Known Subtypes of Severe Insulin Resistance

Donohue syndrome

Donohue syndrome (previously known as leprechaunism) is a rare autosomal recessive condition caused by loss of function mutations in the insulin receptor (INSR) gene1,2. Infant’s with Donohue syndrome demonstrate characteristic facial features including low set ears, large mouth, thickened lips, and widely spaced eyes3. Infants are born small for gestational age, and often feature hirsutism, significant acanthosis nigricans, and nail dysplasia. Patients with Donohue syndrome have severe hyperglycemia often requiring extremely high doses of insulin. Unfortunately, life expectancy is very short and patients typically die from severe infections within the first 2 years of life4.

Rabson Mendenhall syndrome

Similar to Donohue syndrome, Rabson-Mendenhall syndrome is due to loss of function mutations in the INSR gene5–7. However, in this case there remains some functional activity of the insulin receptor. Thus, patients with Rabson-Mendenhall syndrome live later into childhood. Key clinical features include precocious puberty and severe acanthosis nigricans. Patients are at risk for infection and diabetic ketoacidosis8.

Type A insulin resistance syndrome

Type A insulin resistance syndrome is an inherited syndrome that is characterized by hyperinsulinemia with or without glucose intolerance, acanthosis nigricans, and ovarian hyperandrogenism9. Classic type A insulin resistance syndrome normally occurs in lean or muscular adolescent girls observed to have hyperandrogenisms such as amenorrhea, hirsutism, and virilization. Similar conditions of severe insulin resistance with acanthosis nigricans may occur in brothers, prepubertal sisters, and fathers of female probands10.

HAIR-AN syndrome

HAIR-AN syndrome consists of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) . It is a rare disease which is a subset of polycystic ovarian syndrome (PCOS). HAIR-AN is commonly used to describe women with severe insulin resistance. It can be triggered by blocking antibodies against the insulin receptor or genetically absent/reduced insulin receptor number/function11. All women with HAIR-AN experience increased androgen levels12.

Type B insulin resistance syndrome

In contrast to Type A insulin resistance, Type B insulin resistance is an autoimmune condition caused by polyclonal antibodies against the insulin receptor. Typically, Type B insulin resistance presents in adulthood, primarily in middle-aged women. Patients will experience both hypo- and hyper- glycemia based on antibody mediated activation and subsequent down-regulation of the insulin receptor13. Often, Type B insulin resistance is diagnosed in the setting of other autoimmune conditions such as systemic lupus erythematosus, Sjögren syndrome, or mixed connective tissue disease14. Type B insulin resistance syndrome can also be seen as part of a paraneoplastic syndrome in response to Hodgkin disease or myeloma15.

Lipodystrophy Syndromes

Lipodystrophy is a heterogeneous disorder characterized by adipose tissue deficiency, in which patients have an abnormal accumulation of fat throughout the body (generalized) or one area of the body (partial). The condition might either be inherited or acquired from infection, autoimmune diseases, or pressure/injury on a specific area of the body. Similar symptoms from type A insulin resistance syndrome may occur. Patients with lipodystrophy might observe to have the loss of or abnormal distribution of fat. Patients with total lipoatrophy can demonstrate hypertriglyceridemia with associated hepatosplenomegaly16.

Insulin-mediated pseudoacromegaly

Insulin-mediated pseudoacromegaly (IMPA) is a rare SIR syndrome, with only a handful of cases described in the medical literature. Patients with IMPA develop tall stature, obesity, severe acanthosis nigricans, and acromegalic features. They have extremely elevated insulin levels17. Recent evidence link the genetics of IMPA to mutations in the fibroblast growth factor-21 signaling pathway. This pathway is shared with autosomal dominant forms of Kallman syndrome, a genetic disorder that causes idiopathic hypogonadotropic hypogonadism18.

Hyperproinsulinemia

Familial hyperproinsulinemia is caused specific mutations in the β-chain of the insulin gene. These mutations are linked to a profound increase in circulating plasma proinsulin levels. Serum hyperproinsulinemia is more frequent in type 2 diabetes. It has been attributed to either a direct β-cells defect or an indirect effect of cell dysregulation under sustained elevated blood glucose (hyperglycemia). Some evidence suggests that patients with IMPA experience severe hyperproinsulinemia19,20.

References
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  2. Reddy SS, Muller-Wieland D, Kriauciunas K, Kahn CR. Molecular defects in the insulin receptor in patients with leprechaunism and in their parents. J Lab Clin Med. 1989 Aug;114(2):165–170. PMID: 2569023
  3. Donohue WL, Uchida I. Leprechaunism: A euphuism for a rare familial disorder. The Journal of Pediatrics [Internet]. Elsevier; 1954 Nov 1 [cited 2023 Aug 23];45(5):505–519. Available from: https://www.jpeds.com/article/S0022-3476(54)80113-2/abstract PMID: 13212592
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  5. 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 Mar;26(3):283–90.
  6. Kadowaki T, Kadowaki H, Accili D, Taylor SI. Substitution of lysine for asparagine at position 15 in the alpha-subunit of the human insulin receptor. A mutation that impairs transport of receptors to the cell surface and decreases the affinity of insulin binding. J Biol Chem. 1990 Nov 5;265(31):19143–19150. PMID: 2121734
  7. Moncada VY, Hedo JA, Serrano-Rios M, Taylor SI. Insulin-receptor biosynthesis in cultured lymphocytes from an insulin-resistant patient (Rabson-Mendenhall syndrome). Evidence for defect before insertion of receptor into plasma membrane. Diabetes. 1986 Jul;35(7):802–807. PMID: 3721065
  8. Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, Gorden P. Clinical Course of Genetic Diseases of the Insulin Receptor (Type A and Rabson-Mendenhall Syndromes): A 30-Year Prospective. Medicine [Internet]. 2004 Jul [cited 2023 Aug 23];83(4):209. Available from: https://journals.lww.com/md-journal/fulltext/2004/07000/clinical_course_of_genetic_diseases_of_the_insulin.1.aspx
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  10. Iwanishi M, Haruta T, Takata Y, Ishibashi O, Sasaoka T, Egawa K, Imamura T, Naitou K, Itazu T, Kobayashi M. A mutation (Trp1193→Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance. Diabetologia [Internet]. 1993 May 1 [cited 2023 Aug 23];36(5):414–422. Available from: https://doi.org/10.1007/BF00402277
  11. O’Brien B, Dahiya R, Kimble R. Hyperandrogenism, insulin resistance and acanthosis nigricans (HAIR-AN syndrome): an extreme subphenotype of polycystic ovary syndrome. BMJ Case Rep. 2020 Apr 9;13(4). PMCID: PMC7167451
  12. Rager KM, Omar HA. Androgen excess disorders in women: the severe insulin-resistant hyperandrogenic syndrome, HAIR-AN. ScientificWorldJournal. 2006 Jan 24;6:116–121. PMCID: PMC5917269
  13. Willard DL, Stevenson M, Steenkamp D. Type B insulin resistance syndrome. Current Opinion in Endocrinology, Diabetes and Obesity [Internet]. 2016 Aug [cited 2023 Aug 23];23(4):318. Available from: https://journals.lww.com/co-endocrinology/abstract/2016/08000/type_b_insulin_resistance_syndrome.5.aspx
  14. Martins LM, Fernandes VO, Carvalho MMD de, Gadelha DD, Queiroz PC de, Montenegro Junior RM. Type B insulin resistance syndrome: a systematic review. Arch Endocrinol Metab. 2020 Aug;64(4):337–348. PMID: 32813762
  15. Angelidi AM, Filippaios A, Mantzoros CS. Severe insulin resistance syndromes. J Clin Invest [Internet]. [cited 2023 Aug 23];131(4):e142245. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880309/ PMCID: PMC7880309
  16. Brown RJ, Araujo-Vilar D, Cheung PT, Dunger D, Garg A, Jack M, Mungai L, Oral EA, Patni N, Rother KI, von Schnurbein J, Sorkina E, Stanley T, Vigouroux C, Wabitsch M, Williams R, Yorifuji T. The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J Clin Endocrinol Metab. 2016 Dec;101(12):4500–4511. PMCID: PMC5155679
  17. Flier JS, Moller DE, Moses AC, O’Rahilly S, Chaiken RL, Grigorescu F, Elahi D, Kahn BB, Weinreb JE, Eastman R. Insulin-mediated pseudoacromegaly: clinical and biochemical characterization of a syndrome of selective insulin resistance. J Clin Endocrinol Metab. 1993 Jun;76(6):1533–41. PMID: 8388881
  18. Stone SI, Wegner DJ, Wambach JA, Cole FS, Urano F, Ornitz DM. Digenic Variants in the FGF21 Signaling Pathway Associated with Severe Insulin Resistance and Pseudoacromegaly. J Endocr Soc. 2020 Dec 1;4(12):bvaa138. PMCID: PMC7653638
  19. Gabbay KH, Bergenstal RM, Wolff J, Mako ME, Rubenstein AH. Familial hyperproinsulinemia: partial characterization of circulating proinsulin-like material. Proc Natl Acad Sci U S A. 1979 Jun;76(6):2881–2885. PMCID: PMC383713
  20. Chan SJ, Seino S, Gruppuso PA, Schwartz R, Steiner DF. A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2194–2197. PMCID: PMC304615