Differential Hypoglycemic Effect of 2,5-Anhydro-D-Mannitol, a Putative Gluconeogenesis Inhibitor, in Genetically Diabetic (db/db) and Streptozotocin-Induced Diabetic Mice

Kodama, Hiroshi; Fujita, Masataka; Yamaguchi, Isamu

doi:10.1254/jjp.66.331

Cited by 9 publications

(4 citation statements)

References 24 publications

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“…Concomitant with its effects on plasma glucose levels, administration of 2,5-AM also resulted in lower plasma insulin levels in peripheral and portal blood in the resting state. This effect has also been observed in recent studies [1.15], although it seems to happen mainly if insulin levels are elevated [1,8]. Interestingly, peripheral insulin concentrations in the present study were not decreased to a greater extent by the injection of 2.5-AM during exercise than during rest.…”

Section: Perlphenl Ab T Portalsupporting

confidence: 89%

Effects of Portal Injection of 2,5-Anhydro-D-mannitol on Pancreatic Hormone Responses to Exercise in Rats

Désy

Latour²,

Warren³

et al. 1999

Int J Sports Med

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Section: Perlphenl Ab T Portalsupporting

confidence: 89%

Effects of Portal Injection of 2,5-Anhydro-D-mannitol on Pancreatic Hormone Responses to Exercise in Rats

Désy

Latour²,

Warren³

et al. 1999

Int J Sports Med

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“…Potentiating LPK by treatment with the fructose analog 2,5-anhydro-D-mannitol 50 greatly attenuates the hyperglycemia of obese diabetic db/db mice (i.e. with an equivalent leptin receptor defect) but not their STZ-treated wild type controls 51 .…”

Section: Discussionmentioning

confidence: 99%

Non-invasive detection of divergent metabolic signals in insulin deficiency vs. insulin resistance in vivo

Morze

Allu

Chang

et al. 2018

Sci Rep

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The type 2 diabetic phenotype results from mixed effects of insulin deficiency and insulin resistance, but the relative contributions of these two distinct factors remain poorly characterized, as do the respective roles of the gluconeogenic organs. The purpose of this study was to investigate localized in vivo metabolic changes in liver and kidneys of contrasting models of diabetes mellitus (DM): streptozotocin (STZ)-treated wild-type Zucker rats (T1DM) and Zucker diabetic fatty (ZDF) rats (T2DM). Intermediary metabolism was probed using hyperpolarized (HP) [1-13C]pyruvate MRI of the liver and kidneys. These data were correlated with gene expression data for key mediators, assessed using rtPCR. Increased HP [1-13C]lactate was detected in both models, in association with elevated gluconeogenesis as reflected by increased expression of phosphoenolpyruvate carboxykinase. In contrast, HP [1-13C]alanine diverged between the two models, increasing in ZDF rats, while decreasing in the STZ-treated rats. The differences in liver alanine paralleled differences in key lipogenic mediators. Thus, HP [1-13C]alanine is a marker that can identify phenotypic differences in kidneys and liver of rats with T1DM vs. T2DM, non-invasively in vivo. This approach could provide a powerful diagnostic tool for characterizing tissue metabolic defects and responses to treatment in diabetic patients with ambiguous systemic manifestations.

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“…Liver insulin receptor binding was measured as described by Kadama et al (26), with some modifications. Crude liver membranes (ϳ1 mg protein/tube), 20 nCi/tube of 125 Ilabeled human insulin (Novo Nordisk, Bagsvaerd, Denmark) and graded amounts of unlabeled bovine pancreatic insulin were incubated in 0.4 ml of 50 mmol/l Tris ⅐ HCl buffer solution (pH 7.4) containing 2% (wt/vol) BSA and 2 mg/ml bacitracin (Sigma, St. Louis, MO).…”

Section: Animalsmentioning

confidence: 99%

Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance

Kabir¹,

Catalano²,

Ananthnarayan³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

269

175

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-The mechanism by which increased central adiposity causes hepatic insulin resistance is unclear. The "portal hypothesis" implicates increased lipolytic activity in the visceral fat and therefore increased delivery of free fatty acids (FFA) to the liver, ultimately leading to liver insulin resistance. To test the portal hypothesis at the transcriptional level, we studied expression of several genes involved in glucose and lipid metabolism in the fat-fed dog model with visceral adiposity vs. controls (n ϭ 6). Tissue samples were obtained from dogs after 12 wk of either moderate fat (42% calories from fat; n ϭ 6) or control diet (35% calories from fat). Northern blot analysis revealed an increase in the ratio of visceral to subcutaneous (v/s ratio) mRNA expression of both lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor-␥ (PPAR␥). In addition, the ratio for sterol regulatory element-binding transcription factor-1 (SREBP-1) tended to be higher in fat-fed dogs, suggesting enhanced lipid accumulation in the visceral fat depot. The v/s ratio of hormone-sensitive lipase (HSL) increased significantly, implicating a higher rate of lipolysis in visceral adipose despite hyperinsulinemia in obese dogs. In fat-fed dogs, liver SREBP-1 expression was increased significantly, with a tendency for increased fatty acid-binding protein (FABP) expression. In addition, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat-fed animals vs. controls. Moreover, insulin receptor binding was 50% lower in fat-fed dogs. Increased gene expression promoting lipid accumulation and lipolysis in visceral fat, as well as elevated rate-limiting gluconeogenic enzyme expression in the liver, is consistent with the portal theory. Further studies will need to be performed to determine whether FFA are involved directly in this pathway and whether other signals (either humoral and/or neural) may contribute to the development of hepatic insulin resistance observed with visceral obesity. visceral fat; lipolysis; gluconeogenic enzymes; messenger ribonucleic acid; dogs VISCERAL ADIPOSITY HAS BEEN ASSOCIATED with insulin resistance, glucose intolerance, dyslipidemia, and cardiovascular disease (15,18,20). The liver has specifically been implicated as a primary site of insulin resistance observed with visceral obesity. The mechanisms relating visceral fat accumulation and hepatic insulin resistance are not well known, but several possible factors might be implicated. One hypothesis states that visceral fat secretes several substances [tumor necrosis factor-␣ (TNF-␣) (22) and/or resistin (37) or decreased adiponectin (2)] that may induce hepatic insulin resistance. The alternative "portal hypothesis" posits a high rate of lipolysis of visceral adipose tissue leading to increased delivery of free fatty acids (FFA) to the liver via the portal vein, thus contributing to increased fat accumulation and ...

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Differential Hypoglycemic Effect of 2,5-Anhydro-D-Mannitol, a Putative Gluconeogenesis Inhibitor, in Genetically Diabetic (db/db) and Streptozotocin-Induced Diabetic Mice

Cited by 9 publications

References 24 publications

Effects of Portal Injection of 2,5-Anhydro-D-mannitol on Pancreatic Hormone Responses to Exercise in Rats

Effects of Portal Injection of 2,5-Anhydro-D-mannitol on Pancreatic Hormone Responses to Exercise in Rats

Non-invasive detection of divergent metabolic signals in insulin deficiency vs. insulin resistance in vivo

Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance

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