Ketosis-Prone DiabetesA New Subgroup of Patients with Atypical Type 1 and Type 2 Diabetes?
Abbas E. Kitabchi
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Tennessee College of Medicine Memphis, Tennessee 38163
Address all correspondence and requests for reprints to: Abbas E. Kitabchi, Ph.D., M.D., Division of Endocrinology, University of Tennessee College of Medicine, 951 Court Avenue, Room 335M, Memphis, Tennessee 38163. E-mail: akitabchi{at}utmem.edu.
One objective for classification of a disease is the opportunity to study its epidemiology, etiology, and pathogenesis to provide various effective interventions for its prevention and treatment.
The paper of Maldonado et al. (1) in this issue of JCEM reports on the classification of four groups of diabetic patients who presented with diabetic ketoacidosis (DKA). Of the two most common types of hyperglycemic crises, DKA most often occurs in type 1 diabetes (DM-1), and hyperglycemic hyperosmolar state most frequently arises in type 2 diabetes (DM-2). However, the occurrence of these acute metabolic emergencies is not specific to one type of diabetes or the other (2). Maldonado et al. (1) have carefully and meticulously studied a well-defined multiethnic group of patients with diabetes who presented with DKA. The study cohort was divided into four groups based on positive or negative ß-cell insulin function (B+ or B-, respectively), as well as positive or negative autoimmune markers for DM-1 (A+ or A-, respectively). They also studied human leukocyte antigen class II genotype in these patients, profiled their demographic characteristics, and followed their response to insulin therapy on a longitudinal basis.
Based on these criteria, they identified four groups: A+ B-, A- B-, A+ B+, and A- B+. This study demonstrates the heterogeneity associated with DKA and stimulates further discussion regarding the development of standardized nomenclature and a global database to establish a more accurate classification of ketosis-prone diabetes (KPD).
According to the consensus report of the Expert Committee on Diagnosis and Classification of Diabetes Mellitus (3) and the World Health Organization (4), group A+ B- in the work of Maldonado et al. (1) would consist of type 1A diabetes mellitus, whereas A- B- would be considered as type 1 idiopathetic, because this group is nonobese with negative autoimmune markers and requires insulin for prevention of recurrence of DKA. Patients in this group, similar to the type 1A, also have low residual C-peptide but have a strong family history of DM-2, are frequently nonobese, and often are nonwhite with variable insulin requirement. Such patients have been reported in African countries as early as 1985 (5). This group is sometimes referred to as type 1.5 diabetes (6).
The two groups with B+, however, are more heterogenous and share certain characteristics such as positive family history of DM-2, overweight or obese, mostly nonwhite, and often present in DKA as newly diagnosed DM. However, in this group, recurrence of DKA is rare after the initial event and often can initially be treated with diet or oral antidiabetic agents. These two groups have been described globally by various names, including "Flatbush diabetes," "obese DKA," "type 2 DM with DKA," "newly onset with DKA," "idiopathetic type 1 DM," "atypical DM," "type 3 KPD," as well as "KPD B+." Table 1
(courtesy of Dr. Mario Maldonado) summarizes the clinical characteristics and demographics of these patients as reported by various investigators (7, 8, 9, 10, 11, 12, 13, 14). Of the two groups B+ cohorts, A- B+ most likely would consist of a heterogenous group of DM-2 patients with various degrees of insulin resistance and varying degrees of insulin secretory capacity. However, at the time of appearance of DKA, they have relatively lower C-peptide and increased counterregulatory hormones compared with hyperglycemic nonketosis patients (15).
The last group, A+ B+, on the other hand poses the most challenging task as to the exact nomenclature for its classification or assignment of its etiopathological mechanism. Included in this category is a subclassification of individuals who had previously been labeled as latent autoimmune diabetes of adult (16, 17, 18, 19). Maldonado et al. (1) designated 11 patients under the A+ B+ category and further subdivided them into two groups. Although the numbers in each subgroup are not large enough to make a definitive conclusion, the results are provocative enough that one may be tempted to propose certain hypotheses. Of the 11 patients in this category, six are positive for susceptibility gene DQB1*02, five of whom require insulin to prevent recurrence of DKA and have average glycosylated hemoglobin (HbA1c) of about 8.6%. All patients in the second subgroup of five lack DQB*02 genes; four require no insulin for future therapy, and their HbA1c average is about 6.5%. Most interesting in this A+ B+ group is the autoimmune profile of these patients, compared with the A+ B- (type 1A) patients (Table 2
). Whereas in A+ B- group, whose HbA1c is greater than 10%, the major autoantibodies are IA-2 (61%) with 50% glutamic acid decarboxylase (GAD)65 and 17% combined GAD65 + IA-2, the A+ B+ patients exhibit 82% GAD65, only 18% IA-2, and no GAD65 + IA-2 antibodies. It therefore appears that type 1A patients who have higher frequency of IA-2 antibodies and more severe DKA than the group A+ B+ support the recent emerging concept that IA-2 positivity is associated with more aggressive ß-cell destruction in autoimmune diabetes (20).
Based on the above information, it is tempting to hypothesize that of the A+ B+ group the subgroup of six patients, who are more similar to DM-1 than the other subgroup of five, can justifiably be labeled latent autoimmune diabetes of adult. Furthermore, this group could have shared gene background with DM-1similar to the patients reported in the earlier study in which possible genetic interaction has occurred between DM-1 and DM-2 (21). This subgroup may also be considered to have a cluster of DM-1 and DM-2 and thus may benefit from preventive measures, such as immunosuppression of antibodies, including the use of GAD65 antibody vaccination that is now in phase II clinical trial (22). The latter approach, however, requires careful assessment of side effects, including possible theoretical neurological complications that may occur as a consequence of antibody development in the brain tissue.
The second less aggressive subgroup of A+ B+ may have less autoimmune antibody if a more quantitative measurement of GAD65 antibody were used. The etiology of DKA in this group may be secondary to sudden exposure to hyperglycemia causing desensitization of the islets, in contrast to the glucose toxicity that leads to the destruction of pancreatic ß-cells in DM-1 (23). Whereas the former condition may be reversible with establishment of euglycemia, the latter condition may be irreversible (24).
In conclusion, the presentation of Maldonado et al. (1) provides a challenging thesis regarding future directions for studies delineating and classifying common traits of patients who experience DKA and hyperglycemic hyperosmolar state (25). These studies will be instrumental in building accurate multinational database registries with extensive and detailed family histories of DM-1 and DM-2, as well as assessment of prenatal and immediate postnatal environmental factors and nutritional history. Further advancement in this area necessitates agreement in four related areas of clinical investigation: 1) a uniform nomenclature, 2) a standardized assessment for GAD65 antibody and other autoimmune markers (26), 3) a standardized test for assessment of
- and ß-cell capabilities (27), and 4) the utilization of more advanced technical procedures with the use of proteomics and genomics for genetic mapping (28).
Footnotes
The work of the authors and colleagues mentioned were supported in part by General Clinical Research Center Grant RR00211, Division of Research Resources, National Institutes of Health (Bethesda, MD).
Abbreviations: DKA, Diabetic ketoacidosis; DM-1, type 1 diabetes mellitus; DM-2, type 2 diabetes mellitus; GAD, glutamic acid decarboxylase; HbA1c, glycosylated hemoglobin; KPD, ketosis-prone diabetes.
Received September 18, 2003.
Accepted September 18, 2003.
References
- Maldonado M, Hampe CS, Gaur LK, DAmico S, Iyer D, Hammerle LP, Bolgiano D, Rodriguez L, Rajan A, Lernmark Å, Balasubramanyam A 2003 Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and ß-cell functional classification, prospective analysis and clinical outcomes. J Clin Endocrinol Metab 88:50905098[Abstract/Free Full Text]
- Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, Wall BM 2001 Management of hyperglycemic crises in patients with diabetes. Diabetes Care 24:131153[Free Full Text]
- American Diabetes Association 2003 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 25:S5S20
- Alberti KGMM, Zimmet PZ, for the WHO Consultation 1998 Definition, diagnosis and classification of diabetes mellitus and its complications. Diabet Med 15:539553[CrossRef][Medline]
- Ahren B, Corrigan CB 1985 Intermittent need for insulin in a subgroup of diabetic patients in Tanzania. Diabet Med 2:262264[Medline]
- Winter WE, Maclaren NK, Riley WJ, Clarke DW, Kappy MS, Spillar RP 1987 Maturity-onset diabetes of youth in black Americans. N Engl J Med 316:285291[Abstract]
- Banerji MA, Chaiken RL, Huey H, Tuomi T, Norin AJ, Mackay IR, Rowley MJ, Zimmet PZ, Lebovitz HE 1994 GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of human leukocyte antigen DR3 and DR4. Flatbush diabetes. Diabetes 43:741745[Abstract]
- Umpierrez GE, Casals MM, Gebhart SP, Mixon PS, Clark WS, Phillips LS 1995 Diabetic ketoacidosis in obese African-Americans. Diabetes 44:790795[Abstract]
- Umpierrez GE, Woo W, Hagopian WA, Isaacs SD, Palmer JP, Gaur LK, Nepom GT, Clark WS, Mixon PS, Kitabchi AE 1999 Immunogenetic analysis suggests different pathogenesis for obese and lean African-Americans with diabetic ketoacidosis. Diabetes Care 22:15171523[Abstract]
- Pitteloud N, Philippe J 2000 Characteristics of Caucasian type 2 diabetic patients during ketoacidosis and at follow-up. Schweiz Med Wochenschr 130:576582[Medline]
- Yu E, Guo H, Wu T 2001 Factors associated with discontinuing insulin therapy after diabetic ketoacidosis in adult diabetic patients. Diabet Med 18:895899[CrossRef][Medline]
- Pinero-Pilona A, Litonjua P, Aviles-Santa L, Raskin P 2001 Idiopathic type 1 diabetes in Dallas, Texas: a 5-year experience. Diabetes Care 24:10141018[Abstract/Free Full Text]
- Sobngwi E, Vexiau P, Levy V, Lepage V, Mauvais-Jarvis F, Leblanc H, Mbanya JC, Gautier JF 2002 Metabolic and immunogenetic prediction of long-term insulin remission in African patients with atypical diabetes. Diabet Med 19:832835[CrossRef][Medline]
- Mauvais-Jarvis F, Sobngwi E, Porcher R, Riveline J, Kevorkian J, Guillausseau P, Charpentier G, Vexiau P, Gautier JF 2003 type 3 (ketosis-prone) diabetes mellitus: clinical pathophysiology and natural history of ß-cell dysfunction and insulin resistance. Diabetes 52:A502
- Umpierrez GE, Kelly JP, Navarrete JE, Casals MC, Kitabchi AE 1997 Hyperglycemic crises in urban blacks. Arch Intern Med 157:669675[Abstract]
- Groop LC, Bottazzo GF, Doniach D 1986 Islet cell antibodies identify latent type 1 diabetes in patients aged 3575 years at diagnosis. Diabetes 35:237241[Abstract]
- Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR 1993 Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42:359362[Abstract]
- Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, Nissen M, Ehrnstrom BO, Forsen B, Snickars B, Lahti K, Forsblom C, Saloranta C, Taskinen MR, Groop LC 1999 Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48:150157[Abstract]
- Pozzilli P, Di Mario U 2001 Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult). Diabetes Care 24:14601467[Abstract/Free Full Text]
- Borg H, Gottsater A, Fernlund P, Sundkvist G 2002 A 12-year prospective study of the relationship between islet antibodies and ß-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes 51:17541762[Abstract/Free Full Text]
- Haiyan L, Lindholm E, Almgren P, Gustafsson A, Forsblom C, Groop L, Tuomi T 2001 Possible human leukocyte antigen-mediated genetic interaction between type 1 and type 2 diabetes. J Clin Endocrinol Metab 86:574582[Abstract/Free Full Text]
- Lernmark A, Abdulahi P, Agardh C-D, Atkinson MA, Cilio C, Essen-Moller A, Harris RA, Hawa M, Kaufman DL, Klareskog L, Leslie RDG, Lethagen A-L, Londei M, Lynch K, Palmer M, Robertson JA, Tobin AJ 2003 A phase II clinical trial involving alum-formulated GAD65 vaccination of GAD65 autoantibody positive adult diabetes patients. Proc of the 63rd Annual Meeting of the American Diabetes Association, New Orleans, LA, 2003 (Abstract 32-LB)
- Mathis D, Vence L, Benoist C 2001 ß-cell death during progression to diabetes. Nature 414:792798[CrossRef][Medline]
- Robertson RP, Olson LK, Zhang HJ 1994 Differentiating glucose toxicity from glucose desensitization: a new message from the insulin gene. Diabetes 43:10851089[Abstract]
- Sobngwi E, Gautier JF 2002 Adult-onset idiopathic type 1 or ketosis-prone type II diabetes: evidence to revisit diabetes classification. Diabetologia 45:283285[CrossRef][Medline]
- Bingley PJ, Bonifacio E, Mueller PW 2003 Diabetes antibody standardization program: first assay proficiency evaluation. Diabetes 52:11281136[Abstract/Free Full Text]
- The Diabetes Control and Complications Trial (DCCT) 1986 Design and methodological considerations for the feasibility phase. Diabetes 35:530545[Abstract]
- Field LL 2002 Genetic linkage and association studies of type 1 diabetes: challenges and rewards. Diabetologia 45:2135[CrossRef][Medline]