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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal species with genetic or nutritionally induced insulin resistance, diabetes and obesity (diabesity) may be divided into two broad groups: those with resilient pancreatic beta-cells, e.g. ob/ob mice and fa/fa rats, capable of long-lasting compensatory insulin over-secretion, and those with labile beta-cells in which the secretion pressure leads to irreversible beta-cell degranulation, e.g. db/db mice, Macaca mulatta primates, ZDF diabetic rats. Prominent in this group is the Israeli desert gerbil Psammomys obesus (sand rat), which features low insulin receptor density in liver and muscle. On a diet of relatively high energy, the capacity of insulin to activate the receptor tyrosine kinase (TK) is reduced, in the face of hyperinsulinemia. With the following hyperglycemia, the rising insulin resistance imposes a vicious cycle of insulinemia and glycemia, accentuating the TK activation failure and the beta-cell failure. Among various factors affecting the insulin signaling pathway, multisite phosphorylation, including serine and threonine on the receptor beta-subunit, due to overexpression of certain protein kinase C isoforms, seems to be responsible for the inhibition of the critical step of TK phosphorylation activity. The compromised TK activation is reversible by diet restriction which restores to normal the glycemia and insulinemia. The beta-cell response to long-lasting stimulation and the receptor malfunction in diabesity have implications for a similar etiology in human insulin resistance syndrome and type 2 diabetes, particularly in populations emerging from a food scarce environment into nutritional affluence, inappropriate to the human metabolic capacity. It is suggested that the "thrifty gene" is characterized by a low threshold for insulin secretion and low capacity for insulin clearance. Thus, nutritionally-induced hyperinsulinemia is potentiated and becomes the primary phenotypic expression of the thrifty gene, linked to the insulin receptor signaling pathway malfunction.
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PMID:Cellular mechanism of nutritionally induced insulin resistance: the desert rodent Psammomys obesus and other animals in which insulin resistance leads to detrimental outcome. 1021 43

Leptin is an adipocyte-derived blood-borne satiety factor that acts directly on the hypothalamus, thereby regulating food intake and energy expenditure. We have demonstrated that the hypothalamic arcuate nucleus (Arc) is a primary site of the satiety effect of leptin (Neurosci Lett 224:149-152, 1997). To explore the hypothalamic pathway of sympathetic activation of leptin, we examined the effects of a single intravenous or intracerebroventricular injection of recombinant human leptin on catecholamine secretion in rats. We also examined the effects of direct microinjection of leptin into the ventromedial hypothalamus (VMH), Arc, paraventricular nucleus (PVN), and dorsomedial hypothalamus (DMH) in rats. To further assess whether sympathetic activation of leptin is mediated via the VMH, we also examined the effects of a single intravenous injection of leptin in VMH-lesioned rats. A single injection of leptin (0.25-1.0 mg i.v./rat or 0.5-2.0 pg i.c.v./rat) increased plasma norepinephrine (NE) and epinephrine (EPI) concentrations in a dose-dependent manner. Plasma NE and EPI concentrations were increased significantly when leptin was injected directly into the VMH but were unchanged when injected into the Arc, PVN, and DMH. Plasma NE and EPI concentrations were unchanged in VMH-lesioned rats that received a single intravenous injection of leptin. The present study provides evidence that a leptin-induced increase in catecholamine secretion is mediated primarily via the VMH and suggests the presence of distinct hypothalamic pathways mediating the satiety effect and sympathetic activation of leptin.
Diabetes 1999 Sep
PMID:Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. 1048 Jun 9

The effects of one year combined vanadium and insulin treatment (VIT) on blood glucose levels of insulin dependent diabetic (IDD) rats were studied. Rats made diabetic by an i.v. injection of 55-60 mg/kg streptozotocin (STZ), divided into two groups and treated with a low dose of NPH insulin (2-4 U/rat) for two months to survive from hyperglycaemic shock. In group A, hyperglycaemia ameliorated during one year by increasing the daily dose of insulin to 8.2 +/- 0.4 U/100 g (IT) and in group B by switching over to hydrated vanadium solution (1 mg/ml vanadyl oxide sulphate pentahydrate in drinking water; VIT). The results of the study indicated that one year VIT regenerated new beta-cells, and relieved diabetes both during treatment and after withdrawal. However, one year IT showed no trophic effects on the destroyed beta-cells, hence no improvement in the glycaemic status of the animal was seen after withdrawal. The action of VIT was such that in group B normoglycaemeia persisted in 90 per cent of diabetic rats two weeks after insulin withdrawal. But in the same group, 45 days after combined vanadium and insulin withdrawal blood glucose was normal in 60 per cent of the rats, it was between 250-300 mg/dl in 18 per cent and between 350-400 mg/dl in 24 per cent of the rats. In conclusion it appears that long term VIT regenerates pancreatic beta-cells of IDD rats and possibly by improving their secretory functions it relieves diabetes mellitus.
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PMID:Trophic effects of vanadium on beta-cells of STZ-induced insulin dependent diabetic rats & evidence for long-term relief of diabetes mellitus. 1057 57

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.
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PMID:Glucose-induced insulin mRNA accumulation is impaired in islets from neonatal streptozotocin-treated rats. 1074 85

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.
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PMID:Glucose-induced insulin mRNA accumulation is impaired in islets from neonatal streptozotocin-treated rats. 1078 28

Obesity and Type 2 diabetes are now major public health issues in developed nations and have reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican-Americans, African-Americans, and Australian Aborigines. These groups all show hyperinsulinemia and insulin resistance, which have been demonstrated to be future predictors of Type 2 diabetes and have also been suggested as key factors in the etiology of the Metabolic Syndrome. It is now increasingly recognized that Type 2 diabetes is part of a cluster of cardiovascular disease (CVD) risk factors comprising the Metabolic Syndrome. This group is at very high risk of atherosclerosis because each of the risk factors in the Metabolic Syndrome cluster in its own right is an important CVD risk factor. They also contribute cumulatively to atherosclerosis. A key strategy in reducing macrovascular disease lies in the better understanding of the Metabolic Syndrome--glucose intolerance, hypertension, hyperlipidemia, and central obesity. Although it has been suggested that hyperinsulinemia/insulin resistance is the central etiological factor for the Metabolic Syndrome, epidemiological data do not support the idea that this can account for all of the cluster abnormalities. We have animal and human data suggesting that hyperleptinemia rather than, or synergistically with, hyperinsulinemia may play a central role in the genesis of the CVD risk factor cluster that constitutes the syndrome. Studies in Psammomys obesus (the Israeli sand rat) suggest hyperinsulinemia/insulin resistance is an early metabolic lesion in the development of obesity and Type 2 diabetes. This animal also develops other features of the Metabolic Syndrome, making it an excellent model to investigate etiology. Psammomys, when placed on an ad libitum laboratory diet, develops hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes, and dyslipidemia. It also develops hyperleptinemia and leptin insensitivity, and hyperleptinemia is correlated with insulin resistance independent of changes in body weight. It is likely that a similar sequence occurs in the transition from the prediabetic state to Type 2 diabetes in humans. More recently, other potential players in the etiology of the Metabolic Syndrome have been suggested including endothelial dysfunction and acetylation-stimulating protein (ASP). It has been suggested that endothelial dysfunction may be an antecedent for both Type 2 diabetes and the Metabolic Syndrome. In addition, ASP is a serious new candidate for an important role in insulin resistance. The ASP pathway plays a critical role in fatty acid metabolism and storage, and it has been suggested that ineffective storage of fatty acids by adipocytes due to a defect in the ASP pathway may lead to insulin resistance and Type 2 diabetes.
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PMID:Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players. 1084 50

We examined the influence of diabetes mellitus (DM) on the healing of HCl-induced gastric lesions and the healing promoting effect of polaprezinc [N-(3-aminopropionyl)-L-histidinato zinc] on these lesions. Studies were performed on rats injected intraperitoneally with streptozotocin (STZ, 70 mg/kg) five weeks prior to experiments. Diabetic rats had blood glucose levels (BGLs) higher than 350 mg/100 ml. Randomly chosen animals were treated subcutaneously with insulin (4 IU/day/rat) starting 1 week after STZ. Animals were given 1 ml of 0.6 N HCl by oral gavage (per os) following 18 hr of fasting; they were fed normally from 1 hr later and killed at various time points after HCl administration. Polaprezinc (3-30 mg/kg) or its components ZnSO4/7H2O and L-carnosine were given orally, twice daily for four days following HCl treatment. Gastric lesions induced by HCl healed macroscopically to quiescence within 10 days. DM and insulin did not affect the development of HCl-invoked gastric lesions, but the healing of such lesions was markedly impaired in animals with DM. Daily administration of insulin returned high BGLs to significantly lower ranges (190-208 mg/100 ml) and markedly antagonized the healing impairment. Polaprezinc (>10 mg/kg) significantly reversed the delay observed in diabetic rats without any notable effects on BGLs or acid secretion. Similar trends were observed with ZnSO4/7H2O or a mixture of ZnSO4/7H2O and L-carnosine, but not by L-carnosine alone. The mucosal expression of insulin-like growth factor-1 (IGF-I) mRNA was significantly lower in diabetic rats, a dysregulation partially corrected by insulin and polaprezinc. In addition, the delayed healing in diabetic rats was also significantly promoted by the repeated subcutaneous administration of rhIGF-I (>10 microg/kg, twice daily) without any notable effect on BGLs or acid secretion. These results suggest that DM exerted a deleterious influence on the healing of acute gastric lesions in both insulin- and zinc-sensitive manner. The salutary effects of polaprezinc on the impaired healing of gastric lesion in STZ-diabetic animals may at least be partly explained by enhancement of mucosal IGF-I mRNA expression in the stomach.
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PMID:Polaprezinc exerts a salutary effect on impaired healing of acute gastric lesions in diabetic rats. 1087 38

Diabetes is caused by a failure of the pancreas to produce insulin in amounts sufficient to meet the body's needs. A hallmark of diabetes is an absolute (type 1) or relative (type 2) reduction in the mass of pancreatic beta-cells that produce insulin. Mature beta-cells have a lifespan of approximately 48-56 days (rat) and are replaced by the replication of preexisting beta-cells and by the differentiation and proliferation of new beta-cells (neogenesis) derived from the pancreatic ducts. Here, we show that the insulinotropic hormone glucagon-like peptide (GLP)-1, which is produced by the intestine, enhances the pancreatic expression of the homeodomain transcription factor IDX-1 that is critical for pancreas development and the transcriptional regulation of the insulin gene. Concomitantly, GLP-1 administered to diabetic mice stimulates insulin secretion and effectively lowers their blood sugar levels. GLP-1 also enhances beta-cell neogenesis and islet size. Thus, in addition to stimulating insulin secretion, GLP-1 stimulates the expression of the transcription factor IDX-1 while stimulating beta-cell neogenesis and may thereby be an effective treatment for diabetes.
Diabetes 2000 May
PMID:Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. 1090 82

Type 2 diabetes mellitus features an asymptomatic insulin resistance phase preceding the onset of diabetes. Hyperglycemia occurs when a relative insulin deficiency appears, meaning that beta cell secretory dysfunction is a key element in type 2 diabetes pathophysiology. So far, insulin secretion deficiency is explained by pancreatic beta cell "exhaustion" phenomena. Recent data suggest that apoptotic mechanisms could explain insulin deficiency through a reduction in the absolute pancreatic beta cell number. Psammomys obesus (sand rat) is an animal model for type 2 diabetes mellitus, initially characterized by hyperinsulinism followed by insulin deficiency linked with a reduction in the number of pancreatic beta cells. Transition to diabetes can be observed following changes in usual lifestyle of the sand rat. In the desert, caloric intake is low and physical expenditure is heavy. In the laboratory, animals turn diabetic as early as 4 days following a high calorie diet. At a later stage, diabetes is irreversible and animals die from diabetic ketoacidosis. beta cell apoptosis rate is low in non diabetic animals and increases 14-fold by 20 days after diabetes onset. At this stage, cells undergoing apoptosis can be observed, coexisting with necrotic cells without any insulitis. Similar results were obtained in vitro in isolated pancreatic islets that were exposed to increasing glucose concentrations, suggesting that chronic hyperglycemia plays a role in the onset or the deterioration of the process. However, precise mechanisms of apoptosis in this case remain poorly understood. Aminoguanidin does not prevent beta cell apoptosis in vitro, suggesting that advanced glycation products or NO production are not involved in this beta cell destruction process. Similar mechanisms secondary to hyperglycemia could play a role in the diabetes process in man and explain the marked insulin secretory deficiency that is sometimes observed in these patients. In addition to its preventing role on diabetes complication, the obtention of normoglycemia could help maintaining beta cell function.
Diabetes Metab 2000 Jun
PMID:[Type 2 diabetes and beta cell apoptosis]. 1094 45

Ascorbic acid (AA) is a naturally occurring major antioxidant that is essential for the scavenging of toxic free radicals in both plasma and tissues. AA levels in plasma and tissues have been reported to be significantly lower than normal in diabetic animals and humans, and might contribute to the complications found at the late stages of diabetes. In this study, plasma and hepatic AA levels and AA regeneration were studied in the Goto-Kakizaki diabetic rat (GK rat) to elucidate the mechanism of decreasing plasma and hepatic AA levels in diabetes. AA concentrations in the plasma and liver were significantly lower in GK than in control rats. AA levels in primary cultured hepatocytes derived from GK rats were lower than those derived from control Wistar rats with or without dehydroascorbic acid (DHA) in the medium. Among various enzyme activities that reduce DHA to AA, the NADPH-dependent regeneration of AA in the liver was significantly suppressed in GK rats. Northern blot analysis revealed that only the expression of 3-alpha-hydroxysteroid dehydrogenase (AKR) was significantly suppressed in these rats. These results suggest that decreased AA-regenerating activity, probably through decreased expression of AKR, contributes to the decreased AA levels and increased oxidative stress in GK rats.
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PMID:Impaired reductive regeneration of ascorbic acid in the Goto-Kakizaki diabetic rat. 1102 15


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