Effects of high-fat diet and the anti-diabetic drug metformin on circulating GLP-1 and the relative number of intestinal L-cells

Diabetology & Metabolic Syndrome

Åke Sjöholm²  Thomas Nyström¹  Qimin Zhang¹  Camilla Kappe³ 

[1] Department of Clinical Science and Education, Karolinska Institutet, Unit for Diabetes Research, Södersjukhuset, SE-118 83 Stockholm, Sweden;Department of Biochemistry and Molecular Biology, University of South Alabama, College of Medicine, Mobile, AL 36688-0002, USA;Department of Medical Cell Biology, Uppsala University, BMC, SE-751 23 Uppsala, Sweden

关键词: L-cell;    Lipotoxicity;    Insulinotropic;    Glucagon-like peptide-1;    Metformin;   

Others  :  1120470
DOI  :  10.1186/1758-5996-6-70

 received in 2014-01-23, accepted in 2014-05-07,  发布年份 2014

【 摘 要 】

Background

Elevated serum free fatty acids (FFAs) contribute to the pathogenesis of type-2-diabetes (T2D), and lipotoxicity is observed in many cell types. We recently showed that simulated hyperlipidemia induces lipoapoptosis also in GLP-1-secreting L-cells in vitro, while metformin confers lipoprotection.

The aim of this study was to determine if a high fat diet (HFD) reduces the number of enteroendocrine L-cells and/or GLP-1 plasma levels in a rodent model, and potential effects thereupon of metformin treatment.

Methods

C57/Bl6 mice received control/HFD for 12-weeks, and oral administration of metformin/saline for the last 14 days. Blood glucose, glycosylated hemoglobin and plasma insulin and GLP-1 were determined before and after treatment with metformin using ELISAs. GLP-1-immunopositive cells in intestinal tissue sections were quantified using immunohistochemistry.

Results

A HFD increased blood glucose, glycosylated hemoglobin, and fasting plasma insulin (33%, 15% and 70% increase, respectively), in conjunction with reduced oral glucose tolerance, indicating the manifestation of insulin resistance. Metformin counteracted these adverse effects, while also reducing prandial plasma FFAs. The number of GLP-1-positive cells was indicated to be reduced (55% reduction of the number of GLP-1-positive cells, p = 0.134), while there was a trend toward increased prandial plasma GLP-1 despite reduced food intake following a HFD.

Conclusion

HFD-fed mice rapidly develop insulin resistance. Metformin exerts beneficial glucose lowering effects, and is indicated to improve the incretin response. Albeit no significant effect, a HFD tends to reduce the number of GLP-1-positive cells. However, considering concurrent normal or increased plasma GLP-1, any reduction in the number of GLP-1-positive cells, probably does not contribute to development of the glucose intolerance, but may contribute to progression of the diabetic state through eventual loss of a functional incretin response.

【 授权许可】

   
2014 Kappe et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Drucker DJ: The role of gut hormones in glucose homeostasis. J Clin Invest 2007, 117:24-32.
• [2]Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ: Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001, 50:609-613.
• [3]Meier JJ, Nauck MA: Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab Res Rev 2005, 21:91-117.
• [4]Gribble FM, Williams L, Simpson AK, Reimann F: A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line. Diabetes 2003, 52:1147-1154.
• [5]Tolhurst G, Reimann F, Gribble FM: Nutritional regulation of glucagon-like peptide-1 secretion. J Physiol 2009, 587:27-32.
• [6]Kappe C, Patrone C, Holst JJ, Zhang Q, Sjoholm A: Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells. J Gastroenterol 2013, 48:322-332.
• [7]Beglinger S, Drewe J, Schirra J, Goke B, D’Amato M, Beglinger C: Role of fat hydrolysis in regulating glucagon-like Peptide-1 secretion. J Clin Endocrinol Metab 2010, 95:879-886.
• [8]Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM: Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 2012, 61:364-371.
• [9]Reimann F: Molecular mechanisms underlying nutrient detection by incretin-secreting cells. Int Dairy J 2010, 20:236-242.
• [10]Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE: Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 2003, 100:3077-3082.
• [11]Cnop M, Hannaert JC, Hoorens A, Eizirik DL, Pipeleers DG: Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Diabetes 2001, 50:1771-1777.
• [12]Muscelli E, Mari A, Casolaro A, Camastra S, Seghieri G, Gastaldelli A, Holst JJ, Ferrannini E: Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 2008, 57:1340-1348.
• [13]Kappe C, Holst JJ, Zhang Q, Sjoholm A: Molecular mechanisms of lipoapoptosis and metformin protection in GLP-1 secreting cells. Biochem Biophys Res Commun 2012, 427:91-95.
• [14]Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, Ciani S, Messeri G, Rotella CM: Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care 2001, 24:489-494.
• [15]Gundersen HJ, Bendtsen TF, Korbo L, Marcussen N, Moller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sorensen FB, Vesterby A, West MJ: Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 1988, 96:379-394.
• [16]Giannarelli R, Aragona M, Coppelli A, Del Prato S: Reducing insulin resistance with metformin: the evidence today. Diabetes Metab 2003, 29:6S28-6S35.
• [17]Matsui Y, Hirasawa Y, Sugiura T, Toyoshi T, Kyuki K, Ito M: Metformin reduces body weight gain and improves glucose intolerance in high-fat diet-fed C57BL/6 J mice. Biol Pharm Bull 2010, 33:963-970.
• [18]Ahlkvist L, Brown K, Ahren B: Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion. Endocr Connect 2013, 2:69-78.