Ketosis-prone diabetes

Ketosis-prone diabetes (KPD) is an intermediate form of diabetes that has some characteristics of type 1 and some of type 2 diabetes. Type 1 diabetes involves autoimmune destruction of pancreatic beta cells which create insulin. This occurs earlier in a person's life, leading to patients being insulin dependent, and the lack of natural insulin makes patients prone to a condition called diabetic ketoacidosis (DKA). Type 2 diabetes is different in that it is usually caused by insulin resistance in the body in older patients leading to beta cell burnout over time, and is not prone to DKA. KPD is a condition that involves DKA like type 1, but occurs later in life and can regain beta cell function like type 2 diabetes. However, it is distinct from latent autoimmune diabetes of adults (LADA), a form of type 1 sometimes referred to as type 1.5 that does not occur with DKA.[1] There are also distinctions to be made between KPD and LADA as patients who exhibit KPD symptoms can regain beta cell function similar to type 2 diabetics whereas LADA will not exhibit this reclamation of beta cell function.

For another diabetes subtype sometimes called "diabetes type 1.5", see Latent autoimmune diabetes in adults.
Ketosis-prone diabetes
Other namesKPD
SpecialtyEndocrinology

KPD is readily diagnosable because it presents a single characteristic, ketoacidosis, which confirms it as ketosis-prone diabetes.[2] KPD comes in four forms depending upon the presence or absence of β-cell autoantibodies (A+ or A−) and β-cell functional reserve (β+ or β−).[3] Other styles of classification have been used for KPD, including styles incorporating BMI, but the Aβ system has been found to have the highest accuracy and predictive value of all the systems utilized.[4] The autoantibodies used to diagnose the A+ subtypes of KPD include the autoantibodies detected in patients with type 1 diabetes, including Glutamic Acid Decarboxylase 65 (GAD65), Zinc Transporter T8 (ZnT8), Islet Antigen-2 (IA-2), and HLA class II type 1 diabetes susceptibility alleles.[5]

Management

The management of KPD revolves around 3 main components: acutely managing DKA, identification of KPD subtype, and longterm diabetic management similar to that in type 2 diabetes.[6] As patients are likely to initially present in DKA, the acute management of DKA is the first priority. The treatment of DKA in KPD is identical to the treatment of DKA caused by type 1 diabetes and revolves around fluid repletion, electrolyte repletion, and administration of insulin.[7] After the resolution of the DKA episode consideration of what patients to test for KPD should be considered. Most providers would recommend testing for autoantibodies in any patient presenting with a DKA episode, and this thought process should be followed especially in patients who do not fit a classic type 1 diabetes picture of a young patient with classical diabetic symptoms. In order to get a full Aβ diagnosis presence of beta cell function must also be completed using C-peptide levels. After diagnosing the subtype of KPD, long term management with a primary care provider should be done with diabetic education and counseling as patients will require insulin therapy after initial presentation. Routine followups serve an important role during this time to evaluate the changing insulin needs of the patient. Due to the propensity for DKA, insulin is a staple of KPD management, and other anti-glycemic agents should only be added if glucose levels rise while on effective insulin therapy.[8]

Prognosis

The prognosis of KPD combines aspects of both Type 1 and Type 2 diabetes. While the presentation mimics type 1 diabetes with its propensity for DKA, patients with KPD can regain pancreatic beta cell function over time. Specifically patients who have beta cell reserve at the onset of the disease (the β+ subtype) have around a 50% chance to regain full beta cell function and become insulin independent.[9] These cases do make a minority of KPD patients however, and insulin dependence is an expected outcome for most patients. In these cases insulin dependence will reflect that of type 2 diabetes with increased insulin dependence reflecting lifestyle choices and diabetic management. Education for these patients should reflect the education for patients presenting with regular type 2 diabetes.

The presence of beta cell function restoration seems to come down to how much beta cell reserve the patient has at onset but also the presence of autoantibodies. Patients with autoantibodies at presentation have a lower likelihood of having beta cell function restored, a fact that holds true even when the type of KPD is not distinguished by the traditional Aβ subtype system.[10] Lifestyle changes that worsen regular type 2 diabetes are still associated with insulin dependence, such as patients who do not make effective diet and lifestyle changes.[11]

An important factor for beta cell functionality is proper glycemic control, a factor it shares with type 2 diabetes. Patients who maintain proper glycemic control to protect their functioning beta cells exhibited lesser disease courses and regained beta cell functionality at a much higher rate than patients who had looser or less stringent glucose control.[12]

References
  1. Balasubramanyam A, Nalini R, Hampe CS, Maldonado M (May 2008). "Syndromes of ketosis-prone diabetes mellitus". Endocrine Reviews. 29 (3): 292–302. doi:10.1210/er.2007-0026. PMC 2528854. PMID 18292467. There is clearly a spectrum of clinical phenotypes among patients with islet autoantibodies who do not present with ketosis, including those termed “latent autoimmune diabetes in adults” (LADA) (30), “type 1.5 diabetes” (31,32,33), and “slowly progressing type 1 diabetes” (34). A similar spectrum exists in KPD that includes the very different phenotypes of A+β− and A+β+ KPD. A+β− KPD is synonymous with classic, early onset autoimmune type 1 diabetes; A+β+ KPD may overlap with LADA. However, there are differences between LADA, as recently defined by the Immunology of Diabetes Society, and A+β+ KPD patients; most importantly, the definition of LADA excludes patients who require insulin within the first 6 months after diagnosis, whereas the majority (90%) of A+β+ KPD patients present with DKA as the first manifestation of diabetes and therefore require insulin at the start.
  2. Leslie RD, Kolb H, Schloot NC, Buzzetti R, Mauricio D, De Leiva A, et al. (October 2008). "Diabetes classification: grey zones, sound and smoke: Action LADA 1". Diabetes/Metabolism Research and Reviews. 24 (7): 511–519. doi:10.1002/dmrr.877. PMID 18615859. S2CID 205757168.
  3. Nalini R, Gaur LK, Maldonado M, Hampe CS, Rodriguez L, Garza G, et al. (June 2008). "HLA class II alleles specify phenotypes of ketosis-prone diabetes". Diabetes Care. 31 (6): 1195–1200. doi:10.2337/dc07-1971. PMID 18316396.
  4. Balasubramanyam A, Garza G, Rodriguez L, Hampe CS, Gaur L, Lernmark A, Maldonado MR (December 2006). "Accuracy and predictive value of classification schemes for ketosis-prone diabetes". Diabetes Care. 29 (12): 2575–2579. doi:10.2337/dc06-0749. PMID 17130187.
  5. Mulukutla SN, Acevedo-Calado M, Hampe CS, Pietropaolo M, Balasubramanyam A (December 2018). "Autoantibodies to the IA-2 Extracellular Domain Refine the Definition of "A+" Subtypes of Ketosis-Prone Diabetes". Diabetes Care. 41 (12): 2637–2640. doi:10.2337/dc18-0613. PMC 6245211. PMID 30327357.
  6. Umpierrez GE, Smiley D, Kitabchi AE (March 2006). "Narrative review: ketosis-prone type 2 diabetes mellitus". Annals of Internal Medicine. 144 (5): 350–357. doi:10.7326/0003-4819-144-5-200603070-00011. PMID 16520476. S2CID 33296818.
  7. Fayfman M, Pasquel FJ, Umpierrez GE (May 2017). "Management of Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State". The Medical Clinics of North America. 101 (3): 587–606. doi:10.1016/j.mcna.2016.12.011. PMC 6535398. PMID 28372715.
  8. Rasouli N, Elbein SC (December 2004). "Improved glycemic control in subjects with atypical diabetes results from restored insulin secretion, but not improved insulin sensitivity". The Journal of Clinical Endocrinology and Metabolism. 89 (12): 6331–6335. doi:10.1210/jc.2004-1016. PMID 15579799.
  9. Gaba R, Mehta P, Balasubramanyam A (January 2019). "Evaluation and management of ketosis-prone diabetes". Expert Review of Endocrinology & Metabolism. 14 (1): 43–48. doi:10.1080/17446651.2019.1561270. PMID 30612498. S2CID 58611261.
  10. Mauvais-Jarvis F, Sobngwi E, Porcher R, Riveline JP, Kevorkian JP, Vaisse C, et al. (March 2004). "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. 53 (3): 645–653. doi:10.2337/diabetes.53.3.645. PMID 14988248.
  11. Gaba R, Gambhire D, Uy N, Gonzalez EV, Iyer D, Hampe CS, et al. (2015-09-01). "Factors associated with early relapse to insulin dependence in unprovoked A-β+ ketosis-prone diabetes". Journal of Diabetes and Its Complications. 29 (7): 918–922. doi:10.1016/j.jdiacomp.2015.04.013. PMC 4540630. PMID 26071380.
  12. Sobngwi E, Vexiau P, Levy V, Lepage V, Mauvais-Jarvis F, Leblanc H, et al. (October 2002). "Metabolic and immunogenetic prediction of long-term insulin remission in African patients with atypical diabetes". Diabetic Medicine. 19 (10): 832–835. doi:10.1046/j.1464-5491.2002.00802.x. PMID 12358870. S2CID 3087011.
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