Metabolic Effects of Metformin in Humans

Author(s): María M. Adeva-Andany* , Eva Rañal-Muíño , Carlos Fernández-Fernández , Cristina Pazos-García , Matilde Vila-Altesor .

Journal Name: Current Diabetes Reviews

Volume 15 , Issue 4 , 2019

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Abstract:

Background: Both insulin deficiency and insulin resistance due to glucagon secretion cause fasting and postprandial hyperglycemia in patients with diabetes.

Introduction: Metformin enhances insulin sensitivity, being used to prevent and treat diabetes, although its mechanism of action remains elusive.

Results: Patients with diabetes fail to store glucose as hepatic glycogen via the direct pathway (glycogen synthesis from dietary glucose during the post-prandial period) and via the indirect pathway (glycogen synthesis from “de novo” synthesized glucose) owing to insulin deficiency and glucagoninduced insulin resistance. Depletion of the hepatic glycogen deposit activates gluconeogenesis to replenish the storage via the indirect pathway. Unlike healthy subjects, patients with diabetes experience glycogen cycling due to enhanced gluconeogenesis and failure to store glucose as glycogen. These defects raise hepatic glucose output causing both fasting and post-prandial hyperglycemia. Metformin reduces post-prandial plasma glucose, suggesting that the drug facilitates glucose storage as hepatic glycogen after meals. Replenishment of glycogen store attenuates the accelerated rate of gluconeogenesis and reduces both glycogen cycling and hepatic glucose output. Metformin also reduces fasting hyperglycemia due to declining hepatic glucose production. In addition, metformin reduces plasma insulin concentration in subjects with impaired glucose tolerance and diabetes and decreases the amount of insulin required for metabolic control in patients with diabetes, reflecting improvement of insulin activity. Accordingly, metformin preserves β-cell function in patients with type 2 diabetes.

Conclusion: Several mechanisms have been proposed to explain the metabolic effects of metformin, but evidence is not conclusive and the molecular basis of metformin action remains unknown.

Keywords: Diabetes, glucose, GLUT2, insulin resistance, insulin, glucagon.

[1]
Capaldo B, Gastaldelli A, Antoniello S, et al. Splanchnic and leg substrate exchange after ingestion of a natural mixed meal in humans. Diabetes 1999; 48: 958-66.
[2]
Felber JP, Meyer HU, Curchod B, et al. Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry. Diabetologia 1981; 20: 39-44.
[3]
Taylor R, Magnusson I, Rothman DL, et al. Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects. J Clin Invest 1996; 97: 126-32.
[4]
Krssak M, Brehm A, Bernroider E, et al. Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes. Diabetes 2004; 53: 3048-56.
[5]
Kacerovsky M, Jones J, Schmid AI, et al. Postprandial and fasting hepatic glucose fluxes in long-standing type 1 diabetes. Diabetes 2011; 60: 1752-8.
[6]
Boden G, Ray TK, Smith RH, Owen OE. Carbohydrate oxidation and storage in obese non-insulin-dependent diabetic patients. Effects of improving glycemic control. Diabetes 1983; 32: 982-7.
[7]
Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000; 49: 2063-9.
[8]
Kelley D, Mokan M, Veneman T. Impaired postprandial glucose utilization in non-insulin-dependent diabetes mellitus. Metabolism 1994; 43: 1549-57.
[9]
Macauley M, Smith FE, Thelwall PE, Hollingsworth KG, Taylor R. Diurnal variation in skeletal muscle and liver glycogen in humans with normal health and Type 2 diabetes. Clin Sci (Lond) 2015; 128: 707-13.
[10]
DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab 1991; 73: 1294-301.
[11]
Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996; 81: 4059-67.
[12]
Taylor R, Price TB, Katz LD, Shulman RG, Shulman GI. Direct measurement of change in muscle glycogen concentration after a mixed meal in normal subjects. Am J Physiol 1993; 265: E224-9.
[13]
Mitrakou A, Kelley D, Veneman T, et al. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 1990; 39: 1381-90.
[14]
Carey PE, Halliday J, Snaar JEM, Morris PG, Taylor R. Direct assessment of muscle glycogen storage after mixed meals in normal and type 2 diabetic subjects. Am J Physiol Endocrinol Metab 2003; 284: E688-94.
[15]
DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981; 30: 1000-7.
[16]
Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 1990; 322: 223-8.
[17]
Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50: 81-98.
[18]
Repiscak P, Erhardt S, Rena G, Paterson MJ. Biomolecular mode of action of metformin in relation to its copper binding properties. Biochemistry 2014; 53: 787-95.
[19]
Bharatam PV, Patel DS, Iqbal P. Pharmacophoric features of biguanide derivatives: An electronic and structural analysis. J Med Chem 2005; 48: 7615-22.
[20]
Logie L, Harthill J, Patel K, et al. Cellular responses to the metal-binding properties of metformin. Diabetes 2012; 61: 1423-33.
[21]
Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996; 30: 359-71.
[22]
Liang X, Giacomini KM. Transporters involved in metformin pharmacokinetics and treatment response. J Pharm Sci 2017; 106: 2245-50.
[23]
Han TK, Proctor WR, Costales CL, Cai H, Everett RS, Thakker DR. Four cation-selective transporters contribute to apical uptake and accumulation of metformin in Caco-2 cell monolayers. J Pharmacol Exp Ther 2015; 352: 519-28.
[24]
Koepsell H. Role of organic cation transporters in drug-drug interaction. Expert Opin Drug Metab Toxicol 2015; 11: 1619-33.
[25]
Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE. Metformin pathways: Pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 2012; 22: 820-7.
[26]
Dujic T, Zhou K, Yee SW, et al. Variants in pharmacokinetic transporters and glycemic response to metformin: A metgen meta-analysis. Clin Pharmacol Ther 2017; 101: 763-72.
[27]
Kajbaf F, De Broe ME, Lalau J-D. Therapeutic concentrations of metformin: A systematic review. Clin Pharmacokinet 2016; 55: 439-59.
[28]
DeFronzo RA, Buse JB, Kim T, et al. Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: Results from two randomised trials. Diabetologia 2016; 59: 1645-54.
[29]
de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: Randomised placebo controlled trial. BMJ 2010; 340: c2181.
[30]
Out M, Kooy A, Lehert P, Schalkwijk CA, Stehouwer CDA. Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3year trial. J Diabetes Complications 2018; 32: 171-8.
[31]
Giugliano D, Quatraro A, Consoli G, et al. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol 1993; 44: 107-12.
[32]
Aviles-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1999; 131: 182-8.
[33]
Wulffele MG, Kooy A, Lehert P, et al. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002; 25: 2133-40.
[34]
Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169: 616-25.
[35]
Schatz H, Winkler G, Jonatha EM, Pfeiffer EF. Studies on juvenile--type diabetes in children. Assessment of control under treatment with constant and variable doses of insulin with or without addition of biguanides. Diabete Metab 1975; 1: 211-20.
[36]
Gin H, Slama G, Weissbrodt P, et al. Metformin reduces post-prandial insulin needs in type I (insulin-dependent) diabetic patients: assessment by the artificial pancreas. Diabetologia 1982; 23: 34-6.
[37]
Liu C, Wu D, Zheng X, Li P, Li L. Efficacy and safety of metformin for patients with type 1 diabetes mellitus: A meta-analysis. Diabetes Technol Ther 2015; 17: 142-8.
[38]
Anderson JJA, Couper JJ, Giles LC, et al. Effect of metformin on vascular function in children with type 1 diabetes: A 12-month randomized controlled trial. J Clin Endocrinol Metab 2017; 102: 4448-56.
[39]
Livingstone R, Boyle JG, Petrie JR. A new perspective on metformin therapy in type 1 diabetes. Diabetologia 2017; 60: 1594-600.
[40]
Beysel S, Unsal IO, Kizilgul M, Caliskan M, Ucan B, Cakal E. The effects of metformin in type 1 diabetes mellitus. BMC Endocr Disord 2018; 18: 1.
[41]
Pagano G, Tagliaferro V, Carta Q, et al. Metformin reduces insulin requirement in Type 1 (insulin-dependent) diabetes. Diabetologia 1983; 24: 351-4.
[42]
Nosadini R, Avogaro A, Trevisan R, et al. Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes. Diabetes Care 1987; 10: 62-7.
[43]
Musi N, Hirshman MF, Nygren J, et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 2002; 51: 2074-81.
[44]
Top W, Stehouwer C, Lehert P, Kooy A. Metformin and beta-cell function in insulin-treated patients with type 2 diabetes: A randomized placebo-controlled 4.3-year trial. Diabetes Obes Metab 2018; 20: 730-3.
[45]
Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Intern Med 1991; 229: 181-7.
[46]
Fontbonne A, Charles MA, Juhan-Vague I, et al. The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. BIGPRO Study Group. Diabetes Care 1996; 19: 920-6.
[47]
Worsley R, Jane F, Robinson PJ, Bell RJ, Davis SR. Metformin for overweight women at midlife: A double-blind, randomized, controlled trial. Climacteric 2015; 18: 270-7.
[48]
Preiss D, Lloyd SM, Ford I, et al. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. lancet Diabetes Endocrinol 2014; 2: 116--4.
[49]
Aghili R, Malek M, Valojerdi AE, Banazadeh Z, Najafi L, Khamseh ME. Body composition in adults with newly diagnosed type 2 diabetes: Effects of metformin. J Diabetes Metab Disord 2014; 13: 88.
[50]
Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care 1993; 16: 621-9.
[51]
Fery F, Plat L, Balasse EO. Effects of metformin on the pathways of glucose utilization after oral glucose in non-insulin-dependent diabetes mellitus patients. Metabolism 1997; 46: 227-33.
[52]
Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998; 338: 867-72.
[53]
Jackson RA, Hawa MI, Jaspan JB, et al. Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes 1987; 36: 632-40.
[54]
Johnson AB, Webster JM, Sum CF, et al. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metabolism 1993; 42: 1217-22.
[55]
Perriello G, Misericordia P, Volpi E, et al. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes 1994; 43: 920-8.
[56]
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333: 550-4.
[57]
Konopka AR, Esponda RR, Robinson MM, et al. Hyperglucagonemia mitigates the effect of metformin on glucose production in prediabetes. Cell Reports 2016; 15: 1394-400.
[58]
Christensen MMH, Hojlund K, Hother-Nielsen O, et al. Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: A randomised trial. Diabetologia 2015; 58: 2494-502.
[59]
Gin H, Messerchmitt C, Brottier E, Aubertin J. Metformin improved insulin resistance in type I, insulin-dependent, diabetic patients. Metabolism 1985; 34: 923-5.
[60]
Prager R, Schernthaner G, Graf H. Effect of metformin on peripheral insulin sensitivity in non insulin dependent diabetes mellitus. Diabete Metab 1986; 12: 346-50.
[61]
Hother-Nielsen O, Schmitz O, Andersen PH, Beck-Nielsen H, Pedersen O. Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinol (Copenh) 1989; 120: 257-65.
[62]
Widen EI, Eriksson JG, Groop LC. Metformin normalizes nonoxidative glucose metabolism in insulin-resistant normoglycemic first-degree relatives of patients with NIDDM. Diabetes 1992; 41: 354-8.
[63]
Abbasi F, Kamath V, Rizvi AA, Carantoni M, Chen YD, Reaven GM. Results of a placebo-controlled study of the metabolic effects of the addition of metformin to sulfonylurea-treated patients. Evidence for a central role of adipose tissue. Diabetes Care 1997; 20: 1863-9.
[64]
Natali A, 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 2006; 49: 434-41.
[65]
Zhou K, Yee SW, Seiser EL, et al. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet 2016; 48: 1055-9.
[66]
Santer R, Schneppenheim R, Dombrowski A, Gotze H, Steinmann B, Schaub J. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet 1997; 17: 324-6.
[67]
Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: A meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 2017; 60: 1620-9.
[68]
Stephenne X, Foretz M, Taleux N, et al. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 2011; 54: 3101-10.
[69]
Wheaton WW, Weinberg SE, Hamanaka RB, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 2014; 3: e02242.
[70]
Cameron AR, Logie L, Patel K, et al. Metformin selectively targets redox control of complex I energy transduction. Redox Biol 2018; 14: 187-97.
[71]
Andrzejewski S, Gravel S-P, Pollak M, St-Pierre J. Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab 2014; 2: 12.
[72]
Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510: 542-6.
[73]
Polekhina G, Gupta A, Michell BJ, et al. AMPK beta subunit targets metabolic stress sensing to glycogen. Curr Biol 2003; 13: 867-71.
[74]
Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 2002; 51: 2420-5.
[75]
Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 2007; 100: 328-41.
[76]
Arad M, Benson DW, Perez-Atayde AR, et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 2002; 109: 357-62.
[77]
Hawley SA, Ross FA, Chevtzoff C, et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 2010; 11: 554-65.
[78]
An H, He L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Endocrinol 2016; 228: R97-R106.
[79]
Dann SG, Selvaraj A, Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 2007; 13: 252-9.
[80]
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 471-84.
[81]
Tzatsos A, Kandror KV. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol 2006; 26: 63-76.
[82]
Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010; 11: 390-401.
[83]
Buggy JJ, Heurich RO. Mac Dougall et al Role of the glucagon receptor COOH-terminal in glucagon-mediated signaling and receptor internalization. Diabetes 1997; 46: 1400-5.
[84]
Yang L, Yang D, de Graaf C, et al. Conformational states of the full-length glucagon receptor. Nat Commun 2015; 6: 7859.
[85]
Zhang H, Qiao A, Yang L, et al. Structure of the glucagon receptor in complex with a glucagon analogue. Nature 2018; 553: 106-10.
[86]
Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013; 494: 256-60.
[87]
Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015; 528: 262-6.


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VOLUME: 15
ISSUE: 4
Year: 2019
Page: [328 - 339]
Pages: 12
DOI: 10.2174/1573399814666181009125348
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