Evidence that down-regulation of beta-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia.

Orci, Lelio; Ravazzola, Mariella; Baetens, D.; Inman, Lindsey; Amherdt, M; Peterson, Richard G.; Newgard, Christopher B.; Johnson, John H.; Unger, Roger H

doi:10.1073/pnas.87.24.9953

Cited by 145 publications

(98 citation statements)

References 25 publications

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“…A fragment of the tail of each pancreas was fixed in Bouin's solution and processed for immunohistochemistry, as described previously [34]. Sections were treated with guinea pig anti-pork insulin antibody at a dilution of 1:1000 at 20°C for 2 h. After indirect immunofluorescence staining for insulin with FITC-conjugated IgG for 1 h at 20°C, sections were photographed.…”

Section: Methodsmentioning

confidence: 99%

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

et al. 2004

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Aims/hypothesis. Leptin has been shown to activate AMP-activated protein kinase (AMPK), an enzyme that regulates the activities of key enzymes of lipid synthesis and metabolism. We assess here (i) whether AMPK activity is diminished in rodents deficient in leptin or the leptin receptor, and (ii) the effects of treating the diabetes-prone, leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rat with an AMPK activator. Methods. AMPK activity and related parameters were measured in muscle and or liver of fa/fa and ZDF rats and ob/ob mice. We also explored the effect of treatment with the AMPK activator 5-aminoimidazole 4-carboxamide 1-β-D ribofuranoside (AICAR) (7.4 mmol/l, on Monday, Wednesday and Friday for 15 weeks, beginning at 7 weeks of age) on the phenotype of the ZDF rat. Results. AMPK activity was diminished in muscle and/or liver of fa/fa (leptin-receptor-deficient, non-diabetic) and ZDF (leptin-receptor-deficient, diabetesprone) rats and ob/ob mice (leptin-deficient). ZDF rats that had free access to food became hyperglycaemic (22.2 mmol/l) and hyperphagic after 2 to 5 weeks and remained so during the remainder of the study. Treatment of ZDF rats with AICAR prevented the development of diabetes, as well as increases of triglyceride content in liver, muscle and the pancreatic islets. It also attenuated the morphological abnormalities observed in the islets of untreated rats. Rats diet-matched with the AICAR-treated animals developed diabetes of intermediate severity and showed decreases in triglyceride content in the islets, but not in liver or muscle. Conclusions/interpretation. The results indicate that a deficiency of leptin or the leptin receptor is associated with a decrease in AMPK activity in muscle and/or liver. They also suggest that treatment with an AMPK activator prevents the development of diabetes and ectopic lipid accumulation in the ZDF rat.

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Section: Methodsmentioning

confidence: 99%

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

et al. 2004

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“…These new models of obesity-diabetes should prove useful in dissecting the genetic control of beta-cell responses to hyperglycaemia and insulin resistance. [Diabetologia (2002) [6,7], SHR [8], and LA [9]. In rats, it seems that only obese males are subject to developing severe hyperglycaemia and contraction of beta-cell numbers.…”

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confidence: 99%

“…A similar degree of variant diabetes phenotypes have been observed in rats with a leptin receptor deficiency on various inbred Obesity is usually associated with abnormalities in carbohydrate metabolism. In rodents with genetic perturbations of the leptin/leptin receptor system, the obese phenotype is associated with glucose intoler-backgrounds: WKY [5], ZDF [6,7], SHR [8], and LA [9]. In rats, it seems that only obese males are subject to developing severe hyperglycaemia and contraction of beta-cell numbers.…”

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confidence: 99%

Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

Chua¹,

Liu

et al. 2002

Diabetologia

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Aims. Our goal was to identify genetic variants that determine the response to insulin resistance and hyperglycaemia. This report documents the diabetes syndrome of two new congenic strains of mice generated by the transfer of the Lepr db mutation to the FVB/NJ strain and the Lep ob mutation to the DBA/2J strain. Methods. Mice were characterised by measures of blood metabolites and hormones along with challenges with glucose and insulin injections. Histological examinations of the endocrine pancreas and the kidneys were also carried out. Results. Obese mice of the FVB-db congenic strain show long-term hyperglycaemia that is primarily due to severe insulin resistance. The hyperglycaemia in the fed state persists despite escalating secretion of insulin and massive increase of pancreatic beta cells. Obese FVB-db mice show evidence of mesangial matrix expansion, a hallmark of diabetic nephropathy.Leptin-deficient mice of the DBA-ob strain have variable obesity-diabetes. In mice with high insulin (>10 ng/ml), DBA-ob/ob mice maintain their increased adiposity and have a large increase in betacell number. In mice with low insulin (<1 ng/ml) DBA-ob/ob mice have greatly diminished adiposity. These mice have atrophied islets with evidence of increased beta-cell neogenesis from the ductal epithelium. Conclusions. The strain-specific responses suggest the existence of genetic variants that control insulin sensitivity and beta-cell responses in the strains described in this report. These new models of obesity-diabetes should prove useful in dissecting the genetic control of beta-cell responses to hyperglycaemia and insulin resistance. [Diabetologia (2002) [6,7], SHR [8], and LA [9]. In rats, it seems that only obese males are subject to developing severe hyperglycaemia and contraction of beta-cell numbers.The loss of beta cells in these obesity-diabetes models is not mediated by the immune system. Studies have shown that C57BLKS/J db/db (K-db) mice develop their characteristic diabetes phenotype independent of a functional immune system [10]. The response of the beta cell in these obese rodents is subject to dietary influences. When placed on a completely carbohydrate-free diet (CHO-free diet), obese C57BLKS/J db/db mice are able to maintain near-euglycaemia and preserve their pancreatic beta-cell mass [11].While these strain-specific phenotypes have been documented [4], some of the congenic strains have been lost. This report describes the generation and characterisation of several new congenic mouse strains carrying mutations of Lep or Lepr. The FVB congenic strains (FVB-db and FVB-ob) provide a new diabetes phenotype that has not been described previously. Obese FVB mice suffer a prolonged period of hyperglycaemia that produces massive expansion of beta-cell mass. We show data that the early onset of severe insulin resistance probably accounts for the hyperglycaemia of these strains. The islet hyperplasia of obese FVB mice suggests that prolonged hyperglycaemia does not eventually lead to complete betacell atro...

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“…These results suggest that the loss of GLUT 2 does not play a significant role in the aetiology of diabetes in the Kilham Rat Virus-infected diabetes-resistant BB/Wor rat. [Diabetologia (1994) animal models of insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM) [4][5][6][7]. The Zucker diabetic fatty (ZDF) rat displays obesity and insulin resistance.…”

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confidence: 99%

“…animal models of insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM) [4][5][6][7]. The Zucker diabetic fatty (ZDF) rat displays obesity and insulin resistance.…”

mentioning

confidence: 99%

Preservation of GLUT 2 expression in islet beta cells of Kilham Rat Virus (KRV) ? infected diabetes-resistant BB/Wor rats

Stubbs

Guberski

1994

Diabetologia

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Summary Loss of GLUT 2, the glucose transporter isoform of pancreatic beta cells, has been reported to accompany the onset and perhaps contribute to the pathogenesis, of insulin-dependent and non-insulindependent diabetes mellitus in BB/Wor and Zucker fatty rats. In this study we investigated the effect of Kilham Rat Virus infection on GLUT 2 expression in diabetes-resistant BB/Wor rats. Viral antibodyfree diabetes-resistant rats do not develop spontaneous diabetes, but inoculation with Kilham Rat Virus induces autoimmune beta-cell destruction and hyperglycaemia. Pancreas sections from normoglycaemic diabetes-resistant BB/Wor rats were obtained 5, 7 and 25 days after inoculation with Kilham Rat Virus and stained for GLUT 2 using a rabbit polyclonal antibody. At all time points, beta cells displayed GLUT 2 expression comparable to uninfected diabetes-resistant controls. Immunostained insulin content of the beta cells also remained unchanged. Sections were also examined from Kilham Rat Virus inoculated diabetes-resistant rats with lymphocytic insulitis or diabetes. GLUT 2 and insulin immunostaining were unchanged in non-diabetic rats with early insulitis. GLUT 2 beta-cell staining was variably reduced in diabetic rats with established insulitis and reduced beta-cell insulin immunostaining. Hence, the initial stages of Kilham Rat Virus-induced diabetes in diabetes-resistant rats are not accompanied by a significant reduction in GLUT 2 expression. These results suggest that the loss of GLUT 2 does not play a significant role in the aetiology of diabetes in the Kilham Rat Virus-infected diabetes-resistant BB/Wor rat. [Diabetologia (1994) animal models of insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM) [4][5][6][7]. The Zucker diabetic fatty (ZDF) rat displays obesity and insulin resistance. Only male rats develop diabetes with an associated loss of insulin response to glucose [4]. Obese male diabetic ZDF rats revealed decreased beta-cell GLUT 2 protein and mRNA at the onset of diabetes, compared to obese non-diabetic female and lean non-diabetic male Zucker rats [4,6]. Glucose-induced insulin release in obese diabetic ZDF rats was correlated with the level of beta-cell GLUT 2; glucose-induced insulin release by the isolated perfused pancreas was absent in rats with fewer than 60 % GLUT 2 positive beta cells. In contrast, arginine infusions elicited a strong insulin secretory response,

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Evidence that down-regulation of beta-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia.

Abstract: Non-insulin-dependent diabetes mellitus (NIDDM) is attributed to a failure of pancreatic . cells to maintain insulin secretion at a level sufficient to compensate for underlying insulin resistance. In the ZDF rat, a model of

Cited by 145 publications

References 25 publications

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

Preservation of GLUT 2 expression in islet beta cells of Kilham Rat Virus (KRV) ? infected diabetes-resistant BB/Wor rats

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