Insulin resistance: Definition and clinical spectrum
- Christos Mantzoros, MD, DSc
Christos Mantzoros, MD, DSc
- Professor of Medicine
- Harvard Medical School
Insulin resistance can be broadly defined as a subnormal biological response to normal insulin concentrations. By this definition, it may pertain to many biological actions of insulin in many tissues of the body. Typically, however, in clinical practice, insulin resistance refers to a state in which a given concentration of insulin is associated with a subnormal glucose response . The term first came into use several years after the introduction of insulin therapy in 1922 to describe occasional diabetic patients who required increasingly large doses of insulin to control hyperglycemia. Most of these patients developed insulin resistance secondary to antibodies directed against the therapeutic insulin, which at that time was both impure and derived from non-human species . Antiinsulin antibodies are rare in patients treated with recombinant human insulin, and the spectrum of clinical disorders in which insulin resistance plays a major role has changed markedly. Insulin resistance, rather than being a rare complication of the treatment of diabetes, is now recognized as a component of several disorders, including the following (table 1):
●Extreme insulin-resistance syndromes, such as the type B syndrome with autoantibodies against the insulin receptor , and rare inherited disorders, such as Leprechaunism with insulin-receptor mutations  and the lipodystrophic states .
●Impaired glucose tolerance and type 2 diabetes mellitus.
●Obesity, stress, infection, uremia, acromegaly, glucocorticoid excess, and pregnancy, which cause secondary insulin resistance.
●Common disorders such as the metabolic syndrome, hypertension, hyperlipidemia, coronary artery disease, the polycystic ovary syndrome, and ovarian hyperthecosis, in which the mechanism of the associated hyperinsulinemia is unknown. (See "The metabolic syndrome (insulin resistance syndrome or syndrome X)" and "Clinical manifestations of polycystic ovary syndrome in adults" and "Ovarian hyperthecosis".)
- Moller DE, Flier JS. Insulin resistance--mechanisms, syndromes, and implications. N Engl J Med 1991; 325:938.
- Kahn CR, Rosenthal AS. Immunologic reactions to insulin: insulin allergy, insulin resistance, and the autoimmune insulin syndrome. Diabetes Care 1979; 2:283.
- Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med 1976; 294:739.
- Musso C, Cochran E, Moran SA, et al. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore) 2004; 83:209.
- Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med 2000; 160:2050.
- Steiner DF, Tager HS, Chan SJ, et al. Lessons learned from molecular biology of insulin-gene mutations. Diabetes Care 1990; 13:600.
- Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocr Rev 1985; 6:45.
- Buchanan TA, Watanabe RM, Xiang AH. Limitations in surrogate measures of insulin resistance. J Clin Endocrinol Metab 2010; 95:4874.
- Tritos NA, Mantzoros CS. Clinical review 97: Syndromes of severe insulin resistance. J Clin Endocrinol Metab 1998; 83:3025.
- McLaughlin T, Abbasi F, Cheal K, et al. Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann Intern Med 2003; 139:802.
- Ascaso JF, Pardo S, Real JT, et al. Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism. Diabetes Care 2003; 26:3320.
- Barb, D, Mantzoros, C. Diagnosing obesity, diabetes mellitus and the insulin resistance syndrome. In: Obesity and Diabetes, Mantzoros, C. (Eds), Humana Press, Inc., Totowa, NJ 2006. p.129.
- Taylor SI, Grunberger G, Marcus-Samuels B, et al. Hypoglycemia associated with antibodies to the insulin receptor. N Engl J Med 1982; 307:1422.
- Rogers DL. Acanthosis nigricans. Semin Dermatol 1991; 10:160.
- Poretsky L, Piper B. Insulin resistance, hypersecretion of LH, and a dual-defect hypothesis for the pathogenesis of polycystic ovary syndrome. Obstet Gynecol 1994; 84:613.
- Taylor SI, Dons RF, Hernandez E, et al. Insulin resistance associated with androgen excess in women with autoantibodies to the insulin receptor. Ann Intern Med 1982; 97:851.
- Taylor SI, Cama A, Accili D, et al. Mutations in the insulin receptor gene. Endocr Rev 1992; 13:566.
- Moller DE, Cohen O, Yamaguchi Y, et al. Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance. Diabetes 1994; 43:247.
- Dunaif A, Hoffman AR, Scully RE, et al. Clinical, biochemical, and ovarian morphologic features in women with acanthosis nigricans and masculinization. Obstet Gynecol 1985; 66:545.
- Dunaif A, Segal KR, Shelley DR, et al. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992; 41:1257.
- Dunaif A, Xia J, Book CB, et al. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995; 96:801.
- Cohen JC, Hickman R. Insulin resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J Clin Endocrinol Metab 1987; 64:960.
- Barbieri RL, Smith S, Ryan KJ. The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism. Fertil Steril 1988; 50:197.
- Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996; 335:617.
- Dunaif A, Scott D, Finegood D, et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996; 81:3299.
- Elders MJ, Schedewie HK, Olefsky J, et al. Endocrine-metabolic relationships in patients with leprechaunism. J Natl Med Assoc 1982; 74:1195.
- RABSON SM, MENDENHALL EN. Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus; report of 3 cases. Am J Clin Pathol 1956; 26:283.
- Taylor SI. Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes 1992; 41:1473.
- Flier JS, Moller DE, Moses AC, et al. Insulin-mediated pseudoacromegaly: clinical and biochemical characterization of a syndrome of selective insulin resistance. J Clin Endocrinol Metab 1993; 76:1533.
- Flier JS, Young JB, Landsberg L. Familial insulin resistance with acanthosis nigricans, acral hypertrophy, and muscle cramps. N Engl J Med 1980; 303:970.
- Minaker KL, Flier JS, Landsberg L, et al. Phenytoin-induced improvement in muscle cramping and insulin action in three patients with the syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy. Arch Neurol 1989; 46:981.
- Fiorenza CG, Chou SH, Mantzoros CS. Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol 2011; 7:137.
- Björntorp P. "Portal" adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 1990; 10:493.
- Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259:87.
- Ziemke F, Mantzoros CS. Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr 2010; 91:258S.
- Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346:570.
- Mantzoros CS. Whither recombinant human leptin treatment for HIV-associated lipoatrophy and the metabolic syndrome? J Clin Endocrinol Metab 2009; 94:1089.
- Brennan AM, Mantzoros CS. Leptin and adiponectin: their role in diabetes. Curr Diab Rep 2007; 7:1.
- Gavrila A, Chan JL, Yiannakouris N, et al. Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies. J Clin Endocrinol Metab 2003; 88:4823.
- Fargnoli JL, Fung TT, Olenczuk DM, et al. Adherence to healthy eating patterns is associated with higher circulating total and high-molecular-weight adiponectin and lower resistin concentrations in women from the Nurses' Health Study. Am J Clin Nutr 2008; 88:1213.
- Blüher M, Williams CJ, Klöting N, et al. Gene expression of adiponectin receptors in human visceral and subcutaneous adipose tissue is related to insulin resistance and metabolic parameters and is altered in response to physical training. Diabetes Care 2007; 30:3110.
- Magkos F, Mantzoros CS. Body fat redistribution and metabolic abnormalities in HIV-infected patients on highly active antiretroviral therapy: novel insights into pathophysiology and emerging opportunities for treatment. Metabolism 2011; 60:749.
- Tsokos GC, Gorden P, Antonovych T, et al. Lupus nephritis and other autoimmune features in patients with diabetes mellitus due to autoantibody to insulin receptors. Ann Intern Med 1985; 102:176.
- Bourron O, Caron-Debarle M, Hie M, et al. Type B Insulin-resistance syndrome: a cause of reversible autoimmune hypoglycaemia. Lancet 2014; 384:1548.
- DEFINITION AND QUANTIFICATION
- Resistance to endogenous insulin
- Resistance to exogenous insulin
- Biochemical markers
- CLINICAL SPECTRUM
- Abnormal glucose metabolism
- Cutaneous abnormalities
- Hyperandrogenism and reproductive abnormalities
- Linear and acral growth
- Musculoskeletal changes
- Adipose tissue
- Metabolic syndrome