Physical exercise enhances hepatic insulin signaling and inhibits phosphoenolpyruvate carboxykinase activity in diabetes-prone Psammomys obesus

Heled, Yuval; Shapiro, Y; Shani, Yoav; Moran, Daniel S.; Langzam, Lea; Barash, V.; Sampson, Sanford R.; Meyerovitch, Joseph

doi:10.1016/j.metabol.2004.02.001

Cited by 26 publications

(30 citation statements)

References 31 publications

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“…It may be, therefore, that exercise training in this model lowers gluconeogenesis, but not glycogenolysis, or perhaps even hepatic glucose production. Similar to our observation here, regular exercise has been shown to increase G6Pase activity in healthy rats (37). Although there may be a number of contributing factors, we suspect that the dramatically improved glucoregulation observed in the E rats compared with S rats, is a result of a combination of enhanced hepatic insulin sensitivity, improved peripheral insulin sensitivity, and enhancement of ␤-cell function.…”

Section: Discussionsupporting

confidence: 87%

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Exercise maintains euglycemia in association with decreased activation of c-Jun NH₂-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats

Király¹,

Campbell

Park³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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. Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats. Am J Physiol Endocrinol Metab 298: E671-E682, 2010. First published December 8, 2009 doi:10.1152/ajpendo.90575.2008.-Stress-activated systems and oxidative stress are involved in insulin resistance, which, along with ␤-cell failure, contribute to the development of type 2 diabetes mellitus (T2DM). Exercise improves insulin resistance and glucose tolerance, and these adaptations may, in part, be related to reductions in inflammation and oxidative stress. We investigated circulating and tissue-specific markers of inflammation and oxidative stress and insulin-signaling pathways in a rodent model of T2DM, the Zucker diabetic fatty rat, with and without voluntary exercise. At 5 wk of age, Zucker diabetic fatty rats (n ϭ 8 -9/group) were divided into basal (B), voluntary exercise (E), and sedentary control (S) groups. B rats were euthanized at 6 wk of age, and S and E rats were euthanized 10 wk later. E rats ran ϳ5 km/day, which improved insulin sensitivity and maintained fed and fasted glucose levels and glucose tolerance. Ten weeks of exercise also decreased whole body markers of inflammation and oxidative stress in plasma and liver, including lowered circulating IL-6, haptoglobin, and malondialdehyde levels, hepatic protein oxidation, and phosphorylated JNK, the latter indicating decreased JNK activity. Hepatic phosphoenolpyruvate carboxykinase levels and Ser 307 -phosphorylated insulin receptor substrate-1 were also reduced in E compared with S rats. In summary, we show that, in a rodent model of T2DM, voluntary exercise decreases circulating markers of inflammation and oxidative stress and lowers hepatic JNK activation and Ser 307 -phosphorylated insulin receptor substrate-1. These changes in oxidative stress markers and inflammation are associated with decreased hyperglycemia and insulin resistance and reduced expression of the main gluconeogenic enzyme phosphoenolpyruvate carboxykinase.

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Section: Discussionsupporting

confidence: 87%

“…Exercise is well known to improve insulin signaling in skeletal muscle (51) and liver (37). In response to stimuli such as ER stress, oxidative stress, cytokines, and FFA and glucose, JNK is activated and phosphorylates IRS-1 on Ser 307 , thereby impairing insulin action (1,33,64).…”

Section: Discussionmentioning

confidence: 99%

Exercise maintains euglycemia in association with decreased activation of c-Jun NH₂-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats

Király¹,

Campbell

Park³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…Like in humans, physical activity prevented the development of diabetes in DP P. obesus fed the HE diet (21,22). This could result from improved insulin signaling in skeletal muscle and liver, augmenting skeletal muscle glucose uptake and inhibiting hepatic phosphoenolpyruvate carboxykinase activity, a rate-limiting enzyme in hepatic gluconeogenesis that was resistant to hyperinsulinemia in P. obesus (8).…”

Section: Dietary and Genetic Effects On Insulin Sensitivitymentioning

confidence: 99%

Psammomys Obesus, a Model for Environment-Gene Interactions in Type 2 Diabetes

et al. 2005

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Type 2 diabetes is characterized by insulin resistance and progressive ␤-cell failure. Deficient insulin secretion, with increased proportions of insulin precursor molecules, is a common feature of type 2 diabetes; this could result from inappropriate ␤-cell function and/or reduced ␤-cell mass. Most studies using tissues from diabetic patients are retrospective, providing only limited information on the relative contribution of ␤-cell dysfunction versus decreased ␤-cell mass to the "␤-cell failure" of type 2 diabetes. The gerbil Psammomys obesus is a good model to address questions related to the role of insulin resistance and ␤-cell failure in nutritionally induced diabetes. Upon a change from its natural low-calorie diet to the calorie-rich laboratory food, P. obesus develops moderate obesity associated with postprandial hyperglycemia. Continued dietary load, superimposed on its innate insulin resistance, results in depletion of pancreatic insulin stores, with increased proportions of insulin precursor molecules in the pancreas and the blood. Inadequate response of the preproinsulin gene to the increased insulin needs is an important cause of diabetes progression. Changes in ␤-cell mass do not correlate with pancreatic insulin stores and are unlikely to play a role in disease initiation and progression. The major culprit is the inappropriate insulin production with depletion of insulin stores as a consequence. Similar mechanisms could operate during the evolution of type 2 diabetes in humans. Diabetes 54 (Suppl. 2):S137-S144, 2005 NUTRITION-INDUCED DIABETES IN PSAMMOMYS OBESUSPsammomys obesus is a diurnal gerbil that lives in North African and Eastern Mediterranean semi-desert regions. The Israeli P. obesus colony was established at the Hebrew University ϳ30 years ago from animals collected from the arid shores of the Dead Sea. In its native habitat, feeding mainly on the low-calorie Atriplex halimus plant, P. obesus is neither obese nor hyperglycemic. However, in captivity, when fed ad libitum calorie-rich rodent food, it exhibits a tendency to develop moderate obesity and postprandial hyperglycemia (1,2). The observation that not all animals develop hyperglycemia on the calorie-rich diet enabled the selection of two outbred lines of P. obesus by assorted breeding: a diabetes-prone (DP) line, in which Ͼ70% of the animals develop postprandial hyperglycemia within 4 -7 days of calorie-rich diet, and a diabetesresistant (DR) line, in which 60 -70% of the animals are normoglycemic despite the calorie-rich diet (3,4).Once postprandial hyperglycemia develops (nonfasted blood glucose Ͼ8.3 mmol/l), progression of diabetes is very rapid, reaching the end-stage of the disease, characterized by severe hypoinsulinemia, hyperlipidemia, and ketosis, within 4 -6 weeks of initiating the calorie-rich diet ( Fig. 1) (5,6). Although islet destruction is clearly demonstrated at this terminal stage, no signs of autoimmunity are evident at any time (6,7). Hyperglycemia in P. obesus is reversible, except for the hypoinsulinemic end...

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“…Diet increases beta cell mass through hypertrophy to overcome insulin resistance, while exercise training increases beta cell mass through hyperplasia, which is displayed as increased beta cell proliferation and reduced apoptosis (25). In addition, some studies have reported that exercise reduces symptoms of hepatic insulin through reducing hepatic glucose release in hyperinsulinemic conditions (46,47). Nevertheless, some studies have shown that exercise training improves the mass and function of beta cells in type 2 diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Three Months of Resistance Training on TCF7L2 Expression in Pancreas Tissues of Type 2 Diabetic Rats

Eizadi¹,

Ravasi²,

Soory³

et al. 2016

Avicenna J Med Biochem

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Physical exercise enhances hepatic insulin signaling and inhibits phosphoenolpyruvate carboxykinase activity in diabetes-prone Psammomys obesus

Cited by 26 publications

References 31 publications

Exercise maintains euglycemia in association with decreased activation of c-Jun NH₂-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats

Exercise maintains euglycemia in association with decreased activation of c-Jun NH₂-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats

Psammomys Obesus, a Model for Environment-Gene Interactions in Type 2 Diabetes

The Effect of Three Months of Resistance Training on TCF7L2 Expression in Pancreas Tissues of Type 2 Diabetic Rats

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