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Introduction Type 2 diabetes (T2D) occurs when pancreatic βcells fail to compensate for the increased insulin demand in the context of obesity-associated insulin resistance. Thus, developing novel therapeutic strategies to [...], The failure of pancreatic βcells to adapt to an increasing demand for insulin is the major mechanism by which patients progress from insulin resistance to type 2 diabetes (T2D) and is thought to be related to dysfunctional lipid homeostasis within those cells. In multiple animal models of diabetes, females demonstrate relative protection from βcell failure. We previously found that the hormone 17β-estradiol (E2) in part mediates this benefit. Here, we show that treating male Zucker diabetic fatty (ZDF) rats with E2 suppressed synthesis and accumulation of fatty acids and glycerolipids in islets and protected against βcell failure. The antilipogenic actions of E2 were recapitulated by pharmacological activation of estrogen receptor α (ERα) or ERβin a rat βcell line and in cultured ZDF rat, mouse, and human islets. Pancreas-specific null deletion of ERαin mice [(PERα.sup.-/-]) prevented reduction of lipid synthesis by E2 via a direct action in islets, and [PERα.sup.-/-] mice were predisposed to islet lipid accumulation and βcell dysfunction in response to feeding with a high-fat diet. ER activation inhibited βcell lipid synthesis by suppressing the expression (and activity) of fatty acid synthase via a nonclassical pathway dependent on activated Stat3. Accordingly, pancreas-specific deletion of Stat3 in mice curtailed ER-mediated suppression of lipid synthesis. These data suggest that extranuclear ERs may be promising therapeutic targets to prevent βcell failure in T2D.

The physiological mechanisms that preserve pancreatic [beta]-cell mass (BCM) are not fully understood. Although the regulation of islet function by the autonomic nervous system (ANS) is well established, its potential roles in BCM homeostasis and compensatory growth have not been adequately explored. The parasympathetic vagal branch of the ANS serves to facilitate gastrointestinal function, metabolism, and pancreatic islet regulation of glucose homeostasis, including insulin secretion. Given the functional importance of the vagus nerve and its branches to the liver, gut, and pancreas in control of digestion, motility, feeding behavior, and glucose metabolism, it may also play a role in BCM regulation. We have begun to examine the potential roles of the parasympathetic nervous system in short-term BCM maintenance by performing a selective bilateral celiac branch-vagus nerve transection (CVX) in normal Sprague-Dawley rats. CVX resuited in no detectable effects on basic metabolic parameters or food intake through 1 wk postsurgery. Although there were no differences in BCM or apoptosis in this 1-wk time frame, [beta]-cell proliferation was reduced 50% in the CVX rats, correlating with a marked reduction in activated protein kinase B/Akt. Unexpectedly, acinar proliferation was increased 50% in these rats. These data suggest that the ANS, via the vagus nerve, contributes to the regulation of BCM maintenance at the level of cell proliferation and may also mediate the drive for enhanced growth under physiological conditions when insulin requirements have increased. Furthermore, the disparate effects of CVX on [beta]-cell and acinar cells suggest that the endocrine and exocrine pancreas respond to different neural signals in regard to mass homeostasis. [beta]-cell mass; celiac vagotomy doi: 10.1152/ajpendo.00202.2010.

A study was conducted to determine the volume of different compartments in the liver of exercised rats and examine the workings of the hepatic function after exercise. The liver was perfused for 40 minutes through the portal vein in a closed circuit. Results indicated that acute exercise decreases the hepatocyte volume and that the volume change is not correlated to a decresae in hepatic glycogen level.

Objective: C57Bl/6 mice develop obesity and mild hyperglycemia when fed a high-fat diet (HFD). Although diet-induced obesity (DIO) is a widely studied model of type 2 diabetes, little is known about beta-cell failure in these mice.Research Design and Methods: DIO mice were separated in two groups according to body weight gain: low- and high-HFD responders (LDR and HDR). We examined whether mild hyperglycemia in HDR mice is due to reduced beta-cell mass or function and studied islet metabolism and signaling.Results: HDR mice were more obese, hyperinsulinemic, insulin resistant, and hyperglycemic and showed a more altered plasma lipid profile than LDR. LDR mice largely compensated insulin resistance, whereas HDR showed perturbed glucose homeostasis. Neither LDR nor HDR mice showed reduced beta-cell mass, altered islet glucose metabolism, and triglyceride deposition. Insulin secretion in response to glucose, KCl, and arginine was impaired in LDR and almost abolished in HDR islets. Palmitate partially restored glucose- and KCl-stimulated secretion. The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in Ca(2+) was reduced in HDR islets relatively to LDR. Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only. Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets.Conclusions: beta-Cell failure in HDR mice is not due to reduced beta-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca(2+) and lipid signaling, as well as free cholesterol deposition. [ABSTRACT FROM AUTHOR]

Hepatic insulin sensitizing substance (HISS), a putative hormone released from the liver in response to insulin in fed animals, accounts for 50u60% of insulin action. HISS release is regulated by permissive control of the hepatic parasympathetic nerves. The objectives were to develop the rapid insulin sensitivity test (RIST) in conscious rats, and to assess the effects of anesthesia, atropine, feeding, and fasting on insulin action. The RIST index, expressed as milligrams glucose per kilogram body weight required to maintain euglycemia after a 50 mU/kg bolus of insulin, was similar in conscious and anesthetized rats (238.6 ± 42.5 vs. 225.3 ± 30.4 mg/kg). Atropine produced a 56% inhibition of insulin action in fed rats. After a 24 h fast, full HISS-dependent insulin resistance had developed as shown by a low RIST index that was not reduced further by atropine. Fasting caused a 10.5% decrease in insulin action per hour over six hours. HISS-dependent insulin resistance in 24-h fasted rats was reversed 4 h after re-feeding (90.9 ± 12.3 vs. 204.5 ± 30.5 mg/kg). We conclude that HISS-dependent and HISS-independent insulin action, as assessed by the RIST, is similar in conscious and pentobarbital-anesthetized rats. Pharmacological blockade of HISS-dependent insulin action and physiological regulation of HISS action by feedingufasting is confirmed. Re-feeding fasted rats reversed HISS-dependent insulin resistance. Merits of use of the RIST in conscious versus anesthetized rats are discussed. [ABSTRACT FROM AUTHOR]

In obese Zucker Fatty (ZF) rats, a model of β-cell compensation for insulin resistance (IR), there is increased glucose oxidation, anaplerosis and malate-pyruvate cycling in the β-cell, resulting in enhanced insulin secretion. We documented enhanced palmitate-potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, coinciding with elevated esterification and lipolysis without TG accumulation, indicative of an active triacyglycerol/fatty acid (TG/FFA) cycling. Thus, TG/FFA cycling may provide a mechanism by which the β-cell in ZF rat islets escapes glucolipotoxicity and continuously compensates without the development of diabetes. Enhanced lipolysis may also provide lipid signaling molecules for insulin secretion. To examine if dysregulated lipid partitioning, TG/FFA cycling and anaplerosis play a role in β-cell failure, we developed a model of mild type 2 diabetes (T2D): the 60% pancreatectomized (Px) ZF rat. At 5 wks of age, ZF and lean (ZL) rats underwent a 60% Px or a Sham treatment. The Px-ZF rats are characterized by a history of normoglycemia, IR and hyperlipidemia for 2 wks post-Px (compensation phase) followed by hyperglycemia (around 220 mg %) and marked loss of GSIS (failure) without a timber loss off-cell mass. Fatty acid partitioning, TG/FFA cycling and gene expression of enzymes of lipid metabolism and transcription factors implicated in the regulation of these processes were assessed in islets from all groups 3 weeks post-Px. The results reveal alterations in the expression of enzymes and transcription factors that control TG/FFA cycling, anaplerosis and lipid partitioning, in particular pyruvate carboxylase, PPARg and SCD1. Palmitate esterification and fatty acid oxidation were enhanced in Px-ZF islets when compared to controls (ZL and ZF). In addition, the expression of the incretin hormone receptors for GLP1, GIP and FFA (GPR40) were reduced. We propose that altered lipid partitioning, TG/FFA cycling and incretin signaling contribute to Β-cell failure in T2D. [ABSTRACT FROM AUTHOR]

Physical activity improves glycemic control in type 2 diabetes (T2D), but its contribution to preserving β-cell function is uncertain. We evaluated the role of physical activity on β-cell secretory function and glycerolipid/fatty acid (GL/FA) cycling in male Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats engaged in voluntary running for 6 wk (ZDF-A). Inactive Zucker lean and ZDF (ZDF-I) rats served as controls. ZDF-I rats displayed progressive hyperglycemia with β-cell failure evidenced by falling insulinemia and reduced insulin secretion to oral glucose. Isolated ZDF-I rat islets showed reduced glucose-stimulated insulin secretion expressed per islet and per islet protein. They were also characterized by loss of the glucose regulation of fatty acid oxidation and GL/FA cycling, reduced mRNA expression of key β-cell genes, and severe reduction of insulin stores. Physical activity prevented diabetes in ZDF rats through sustaining β-cell compensation to insulin resistance shown in vivo and in vitro. Surprisingly, ZDF-A islets had persistent defects in fatty acid oxidation, GL/FA cycling, and β-cell gene expression. ZDF-A islets, however, had preserved islet insulin mRNA and insulin stores compared with ZDF-I rats. Physical activity did not prevent hyperphagia, dyslipidemia, or obesity in ZDF rats. In conclusion, islets of ZDF rats have a susceptibility to failure that is possibly due to altered β-cell fatty acid metabolism. Depletion of pancreatic islet insulin stores is a major contributor to islet failure in this T2D model, preventable by physical activity.

The physiological mechanisms that preserve pancreatic β-cell mass (BCM) are not fully understood. Although the regulation of islet function by the autonomic nervous system (ANS) is well established, its potential roles in BCM homeostasis and compensatory growth have not been adequately explored. The parasympathetic vagal branch of the ANS serves to facilitate gastrointestinal function, metabolism, and pancreatic islet regulation of glucose homeostasis, including insulin secretion. Given the functional importance of the vagus nerve and its branches to the liver, gut, and pancreas in control of digestion, motility, feeding behavior, and glucose metabolism, it may also play a role in BCM regulation. We have begun to examine the potential roles of the parasympathetic nervous system in short-term BCM maintenance by performing a selective bilateral celiac branch-vagus nerve transection (CVX) in normal Sprague-Dawley rats. CVX resulted in no detectable effects on basic metabolic parameters or food intake through 1 wk postsurgery. Although there were no differences in BCM or apoptosis in this 1-wk time frame, β-cell proliferation was reduced 50% in the CVX rats, correlating with a marked reduction in activated protein kinase B/Akt. Unexpectedly, acinar proliferation was increased 50% in these rats. These data suggest that the ANS, via the vagus nerve, contributes to the regulation of BCM maintenance at the level of cell proliferation and may also mediate the drive for enhanced growth under physiological conditions when insulin requirements have increased. Furthermore, the disparate effects of CVX on β-cell and acinar cells suggest that the endocrine and exocrine pancreas respond to different neural signals in regard to mass homeostasis.