at appropriate frequencies useful for identifying two terms strictly related to extra- and intra-cellular water. The new formulas do not include body weight, but they include the body volume, a parameter more closely related to the biophysical reference model. Fifty-five overweight females, body mass index ranging from 26.8 to 50.2 kg/m2, were enrolled in the study. The proposed equations, taking advantage of two impedance values at appropriate frequencies, better predict total body water in obese women. This was particularly evident when the results obtained with the multifrequency bioelectric impedance analysis and deuterium isotopic oxide dilution method were compared. Although this last method is considered the "gold standard," it is not suitable for use in routine clinical practice. In conclusion, evaluation of total body composition by means of bioelectric impedance analysis might be included in programs for the prevention of non-insulin-dependent diabetes and for monitoring weight loss during overt pathology.