Modification of insulin resistance by diazoxide in obese Zucker rats.

Alemzadeh, Ramin; Slonim, Alfred E.; Zdanowicz, Martin M.; Maturo, Joseph M.

doi:10.1210/endo.133.2.8344209

Cited by 61 publications

(32 citation statements)

References 3 publications

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“…Finally, from a preventative perspective, our results suggest that attenuation of hyperinsulinemia might be an option in the primary prevention of type 2 diabetes, just as restoration of insulin sensitivity and early-phase insulin secretion may delay or prevent deterioration of glucose tolerance. Pharmacological attenuation of insulin hypersecretion, such as with diazoxide, has previously been reported to improve (53) and even prevent (54) glucose intolerance in rodent models of obesity and type 2 diabetes and, more recently, to exert beneficial metabolic effects also in obese humans (55). In this respect, it is important to point out that our findings were exclusively obtained in individuals with NGT, not IGT, at baseline.…”

Section: Discussionmentioning

confidence: 72%

A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia.

et al. 2000

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Fasting hyperinsulinemia is a widely used surrogate measure of insulin resistance and predicts type 2 diabetes in various populations. Whether fasting hyperinsulinemia predicts diabetes independent of insulin resistance is unknown. In 319 Pima Indians with normal glucose tolerance, fasting plasma insulin concentration and insulin-stimulated glucose disposal (M) (hyperinsulinemic clamp) were inversely related, but at any given M, there was substantial variation, with some subjects being hyperinsulinemic and others being hypoinsulinemic relative to their degree of insulin sensitivity. In 262 of the 319 subjects followed prospectively over 6.4 ± 3.9 years, a high fasting plasma insulin concentration was a significant independent predictor of diabetes, in addition to low M and low acute insulin response (AIR) (intravenous glucose challenge). In 161 of the 319 subjects with follow-up measurements of M and AIR (5.1 ± 3.9 years), a high relative fasting plasma insulin concentration predicted a decline in AIR but not in M before the onset of diabetes. The adjusted fasting plasma insulin concentration was a familial trait (heritability of 0.52) and in a genomewide scan, there was suggestive evidence of linkage (logarithm of odds score 1.77) to a region on chromosome 3q, which harbors the gene encoding GLUT2. These results provide the first prospective evidence in humans that fasting hyperinsulinemia itself has a primary role in the pathogenesis of diabetes, independent of insulin resistance. Whether amelioration of basal insulin hypersecretion will prevent diabetes remains to be elucidated.

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Section: Discussionmentioning

confidence: 72%

A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia.

et al. 2000

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“…These findings support a tight correlation between hepatic glycogen content and G-6-Pase activity at any given time as previously shown (55) and are consistent with our observations in DZ obese rats. On the other hand, the lack of a DZ effect on GK and G-6-Pase activities in lean rats, despite the increase in GS activity and glycogen content, is probably due to opposing effects of enhanced hepatic glucose uptake and mild hyperglycemia (23,24) on these enzymes.…”

Section: Discussionmentioning

confidence: 94%

“…Persistent hyperinsulinemia and insulin resistance in obese Zucker rats is believed to increase simultaneously activities of glycolytic and gluconeogenic enzymes even in the fasted state, leading to enhanced glycolysis and lipogenesis (22). Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, has been shown to cause enhanced insulin sensitivity in isolated adipocytes, down-regulation of lipid metabolizing enzymes in adipose tissue, improved glucose tolerance and weight reduction in obese Zucker rats (23)(24)(25). To investigate the effect of chronic insulin suppression on hepatic glucose metabolism, we measured the Glut-2 protein expression and the activities of key insulin-sensitive enzymes regulating hepatic gluconeogenesis namely GK, G-6-Pase, active glycogen synthase (GSa), active glycogen phosphorylase (GPa) and PEPCK in diazoxide-treated obese and lean Zucker rats.…”

Section: Introductionmentioning

confidence: 99%

Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats

Alemzadeh

Holshouser²,

Massey³

et al. 2002

European Journal of Endocrinology

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Objectives: Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucosemediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused downregulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis. Methods: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks. Results: DZ-treated animals showed lower fasting plasma insulin levels ðP , 0:001Þ than their controls. Plasma glucose levels were lower in DZ obese rats than in controls ðP , 0:001Þ; without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase ðP , 0:001Þ and glucose-6-phosphatase ðP , 0:0001Þ and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls ðP , 0:001Þ: However, DZ-treated lean rats demonstrated higher PEPCK activity than controls ðP , 0:002Þ: DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content ðP , 0:01Þ; glycogen synthase activity ðP , 0:0001Þ and glycogen content ðP , 0:02Þ compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals ðP , 0:02Þ: Conclusions: Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.

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“…It has also been reported to reduce weight gain in obese Zucker rats [4], prevent development of insulin resistance in a rat model [5], and preserve residual insulin secretion in Type 1 diabetic humans [6]. Potentially, therefore, KCOs selective for the pancreatic beta cell K ATP channel could be of clinical value for treating disease states in which suppression of insulin secretion and beta-cell activity are beneficial.…”

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confidence: 99%

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

et al. 2003

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Aims/hypothesis. We investigated the pharmacological properties of two novel ATP sensitive potassium (K ATP ) channel openers, 6-Chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NNC 55-0118) and 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NN414), on the cloned cardiac (Kir6.2/SUR2A), smooth muscle (Kir6.2/SUR2B) and pancreatic beta cell (Kir6.2/ SUR1) types of K ATP channel. Methods. We studied the effects of these compounds on whole-cell currents through cloned K ATP channels expressed in Xenopus oocytes or mammalian cells (HEK293). We also used inside-out macropatches excised from Xenopus oocytes. Results. In HEK 293 cells, NNC 55-0118 and NN414 activated Kir6.2/SUR1 currents with EC 50 values of 0.33 µmol/l and 0.45 µmol/l, respectively, compared with that of 31 µmol/l for diazoxide. Neither compound activated Kir6.2/SUR2A or Kir6.2/SUR2B channels expressed in oocytes, nor did they activate Kir6.2 expressed in the absence of SUR. Current activation was dependent on the presence of intracellular MgATP, but was not supported by MgADP. Conclusion/interpretation. Both NNC 55-0118 and NN414 selectively stimulate the pancreatic beta-cell type of K ATP channel with a higher potency than diazoxide, by interaction with the SUR1 subunit. The high selectivity and efficacy of the compounds could prove useful for treatment of disease states where inhibition of insulin secretion is beneficial. [Diabetologia (2003[Diabetologia ( ) 46:1375[Diabetologia ( -1382

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Modification of insulin resistance by diazoxide in obese Zucker rats.

Cited by 61 publications

References 3 publications

A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia.

A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia.

Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

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