Search

Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic [alpha] cells in response to low blood glucose. To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor ([Gcgr.sup.-/-]). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. [Gcgr.sup.-/-] mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to [alpha] cell, and to a lesser extent, [delta] cell proliferation. In addition, increased proglucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1-37) and GLP-1 amide (1-36 amide) content and a 3- to 10-fold increase in circulating GLP-1 amide. [Gcgr.sup.-/-] mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and [alpha] and [delta] cell numbers. Furthermore, the lean phenotype of [Gcgr.sup.-/-] mice suggests glucagon action may be involved in the regulation of whole body composition.

Byline: F. Otobone, V. Sela, S. Obici, L. Moreira, DAG. Cortez, E. Audi Objective : We examined the involvement of 5-HT neurotransmission on the antidepressant-like effect of the dichloromethane (DcM) [...]

Byline: JVC. Martins, F. Otobone, V. Sela, S. Obici, M. Trombelli, D. Garcia Cortez, E. Audi Kielmeyera coriacea Mart. is a tree that belongs to the family Clusiacea , popularly [...]

Objective: We examined the involvement of 5-HT neurotransmission on the antidepressantlike effect of the dichloromethane (DcM) fraction of an extract from Kielmeyera coriacea stems. Materials and Methods: Male Wistar rats treated chronically (45 days, gavage) with the DcM fraction received an intradorsal raphe nucleus (DRN) microinjection of saline or 5-HT1A receptor ligands and were evaluated in the forced swimming test (FST) and in the open-field test (OFT). Results: The DcM fraction (5.0 mg/kg) reduced immobility time in the FST without altering locomotion in the OFT. IntraDRN microinjection of the 5-HT1A receptor agonist, (+)-8- OH-DPAT (0.10; 0.20 or 0.33 μg) increased immobility time and reduced locomotion at the higher dose whereas the 5-HT1A antagonists, (-)-pindolol (0.10; 0.20 or 0.40 μg) or WAY100635 (0.11; 0.22 or 0.43 μg) did not produce any effect in the behavioral tests. IntraDRN (+)-8-OH-DPAT (0.20 or 0.33 μg) in rats treated with the DcM fraction (5.0 mg/kg) blocked the changes in the immobility time or in locomotion produced by each drug. Intra-DRN (-)-pindolol (0.10 μg) or WAY100635 (0.43 μg) in rats treated with a subactive dose of the DcM fraction (4.0 mg/kg) synergistically reduced immobility time in the FST. Conclusion: The DcM fraction of Kielmeyera coriacea produced an antidepressant-like effect in the FST and interacted with 5-HT1A receptor ligands. Activation of 5-HT1A receptors into DRN by (+) 8-OH-DPAT produced detectable changes in the FST or in the OFT. [ABSTRACT FROM AUTHOR]

In common forms of obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia coexist. Here, we demonstrate rapid induction of insulin and leptin resistance by short-term overfeeding. After 3 and 7 days on the assigned diet regimen, rats were tested for their biological responses to acute elevations in plasma insulin and leptin concentrations. Severe resistance to the metabolic effects of both leptin and insulin ensued after just 3 days of overfeeding. During the insulin clamp studies, glucose production was decreased by approximately 70% in control rats and 28-53% in overfed rats. Similarly, leptin infusion doubled the contribution of gluconeogenesis to glucose output in control rats but failed to modify gluconeogenesis in overfed animals. These findings demonstrate a paradoxical and rapid collapse of the leptin system in response to nutrient excess. This partial failure is tightly coupled with the onset of insulin resistance. [ABSTRACT FROM AUTHOR]

Intracerebroventricular (ICV) administration of the longchain fatty acid (LCFA), oleic acid, inhibits glucose production in conscious rats. Here, we hypothesize that acute changes in the nutritional status modulate this central action of oleic acid. Thus, we examined the effects of ICV oleic acid on glucose production following three days of over-feeding or of caloric restriction. To induce voluntary over-feeding, 12 week old Sprague-Dawley rats were fed a highly palatable high-fat diet (33% of calories from fat), Ad Libitum (AL) diet, or calorie restricted diet, (CR, 70% of the pre-intervention caloric intake) for three days. The AL group failed to adapt to the higher calorie content of the diet and markedly enhanced daily energy intake despite increased plasma concentrations of both insulin and leptin. Oleic Acid (OA) or Vehicle (CON) was administered ICV to the AL (n=15) or CR group (n=16). Rats also received infusion of [³H]-glucose throughout, and a pancreatic-insulin (1mU/kgHmin) clamp during the last two hours, of the ICV infusions. ICV vehicle (CON) did not significantly modify glucose metabolism in either AL or CR rats. However, in the presence of fixed and approximately basal plasma insulin levels, glucose infusion (approximately 6 mg/kgHmin) was required in order to prevent hypoglycemia during ICV OA delivery to CR rats but not to AL rats. This increase in whole body insulin action in the CR group was entirely accounted for by a marked inhibition of glucose production (GP) by ICV OA (by 67.9%, to 2.84 mg/kgHmin; p<0.01 vs CON). Conversely, ICV OA failed to significantly decrease GP in the AL group (by 10.4%, to 8.8g mg/kgHmin; p>0.05 vs CON). Thus, just three days of voluntary overfeeding leads to the development of severe hypothalamic resistance to OA. The lack of hypothalamic response to OA is likely to contribute to the rapid onset of hepatic insulin resistance in this model. [ABSTRACT FROM AUTHOR]

Background: While bariatric surgery has been shown to improve type 2 diabetes (DM) control in the obese population, the effect on long-term DM complications has been less thoroughly investigated. The purpose of this study was to assess the development of microvascular and macrovascular complications in obese DM patients undergoing bariatric surgery., Methods: New York patients' records from the SPARCS database in years 2006-2012 were used to identify obese patients with DM. Patients undergoing bariatric surgery were compared with patients managed medically, matched for age and gender. Patients were grouped based on baseline presence of controlled or uncontrolled DM and followed over time for the development of micro- and macrovascular complications. Cumulative incidence of complications was estimated with death treated as a competing risk event. Multivariable proportional sub-distribution hazards models were used to compare the risk of complications among different patient groups after adjusting for possible confounding factors., Results: A total of 88,981 patients were reviewed, including 15,585 (18%) that were treated with bariatric surgery. Surgery patients had significantly lower risk of microvascular complications compared to non-surgery patients (controlled diabetes: HR = 0.40, 95% CI 0.37-0.42; uncontrolled diabetes: HR = 0.51, 95% CI 0.37-0.71). Similarly, the surgical patients were noted to have a significantly lower risk for macrovascular complications compared to non-surgery patients (controlled diabetes: HR = 0.43, 95% CI 0.40-0.46; uncontrolled diabetes: HR = 0.44, 95% CI 0.28-0.69). Cumulative incidence of microvascular complications was lower at 1, 5 and 9 years for the surgical groups for controlled and uncontrolled DM. Similar trends were observed for the macrovascular complications., Conclusions: Bariatric surgery appears to prevent complications of DM. Bariatric surgery patients with DM experienced significantly lower rates of microvascular and macrovascular complications, compared to non-surgically treated comparison group. Bariatric surgery was noted to offer protective benefits for both complicated and non-complicated DM patients. This reduced rate of complications was sustained in the long term.

Objective: The aim of this study was to determine whether downstream [peroxisome proliferator-activated-receptor alpha (PPARα) and the G-protein coupled receptor, GPR119] and upstream (a fatty acid translocase, CD36) signaling targets of N-oleoylethanolamide (OEA) were necessary for weight loss, metabolic improvements, and diet preference following vertical sleeve gastrectomy (VSG)., Summary Background Data: OEA is an anorectic N-acylethanolamine produced from dietary fats within the intestinal lumen that can modulate lipid metabolism, insulin secretion, and energy expenditure by activating targets such as PPARα and GPR119., Methods: Diet-induced obese mice, including wild-type or whole body knockout (KO) of PPARα, GPR119, and CD36, were stratified to either VSG or sham surgery before body weight, body composition, diet preference, and glucose and lipid metabolic endpoints were assessed., Results: We found increased duodenal production of OEA and expression of both GPR119 and CD36 were upregulated in wild-type mice after VSG. However, weight loss and glucose tolerance were improved in response to VSG in PPARαKO, GPR119KO, and CD36KO mice. In fact, VSG corrected hepatic triglyceride dysregulation in CD36KO mice, and circulating triglyceride and cholesterol levels in PPARαKO mice. Lastly, we found PPARα-mediated signaling contributes to macronutrient preference independent of VSG, while removal of CD36 signaling blunts the VSG-induced shift toward carbohydrate preference., Conclusions: In the search for more effective and less invasive therapies to help reverse the global acceleration of obesity and obesity-related disease OEA is a promising candidate; however, our data indicate that it is not an underlying mechanism of the effectiveness of VSG.

Exercise is an effective therapy against the metabolic syndrome. However, the molecular pathways underlying the advantageous effects of exercise are elusive. Glucagon receptor signaling is essential for exercise benefits, and recent evidence indicates that a downstream effector of glucagon, fibroblast growth factor 21 (FGF21), is implicated in this response. Therefore, we tested the hypothesis that FGF21 action is necessary in mediating metabolic effects of exercise. We utilized acute exhaustive treadmill exercise in Wistar rats to identify a putative, concomitant increase in plasma glucagon and FGF21 with the increase in glucose and lactate following exercise. To test the necessity of FGF21 action in the exercise response, we exposed FGF21 congenitally deficient mice (Fgf21(-/-)) and their wild-type (Wt) littermates to chronic high-fat (HF) feeding and inoperable (sedentary) or operable (exercise) voluntary running wheels. Physiological tests were performed to assess the role of FGF21 in the beneficial effect of exercise on glucose metabolism. Wt and Fgf21(-/-) littermates exhibited similar running behavior, and exercise was effective in suppressing weight and fat mass gain and dyslipidemia independently of genotype. However, exercise failed to positively affect hepatic triglyceride content and glucose tolerance in HF diet-fed Fgf21(-/-) mice. Furthermore, Fgf21(-/-) mice exhibited an impaired adaptation to exercise training, including reduced AMP-activated protein kinase activity in skeletal muscle. This study demonstrates that FGF21 action is necessary to achieve the full metabolic benefits of exercise during chronic HF feeding., (Copyright © 2016 the American Physiological Society.)

Although ginseng has been reported to ameliorate hyperglycemia in animal models and clinical studies, the molecular mechanisms are largely unknown. We previously reported that chronic treatment with ginsenoside Rb1 (Rb1), a major component of ginseng, significantly reduced fasting glucose and improved glucose tolerance in high-fat diet (HFD)-induced obese rats. These effects were greater than those observed in pair-fed rats, suggesting a direct effect of Rb1 on glucose homeostasis, and this possibility was confirmed in the present study. In lean rats fed standard rodent chow, 5-day treatment with Rb1 significantly improved glucose tolerance and enhanced insulin sensitivity. Notably, those effects were not accompanied by reduced food intake or changed body weight. To elucidate the underlying molecular mechanisms, rats fed a HFD for 4 weeks were treated with Rb1 for 5 days. Subsequently, euglycemic-hyperinsulinemic clamp studies found that compared to vehicle, Rb1, while not changing food intake or body weight, significantly increased glucose infusion rate required to maintain euglycemia. Consistent with this, insulin-induced inhibition of hepatic gluconeogenesis was significantly enhanced and hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase gene expression was suppressed. Additionally, glucose uptake was significantly increased in skeletal muscle. While proximal insulin signaling was not changed after Rb1 treatment, increased phosphorylation of TBC1D4, a downstream target of AMPK signaling, appears to be a key part of the mechanism for Rb1-stimulated glucose uptake in skeletal muscle. These findings indicate that Rb1 has multiple effects on glucose homeostasis, and provide strong rationale for further evaluation of its potential therapeutic role., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)