SNOMEDCT: 890171006; ICD10CM: E10; DO: 1837;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q32.1 | {Diabetes mellitus, ketosis-prone, susceptibility to} | 612227 | Autosomal dominant; Autosomal recessive | 3 | PAX4 | 167413 |
A number sign (#) is used with this entry because of evidence that susceptibility to ketosis-prone diabetes mellitus is conferred by homozygous mutation in the PAX4 gene (167413) on chromosome 7q32. One patient has been found to be heterozygous for mutation in PAX4.
In addition to classic type 1 (see 222100) and type 2 (see 125853) diabetes mellitus, atypical presentations are seen, particularly in populations of African ancestry. Ketosis-prone diabetes, the most common atypical form, is characterized by an acute initial presentation with severe hyperglycemia and ketosis, as seen in classic type 1 diabetes, but after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. Metabolic studies show a markedly blunted insulin secretory response to glucose, partially reversible with the improvement of blood glucose control. Variable levels of insulin resistance are observed, especially in obese patients. Pancreatic beta-cell autoimmunity is a rare finding, and association with type 1 susceptibility HLA alleles is variable (Sobngwi et al., 2002).
Maldonado et al. (2003) studied 103 patients with diabetic ketoacidosis (DKA), classifying them into 4 groups according to the presence or absence of autoimmune markers for type 1 diabetes (A+ or A-) and the presence or absence of beta-cell functional reserve (beta+ or beta-). There were 18 patients in the A+beta- group, 23 in the A-beta- group, 11 in the A+beta+ group, and 51 in the A-beta+ group. Collectively, the 2 beta- groups differed from the 2 beta+ groups in earlier onset and longer duration of diabetes, lower body mass index (BMI), less glycemic improvement, and persistent insulin requirement. HLA class II genotyping showed that the A-beta- group differed from the A+beta- group in having significantly lower frequencies of 2 alleles strongly associated with autoimmune type 1 diabetes susceptibility, DQA*03 (see 146880) and DQB1*02 (see 604305). Similarly, the A-beta+ group differed from the A+beta+ group in having a lower frequency of DQB1*02. Maldonado et al. (2003) concluded that ketosis-prone diabetes comprises at least 4 etiologically distinct syndromes separable by autoantibody status, HLA genotype, and beta-cell functional reserve.
Umpierrez et al. (2006) reviewed the diagnostic and clinical features of patients with ketosis-prone diabetes mellitus from 9 published studies. The authors stated that more than half of African Americans with a new diagnosis of diabetic ketoacidosis have clinical, metabolic, and immunologic features of type 2 diabetes on follow-up, and that this clinical presentation is also observed in Hispanic individuals and those from other minority ethnic groups. The 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. The onset of disease is acute, with a few days to weeks of polyuria, polydipsia, and weight loss, and there is no precipitating cause for the metabolic decompensation. At presentation, patients have markedly impaired insulin secretion and insulin action, but intense diabetic management results in significant improvement in beta-cell function and insulin sensitivity, sufficient to allow discontinuation of insulin therapy within a few months of follow-up; the period of near-normoglycemic remission may last for a few months to several years.
Balasubramanyam et al. (2008) reviewed the syndromes of ketosis-prone diabetes mellitus with regard to the natural history, pathophysiology, and treatment of the subgroups of KPD.
Because of the importance of sustained preservation of beta-cell function to the clinical outcomes of patients with KPD, Balasubramanyam et al. (2006) analyzed clinical, biochemical, and serologic data from 294 consecutive patients presenting with diabetic ketoacidosis (DKA) and classified them according to 4 schemes (using American Diabetes Association (ADA) criteria, modified ADA criteria, a BMI-based scheme, and the 'AB' system), then tested the ability of each classification scheme to predict preserved or absent beta-cell function 12 months after the initial episode of DKA. The 'AB' classification scheme was the most accurate overall, with a sensitivity and specificity of 99.4% and 95.9%, respectively.
Sobngwi et al. (2002) reviewed published reports of ketosis-prone atypical diabetes and estimated the prevalence of atypical diabetes to be 0.1 to 0.8% in Africa and 1.2 to 1.6% in the Caribbean. The authors suggested that the prevalence might be higher in obese African migrants living in the United States and Europe.
Mauvais-Jarvis et al. (2004) screened 101 unrelated west African patients with KPD for mutations in the PAX4 gene and identified a variant (R133W; 167413.0002), specific to the population of west African ancestry, which predisposes to KPD under a recessive model. Homozygous R133W PAX4 carriers were found in 4% of subjects with KPD, but not in 355 controls or 147 subjects with common type 2 or type 1 diabetes. In addition, 1 Cameroonian KPD patient was heterozygous for a rare PAX4 variant (R37W; 167413.0003) that was not found in 255 controls of west African ancestry and that showed a more severe biochemical phenotype than R133W. Clinical investigation of the homozygous R133W carriers and the R37W carrier demonstrated a more severe alteration in insulin secretory reserve during a glucagon-stimulation test compared to other KPD subjects. Mauvais-Jarvis et al. (2004) concluded that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggested that KPD, like maturity-onset diabetes of the young (MODY; see 606391), is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes.
In 185 adults presenting with diabetic ketoacidosis who were followed for a mean of 5.5 years with measurements of autoantibodies, beta-cell functional reserve, insulin sensitivity, and insulin requirements, Nalini et al. (2008) analyzed HLA class II alleles at the DQA1, DQB1, and DRB1 (142857) loci. Susceptibility alleles were more frequent in the 2 A+ than in the 2 A- KPD subgroups (p less than 0.0001); in the latter, the frequency was no greater than in controls, except for DQB1*0302. Susceptibility alleles differentiated the 2 clinically similar B- subgroups, being more frequent in A+B- than in A-B- KPD (p less than 0.01). Resistance alleles were more frequent in the 2 B+ than in the 2 B- KPD subgroups (p less than 0.01). The frequencies of certain susceptibility (e.g., DQB1*02) and resistance (DQB1*0602) alleles were higher in African American A-B+ KPD patients than in African American controls. DQB1*0302 was more frequent in all KPD subgroups compared to controls. Nalini et al. (2008) concluded that HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes help specify the 4 KPD subgroups and may influence long-term beta-cell functional reserve.
Ketosis-prone diabetes has been classified by the American Diabetes Association as 'idiopathic type 1 diabetes' or 'type 1b' (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1997, 2003); American Diabetes Association, 2008).
Kitabchi (2003), commenting on Maldonado et al. (2003), noted that according to the consensus report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003), the A+B- group would consist of type 1A diabetes, whereas the A-B- group would be considered type 1B (idiopathic); and that the B+ groups, in which the recurrence of DKA is rare and patients can often be treated with diet or oral agents, have been described globally by various names, including 'Flatbush diabetes,' 'obese DKA,' 'type 2 diabetes mellitus with DKA,' 'newly onset with DKA,' 'idiopathic type 1 diabetes mellitus,' 'atypical diabetes mellitus,' 'type 3 KPD,' and 'KPD B+.'
Umpierrez (2006), commenting on Balasubramanyam et al. (2006), stated that the ADA/WHO classification should be revised to reclassify patients with 'idiopathic' or 'type 1B' diabetes as having 'ketosis-prone type 2 diabetes.'
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 31 (suppl. 1): S55-S60, 2008. [PubMed: 18165338] [Full Text: https://doi.org/10.2337/dc08-S055]
Balasubramanyam, A., Garza, G., Rodriguez, L., Hampe, C. S., Gaur, L., Lernmark, A., Maldonado, M. R. Accuracy and predictive value of classification schemes for ketosis-prone diabetes. Diabetes Care 29: 2575-2579, 2006. [PubMed: 17130187] [Full Text: https://doi.org/10.2337/dc06-0749]
Balasubramanyam, A., Nalini, R., Hampe, C. S., Maldonado, M. Syndromes of ketosis-prone diabetes mellitus.. Endocr. Rev. 29: 292-302, 2008. [PubMed: 18292467] [Full Text: https://doi.org/10.1210/er.2007-0026]
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20 (suppl. 1): 1183-1197, 1997. [PubMed: 9203460] [Full Text: https://doi.org/10.2337/diacare.20.7.1183]
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26 (suppl. 1): S5-S20, 2003. [PubMed: 12502614] [Full Text: https://doi.org/10.2337/diacare.26.2007.s5]
Kitabchi, A. E. Ketosis-prone diabetes--a new subgroup of patients with atypical type 1 and type 2 diabetes? (Editorial) J. Clin. Endocr. Metab. 88: 5087-5089, 2003. [PubMed: 14602730] [Full Text: https://doi.org/10.1210/jc.2003-031656]
Maldonado, M., Hampe, C. S., Gaur, L. K., D'Amico, S., Iyer, D., Hammerle, L. P., Bolgiano, D., Rodriguez, L., Rajan, A., Lernmark, A., Balasubramanyam, A. Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes. J. Clin. Endocr. Metab. 88: 5090-5098, 2003. [PubMed: 14602731] [Full Text: https://doi.org/10.1210/jc.2003-030180]
Mauvais-Jarvis, F., Smith, S. B., Le May, C., Leal, S. M., Gautier, J.-F., Molokhia, M., Riveline, J.-P., Rajan, A. S., Kevorkian, J.-P., Zhang, S., Vexiau, P., German, M. S., Vaisse, C. PAX4 gene variations predispose to ketosis-prone diabetes. Hum. Molec. Genet. 13: 3151-3159, 2004. [PubMed: 15509590] [Full Text: https://doi.org/10.1093/hmg/ddh341]
Nalini, R., Gaur, L. K., Maldonado, M., Hampe, C. S., Rodgriguez, L., Garza, G., Lernmark, A., Balasubramanyam, A. HLA class II alleles specify phenotypes of ketosis-prone diabetes. Diabetes Care 31: 1195-1200, 2008. [PubMed: 18316396] [Full Text: https://doi.org/10.2337/dc07-1971]
Sobngwi, E., Mauvais-Jarvis, F., Vexiau, P., Mbanya, J.-C., Gautier, J.-F. Diabetes in Africans. Part 2. Ketosis-prone atypical diabetes mellitus. Diabetes Metab. 28: 5-12, 2002. [PubMed: 11938022]
Umpierrez, G. E., Smiley, D., Kitabchi, A. E. Ketosis-prone type 2 diabetes mellitus. Ann. Intern. Med. 144: 350-357, 2006. [PubMed: 16520476] [Full Text: https://doi.org/10.7326/0003-4819-144-5-200603070-00011]
Umpierrez, G. E. Ketosis-prone type 2 diabetes: time to revise the classification of diabetes. (Editorial) Diabetes Care 29: 2755-2757, 2006. [PubMed: 17130220] [Full Text: https://doi.org/10.2337/dc06-1870]