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Current Diabetes Reviews

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ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

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Review Article

Non-glycemic Adverse Effects of Insulin

Author(s): Alissa M. Guarneri and Robert P. Hoffman*

Volume 18, Issue 2, 2022

Published on: 29 January, 2021

Article ID: e012821190877 Pages: 7

DOI: 10.2174/1573399817666210129104420

Price: $65

Abstract

Insulin is primarily considered for its glycemic effects in patients with diabetes. There are, however, non-glycemic adverse effects of insulin that may significantly impact patient health and interfere with glycemic control. Insulinogenic edema primarily occurs with rapid improvement in glycemic control either in patients with newly discovered diabetes or in patients with poorly-controlled diabetes. Insulin-induced sympathetic activation, vasodilation, changes in vascular permeability, and most importantly, sodium retention play significant etiologic roles in the development of edema. Clinically, it is usually self-limited, but significant complications can develop. Allergic reactions to all insulin preparations and various compounds used in insulin formulations with a wide range of severity have been reported. Frequently, changing the type of insulin or delivery method is sufficient, but more advanced treatments such as insulin desensitization and anti-IgE antibody treatment may be needed. Lipohypertrophy and lipoatrophy frequently develop with the overuse of injection sites. Lipohypertrophy can affect tissue insulin absorption and glycemic control.

Keywords: Insulin, adverse effects, edema, allergy, lipohypertrophy, lipoatrophy.

[1]
Leifer A. A case of insulin edema. JAMA 1928; 90: 60-1.
[2]
Lawrence JR, Dunnigan MG. Diabetic (insulin) oedema. BMJ 1979; 2(6187): 445.
[http://dx.doi.org/10.1136/bmj.2.6187.445-a] [PMID: 486988]
[3]
Saule H. Insulin-induced edema in adolescents with type 1 diabetes mellitus. Dtsch Med Wochenschr 1991; 116(31-32): 1191-4.
[PMID: 1860423]
[4]
Kan Y, Anno T, Kawasaki F, et al. Bilateral lower limb edema induced by rapid improvement of glycemic control with insulin therapy in a subject with poorly controlled type 2 diabetes. Acta Diabetol 2017; 54(6): 611-3.
[http://dx.doi.org/10.1007/s00592-017-0997-7] [PMID: 28451823]
[5]
Chelliah A, Burge MR. Insulin edema in the twenty-first century: Review of the existing literature. J Investig Med 2004; 52(2): 104-8.
[http://dx.doi.org/10.1136/jim-52-02-18] [PMID: 15068225]
[6]
Folgerø T, Storbakk N, Torbergsen T, Oian P. Mutations in mitochondrial transfer ribonucleic acid genes in preeclampsia. Am J Obstet Gynecol 1996; 174(5): 1626-30.
[http://dx.doi.org/10.1016/S0002-9378(96)70619-1] [PMID: 9065142]
[7]
Hirano M, Konishi K, Arata N, et al. Renal complications in a patient with A-to-G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Intern Med 2002; 41(2): 113-8.
[http://dx.doi.org/10.2169/internalmedicine.41.113] [PMID: 11868597]
[8]
Janssen GM, Maassen JA, van Den Ouweland JM. The diabetes-associated 3243 mutation in the mitochondrial tRNA(Leu(UUR)) gene causes severe mitochondrial dysfunction without a strong decrease in protein synthesis rate. J Biol Chem 1999; 274(42): 29744-8.
[http://dx.doi.org/10.1074/jbc.274.42.29744] [PMID: 10514449]
[9]
Mangiafico RA, Zeviani M, Bartoloni G, Fiore CE. Accelerated cardiomyopathy in maternally inherited diabetes and deafness. Int J Clin Pharmacol Res 2004; 24(1): 15-21.
[PMID: 15575173]
[10]
Suzuki S. Diabetes mellitus with mitochondrial gene mutations in Japan. Ann N Y Acad Sci 2004; 1011: 185-92.
[http://dx.doi.org/10.1196/annals.1293.019] [PMID: 15126296]
[11]
Suzuki Y, Taniyama M, Muramatsu T, et al. Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation: Clinical features and coenzyme Q10 treatment. Mol Aspects Med 1997; 18(Suppl.): S181-8.
[http://dx.doi.org/10.1016/S0098-2997(97)00041-1] [PMID: 9266520]
[12]
Laroche S, Wucher H, Nguyen YL, Timsit J, Larger E. Case report: Insulin edema and acute renal failure. Diabetes Care 2013; 36(5)
[http://dx.doi.org/10.2337/dc12-2137] [PMID: 23613606]
[13]
Mamoulakis D, Bitsori M, Galanakis E, Raissaki M, Kalmanti M. Insulin-induced oedema in children and adolescents. J Paediatr Child Health 2006; 42(10): 655-7.
[http://dx.doi.org/10.1111/j.1440-1754.2006.00911.x] [PMID: 16972977]
[14]
Lee P, Kinsella J, Borkman M, Carter J. Bilateral pleural effusions, ascites, and facial and peripheral oedema in a 19-year-old woman 2 weeks following commencement of insulin lispro and detemiran unusual presentation of insulin oedema. Diabet Med 2007; 24(11): 1282-5.
[http://dx.doi.org/10.1111/j.1464-5491.2007.02241.x] [PMID: 17956453]
[15]
Kalambokis GN, Tsatsoulis AA, Tsianos EV. The edematogenic properties of insulin. Am J Kidney Dis 2004; 44(4): 575-90.
[http://dx.doi.org/10.1016/S0272-6386(04)00960-6] [PMID: 15384008]
[16]
Rosenbloom AL, Giordano BP. Chronic overtreatment with insulin in children and adolescents. Am J Dis Child 1977; 131(8): 881-5.
[PMID: 888803]
[17]
Greco D. Severe weight gain and generalized insulin edema after the starting of an insulin pump. Can J Diabetes 2015; 39(1): 21-3.
[http://dx.doi.org/10.1016/j.jcjd.2014.07.001] [PMID: 25282002]
[18]
Myers WT, Wintergerst KA, Kingery SE, Foster MB. Case 2: Generalized anasarca in 15-year-old girl with type 1 diabetes mellitus. Pediatr Rev 2016; 37(2): 81-2.
[http://dx.doi.org/10.1542/pir.2015-0088] [PMID: 26834228]
[19]
Walmsley RS. Refeeding syndrome: Screening, incidence, and treatment during parenteral nutrition. J Gastroenterol Hepatol 2013; 28(Suppl. 4): 113-7.
[http://dx.doi.org/10.1111/jgh.12345] [PMID: 24251716]
[20]
Fujiwara M, Ando I, Satoh K, et al. Biochemical evidence of cell starvation in diabetic hemodialysis patients. PLoS One 2018; 13(9)
[http://dx.doi.org/10.1371/journal.pone.0204406] [PMID: 30261059]
[21]
Burstal RJ, Reilly JR, Burstal B. Fasting or starving? Measurement of blood ketone levels in 100 fasted elective and emergency adult surgical patients at an Australian tertiary hospital. Anaesth Intensive Care 2018; 46(5): 463-7.
[http://dx.doi.org/10.1177/0310057X1804600506] [PMID: 30189819]
[22]
Mahdi H, Gough S, Gill KK, Mahon B. Acute spontaneous compartment syndrome in recent onset type 1 diabetes. Emerg Med J 2007; 24(7): 507-8.
[http://dx.doi.org/10.1136/emj.2007.046425] [PMID: 17582052]
[23]
Sheehan JP, Sisam DA, Schumacher OP. Insulin-induced cardiac failure. Am J Med 1985; 79(1): 147-8.
[http://dx.doi.org/10.1016/0002-9343(85)90562-5] [PMID: 4014301]
[24]
Saudek CD, Boulter PR, Knopp RH, Arky RA. Sodium retention accompanying insulin treatment of diabetes mellitus. Diabetes 1974; 23(3): 240-6.
[http://dx.doi.org/10.2337/diab.23.3.240] [PMID: 4206082]
[25]
Nosadini R, Sambataro M, Thomaseth K, et al. Role of hyperglycemia and insulin resistance in determining sodium retention in non-insulin-dependent diabetes. Kidney Int 1993; 44(1): 139-46.
[http://dx.doi.org/10.1038/ki.1993.224] [PMID: 8355455]
[26]
Nørgaard K, Jensen T, Skøtt P, et al. Effects of insulin on renal haemodynamics and sodium handling in normal subjects. Scand J Clin Lab Invest 1991; 51(4): 367-76.
[http://dx.doi.org/10.1080/00365519109091628] [PMID: 1947721]
[27]
Brands MW, Bell TD, Rodriquez NA, Polavarapu P, Panteleyev D. Chronic glucose infusion causes sustained increases in tubular sodium reabsorption and renal blood flow in dogs. Am J Physiol Regul Integr Comp Physiol 2009; 296(2): R265-71.
[http://dx.doi.org/10.1152/ajpregu.90528.2008] [PMID: 19073906]
[28]
Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 1991; 87(6): 2246-52.
[http://dx.doi.org/10.1172/JCI115260] [PMID: 2040704]
[29]
Rooney DP, Edgar JD, Sheridan B, Atkinson AB, Bell PM. The effects of low dose insulin infusions on the renin angiotensin and sympathetic nervous systems in normal man. Eur J Clin Invest 1991; 21(4): 430-5.
[http://dx.doi.org/10.1111/j.1365-2362.1991.tb01391.x] [PMID: 1936111]
[30]
Trovati M, Massucco P, Anfossi G, et al. Insulin influences the renin-angiotensin-aldosterone system in humans. Metabolism 1989; 38(6): 501-3.
[http://dx.doi.org/10.1016/0026-0495(89)90207-2] [PMID: 2542723]
[31]
Hoffman RP, Hausberg M, Sinkey CA, Anderson EA. Hyperglycemia without hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Diabetes Complications 1999; 13(1): 17-22.
[http://dx.doi.org/10.1016/S1056-8727(98)00019-1] [PMID: 10232705]
[32]
Hoffman RP, Sinkey CA, Anderson EA. Hypoglycemia increases muscle sympathetic nerve activity in IDDM and control subjects. Diabetes Care 1994; 17(7): 673-80.
[http://dx.doi.org/10.2337/diacare.17.7.673] [PMID: 7924776]
[33]
Adler GK, Bonyhay I, Curren V, Waring E, Freeman R. Hypoglycaemia increases aldosterone in a dose-dependent fashion. Diabet Med 2010; 27(11): 1250-5.
[http://dx.doi.org/10.1111/j.1464-5491.2010.03087.x] [PMID: 20950382]
[34]
Bie-Olsen LG, Pedersen-Bjergaard U, Kjaer TW, Lonsdale MN, Law I, Thorsteinsson B. Differences in cortical and pituitary activity in response to hypoglycaemia and cognitive testing in healthy men with different basal activity of the renin-angiotensin system. J Renin Angiotensin Aldosterone Syst 2010; 11(3): 173-9.
[http://dx.doi.org/10.1177/1470320310364182] [PMID: 20215476]
[35]
Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129(5): 587-97.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.005081] [PMID: 24334175]
[36]
Cuneo RC, Livesey JH, Nicholls MG, Espiner EA, Donald RA. Effects of alpha-1 adrenergic blockade on the hormonal response to hypoglycaemic stress in normal man. Clin Endocrinol (Oxf) 1987; 26(1): 1-8.
[http://dx.doi.org/10.1111/j.1365-2265.1987.tb03632.x] [PMID: 3026690]
[37]
Baron AD, Brechtel G. Insulin differentially regulates systemic and skeletal muscle vascular resistance. Am J Physiol 1993; 265(1 Pt 1): E61-7.
[PMID: 8338155]
[38]
Dye AS, Huang H, Bauer JA, Hoffman RP. Hyperglycemia increases muscle blood flow and alters endothelial function in adolescents with type 1 diabetes. Exp Diabetes Res 2012; 2012
[http://dx.doi.org/10.1155/2012/170380] [PMID: 22701470]
[39]
Gudbjörnsdóttir S, Sjöstrand M, Strindberg L, Wahren J, Lönnroth P. Direct measurements of the permeability surface area for insulin and glucose in human skeletal muscle. J Clin Endocrinol Metab 2003; 88(10): 4559-64.
[http://dx.doi.org/10.1210/jc.2003-030434] [PMID: 14557422]
[40]
Hilsted J, Christensen NJ. Dual effect of insulin on plasma volume and transcapillary albumin transport. Diabetologia 1992; 35(2): 99-103.
[http://dx.doi.org/10.1007/BF00402539] [PMID: 1547928]
[41]
Rennings AJ, Smits P, Stewart MW, Tack CJ. Fluid retention and vascular effects of rosiglitazone in obese, insulin-resistant, nondiabetic subjects. Diabetes Care 2006; 29(3): 581-7.
[http://dx.doi.org/10.2337/diacare.29.03.06.dc05-01467] [PMID: 16505510]
[42]
Oomen PHN, Kant GD, Dullaart RPF, Reitsma WD, Smit AJ. Acute hyperglycemia and hyperinsulinemia enhance vasodilatation in Type 1 diabetes mellitus without increasing capillary permeability and inducing endothelial dysfunction. Microvasc Res 2002; 63(1): 1-9.
[http://dx.doi.org/10.1006/mvre.2001.2347] [PMID: 11749067]
[43]
Clark JA, Burny I, Sarnaik AP, Audhya TK. Acute thiamine deficiency in diabetic ketoacidosis: Diagnosis and management. Pediatr Crit Care Med 2006; 7(6): 595-9.
[http://dx.doi.org/10.1097/01.PCC.0000244463.59230.DA] [PMID: 17006386]
[44]
Rosner EA, Strezlecki KD, Clark JA, Lieh-Lai M. Low thiamine levels in children with type 1 diabetes and diabetic ketoacidosis: A pilot study. Pediatr Crit Care Med 2015; 16(2): 114-8.
[http://dx.doi.org/10.1097/PCC.0000000000000302] [PMID: 25560422]
[45]
Arora S, Lidor A, Abularrage CJ, et al. Thiamine (vitamin B1) improves endothelium-dependent vasodilatation in the presence of hyperglycemia. Ann Vasc Surg 2006; 20(5): 653-8.
[http://dx.doi.org/10.1007/S10016-006-9055-6] [PMID: 16741654]
[46]
Lei Y, Zheng MH, Huang W, Zhang J, Lu Y. Wet beriberi with multiple organ failure remarkably reversed by thiamine administration: A case report and literature review. Medicine (Baltimore) 2018; 97(9): e0010.
[http://dx.doi.org/10.1097/MD.0000000000010010] [PMID: 29489643]
[47]
Nakamura H, Utsunomiya A, Ishida Y, Horita T. Thiamine deficiency in a nondrinker and secondary pulmonary edema after thiamine replenishment. Intern Med 2020; 59(3): 373-6.
[http://dx.doi.org/10.2169/internalmedicine.3585-19] [PMID: 31534090]
[48]
Haastrup MB, Henriksen JE, Mortz CG, Bindslev-Jensen C. Insulin allergy can be successfully managed by a systematic approach. Clin Transl Allergy 2018; 8: 35.
[http://dx.doi.org/10.1186/s13601-018-0223-x] [PMID: 30258565]
[49]
Badik J, Chen J, Letvak K, So TY. Hypersensitivity reaction to insulin glargine and insulin detemir in a pediatric patient: A case report. J Pediatr Pharmacol Ther 2016; 21(1): 85-91.
[http://dx.doi.org/10.5863/1551-6776-21.1.85] [PMID: 26997933]
[50]
Mastrorilli C, Rizzuti L, Cangelosi AM, Iovane B, Chiari G, Caffarelli C. Long-acting insulin allergy in a diabetic child. Int J Immunopathol Pharmacol 2017; 30(2): 174-7.
[http://dx.doi.org/10.1177/0394632017700431] [PMID: 28368217]
[51]
Kim GJ, Kim SB, Jo SI, et al. Two cases of allergy to insulin in gestational diabetes. Endocrinol Metab (Seoul) 2015; 30(3): 402-7.
[http://dx.doi.org/10.3803/EnM.2015.30.3.402] [PMID: 26435137]
[52]
Watanabe K, Kusunoki Y, Katsuno T, et al. A case of type 1 diabetes mellitus with which localized insulin allergy was markedly alleviated by switching to insulin glulisine. Acta Diabetol 2016; 53(5): 845-8.
[http://dx.doi.org/10.1007/s00592-016-0841-5] [PMID: 26838553]
[53]
Nemoto KI, Ugi S, Ogaku S, et al. A case of local delayed-type allergy to zinc-containing insulin as a cause of diabetic ketoacidosis in a patient with type 1 diabetes mellitus undergoing continuous subcutaneous insulin infusion. Diabetol Int 2016; 7(4): 447-50.
[http://dx.doi.org/10.1007/s13340-016-0264-0] [PMID: 30603298]
[54]
Wu W, Cheng H, Bu R. Protamine-containing insulin allergy and renal dysfunction in a patient with type 2 diabetes. J Diabetes Investig 2015; 6(5): 591-3.
[http://dx.doi.org/10.1111/jdi.12332] [PMID: 26417419]
[55]
Chen YM, Huang H. Allergy to soft cannula of insulin pump in diabetic patient. Pak J Med Sci 2017; 33(1): 245-7.
[http://dx.doi.org/10.12669/pjms.331.11554] [PMID: 28367209]
[56]
Hoffman RP. Latex hypersensitivity in a child with diabetes. Arch Pediatr Adolesc Med 2000; 154(3): 281-2.
[http://dx.doi.org/10.1001/archpedi.154.3.281] [PMID: 10710028]
[57]
Chakraborty PP, Biswas SN, Patra S. Faulty injection technique: A preventable but often overlooked factor in insulin allergy. Diabetes Ther 2016; 7(1): 163-7.
[http://dx.doi.org/10.1007/s13300-016-0151-5] [PMID: 26843018]
[58]
Mishra S, Connors L, Tugwell B. Role of omalizumab in insulin hypersensitivity: A case report and review of the literature. Diabet Med 2018; 35(5): 663-6.
[http://dx.doi.org/10.1111/dme.13591] [PMID: 29381818]
[59]
Raile K, Noelle V, Landgraf R, Schwarz HP. Insulin antibodies are associated with lipoatrophy but also with lipohypertrophy in children and adolescents with type 1 diabetes. Exp Clin Endocrinol Diabetes 2001; 109(8): 393-6.
[http://dx.doi.org/10.1055/s-2001-18991] [PMID: 11748486]
[60]
Tsadik AG, Atey TM, Nedi T, Fantahun B, Feyissa M. Effect of insulin-induced lipodystrophy on glycemic control among children and adolescents with diabetes in tikur anbessa specialized hospital, addis ababa, Ethiopia. J Diabetes Res 2018; 2018: 4910962.
[http://dx.doi.org/10.1155/2018/4910962] [PMID: 30116742]
[61]
Singha A, Bhattarcharjee R, Ghosh S, Chakrabarti SK, Baidya A, Chowdhury S. Concurrence of lipoatrophy and lipohypertrophy in children with type 1 diabetes using recombinant human insulin: Two case reports. Clin Diabetes 2016; 34(1): 51-3.
[http://dx.doi.org/10.2337/diaclin.34.1.51] [PMID: 26807009]
[62]
Gradel AKJ, Porsgaard T, Lykkesfeldt J, et al. Factors affecting the absorption of subcutaneously administered insulin: Effect on variability. J Diabetes Res 2018; 2018: 1205121.
[http://dx.doi.org/10.1155/2018/1205121] [PMID: 30116732]
[63]
Alemzadeh R, Loppnow C, Parton E, Kirby M. Glucose sensor evaluation of glycemic instability in pediatric type 1 diabetes mellitus. Diabetes Technol Ther 2003; 5(2): 167-73.
[http://dx.doi.org/10.1089/152091503321827821] [PMID: 12871606]
[64]
Berhe T, Postellon D, Wilson B, Stone R. Feasibility and safety of insulin pump therapy in children aged 2 to 7 years with type 1 diabetes: A retrospective study. Pediatrics 2006; 117(6): 2132-7.
[http://dx.doi.org/10.1542/peds.2005-2363] [PMID: 16740857]
[65]
Radermecker RP, Piérard GE, Scheen AJ. Lipodystrophy reactions to insulin: Effects of continuous insulin infusion and new insulin analogs. Am J Clin Dermatol 2007; 8(1): 21-8.
[http://dx.doi.org/10.2165/00128071-200708010-00003] [PMID: 17298103]
[66]
Saberi S, Esfandiari NH, MacEachern MP, Tan MH. Detemir plus aspart and glulisine induced lipoatrophy: 2015 literature review and report of a new case. Clin Diabetes Endocrinol 2015; 1: 10.
[http://dx.doi.org/10.1186/s40842-015-0013-5] [PMID: 28702229]
[67]
Hoffman RP. Metabolic syndrome racial differences in adolescents. Curr Diabetes Rev 2009; 5(4): 259-65.
[http://dx.doi.org/10.2174/157339909789804332] [PMID: 19925390]
[68]
Baillargeon JP, Carpentier A. Role of insulin in the hyperandrogenemia of lean women with polycystic ovary syndrome and normal insulin sensitivity. Fertil Steril 2007; 88(4): 886-93.
[http://dx.doi.org/10.1016/j.fertnstert.2006.12.055] [PMID: 17559844]
[69]
Nathan DM, Genuth S, Lachin J, et al. Diabetes control and complications trial research group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14): 977-86.
[http://dx.doi.org/10.1056/NEJM199309303291401] [PMID: 8366922]
[70]
Diabetes control and complications trial (DCCT)/epidemiology of diabetes interventions and complications (edic) study research group. Mortality in type 1 diabetes in the DCCT/EDIC versus the general population. Diabetes Care 2016; 39(8): 1378-83.
[PMID: 27411699]
[71]
Arden GB, Sivaprasad S. Hypoxia and oxidative stress in the causation of diabetic retinopathy. Curr Diabetes Rev 2011; 7(5): 291-304.
[http://dx.doi.org/10.2174/157339911797415620] [PMID: 21916837]
[72]
Lachin JM, White NH, Hainsworth DP, Sun W, Cleary PA, Nathan DM. Diabetes control and complications trial (DCCT)/epidemiology of diabetes interventions and complications (EDIC) research group. Effect of intensive diabetes therapy on the progression of diabetic retinopathy in patients with type 1 diabetes: 18 years of follow-up in the DCCT/EDIC. Diabetes 2015; 64(2): 631-42.
[http://dx.doi.org/10.2337/db14-0930] [PMID: 25204977]

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