Glucose plus metformin compared with glucose alone on β‑cell function in mouse pancreatic islets

Hashemitabar,Mahmoud; Bahramzadeh,Somayeh; Saremy,Sadegh; Nejaddehbashi,Freshteh

doi:10.3892/br.2015.476

Glucose plus metformin compared with glucose alone on β‑cell function in mouse pancreatic islets

Authors:
- Mahmoud Hashemitabar
- Somayeh Bahramzadeh
- Sadegh Saremy
- Freshteh Nejaddehbashi
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Affiliations: Cellular and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan 61357‑15794, Iran
Published online on: June 11, 2015 https://doi.org/10.3892/br.2015.476
Pages: 721-725

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Abstract

Metformin is currently the first drug of choice for treatment of type II diabetes. The primary function of metformin is to decrease hepatic glucose production mainly by inhibiting gluconeogenesis. The aim of the present study was to investigate the effects of glucose alone (control groups) and glucose and metformin (treatment groups) on pancreatic islets functions. Pancreatic islets were isolated by collagenase digestion and incubated for 24 or 48 h in RPMI‑1640 containing 5 mmol/l glucose (control groups 1 and 2, respectively) or 24 h with 25 mmol/l glucose (control group 3) and 15 µmol/l metformin (treatment groups 1, 2 and 3, corresponding to the control groups, respectively). Subsequently, the rate of insulin output from islets, pancreatic and duodenal homeobox 1 (Pdx‑1) and insulin genes expression and islet viability were assayed. The rate of insulin secretion in a 5 mmol/l glucose concentration in the 48 h treatment group increased significantly compared with that of the 24 h treatment group (P<0.05). An increase of the glucose concentration (25 mmol/l) caused insulin secretion to increase compared with that of 5 mmol/l glucose. Pdx‑1 gene expression in treatment group 2 significantly decreased compared with the control group 2 (P<0.05). The the Pdx‑1 gene expression in treatment group 2 decreased compared with that of the treatment group 1. The expression of the insulin gene in treatment group 1 increased compared with control group 1, and in treatment group 2, there was a 2‑fold increase in insulin gene expression compared with control group 2. The insulin gene expression in treatment group 2 increased compared with treatment group 1. The percentage of islet cell viability was increased in treatment group 3 by ~40% compared with the islet cells of treatment groups 1 and 2 (P<0/05). These data indicate that glucose and metformin have direct effects on β‑cell function.

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1	American Diabetes Association, . Diagnosis and classification of diabetes mellitus. Diabetes Care. 29:(Suppl 1). S43–S48. 2006.PubMed/NCBI
2	Szkudelski T, Zywert A and Szkudelska K: Metabolic disturbances and defects in insulin secretion in rats with streptozotocin-nicotinamide-induced diabetes. Physiol Res. 62:663–670. 2013.PubMed/NCBI
3	Wang H, Kouri G and Wollheim CB: ER stress and SREBP-1 activation are implicated in β-cell glucolipotoxicity. J Cell Sci. 118:3905–3915. 2005. View Article : Google Scholar : PubMed/NCBI
4	Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA and Butler PC: β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes. 52:102–110. 2003. View Article : Google Scholar : PubMed/NCBI
5	Weir GC, Laybutt DR, Kaneto H, Bonner-Weir S and Sharma A: Beta-cell adaptation and decompensation during the progression of diabetes. Diabetes. 50:(Suppl 1). S154–S159. 2001. View Article : Google Scholar : PubMed/NCBI
6	Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M and Andreelli F: Cellular and molecular mechanisms of metformin: An overview. Clin Sci (Lond). 122:253–270. 2012. View Article : Google Scholar : PubMed/NCBI
7	Gunton JE, Delhanty PJ, Takahashi S and Baxter RC: Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrinol Metab. 88:1323–1332. 2003. View Article : Google Scholar : PubMed/NCBI
8	Cusi K, Consoli A and DeFronzo RA: Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 81:4059–4067. 1996. View Article : Google Scholar : PubMed/NCBI
9	Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, et al: Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 49:2063–2069. 2000. View Article : Google Scholar : PubMed/NCBI
10	Natali A and Ferrannini E: Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: A systematic review. Diabetologia. 49:434–441. 2006. View Article : Google Scholar : PubMed/NCBI
11	Gregorio F, Filipponi P, Ambrosi F, Cristallini S, Marchetti P, Calafiore R, Navalesi R and Brunetti P: Metformin potentiates B-cell response to high glucose: An in vitro study on isolated perfused pancreas from normal rats. Diabete Metab. 15:111–117. 1989.PubMed/NCBI
12	Marchetti P, Scharp DW, Giannarelli R, Benzi L, Cicchetti P, Ciccarone AM, Lacy PE and Navalesi R: Metformin potentiates glucose-stimulated insulin secretion. Diabetes Care. 19:781–782. 1996. View Article : Google Scholar : PubMed/NCBI
13	Lacy PE, Kostianovsky M and Louis S: Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 16:35–39. 1967. View Article : Google Scholar : PubMed/NCBI
14	Perfetti R, Zhou J, Doyle ME and Egan JM: Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology. 141:4600–4605. 2000. View Article : Google Scholar : PubMed/NCBI
15	Panza JL, Wagner WR, Rilo HL, Rao RH, Beckman EJ and Russell AJ: Treatment of rat pancreatic islets with reactive PEG. Biomaterials. 21:1155–1164. 2000. View Article : Google Scholar : PubMed/NCBI
16	Marselli L, Dotta F, Piro S, Santangelo C, Masini M, Lupi R, Realacci M, del Guerra S, Mosca F, Boggi U, et al: Th2 cytokines have a partial, direct protective effect on the function and survival of isolated human islets exposed to combined proinflammatory and Th1 cytokines. J Clin Endocrinol Metab. 86:4974–4978. 2001. View Article : Google Scholar : PubMed/NCBI
17	Lupi R, Del Guerra S, Marselli L, Bugliani M, Boggi U, Mosca F, Marchetti P and Del Prato S: Rosiglitazone prevents the impairment of human islet function induced by fatty acids: Evidence for a role of PPARgamma2 in the modulation of insulin secretion. Am J Physiol Endocrinol Metab. 286:E560–E567. 2004. View Article : Google Scholar : PubMed/NCBI
18	Janjic D and Wollheim CB: Islet cell metabolism is reflected by the MTT (tetrazolium) colorimetric assay. Diabetologia. 35:482–485. 1992. View Article : Google Scholar : PubMed/NCBI
19	Wang ZQ, Lu FE, Leng SH, Fang XS, Chen G, Wang ZS, Dong LP and Yan ZQ: Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity. World J Gastroenterol. 14:6004–6011. 2008. View Article : Google Scholar : PubMed/NCBI
20	Fernandez-Alvarez J, Conget I, Rasschaert J, Sener A, Gomis R and Malaisse WJ: Enzymatic, metabolic and secretory patterns in human islets of type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 37:177–181. 1994. View Article : Google Scholar : PubMed/NCBI
21	Deng S, Vatamaniuk M, Huang X, Doliba N, Lian M-M, Frank A, Velidedeoglu E, Desai NM, Koeberlein B, Wolf B, et al: Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes. 53:624–632. 2004. View Article : Google Scholar : PubMed/NCBI
22	Marchetti P, Del Guerra S, Marselli L, Lupi R, Masini M, Pollera M, Bugliani M, Boggi U, Vistoli F, Mosca F, et al: Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab. 89:5535–5541. 2004. View Article : Google Scholar : PubMed/NCBI
23	Leclerc I, Woltersdorf WW, da Silva Xavier G, Rowe RL, Cross SE, Korbutt GS, Rajotte RV, Smith R and Rutter GA: Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: Impact on glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab. 286:E1023–E1031. 2004. View Article : Google Scholar : PubMed/NCBI
24	Lin J-M, Fabregat ME, Gomis R and Bergsten P: Pulsatile insulin release from islets isolated from three subjects with type 2 diabetes. Diabetes. 51:988–993. 2002. View Article : Google Scholar : PubMed/NCBI
25	Richardson H, Campbell SC, Smith SA and Macfarlane WM: Effects of rosiglitazone and metformin on pancreatic beta cell gene expression. Diabetologia. 49:685–696. 2006. View Article : Google Scholar : PubMed/NCBI
26	Kefas BA, Cai Y, Kerckhofs K, Ling Z, Martens G, Heimberg H, Pipeleers D and Van de Casteele M: Metformin-induced stimulation of AMP-activated protein kinase in β-cells impairs their glucose responsiveness and can lead to apoptosis. Biochem Pharmacol. 68:409–416. 2004. View Article : Google Scholar : PubMed/NCBI