Mechanisms of Glucose Homeostasis After Roux-en-Y Gastric Bypass Surgery in the Obese, Insulin-Resistant Zucker Rat

Departments of Surgery, Pennsylvania State University College of Medicine, Hershey, 17033, USA.
Annals of surgery (Impact Factor: 8.33). 02/2009; 249(2):277-85. DOI: 10.1097/SLA.0b013e3181904af0
Source: PubMed


Obesity-related diabetes is caused by insulin resistance and beta-cell dysfunction. The current study examines changes in food intake, weight loss, body fat depots, oxygen consumption, insulin sensitivity, and incretin levels as potential mechanisms for improved glucose tolerance after Roux-en-Y gastric bypass (RYGB).
Three groups of genetically obese Zucker rats were studied: RYGB, sham surgery pair-fed (PF), and sham surgery ad libitum (AL) fed rats. Changes in body weight, visceral and subcutaneous fat depots, oral glucose tolerance, insulin sensitivity, and the plasma concentrations of insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide, and peptide YY (PYY) were measured.
Body weight and subcutaneous fat were decreased after RYGB, compared with the PF and AL groups. The reduction in visceral fat after RYGB appeared largely because of food restriction. Glucose tolerance and insulin sensitivity were significantly improved in only the RYGB group (P < 0.05 vs. AL, PF). Euglycemic, hyperinsulinemic clamp studies indicated RYGB improved the ability of insulin to stimulate peripheral (eg, skeletal muscle) glucose uptake. Fasting total GLP-1, glucose-dependent insulinotropic peptide, and PYY levels were similar between the groups, whereas postprandial plasma levels of intact GLP-1 (7-36) amide, total GLP-1, and PYY were increased in the RYGB group compared with PF and AL controls.
Glucose homeostasis after RYGB is associated with decreased subcutaneous fat, increased postprandial PYY, GLP-1, and insulin, as well as improved insulin sensitivity/action. Changes in food intake and visceral fat do not seem to explain improvements in insulin action after RYGB in the Zucker rat model.

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Available from: Robert N Cooney, Jan 03, 2014
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    • "Of these, the hyperinsulinemic euglycemic clamp is the gold-standard method. Hyperinsulinemic clamp studies were performed as previously described [23]. Rats were placed under general anesthesia (3% Pelltobarbitalum Natricum, 60 mg/kg, intraperitoneally) and catheters were inserted into the right jugular vein and the carotid arteries of rats and exteriorized from the back of the neck subcutaneously. "
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    ABSTRACT: Increased lipid accumulation and mitochondrial dysfunction within skeletal muscle have been shown to be strongly associated with insulin resistance. However, the role of mitofusion-2 (MFN2), a key factor in mitochondrial function and energy metabolism, in skeletal muscle lipid intermediate accumulation remains to be elucidated. A high-fat diet resulted in insulin resistance as well as accumulation of cytosolic lipid intermediates and down-regulation of MFN2 and CPT1 in skeletal muscle in rats, while MFN2 overexpression improved insulin sensitivity and reduced lipid intermediates in muscle, possibly by upregulation of CPT1 expression. MFN2 overexpression can rescue insulin resistance, possibly by upregulating CPT1 expression leading to reduction in the accumulation of lipid intermediates in skeletal muscle. These observations contribute to the investigations of new diabetes therapies.
    Full-text · Article · Jul 2013 · Journal of Biomedical Science
    • "Bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) are one of the most effective treatments for morbid obesity. RYGB results in a dramatic weight loss together with improvements in glycemic control in both human patients [1] [2] and rodent models [3] [4] [5]. Importantly, the improvements in glucose homeostasis and diabetes resolution appear to be dissociated from the surgery-induced weight loss [6] [7]. "
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    ABSTRACT: Background Roux-en Y gastric bypass (RYGB) and ileal transposition (IT) surgeries produce weight loss and improve diabetic control; however, the mechanisms of glycemic improvements are largely unknown. Because skeletal muscle and liver play a key role in glucose homeostasis, we compared the effects of RYGB and IT surgeries on key molecules of glucose and lipid metabolism in muscle and liver. Methods Sprague-Dawley rats were subjected to RYGB, IT, or sham surgeries; sham-animals were ad-lib fed or pair-fed to RYGB rats (n = 7-9/group). At 8 weeks postoperatively, blood samples were collected for glucagon-like peptide-1 (GLP-1) and insulin analyses by ELISA. Leg muscle and liver tissues were analyzed for mRNA (RT-qPCR) and/or protein abundance (western blotting) of important molecules of glucose and lipid metabolism [glucose transporter-4 (GLUT-4), hexokinase, phosphofructokinase (PFK), adenosine monophosphate activated protein kinase-α (AMPKα), cytochrome C oxidase-IV (COX-IV), citrate synthase, carnitine palmitoyl transferase-1 (CPT-1), medium-chain acyl-CoA dehydrogenase (MCAD), peroxisome proliferator-activated receptor gamma co-activator 1 α (PGC-1 α), PGC-1-related coactivator (PRC), uncoupling protein-3 (UCP-3)]. Results Plasma GLP-1 concentrations were increased comparably with RYGB and IT. RYGB and IT increased muscle GLUT-4 protein content, muscle hexokinase mRNA, and liver PFK mRNA. IT increased muscle AMPKα and COX-IV protein content and liver citrate synthase activity. IT increased muscle CPT-1, MCAD and PRC mRNA, whereas RYGB increased UCP-3 mRNA in muscle and liver, and PGC-1 α mRNA in liver. Conclusion The data suggest that RYGB and IT surgeries lead to enhanced GLP-1 secretion and produce similar stimulatory effects on important molecules of glucose metabolism but differential effects on key molecules of lipid oxidation in muscle and liver.
    No preview · Article · Jan 2013 · Surgery for Obesity and Related Diseases
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    • "Because SRSG is basically a restrictive procedure that does not affect incretin expression, it was expected that the results obtained from this procedure would be inferior to those obtained from procedures in which a duodenal switch is performed with regard to glucose homeostasis.23,24,27,28 In the present study, glucose levels might have decreased as a result of the marked weight loss observed in all patients, which led to increased insulin sensitivity and decreased leptin production, and thus to increased insulin secretion and remission of GI and T2DM, as noted in previous studies.6,39 Other hormones produced in adipose tissue might also have been involved in the notable rate of glycemic control observed in the present study. "
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