Skip to main content
Top

11-14-2017 | Insulin resistance | Review | Article

A Review of Insulin Resistance in Type 1 Diabetes: Is There a Place for Adjunctive Metformin?

Journal: Diabetes Therapy

Authors: Gagan Priya, Sanjay Kalra

Publisher: Springer Healthcare

Abstract

There is a rising trend of overweight and obesity among individuals with type 1 diabetes. This is often associated with insulin resistance, increased insulin dose requirements and poor glycemic control. Insulin resistance is also seen during puberty and is strongly related to increased risk of cardiovascular disease. The role of metformin as an adjunct to ongoing intensive insulin therapy in type 1 diabetics has been evaluated in several randomized trials, including the recently concluded T1D Exchange Network trial in adolescents and the REMOVAL trial in adults. Metformin reduces the insulin dose requirement, insulin-induced weight gain, and total and LDL cholesterol, but results in an increased risk of gastrointestinal adverse effects and a minor increase in the risk of hypoglycemia. In addition, metformin has been shown to reduce maximal carotid intima media thickness and therefore may extend cardioprotective benefits in type 1 diabetes. The role of metformin as adjunctive therapy in type 1 diabetes needs to be explored further in outcome trials.
Literature
1.
Sherr J, Tsalikian E, Fox L, et al. Dysregulation of alpha-cell function in youth during the first 2 years of T1D: recipricol abnormalities in glucagon responses to mixed meal feedings and hypoglycemia. Diabetes. 2012;61(Supplement 1):A52–3.
2.
Livingstone R, Boyle JG, Petrie JR. Removal study team. A new perspective on metformin therapy in type 1 diabetes. Diabetologia. 2017;. https://​doi.​org/​10.​1007/​s00125-017-4364-6.PubMedCentral
3.
Munir KM, Davis SN. The treatment of type 1 diabetes mellitus with agents approved for type 2 diabetes mellitus. Expert Opin Pharmacother. 2015;16(15):2331–41. https://​doi.​org/​10.​1517/​14656566.​2015.​1084502.CrossRefPubMed
4.
Polsky S, Ellis SL. Obesity, insulin resistance, and type 1 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2015;22:277–82. https://​doi.​org/​10.​1097/​MED.​0000000000000170​.CrossRefPubMed
5.
Libman IM, Pietropaolo M, Arslanian SA, LaPorte RE, Becker DJ. Changing prevalence of overweight children and adolescents at onset of insulin-treated diabetes. Diabetes Care. 2003;26(10):2871–5. https://​doi.​org/​10.​2337/​diacare.​26.​10.​2871.CrossRefPubMed
6.
Liu LL, Lawrence JM, Davis C, Liese AD, Pettitt DJ, Pihoker C, Dabelea D, Hamman R, Waitzfelder B, Kahn HS. Prevalence of overweight and obesity in youth with diabetes in USA: the SEARCH for Diabetes in Youth study. Pediatr Diabetes. 2010;11(1):4–11.CrossRefPubMed
7.
DuBose SN, Hermann JM, Tamborlane WV, Beck RW, Dost A, DiMeglio LA, Schwab KO, Holl RW, Hofer SE, Maahs DM. Type 1 diabetes exchange clinic network and diabetes prospective follow-up registry. Obesity in youth with type 1 diabetes in Germany, Austria, and the United States. J Pediatr. 2015;167(3):627-32.e1-4. https://​doi.​org/​10.​1016/​j.​jpeds.​2015.​05.​046 (Epub 2015 Jul 8).CrossRefPubMed
8.
Wilkin TJ. The accelerator hypothesis: weight gain as the missing link between type I and type II diabetes. Diabetologia. 2001;44(7):914–22.CrossRefPubMed
9.
Hypponen E, Virtanen SM, Kenward MG, Knip M, Akerblom HK. Childhood Diabetes in Finlad Study Group. Obesity, increased linear growth and risk of type 1 diabetes in children. Diabetes Care. 2000;23(12):1755–60.CrossRefPubMed
10.
Klupa T. Metformin in type 1 diabetes mellitus? Revisiting treatment dogmas in diabetes. Pol Arch Med Wewn. 2016;126(7–8):461–2. https://​doi.​org/​10.​20452/​pamw.​3533.PubMed
11.
Purnell JQ, Zinman B, Brunzell JD. DCCT/EDIC Research Group. The effect of excess weight gain with intensive diabetes mellitus treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes mellitus results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) Study. Circulation. 2013;127:180–7.CrossRefPubMed
12.
Conway B, Miller RG, Costacou T, Fried L, Kelsey S, Evans RW, Orchard TJ. Temporal patterns in overweight and obesity in type 1 diabetes. Diabet Med. 2010;27(4):398–404. https://​doi.​org/​10.​1111/​j.​1464-5491.​2010.​02956.​x.CrossRefPubMedPubMedCentral
13.
Kaul K, Apostolopoulou M, Roden M. Insulin resistance in type 1 diabetes mellitus. Metabolism. 2015;64(12):1629–39. https://​doi.​org/​10.​1016/​j.​metabol.​2015.​09.​002 (Epub 2015 Sep 11).CrossRefPubMed
14.
Bacha F, Klinepeter Bartz S. Insulin resistance, role of metformin and other non-insulin therapies in pediatric type 1 diabetes. Pediatric Diabetes. 2016;17:545–58.CrossRefPubMed
15.
DeFronzo RA, Hendler R, Simonson D. Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes. 1982;31(9):795–801.CrossRefPubMed
16.
Minges KE, Whittemore R, Grey M. Overweight and obesity in youth with type 1 diabetes. Annu Rev Nurs Res. 2013;31:47–69. https://​doi.​org/​10.​1891/​0739-6686.​31.​47.CrossRefPubMedPubMedCentral
17.
Nadeau KJ, Regensteiner JG, Bauer TA, et al. Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function. J Clin Endocrinol Metab. 2010;95(2):513–21.CrossRefPubMed
18.
Van Vliet M, Van der Heyden JC, Diamant M, Van der Rosenstiel IA, Schindhelm RK, Aanstoot HJ, Veeze HJ. Overweight is highly prevalent in children with type 1 diabetes and associates with cardiometabolic risk. J Pediatr. 2010;156(6):923–9.CrossRefPubMed
19.
Livingstone SJ, Levin D, Looker HC, Lindsay RS, Wild SH, Joss N, Leese G, Leslie P, McCrimmon RJ, Metcalfe W, et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA. 2015;313:37–44.CrossRefPubMedPubMedCentral
20.
Specht BJ, Wadwa RP, Snell-Bergeon JK, Nadeau KJ, Bishop FK, Maahs DM. Estimated insulin sensitivity and cardiovascular disease risk factors in adolescents with and without type 1 diabetes. J Pediatr. 2013;162(2):297–301. https://​doi.​org/​10.​1016/​j.​jpeds.​2012.​07.​036.CrossRefPubMed
21.
Orchard TJ, Olson JC, Erbey JR, Williams K, Forrest KY, Smithline Kinder L, Ellis D, Becker DJ. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care. 2003;26:1374–9.CrossRefPubMed
22.
Schauer IE, Snell-Bergeon JK, Bergman BC, et al. Insulin resistance, defective insulin-mediated fatty acid suppression, and coronary artery calcification in subjects with and without type 1 diabetes: the CACTI study. Diabetes. 2011;60:306–14.CrossRefPubMed
23.
Thomas I, Gregg B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes. 2017;18(1):10–6. https://​doi.​org/​10.​1111/​pedi.​12473.CrossRefPubMed
24.
Gin H, Messerchmitt C, Brottier E, Aubertin J. Metformin improved insulin resistance in type I, insulin-dependent, diabetic patients. Metabolism. 1985;34(10):923–5.CrossRefPubMed
25.
Moon RJ, Bascombe LA, Holt RI. The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient well-being. Diabetes Obes Metab. 2007;9(1):143–5.CrossRefPubMed
26.
Urakami T, Morimoto S, Owada M, Harada K. Usefulness of the addition of metformin to insulin in pediatric patients with type 1 diabetes mellitus. Pediatr Int. 2005;47(4):430–3. https://​doi.​org/​10.​1111/​j.​1442-200x.​2005.​02075.​x PMID: 16091082.CrossRefPubMed
27.
Gómez R, Mokhashi MH, Rao J, Vargas A, Compton T, McCarter R, Chalew SA. Metformin adjunctive therapy with insulin improves glycemic control in patients with type 1 diabetes mellitus: a pilot study. J Pediatr Endocrinol Metab. 2002;15(8):1147–51.CrossRefPubMed
28.
Khan AS, McLoughney CR, Ahmed AB. The effect of metformin on blood glucose control in overweight patients with type 1 diabetes. Diabet Med. 2006;23(10):1079–84.CrossRefPubMed
29.
Pagano G, Tagliaferro V, Carta Q, Caselle MT, Bozzo C, Vitelli F, Trovati M, Cocuzza E. Metformin reduces insulin requirement in type 1 (insulin-dependent) diabetes. Diabetologia. 1983;24(5):351–4.CrossRefPubMed
30.
Jacobsen IB, Henriksen JE, Beck-Nielsen H. The effect of metformin in overweight patients with type 1 diabetes and poor metabolic control. Basic Clin Pharmacol Toxicol. 2009;105(3):145–9. https://​doi.​org/​10.​1111/​j.​1742-7843.​2009.​00380.​x Epub 2009 May 26.CrossRefPubMed
31.
Meyer L, Böhme P, Delbachian I, Lehert P, Cugnardey N, Drouin P, Guerci B. The benefits of metformin therapy during continuous subcutaneous insulin infusion treatment of type 1 diabetic patients. Diabetes Care. 2002;25:2153–8.CrossRefPubMed
32.
Lund SS, Tarnow L, Astrup AS, et al. Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control: a randomized study. PLoS ONE. 2008;3(10):e3363.CrossRefPubMedPubMedCentral
33.
Pang TT, Narendran P. Addressing insulin resistance in type 1 diabetes. Diabet Med. 2008;25:1015–24.CrossRefPubMed
34.
Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia. 2010;53(5):809–20.CrossRefPubMed
35.
Liu C, Wu D, Zheng X, et al. Efficacy and safety of metformin for patients with type 1 diabetes mellitus: a meta-analysis. Diabetes Technol Ther. 2015;17:142–8.CrossRefPubMed
36.
Staels F, Moyson C, Mathieu C. Metformin as add-on to intensive insulin therapy in type 1 diabetes mellitus. Diabetes Obes Metab. 2017. https://​doi.​org/​10.​1111/​dom.​12948.PubMed
37.
Petrie JR, Chaturvedi N, Ford I, Brouwers MCGJ, Greenlaw N, Tillin T, Hramiak I, Hughes AD, Jenkins AJ, Klein BEK, Klein R, Ooi TC, Rossing P, Stehouwer CDA, Sattar N, Colhoun HM, REMOVAL Study Group. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5(8):597–609. https://​doi.​org/​10.​1016/​S2213-8587(17)30194-8 (Epub 2017 Jun 11).CrossRefPubMedPubMedCentral
38.
Escobar-Morreale HF, Roldan B, Barrio R, Alonso M, Sancho J, de la Calle H, Garcia-Robles R. High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2000;85:4182–7.PubMed
39.
Codner E, Escobar-Morreale HF. Clinical review: Hyperandrogenism and polycystic ovary syndrome in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2007;92:1209–16.CrossRefPubMed
40.
Roldan B, Escobar-Morreale HF, Barrio R, de La Calle H, Alonso M, Garcia-Robles R, Sancho J. Identification of the source of androgen excess in hyperandrogenic type 1 diabetic patients. Diabetes Care. 2001;24:1297–9.CrossRefPubMed
41.
Codner E, Iniguez G, Lopez P, Mujica V, Eyzaguirre FC, Asenjo S, et al. Metformin for the treatment of hyperandrogenism in adolescents with type 1 diabetes mellitus. Hormone research in paediatrics. 2013;80(5):343–9. https://​doi.​org/​10.​1159/​000355513 PMID: 24280743.CrossRefPubMed
42.
DCCT Research Group. Effect of intensive diabetes treatment on the development and progression of long term complications in adolescents with insulin-dependent diabetes mellitus. Diabetes Control and Complications Trial. J Pediatrics. 1994;125:177–88.CrossRef
43.
Ferguson AW, De La Harpe PL, Farquhar JW. Dimethyldiguanide in the treatment of diabetic children. Lancet. 1961;1:1367–9.CrossRefPubMed
44.
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.PubMed
45.
Sarnblad S, Kroon M, Aman J. Metformin as additional therapy in adolescents with poorly controlled type 1 diabetes: randomised placebo-controlled trial with aspects on insulin sensitivity. Eur J Endocrinol. 2003;149:323–9.CrossRefPubMed
46.
Setoodeh A, Didban A, Rabbani A, Sayarifard A, Abbasi F, Sayarifard F, Hoseinzade F. The effect of metformin as an adjunct therapy in adolescents with type 1 diabetes. J Clin Diagnostic Res. 2017;11(4):SC01–4. https://​doi.​org/​10.​7860/​JCDR/​2017/​24901.​9725.
47.
Hamilton J, Cummings E, Zdravkovic V, Finegood D, Daneman D. Metformin as an adjunct therapy in adolescents with type 1 diabetes and insulin resistance: a randomized controlled trial. Diabetes Care. 2003;26(1):138–43 PMID: 12502670.CrossRefPubMed
48.
Abdelghaffar S, Attia AM. Metformin added to insulin therapy for type 1 diabetes mellitus in adolescents. Cochrane Database of Systematic Reviews. 2009;1:CD006691. https://​doi.​org/​10.​1002/​14651858.​CD006691.​pub2.
49.
Nwosu BU, Maranda L, Cullen K, Greenman L, Fleshman J, McShea N, Barton BA, Lee MM. A randomized, double-blind, placebo-controlled trial of adjunctive metformin therapy in overweight/obese youth with type 1 diabetes. PLoS ONE. 2015;10(9):e0137525. https://​doi.​org/​10.​1371/​journal.​pone.​0137525.CrossRefPubMedPubMedCentral
50.
Nadeau K, Chow K, Alam L, Lindquist K, Cambell S, McFann K, Klingensmith G, Walravens P. Effects of low dose metformin in adolescents with type 1 diabetes mellitus: a randomized, double-blinded placebo-controlled study. Pediatr Diabetes. 2015;16(3):196–203. https://​doi.​org/​10.​1111/​pedi.​12140.CrossRefPubMed
51.
Pandey AK, Gutch M, Mittal M, Kumar S, Razi SM. Can metformin be used in type 1 diabetes with insulin resistance: experience from tertiary care health center. J Assoc Physicians India. 2016;64(1):91.
52.
Al Khalifah RA, Alnhdi A, Alghar H, Alanazi M, Florez ID. The effect of adding metformin to insulin therapy for type 1 diabetes mellitus children: a systematic review and meta-analysis. Pediatr Diabetes. 2017;. https://​doi.​org/​10.​1111/​pedi.​12493.PubMed
53.
Konrad K, Datz N, Engelsberger I, Gurlich-Henn J, Hoertenhuber T, Knauth B, Meissner T, Wiegand S, Woelfle J, Holl RW. German/Austrian DPV Initiative. Current use of metformin in addition to insulin in pediatric patients with type 1 diabetes mellitus: an analysis based on a large diabetes registry in Germany and Austria. Pediatr Diabetes. 2015;16(7):529–37. https://​doi.​org/​10.​1111/​pedi.​12203 Epub 2014 Aug 18.CrossRefPubMed
54.
Libman IM, Miller KM, DiMeglio LA, T1D Exchange Clinic Network Metformin RCT Study Group. Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes: a randomized clinical trial. JAMA. 2015;314(21):2241–50. https://​doi.​org/​10.​1001/​jama.​2015.​16174.CrossRefPubMed
55.
Burchardt P, Zawada A, Tabaczewski P, Naskręt D, Kaczmarek J, Marcinkaniec J, Wierusz-Wysocka B, Wysocki H. Metformin added to intensive insulin therapy reduces plasma levels of glycated but not oxidized low–density lipoprotein in young patients with type 1 diabetes and obesity in comparison with insulin alone: a pilot study. Pol Arch Med Wewn. 2013;123(10):526–32 Epub 2013 Aug 8.PubMed
56.
Lund SS, Tarnow L, Astrup AS, et al. Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes. Diabetes Obes Metab. 2009;11(10):966–77.CrossRefPubMed
57.
Pitocco D, Zaccardi F, Tarzia P, et al. Metformin improves endothelial function in type 1 diabetic subjects: a pilot, placebo-controlled randomized study. Diabetes Obes Metab. 2013;15:427–31.CrossRefPubMed
58.
Ahmed FW, Rider R, Glanville M, Narayanan K, Razvi S, Weaver JU. Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study. Cardiovasc Diabetol. 2016;15:116. https://​doi.​org/​10.​1186/​s12933-016-0413-6.CrossRefPubMedPubMedCentral
59.
Matsumoto K, Gera Y, Abe Y, Tominanga T, Yeki Y, Miyake S. Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. Diabetes Res Clin Pract. 2004;64:225–8.CrossRefPubMed
60.
Burchardt P, Zawada A, Kaczmarek J, et al. Association between adjunctive metformin therapy in young type 1 diabetes patients with excess body fat and reduction of carotid intima-media thickness. Pol Arch Med Wewn. 2016;126(7–8):514–20. https://​doi.​org/​10.​20452/​pamw.​3527.PubMed
61.
Miller KM, Foster NC, Beck RW, et al. Current state of type 1 diabetes treatment in the U.S.: updated data from the T1D Exchange clinic registry. Diabetes Care. 2015;38:971–8.CrossRefPubMed
62.
Morris AD, Boyle DI, MacAlpine R, et al. The diabetes audit and research in Tayside Scotland (DARTS) study: electronic record linkage to create a diabetes register. DARTS/MEMO Collaboration. BMJ. 1997;315:524–8.PubMed
63.
American Diabetes Association (2017) Standards ofmedical care in diabetes. Diabetes Care 2017; 40 (Suppl 1):S1–S135.
64.
National Institute of Clinical Excellence (2016). Type 1 diabetes in adults: diagnosis and management of type 1 diabetes. Available from https://​www.​nice.​org.​uk/​guidance/​ng17?​unlid=​4305921920163918​4149.

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform. 

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »