Narrative Review: Ketosis-Prone Type 2 Diabetes Mellitus
Publication: Annals of Internal Medicine
Volume 144, Number 5
Abstract
Several investigators have reported that more than half of African-American persons with new diagnoses of diabetic ketoacidosis have clinical, metabolic, and immunologic features of type 2 diabetes during follow-up. These patients are usually obese, have a strong family history of diabetes, have a low prevalence of autoimmune markers, and lack a genetic association with HLA. Their initial presentation is acute, with a few days to weeks of polyuria, polydipsia, and weight loss and lack of a precipitating cause of metabolic decompensation. At presentation, they have markedly impaired insulin secretion and insulin action, but intensified diabetic management results in significant improvement in β-cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within a few months of follow-up. On discontinuation of insulin therapy, the period of near-normoglycemic remission may last for a few months to several years. The absence of autoimmune markers and the presence of measurable insulin secretion have proven useful in predicting near-normoglycemic remission and long-term insulin dependence in adult patients with a history of diabetic ketoacidosis. This clinical presentation is commonly reported in African and African-American persons but is also observed in Hispanic persons and those from other minority ethnic groups. The underlying mechanisms for β-cell dysfunction in ketosis-prone type 2 diabetes are not known; however, preliminary evidence suggests an increased susceptibility to glucose desensitization.
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References
1.
Winter WE, Maclaren NK, Riley WJ, Clarke DW, Kappy MS, Spillar RP. Maturity-onset diabetes of youth in black Americans. N Engl J Med. 1987;316:285-91. [PMID: 3543673]
2.
Umpierrez GE, Casals MM, Gebhart SP, Mixon PS, Clark WS, Phillips LS. Diabetic ketoacidosis in obese African-Americans. Diabetes. 1995;44:790-5. [PMID: 7789647]
3.
Umpierrez GE, Woo W, Hagopian WA, Isaacs SD, Palmer JP, Gaur LK, et al. Immunogenetic analysis suggests different pathogenesis for obese and lean African-Americans with diabetic ketoacidosis. Diabetes Care. 1999;22:1517-23. [PMID: 10480519]
4.
Banerji MA, Chaiken RL, Huey H, Tuomi T, Norin AJ, Mackay IR, et al. GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of human leukocyte antigen DR3 and DR4. Flatbush diabetes. Diabetes. 1994;43:741-5. [PMID: 8194658]
5.
McFarlane SI, Chaiken RL, Hirsch S, Harrington P, Lebovitz HE, Banerji MA. Near-normoglycaemic remission in African-Americans with Type 2 diabetes mellitus is associated with recovery of beta cell function. Diabet Med. 2001;18:10-6. [PMID: 11168335]
6.
Mauvais-Jarvis F, Sobngwi E, Porcher R, Riveline JP, Kevorkian JP, Vaisse C, et al. Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin: clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance. Diabetes. 2004;53:645-53. [PMID: 14988248]
7.
Sobngwi E, Vexiau P, Levy V, Lepage V, Mauvais-Jarvis F, Leblanc H, et al. Metabolic and immunogenetic prediction of long-term insulin remission in African patients with atypical diabetes. Diabet Med. 2002;19:832-5. [PMID: 12358870]
8.
Banerji MA, Chaiken RL, Lebovitz HE. Long-term normoglycemic remission in black newly diagnosed NIDDM subjects. Diabetes. 1996;45:337-41. [PMID: 8593939]
9.
Wilson C, Krakoff J, Gohdes D. Ketoacidosis in Apache Indians with non–insulin-dependent diabetes mellitus. Arch Intern Med. 1997;157:2098-100. [PMID: 9382666]
10.
Aizawa T, Katakura M, Taguchi N, Kobayashi H, Aoyagi E, Hashizume K, et al. Ketoacidosis-onset noninsulin dependent diabetes in Japanese subjects. Am J Med Sci. 1995;310:198-201. [PMID: 7485223]
11.
Nagasaka S, Ishikawa S, Itabashi N, Rokkaku K, Saito T. Ketoacidosis-onset type 2 diabetes in Japanese. Association with the widespread distribution of soft drinks and vending machines [Letter]. Diabetes Care. 1998;21:1376-8. [PMID: 9702460]
12.
Tan KC, Mackay IR, Zimmet PZ, Hawkins BR, Lam KS. Metabolic and immunologic features of Chinese patients with atypical diabetes mellitus. Diabetes Care. 2000;23:335-8. [PMID: 10868861]
13.
Yan SH, Sheu WH, Song YM, Tseng LN. The occurrence of diabetic ketoacidosis in adults. Intern Med. 2000;39:10-4. [PMID: 10674841]
14.
Hsin Yu E, Guo HR, Wu TJ. Factors associated with discontinuing insulin therapy after diabetic ketoacidosis in adult diabetic patients. Diabet Med. 2001;18:895-9. [PMID: 11703434]
15.
Maldonado M, Hampe CS, Gaur LK, D'Amico S, Iyer D, Hammerle LP, et al. Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes. J Clin Endocrinol Metab. 2003;88:5090-8. [PMID: 14602731]
16.
Piñero-Piloña A, Litonjua P, Aviles-Santa L, Raskin P. Idiopathic type 1 diabetes in Dallas, Texas: a 5-year experience. Diabetes Care. 2001;24:1014-8. [PMID: 11375362]
17.
Maldonado MR, Otiniano ME, Lee R, Rodriguez L, Balasubramanyam A. Characteristics of ketosis-prone diabetes in a multiethnic indigent community. Ethn Dis. 2004;14:243-9. [PMID: 15132210]
18.
Sobngwi E, Gautier JF. Adult-onset idiopathic Type I or ketosis-prone Type II diabetes: evidence to revisit diabetes classification. Diabetologia. 2002;45(2):283-5.
19.
Sobngwi E, Mauvais-Jarvis F, Vexiau P, Mbanya JC, Gautier JF. Diabetes in Africans. Part 2: Ketosis-prone atypical diabetes mellitus. Diabetes Metab. 2002;28:5-12. [PMID: 11938022]
20.
Piñero-Piloña A, Raskin P. Idiopathic Type 1 diabetes. J Diabetes Complications. 2001;15:328-35. [PMID: 11711327]
21.
Dodu SR. Diabetes in the tropics. Br Med J. 1967;2:747-50. [PMID: 5338030]
22.
Oli JM. Remittant diabetes mellitus in Nigeria. Trop Geogr Med. 1978;30:57-62. [PMID: 675828]
23.
Adadevoh BK. “Temporary diabetes” in adult Nigerians. Trans R Soc Trop Med Hyg. 1968;62:528-30. [PMID: 5671539]
24.
Ducorps M, Ndong W, Jupkwo B, Belmejdoub G, Thiolet C, Mayaudon H, et al. [Diabetes in Cameroon. Classification difficulties in Africa]. Med Trop (Mars). 1996;56:264-70. [PMID: 9026594]
25.
Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE. Hyperglycemic crises in urban blacks. Arch Intern Med. 1997;157:669-75. [PMID: 9080921]
26.
Banerji MA, Lebovitz HE. Remission in non–insulin-dependent diabetes mellitus: clinical characteristics of remission and relapse in black patients. Medicine (Baltimore). 1990;69:176-85. [PMID: 2345523]
27.
Balasubramanyam A, Zern JW, Hyman DJ, Pavlik V. New profiles of diabetic ketoacidosis: type 1 vs type 2 diabetes and the effect of ethnicity. Arch Intern Med. 1999;159:2317-22. [PMID: 10547172]
28.
Kitabchi AE. Ketosis-prone diabetes—a new subgroup of patients with atypical type 1 and type 2 diabetes? [Editorial]. J Clin Endocrinol Metab. 2003;88:5087-9. [PMID: 14602730]
29.
Ellemann K, Soerensen JN, Pedersen L, Edsberg B, Andersen OO. Epidemiology and treatment of diabetic ketoacidosis in a community population. Diabetes Care. 1984;7:528-32. [PMID: 6439530]
30.
Ahrén B, Corrigan CB. Intermittent need for insulin in a subgroup of diabetic patients in Tanzania. Diabet Med. 1985;2:262-4. [PMID: 2951079]
31.
Yamada K, Nonaka K. Diabetic ketoacidosis in young obese Japanese men [Letter]. Diabetes Care. 1996;19:671. [PMID: 8725872]
32.
Faich GA, Fishbein HA, Ellis SE. The epidemiology of diabetic acidosis: a population-based study. Am J Epidemiol. 1983;117:551-8. [PMID: 6405612]
33.
Umpierrez GE, Clark WS, Steen MT. Sulfonylurea treatment prevents recurrence of hyperglycemia in obese African-American patients with a history of hyperglycemic crises. Diabetes Care. 1997;20:479-83. [PMID: 9096964]
34.
Schiel R, Müller UA. GAD autoantibodies in a selection-free population of insulin-treated diabetic patients: indicator of a high prevalence of LADA? Diabetes Res Clin Pract. 2000;49:33-40. [PMID: 10808061]
35.
Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non–insulin-dependent onset of disease. Diabetes. 1993;42:359-62. [PMID: 8425674]
36.
Zimmet P, Turner R, McCarty D, Rowley M, Mackay I. Crucial points at diagnosis. Type 2 diabetes or slow type 1 diabetes. Diabetes Care. 1999;22 Suppl 2 B59-64. [PMID: 10097901]
37.
Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes. 1999;48:150-7. [PMID: 9892237]
38.
Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care. 2001;24:1460-7. [PMID: 11473087]
39.
Groop LC, Bottazzo GF, Doniach D. Islet cell antibodies identify latent type I diabetes in patients aged 35-75 years at diagnosis. Diabetes. 1986;35:237-41. [PMID: 3510930]
40.
Hagopian WA, Karlsen AE, Gottsäter A, Landin-Olsson M, Grubin CE, Sundkvist G, et al. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J Clin Invest. 1993;91:368-74. [PMID: 8423232]
41.
Kobayashi T. Subtype of insulin-dependent diabetes mellitus (IDDM) in Japan: slowly progressive IDDM—the clinical characteristics and pathogenesis of the syndrome. Diabetes Res Clin Pract. 1994;24 Suppl S95-9. [PMID: 7859641]
42.
Borg H, Gottsäter A, Fernlund P, Sundkvist G. A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes. 2002;51:1754-62. [PMID: 12031962]
43.
Kobayashi T, Itoh T, Kosaka K, Sato K, Tsuji K. Time course of islet cell antibodies and beta-cell function in non–insulin-dependent stage of type I diabetes. Diabetes. 1987;36:510-7. [PMID: 3545950]
44.
Kobayashi T, Nakanishi K, Murase T, Kosaka K. Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes. 1996;45:622-6. [PMID: 8621013]
45.
Boutin P, Gresh L, Cisse A, Hara M, Bell G, Babu S, et al. Missense mutation Gly574Ser in the transcription factor HNF-1alpha is a marker of atypical diabetes mellitus in African-American children [Letter]. Diabetologia. 1999;42:380-1. [PMID: 10096793]
46.
Mauvais-Jarvis F, Boudou P, Sobngwi E, Riveline JP, Kevorkian JP, Villette JM, et al. The polymorphism Gly574Ser in the transcription factor HNF-1alpha is not a marker of adult-onset ketosis-prone atypical diabetes in Afro-Caribbean patients [Letter]. Diabetologia. 2003;46:728-9 [PMID: 12743700].
47.
Shimajiri Y, Sanke T, Furuta H, Hanabusa T, Nakagawa T, Fujitani Y, et al. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese. Diabetes. 2001;50:2864-9. [PMID: 11723072]
48.
Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature. 1997;386:399-402. [PMID: 9121556]
49.
Mauvais-Jarvis F, Smith SB, Le May C, Leal SM, Gautier JF, Molokhia M, et al. PAX4 gene variations predispose to ketosis-prone diabetes. Hum Mol Genet. 2004;13:3151-9. [PMID: 15509590]
50.
Maldonado MR, Otiniano ME, Lee R, Rodriguez L, Balasubramanyam A. Ethnic differences in beta-cell functional reserve and clinical features in patients with ketosis-prone diabetes [Letter]. Diabetes Care. 2003;26:2469. [PMID: 12882882]
51.
Rasouli N, Elbein SC. Improved glycemic control in subjects with atypical diabetes results from restored insulin secretion, but not improved insulin sensitivity. J Clin Endocrinol Metab. 2004;89:6331-5. [PMID: 15579799]
52.
Pitteloud N, Philippe J. Characteristics of Caucasian type 2 diabetic patients during ketoacidosis and at follow-up. Schweiz Med Wochenschr. 2000;130:576-82. [PMID: 10842773]
53.
Gosmanov AR, Umpierrez GE, Cuervo R, Karabell AH, Thomason DB. Beta cell function and muscle insulin signaling in obese African Americans with atypical diabetes. Diabetes. 2003;52 Suppl 1 A287.
54.
Stride A, Hattersley AT. Different genes, different diabetes: lessons from maturity-onset diabetes of the young. Ann Med. 2002;34:207-16. [PMID: 12173691]
55.
Leahy JL, Bonner-Weir S, Weir GC. Beta-cell dysfunction induced by chronic hyperglycemia. Current ideas on mechanism of impaired glucose-induced insulin secretion. Diabetes Care. 1992;15:442-55. [PMID: 1559411]
56.
Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care. 1990;13:610-30. [PMID: 2192847]
57.
Yki-Järvinen H. Glucose toxicity. Endocr Rev. 1992;13:415-31. [PMID: 1425483]
58.
Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86:4047-58. [PMID: 11549624]
59.
Porte D Jr, Kahn SE. Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes. 2001;50 Suppl 1 S160-3. [PMID: 11272181]
60.
Volinic JL, Lee JH, Eto K, Kaur V, Thomas MK. Overexpression of the coactivator bridge-1 results in insulin deficiency and diabetes. Mol Endocrinol. 2006;20:167-82. [PMID: 16099819]
61.
Melloul D, Marshak S, Cerasi E. Regulation of pdx-1 gene expression. Diabetes. 2002;51 Suppl 3 S320-5. [PMID: 12475770]
62.
Harmon JS, Gleason CE, Tanaka Y, Oseid EA, Hunter-Berger KK, Robertson RP. In vivo prevention of hyperglycemia also prevents glucotoxic effects on PDX-1 and insulin gene expression. Diabetes. 1999;48:1995-2000. [PMID: 10512364]
63.
McKinnon CM, Docherty K. Pancreatic duodenal homeobox-1, PDX-1, a major regulator of beta cell identity and function. Diabetologia. 2001;44:1203-14. [PMID: 11692168]
64.
Robertson RP, Olson LK, Zhang HJ. Differentiating glucose toxicity from glucose desensitization: a new message from the insulin gene. Diabetes. 1994;43:1085-9. [PMID: 8070607]
65.
Osman AA, Pendergrass M, Koval J, Maezono K, Cusi K, Pratipanawatr T, et al. Regulation of MAP kinase pathway activity in vivo in human skeletal muscle. Am J Physiol Endocrinol Metab. 2000;278:992-9. [PMID: 10827000]
66.
Cefalu WT. Insulin resistance: cellular and clinical concepts. Exp Biol Med (Maywood). 2001;226:13-26. [PMID: 11368233]
67.
Gosmanov AR, Umpierrez GE, Karabell AH, Cuervo R, Thomason DB. Impaired expression and insulin-stimulated phosphorylation of Akt-2 in muscle of obese patients with atypical diabetes. Am J Physiol Endocrinol Metab. 2004;287:8-E15. [PMID: 15010337]
68.
Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, et al. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care. 2003;26 Suppl 1 S109-17. [PMID: 12502633]
69.
Aguilera E, Casamitjana R, Ercilla G, Oriola J, Gomis R, Conget I. Adult-onset atypical (type 1) diabetes: additional insights and differences with type 1A diabetes in a European Mediterranean population. Diabetes Care. 2004;27:1108-14. [PMID: 15111529]
70.
Fajans SS. Scope and heterogeneous nature of MODY. Diabetes Care. 1990;13:49-64. [PMID: 2404717]
71.
Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med. 2001;345:971-80. [PMID: 11575290]
72.
Winter WE, Silverstein JH. Molecular and genetic bases for maturity onset diabetes of youth. Curr Opin Pediatr. 2000;12:388-93. [PMID: 10943822]
73.
Froguel P, Velho G. Molecular genetics of maturity-onset diabetes of the young. Trends Endocrinol Metab. 1999;10:142-146. [PMID: 10322408]
74.
Frayling TM, Evans JC, Bulman MP, Pearson E, Allen L, Owen K, et al. beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes. 2001;50 Suppl 1 S94-100. [PMID: 11272211]
75.
Barman KK, Premalatha G, Mohan V. Tropical chronic pancreatitis. Postgrad Med J. 2003;79:606-15. [PMID: 14654569]
76.
Mohan V, Premalatha G, Pitchumoni CS. Tropical chronic pancreatitis: an update. J Clin Gastroenterol. 2003;36:337-46. [PMID: 12642742]
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Annals of Internal Medicine
Volume 144 • Number 5 • 7 March 2006
Pages: 350 - 357
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Published online: 7 March 2006
Published in issue: 7 March 2006
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© 2006 American College of Physicians.
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Narrative Review: Ketosis-Prone Type 2 Diabetes Mellitus. Ann Intern Med.2006;144:350-357. [Epub 7 March 2006]. doi:10.7326/0003-4819-144-5-200603070-00011
Narrative Review: Ketosis-Prone Type 2 Diabetes Mellitus. Ann Intern Med.2006;144:350-357. [Epub 7 March 2006]. doi:10.7326/0003-4819-144-5-200603070-00011
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