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Current Diabetes Reports

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11.07.2022 | Pathogenesis of Type 2 Diabetes and Insulin Resistance (M-E Patti, Section Editor)

Lipodystrophy for the Diabetologist—What to Look For

verfasst von: Nivedita Patni, Abhimanyu Garg

Erschienen in: Current Diabetes Reports | Ausgabe 9/2022

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Abstract

Purpose of Review

Genetic or acquired lipodystrophies are characterized by selective loss of body fat along with predisposition towards metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, polycystic ovarian syndrome, and acanthosis nigricans. In this review, we discuss the various subtypes and when to suspect and how to diagnose lipodystrophy.

Recent Findings

The four major subtypes are autosomal recessive, congenital generalized lipodystrophy (CGL); acquired generalized lipodystrophy (AGL), mostly an autoimmune disorder; autosomal dominant or recessive familial partial lipodystrophy (FPLD); and acquired partial lipodystrophy (APL), an autoimmune disorder. Diagnosis of lipodystrophy is mainly based upon physical examination findings of loss of body fat and can be supported by body composition analysis by skinfold measurements, dual-energy x-ray absorptiometry, and whole-body magnetic resonance imaging. Confirmatory genetic testing is helpful in the proband and at-risk family members with suspected genetic lipodystrophies. The treatment is directed towards the specific comorbidities and metabolic complications, and there is no treatment to reverse body fat loss. Metreleptin should be considered as the first-line therapy for metabolic complications in patients with generalized lipodystrophy and for prevention of comorbidities in children. Metformin and insulin therapy are the best options for treating hyperglycemia and fibrates and/or fish oil for hypertriglyceridemia.

Summary

Lipodystrophy should be suspected in lean and muscular subjects presenting with diabetes mellitus, hypertriglyceridemia, non-alcoholic fatty liver disease, polycystic ovarian syndrome, or amenorrhea. Diabetologists should be aware of lipodystrophies and consider genetic varieties as an important subtype of monogenic diabetes.

Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004;350(12):1220–34.PubMedCrossRef

Chiquette E, et al. Estimating the prevalence of generalized and partial lipodystrophy: findings and challenges. Diabetes Metab Syndr Obes. 2017;10:375–83.PubMedPubMedCentralCrossRef

Andre P, et al. Metabolic and cardiac phenotype characterization in 37 atypical Dunnigan patients with nonfarnesylated mutated prelamin A. Am Heart J. 2015;169(4):587–93.PubMedCrossRef

Gonzaga-Jauregui C, et al. Clinical and Molecular prevalence of lipodystrophy in an unascertained large clinical care cohort. Diabetes. 2020;69(2):249–58.PubMedCrossRef

Udler MS, et al. Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis. PLoS Med. 2018;15(9):e1002654.PubMedPubMedCentralCrossRef

Patni N, Garg A. Congenital generalized lipodystrophies--new insights into metabolic dysfunction. Nat Rev Endocrinol. 2015;11(9):522–34.PubMedPubMedCentralCrossRef

Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore). 2003;82(2):129–46.CrossRef

Dunnigan MG, et al. Familial lipoatrophic diabetes with dominant transmission. A new syndrome Q J Med. 1974;43(169):33–48.PubMed

Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore). 2004;83(1):18–34.CrossRef

10.

Agarwal AK, et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002;31(1):21–3.PubMedCrossRef

11.

Magre J, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001;28(4):365–70.PubMedCrossRef

12.

Kim CA, et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008;93(4):1129–34.PubMedCrossRef

13.

Hayashi YK, et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest. 2009;119(9):2623–33.PubMedPubMedCentralCrossRef

14.

Payne F, et al. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease. Proc Natl Acad Sci U S A. 2014;111(24):8901–6.PubMedPubMedCentralCrossRef

15.

Rubio-Cabezas O, et al. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med. 2009;1(5):280–7.PubMedPubMedCentralCrossRef

16.

Albert JS, et al. Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N Engl J Med. 2014;370(24):2307–15.PubMedPubMedCentralCrossRef

17.

Farhan SM, et al. A novel LIPE nonsense mutation found using exome sequencing in siblings with late-onset familial partial lipodystrophy. Can J Cardiol. 2014;30(12):1649–54.PubMedCrossRef

18.

Donadille B, et al. Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome. Orphanet J Rare Dis. 2013;8:106.PubMedPubMedCentralCrossRef

19.

Herbst KL, et al. Kobberling type of familial partial lipodystrophy: an underrecognized syndrome. Diabetes Care. 2003;26(6):1819–24.PubMedCrossRef

20.

Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000;9(1):109–12.PubMedCrossRef

21.

Shackleton S, et al. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet. 2000;24(2):153–6.PubMedCrossRef

22.

Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002;87(1):408–11.PubMed

23.

George S, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304(5675):1325–8.PubMedPubMedCentralCrossRef

24.

Gandotra S, et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med. 2011;364(8):740–8.PubMedPubMedCentralCrossRef

25.

Dyment DA, et al. Biallelic mutations at PPARG cause a congenital, generalized lipodystrophy similar to the Berardinelli-Seip syndrome. Eur J Med Genet. 2014;57(9):524–6.PubMedCrossRef

26.

Novelli G, et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet. 2002;71(2):426–31.PubMedPubMedCentralCrossRef

27.

Agarwal AK, et al. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet. 2003;12(16):1995–2001.PubMedCrossRef

28.

Lessel D, et al. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet. 2014;46(11):1239–44.PubMedPubMedCentralCrossRef

29.

Cabanillas R, et al. Nestor-Guillermo progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am J Med Genet A. 2011;155A(11):2617–25.PubMedCrossRef

30.

Eriksson M, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423(6937):293–8.PubMedCrossRef

31.

De Sandre-Giovannoli A, et al. Lamin a truncation in Hutchinson-Gilford progeria. Science. 2003;300(5628):2055.PubMedCrossRef

32.

Graul-Neumann LM, et al. Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene. Am J Med Genet A. 2010;152A(11):2749–55.PubMedCrossRef

33.

Garg A, et al. Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome. Am J Med Genet A. 2015;167A(8):1796–806.PubMedPubMedCentralCrossRef

34.

Weedon MN, et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet. 2013;45(8):947–50.PubMedPubMedCentralCrossRef

35.

Masotti A, et al. Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6. Am J Hum Genet. 2015;96(2):295–300.PubMedPubMedCentralCrossRef

36.

Thauvin-Robinet C, et al. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet. 2013;93(1):141–9.PubMedPubMedCentralCrossRef

37.

Agarwal AK, et al. PSMB8 encoding the beta5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet. 2010;87(6):866–72.PubMedPubMedCentralCrossRef

38.

Corvillo F, et al. Autoantibodies Against Perilipin 1 as a Cause of Acquired Generalized Lipodystrophy. Front Immunol. 2018;9:2142.PubMedPubMedCentralCrossRef

39.

Garg A. Lipodystrophies. Am J Med. 2000;108(2):143–52.PubMedCrossRef

40.

Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96(11):3313–25.PubMedPubMedCentralCrossRef

41.

Nolis T. Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies. J Hum Genet. 2014;59(1):16–23.PubMedCrossRef

42.

Hussain I, Patni N, Garg A. Lipodystrophies, dyslipidaemias and atherosclerotic cardiovascular disease. Pathology. 2019;51(2):202–12.PubMedCrossRef

43.

Pardini VC, et al. Leptin levels, beta-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatrophic diabetes. J Clin Endocrinol Metab. 1998;83:503–8.PubMed

44.

Seip M, Trygstad O. Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr Suppl. 1996;413:2–28.PubMedCrossRef

45.

Westvik J. Radiological features in generalized lipodystrophy. Acta Paediatr Suppl. 1996;413:44–51.PubMedCrossRef

46.

Brunzell JD, Shankle SW, Bethune JE. Congenital generalized lipodystrophy accompanied by cystic angiomatosis. Ann Intern Med. 1968;69(3):501–16.PubMedCrossRef

47.

Fleckenstein JL, et al. The skeleton in congenital, generalized lipodystrophy: evaluation using whole-body radiographic surveys, magnetic resonance imaging and technetium-99m bone scintigraphy. Skelet Radiol. 1992;21(6):381–6.CrossRef

48.

Chandalia M, et al. Postmortem findings in congenital generalized lipodystrophy. J Clin Endocrinol Metab. 1995;80(10):3077–81.PubMed

49.

Anonymous. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 1-1975. N Engl J Med. 1975;292(1):35–41.CrossRef

50.

Garg A, et al. Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy. J Clin Endocrinol Metab. 1992;75(2):358–61.PubMed

51.

Haque WA, et al. Serum adiponectin and leptin levels in patients with lipodystrophies. J Clin Endocrinol Metab. 2002;87(5):2395–8.PubMedCrossRef

52.

Antuna-Puente B, et al. Higher adiponectin levels in patients with Berardinelli-Seip congenital lipodystrophy due to seipin as compared with 1-acylglycerol-3-phosphate-o-acyltransferase-2 deficiency. J Clin Endocrinol Metab. 2010;95(3):1463–8.PubMedCrossRef

53.

Van Maldergem L, et al. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet. 2002;39(10):722–33.PubMedPubMedCentralCrossRef

54.

Agarwal AK, et al. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab. 2003;88(10):4840–7.PubMedCrossRef

55.

Upreti V, et al. An unusual cause of delayed puberty: Berardinelli- Seip syndrome. J Pediatr Endocrinol Metab. 2012;25(11-12):1157–60.PubMedCrossRef

56.

Maguire M, et al. Pregnancy in a woman with congenital generalized lipodystrophy: leptin's vital role in reproduction. Obstet Gynecol. 2012;119(2 Pt 2):452–5.PubMedPubMedCentralCrossRef

57.

Jiang M, et al. Lack of testicular seipin causes teratozoospermia syndrome in men. Proc Natl Acad Sci U S A. 2014;111(19):7054–9.PubMedPubMedCentralCrossRef

58.

Ebihara C, et al. Seipin is necessary for normal brain development and spermatogenesis in addition to adipogenesis. Hum Mol Genet. 2015;24(15):4238–49.PubMedCrossRef

59.

Karhan AN, et al. Biallelic CAV1 null variants induce congenital generalized lipodystrophy with achalasia. Eur J Endocrinol. 2021;185(6):841–54.PubMedCrossRef

60.

Cao H, et al. Heterozygous CAV1 frameshift mutations (MIM 601047) in patients with atypical partial lipodystrophy and hypertriglyceridemia. Lipids Health Dis. 2008;7:3.PubMedPubMedCentralCrossRef

61.

Patni N, Hegele RA, Garg A. Caveolar dysfunction and lipodystrophies. Eur J Endocrinol. 2022;186(3):C1–4.PubMedCrossRef

62.

Garg A. Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 2000;85(5):1776–82.PubMed

63.

Patni N, et al. Regional body fat changes and metabolic complications in children with Dunnigan lipodystrophy-causing LMNA Variants. J Clin Endocrinol Metab. 2018;104(4):1099–108.PubMedCentralCrossRef

64.

Garg A, Peshock RM, Fleckenstein JL. Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 1999;84(1):170–4.PubMed

65.

Haque WA, et al. Risk factors for diabetes in familial partial lipodystrophy, Dunnigan variety. Diabetes Care. 2003;26(5):1350–5.PubMedCrossRef

66.

Hegele RA. Premature atherosclerosis associated with monogenic insulin resistance. Circulation. 2001;103(18):2225–9.PubMedCrossRef

67.

Patni N, et al. A novel syndrome of generalized lipodystrophy associated with pilocytic astrocytoma. J Clin Endocrinol Metab. 2015;100(10):3603–6.PubMedPubMedCentralCrossRef

68.

Haddad N, et al. Acquired generalized lipodystrophy under immune checkpoint inhibition. Br J Dermatol. 2020;182(2):477–80.PubMedCrossRef

69.

Jehl A, et al. Acquired generalized lipodystrophy: a new cause of anti-PD-1 immune-related diabetes. Diabetes Care. 2019;42(10):2008–10.PubMedCrossRef

70.

Savage DB, et al. Complement abnormalities in acquired lipodystrophy revisited. J Clin Endocrinol Metab. 2009;94(1):10–6.PubMedCrossRef

71.

Park JY, et al. Type 1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of long-term leptin therapy. J Clin Endocrinol Metab. 2008;93(1):26–31.PubMedCrossRef

72.

Kumar R, et al. Acquired generalised lipodystrophy and type 1 diabetes mellitus in a child: a rare and implacable association. BMJ Case Rep. 2018;2018:bcr-2018.

73.

Srinivasan S, et al. A polygenic lipodystrophy genetic risk score characterizes risk independent of BMI in the diabetes prevention program. J Endocr Soc. 2019;3(9):1663–77.PubMedPubMedCentralCrossRef

74.

Handelsman Y, et al. The clinical approach to the detection of lipodystrophy - an AACE consensus statement. Endocr Pract. 2013;19(1):107–16.PubMedPubMedCentralCrossRef

75.

Brown RJ, et al. The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline. J Clin Endocrinol Metab. 2016;101(12):4500–11.PubMedPubMedCentralCrossRef

76.

Jackson AS, Pollock ML. Generalized equations for predicting body density of men. Br J Nutr. 1978;40(3):497–504.PubMedCrossRef

77.

Jackson AS, Pollock ML, Ward A. Generalized equations for predicting body density of women. Med Sci Sports Exerc. 1980;12(3):175–81.PubMedCrossRef

78.

Dezenberg CV, et al. Predicting body composition from anthropometry in pre-adolescent children. Int J Obes Relat Metab Disord. 1999;23(3):253–9.PubMedCrossRef

79.

Vasandani C, et al. Diagnostic value of anthropometric measurements for familial partial lipodystrophy, Dunnigan Variety. J Clin Endocrinol Metab. 2020;105(7)2132-2141.PubMedCentralCrossRef

80.

Javor ED, et al. Proteinuric nephropathy in acquired and congenital generalized lipodystrophy: baseline characteristics and course during recombinant leptin therapy. J Clin Endocrinol Metab. 2004;89(7):3199–207.PubMedCrossRef

81.

Akinci B, et al. Renal complications of lipodystrophy: a closer look at the natural history of kidney disease. Clin Endocrinol. 2018;89(1):65–75.CrossRef

82.

Musso C, et al. Spectrum of renal diseases associated with extreme forms of insulin resistance. Clin J Am Soc Nephrol. 2006;1(4):616–22.PubMedCrossRef

83.

Oral EA, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346(8):570–8.PubMedCrossRef

84.

Beltrand J, et al. Metabolic correction induced by leptin replacement treatment in young children with Berardinelli-Seip congenital lipoatrophy. Pediatrics. 2007;120(2):e291–6.PubMedCrossRef

85.

Simha V, et al. Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. J Clin Endocrinol Metab. 2012;97(3):785–92.PubMedCrossRef

86.

Diker-Cohen T, et al. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab. 2015;100(5):1802–10.PubMedPubMedCentralCrossRef

87.

Luedtke A, et al. Thiazolidinedione response in familial lipodystrophy patients with LMNA mutations: a case series. Horm Metab Res. 2012;44(4):306–11.PubMedCrossRef

88.

Simha V, Rao S, Garg A. Prolonged thiazolidinedione therapy does not reverse fat loss in patients with familial partial lipodystrophy, Dunnigan variety. Diabetes Obes Metab. 2008;10(12):1275–6.PubMedCrossRef

89.

Banning F, et al. Insulin secretory defect in familial partial lipodystrophy Type 2 and successful long-term treatment with a glucagon-like peptide 1 receptor agonist. Diabet Med. 2017;34(12):1792–4.PubMedCrossRef

90.

Oliveira J, et al. Glucagon-like peptide-1 analogues - an efficient therapeutic option for the severe insulin resistance of lipodystrophic syndromes: two case reports. J Med Case Rep. 2017;11(1):12.PubMedPubMedCentralCrossRef

91.

Melvin A, et al. Roux-en-Y gastric bypass surgery in the management of familial partial lipodystrophy type 1. J Clin Endocrinol Metab. 2017;102(10):3616–20.PubMedPubMedCentralCrossRef

92.

Grundfest-Broniatowski S, et al. Successful treatment of an unusual case of FPLD2: The role of Roux-en-Y gastric bypass-case report and literature review. J Gastrointest Surg. 2017;21(4):739–43.PubMedCrossRef

93.

Kozusko K, et al. Clinical and molecular characterization of a novel PLIN1 frameshift mutation identified in patients with familial partial lipodystrophy. Diabetes. 2015;64(1):299–310.PubMedCrossRef

94.

Ciudin A, et al. Successful treatment for the Dunnigan-type familial partial lipodystrophy with Roux-en-Y gastric bypass. Clin Endocrinol. 2011;75(3):403–4.CrossRef

95.

McGrath NM, Krishna G. Gastric bypass for insulin resistance due to lipodystrophy. Obes Surg. 2006;16(11):1542–4.PubMedCrossRef

96.

Utzschneider KM, Trence DL. Effectiveness of gastric bypass surgery in a patient with familial partial lipodystrophy. Diabetes Care. 2006;29(6):1380–2.PubMedCrossRef

97.

Mandel-Brehm C, et al. Autoantibodies to perilipin-1 define a subset of acquired generalized lipodystrophy. Diabetes. 2022; db211172 (online ahead of print).

Titel: Lipodystrophy for the Diabetologist—What to Look For
verfasst von: Nivedita Patni
Abhimanyu Garg
Publikationsdatum: 11.07.2022
Verlag: Springer US
Erschienen in: Current Diabetes Reports / Ausgabe 9/2022
Print ISSN: 1534-4827
Elektronische ISSN: 1539-0829
DOI: https://doi.org/10.1007/s11892-022-01485-w

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