Atypical Forms of Diabetes Mellitus (DM) 16th Postgraduate Course of Diabetes. 18th, Nov. 2017 Atypical Forms of Diabetes Mellitus (DM) Chang Hee Jung Department of Internal Medicine, Asan Medical Center Univ. of Ulsan College of Medicine

Obesity as a Disease Agenda Ketosis-Prone Type 2 Diabetes (KPT2D) Latent Autoimmune Diabetes in Adults (LADA) Fulminant Type 1 Diabetes (Fulminant T1DM) Double Diabetes (DD) Summary

Obesity as a Disease Agenda Ketosis-Prone Type 2 Diabetes (KPT2D) Latent Autoimmune Diabetes in Adults (LADA) Fulminant Type 1 Diabetes (Fulminant T1DM) Double Diabetes (DD) Summary

Obesity as a Disease History of KPD First described in 1987 by Winter et al. as “Maturity-Onset Diabetes of Youth in Black Americans” “Atypical diabetes” Characteristics (n=12) - Apparent insulin dependence at the time of presentation, followed by absence of dependence months to years later - Strong family history, Obesity (46%) - Islet-cell autoantibody (-) - Intermediate insulin secretion between non-diabetic control and classic insulin-dependence diabetes - Free of insulin after initial insulin treatment N Engl J Med. 1987;316:285-91

Obesity as a Disease Many Terminologies Sub-Saharan Countries Temporary Diabetes in adult Nigerians Atypical Diabetes Flatbush diabetes (Afro-Caribbean patients) Type 1.5 diabetes or Diabetes type 1B Ketosis-prone diabetes Since 2002 by Sobngwi in a review of diabetes in West African (Diabetes Metab 2002;28:5-12.) Br Med J. 1967;2:747-50. Trans R Soc Trop Med Hyg. 1968,62:528-30

African-American and Hispanic Prevalence of KPT2D Obesity as a Disease New Diagnoses of DKA 20-50% ~10% African-American and Hispanic Asian and White Ann Intern Med. 2006;144:350-357.

Obesity as a Disease Classification of KPD System Types ADA system 1) Type 1a Type 1b (idiopathic type 1) Modified ADA system 2) KPD-ID (insulin dependent) KPD-NID (non-insulin dependent) BMI system 3) Lean (BMI <28 kg/m2) KPD Obese (BMI ≥28 kg/m2) KPD Aβ system 4) A+β- Baylor College of Medicine & A+β+ University of Washington A-β- A-β+ (the largest KPD subgroup in US) 1)Diabetes Care 2016;39:S13-S22. 2) Diabetes 2004 Mar;53(3):645-53. 3) Diabetes Care. 1999;22(9):1517-1523 4) J Clin Endocrinol Metab. 2003;88(11):5090.

Obesity as a Disease KPD-Aβ system Type 1 diabetes Ketosis-prone Type 2 diabetes (KPT2D) LADA는 대개 처음 부터 인슐린을 필요로 하진 않기 때문에 다르지만 Overlap with LADA (Slowly progressing type 1 diabetes) J Clin Endocrinol Metab 2003;88:5090-5098.

The most accurate classification method Aβ system: The most accurate classification method Obesity as a Disease Prediction for the preserved β-cell function after 12 mo after the index DKA Perserved b-cell function 12 months after the index DKA Diabetes Care 2006;29:2575-2579

Ketosis-prone type 2 diabetes (KPT2D) Obesity as a Disease A-β+, A+β+ More Specifically KPT2D A-β+ A-β+ Unprovoked DKA New onset diabetes Endocrine Review 2008;29:292-302.

Clinical Presentation of KPT2D Obesity as a Disease Obese, middle-aged persons with newly diagnosed diabetes Black or Hispanic> Present with unprovoked DKA History of 3P symptoms for less than 4~6 weeks M>F Ann Intern Med. 2006;144:350-357.

Clinical Presentation of KPT2D -3 Tertiary Hospital Experience- Obesity as a Disease Seok H & Jung CH et al. Diabetes Metab Res Rev 2013;29:507-513

Obesity as a Disease Aβ subgroup of KPD KPT2D J Clin Endocrinol Metab 2003;88:5090-5098.

Obesity as a Disease Clinical Course of KPT2D (A-β+, A+β+) ~60% 40-70% Near-normoglycemic remission in KPT2D (up to 20 months) Recurrence of hyperglycemia or ketosis (within 2 years) Ann Intern Med. 2006;144:350-357.

A+β+ KPD: 50% chance of insulin-off Obesity as a Disease The relative level of initial β-cell functional reserve or C-peptide response to glucagon does not predict the insulin dependency. Epitope specificity of the GAD65 autoantibody (vs. A+β-) HLA alleles (DQB1*02, DRB1*03, DRB1*04, DQB1*0302) Endocrine Review 2008;29:292-302.

A-β+ KPD: The largest KPD Obesity as a Disease Unprovoked A-β+ KPD Provoked A-β+ KPD Prevalence 50% Precipitating factor None Yes Duration of Diabetes New onset Long-standing M:F 2.6:1 0.7:1 β-cell improvement 2-fold greater Glycemic control Twice the frequency of HbA1c <7.0% Insulin discontinuation HLA DQB1*0602 (resistance allele for autoimmune diabetes) DQB1*0302, DRB1*04 (susceptible alleles for autoimmune diabetes) These data suggest that patients with provoked or provoked A-β+ KPD have distinct underlying mechanisms of β-cell dysfunction. Endocrine Review 2008;29:292-302.

Clinical Course of KPT2D Obesity as a Disease Unprovoked DKA Ann Intern Med. 2006;144:350-357.

Clinical Course of KPT2D -3 Tertiary Hospital Experience- Obesity as a Disease Seok H & Jung CH et al. Diabetes Metab Res Rev 2013;29:507-513

Clinical Course of KPT2D -3 Tertiary Hospital Experience- Obesity as a Disease Seok H & Jung CH et al. Diabetes Metab Res Rev 2013;29:507-513

Clinically distinct patterns of Autoimmune pathway in β-cell A+β- and A+β+ Obesity as a Disease Clinically distinct patterns of β-cell loss, such as Different latencies Variable degrees of β-cell destruction Epitope specificity? Autoimmune pathway in β-cell Endocrine Review 2008;29:292-302. J Clin Endocrinol Metab. 2007;92:462-407.

Obesity as a Disease A-β- (Type 1b diabetes) Untested autoantibodies (eq. zinc transporter or SOX13). Misclassified as “A-” because of a decline in autoantibody over time. Strong family history - Genes required for beta cell function may be defective eq. TCF1, PAX-4, and PDX-1 A role for cellular islet autoimmunity, not humoral islet autoimmune markers Endocrine Review 2008;29:292-302

A-β+ (Major form of KPD) Obesity as a Disease Conflicting results on HLA susceptibility alleles Although genetic susceptibility is likely, it is not known whether this model is polygenic or has a major gene influence. - A point mutation in the HNF1-α gene (conflicting results) - A missense mutation of PAX4 ? - May be more population-specific rather than causal Ann Intern Med. 2006;144:350-357.

Unprovoked A-β+ : G6PD deficiency? Obesity as a Disease Lancet. 2010;376:739-741.

Unprovoked A-β+ : G6PD deficiency? Obesity as a Disease G6PD deficiency contributing to depressed β-cell defense against oxidant stress in the face of acute hyperglycemia? (no genetic mutation) Residual erythrocyte G6PD activity J Clin Endocrinol Metab. 2005 Aug;90(8):4446-51.

Proposed mechanism of unprovoked A-β+ KPD Obesity as a Disease J Clin Endocrinol Metab. 2005 Aug;90(8):4446-51.

Obesity as a Disease Unprovoked A-β+: Metabolomics-Kinetics Approach Defective oxidation of ketones & Accelerated leucine catabolism BCAT: Branch chain aminotrasferase BCKDH: branch chain ketoacid dehydrogenase Diabetes. 2013;62(3):912-22.

Obesity as a Disease Provoked A-β+: Strong T-cell responses Provoked: progressive beta-cell loss over time Unprovoked: sustained beta-cell functional reserve + Islet-specific T-cell reactivity Proinflammatory monocytes Diabetes Care. 2013;36:4098-4103.

Acute management of DKA Management shortly after resolution of DKA Management of KPD Obesity as a Disease Acute management of DKA Management shortly after resolution of DKA Long-term management Endocrine Review 2008;29:292-302

Obesity as a Disease Management shortly after resolution of DKA (2-10 wk) Obesity as a Disease Assessment of β-cell secretory reserve β- β+ Fasting C-peptide (RIA) < 1 ng/ml (0.33 nmol/L) ≥1 ng/ml (0.33 nmol/L) Glucagon-stimulated C-peptide <1.5 ng/ml (0.5 nmol/L) ≥1.5 ng/ml (0.5 nmol/L) J Clin Endocrinol Metab 2003;88:5090-5098.

Management shortly after resolution of DKA (2-10 wk) Obesity as a Disease J Clin Endocrinol Metab 2003;88:5090-5098.

C-peptide to glucose ratio at 6 months Obesity as a Disease autoAb 있는 group 섞여 있음. 11 = 1.9 정도 Diabet. Med 2005;22:1744-1750.

Obesity as a Disease Management shortly after resolution of DKA (2-10 wk) Obesity as a Disease Assessment of β-cell autoimmunity (GAD-Ab, IA-2, ZnT8) β- (A- or A+) Not helpful in therapeutic decision making (insulin maintain) β+ 50% A+β+ 50% β- HLA genotyping ? (HLADQB1*02) Endocrine Review 2008;29:292-302

Obesity as a Disease Long-term management β- (A- or A+) A-β+ A+β+ Insulin treatment Unprovoked vs. Provoked A-β+ New onset diabetes vs. long standing Routine evaluation of β-cell function every 6 month to track its evolution autoAb 있는 group 섞여 있음 A+β+ HLA susceptibility alleles might help. Diabet. Med 2005;22:1744-1750.

Obesity as a Disease Agenda Ketosis-Prone Type 2 Diabetes (KPT2D) Latent Autoimmune Diabetes in Adults (LADA) Fulminant Type 1 Diabetes (Fulminant T1DM) Double Diabetes (DD) Summary

Obesity as a Disease LADA Adult-onset diabetes with circulating islet autoantibodies, but not requiring insulin therapy initially. Alternate references - Type 1.5 diabetes, Non-insulin requiring autoimmune diabetes - Slowly progressive type 1 diabetes Typical characteristics - Age of onset > 30 years - Gradual onset with initial improvement to OHAs/lifestyle changes - BMI < 25 kg/m2 - Personal family history of autoimmune disease Attentiveness : 친절함 Diabetes Care. 2006;29:970-975

Obesity as a Disease Three Main Criteria -Immunology of Diabetes Society- Obesity as a Disease Age of onset > 30 years Islet autoantibody + Attentiveness : 친절함 No insulin requirement for at least 6 months after diagnosis Very subjective Diabetologia. 2005;48:2206-2212

Obesity as a Disease Epidemiology of LADA 4-14% autoAb + Among T2DM Attentiveness : 친절함 Among T2DM Nat Rev Endocrinol. 2017;13:674-686

Clinical Heterogeneity of LADA Obesity as a Disease Attentiveness : 친절함 Diabetes 1999; 48(1): 150-157

Clinical Heterogeneity of LADA Severe autoimmunity (eq. TPO-Ab+) Obesity as a Disease Severe autoimmunity (eq. TPO-Ab+) Higher HbA1c Lower BMI Attentiveness : 친절함 Lower MetS Diabetes Care. 2007;30:932-8.

Clinical Heterogeneity of LADA High GAD (10 cut off) vs. Low GAD Obesity as a Disease 10 기준 GAD (+) vs. (-) High GAD (10 cut off) vs. Low GAD Diabet Med. 2011;28(3):319-24.

Screening tools for GAD (+) LADA Obesity as a Disease 2개 이상 Autoimmune thyroid disease, celiac disease, Addison’s disease, vitiligo, RA, Pernicious anemia, autoimmune hepatitis Diabetes Care. 2006;29(5):970-5.

Complications: Is there any difference? Obesity as a Disease Retinopathy 2개 이상 Nat Rev Endocrinol. 2017;13:674-686

Complications: Is there any difference? Obesity as a Disease CVD 2개 이상 Atherogenesis in autoimmune diabetes? Nat Rev Endocrinol. 2017;13:674-686

Complications: Is there any difference? Obesity as a Disease 2개 이상 Acta Diabetol. 2013;50(2):129-34

Obesity as a Disease Treatment of LADA Lower GAD titer, old age 도 ? It does not consider the clinical heterogeneity of LADA (eq. low GAD Ab titer, later onset of LADA). Cochrane Database Syst Rev. 2011;(9):CD006165

Insulin vs. SU (Pilot Study) for β cell preservation Obesity as a Disease Lower GAD titer, old age 도 ? Diabetes. 1996;45(5):622-6.

Insulin vs. SU (RCT) for β cell preservation Obesity as a Disease C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Insulin intervention to preserve beta-cell function is effective and safe for patients with LADA. J Clin Endocrinol Metab. 2008;93(6):2115-21

Incretin Treatment: DPP4i for β cell preservation in LADA Obesity as a Disease C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 J Clin Endocrinol Metab. 2014;99(5):E876-80

Incretin Treatment: GLP-1 RA for β cell preservation in LADA Obesity as a Disease Fasting C-peptide AutoAb C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Diabetes Care. 2016;39(2):250-7.

Incretin Treatment: GLP-1 RA for β cell preservation in LADA Obesity as a Disease HbA1 reduction Insulin dose reduction Wt. reduction C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Diabetes Care. 2016;39(2):250-7.

Obesity as a Disease Role of Obesity in LADA C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Nat Rev Endocrinol. 2017;13:674-686

Insulin sensitizer in LADA Obesity as a Disease C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Diabetes Metab Res Rev. 2005;21(2):203-8.

LADA: Heterogeneous group! Obesity as a Disease C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Nat Rev Endocrinol. 2017;13:674-686

Obesity as a Disease Agenda Ketosis-Prone Type 2 Diabetes (KPT2D) Latent Autoimmune Diabetes in Adults (LADA) Fulminant Type 1 Diabetes (Fulminant T1DM) Double Diabetes (DD) Summary

Fulminant T1DM, First suggestion in 2000 by Osaka IDDM Study Group Red: islet Green: CD3+ T lymphocytes GAD(+) GAD(-), Low HbA1c N Engl J Med 2000; 342:301-307

Clinical characteristics N Engl J Med 2000; 342:301-307

Immune mediated or not ? Fulminant autoimmune type 1 diabetes during INF-alpha therapy: a case of Th1-mediated disease? Diabetes Med 2002;18:329 T-cell-mediated autoimmunity may be involved in fulminant type 1 diabetes Diabetes Care 2002;25:635 Nonimmune “Fulminant” type 1 diabetes presenting with DKA during preg Obstet Gynecol 2002;99:877 A case of fulminant type 1 diabetes with elevated RF and the temporal presence of thyroid-stimulating hormone receptor Ab Diabetes Care 2002;25:935 A case of fulminant type 1 diabetes with strong evidence of autoimmunity Diabetes Care 2002;1482-3 A case of fulminant type 1 diabetes with transiently positive anti GAD Ab Endocr J 2003;50:225

Genetic factor ? Association of HLA-DQ genotype in autoAb negative and rapid-onset type 1 diabetes Diabetes Care 2002;25:2302-7 Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus Diabetologia 2005;48:294-300 Fulminant autoAb negative and type 1A diabetes phenotypes in a Korean HLA identical dizygotic twin Diabetes Care 2005; 28(9): 2330-233

Involvement of autoimmunity 처음에는 GAD Ab음성이다가 1년뒤 high titier로 검출됨. Ann N Y Acad Sci 2003;1005:359-61

Involvement of viral infection EMC: Encephlomyocarditis-virus Enterovirus IgA 이밖에도 Coxsackie B4 virus, influenza virus, HAV 와의 관련 보고 Diabetologia 2004;47:1854, 2005;48:290

Tentative hypothesis of fulminant type 1 DM Endocr J 2006;53:577

Criteria for definite diagnosis of fulminant T1DM DKA with HbA1c < 8.5% Markedly elevated amylase/lipase, URI Sx+ Report of JDS 2005

Obesity as a Disease Agenda Ketosis-Prone Type 2 Diabetes (KPT2D) Latent Autoimmune Diabetes in Adults (LADA) Fulminant Type 1 Diabetes (Fulminant T1DM) Double Diabetes (DD) Summary

Obesity as a Disease Double Diabetes (DD) Double diabetes is when someone with T1DM develops insulin resistance, the key feature of T2DM. The hypothesis emerged that a subgroup of patients with T1DM existed who were at risk of developing T2DM in later life, but would never be diagnosed as having T2DM because they had already developed hyperglycemia as a result of T1DM C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Nat Rev Endocrinol. 2012;8:476-485

Insulin Resistance in T1DM Obesity as a Disease Diabetes. 2000;49(4):626-32.

Insulin Resistance in T1DM Obesity as a Disease Diabetes Care. 2003;26(5):1374-9.

Proposed model of increasing coronary risk in T1DM Obesity as a Disease C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Nat Rev Endocrinol. 2012;8:476-485

Reversing insulin resistance in T1DM Lifestyle intervention Obesity as a Disease Lifestyle intervention Diabete Care. 1990;13:9-15 Diabetes Care. 1985;8:461-465 Diabetes Care. 1984;7:520-527. Glycogen synthase activity↑ Metformin C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 TZD Nat Rev Endocrinol. 2012;8:476-485

Obesity as a Disease Metformin in T1DM Insulin dose HbA1c 6 단위 정도 감소 Diabetologia. 2010;53:809-920

Obesity as a Disease Metformin in T1DM C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Lancet Diabetes Endocrinol. 2017;5(8):597-609

Obesity as a Disease TZD in T1DM Diabetes Care. 2005;28(7):1562-7. C-peptide 일정 level 이하로 감소 하는 것을 insulin dependency로 정의 Diabetes Care. 2005;28(7):1562-7.

Obesity as a Disease Summary (1) KPD is an emerging heterogeneous syndrome characterized by the presence of DKA in patients who may lack the typical clinical phenotype of autoimmune type 1 diabetes. Among the four difference classification schemes for KPD, the Aβ classification most accurately predicts long-term insulin dependence 12 months after DKA presentation. autoAb 있는 group 섞여 있음

Obesity as a Disease Summary (2) Patients with poor beta cell function (β-) after resolution of the index DKA event typically require long-term insulin therapy, regardless of the status of ‘A’. Patients with A-β+ are often able to discontinue insulin (especially unprovoked DKA as the initial manifestation of diabetes). Patients with A+β+ have a variable course with some demonstrating progressive beta cell deterioration and others long-term preservation. These patients may benefit from HLA genotyping to provide additional prognostic markers of clinical behavior. autoAb 있는 group 섞여 있음

Obesity as a Disease Summary (3) The extensive heterogeneity of LADA makes it difficult to determine a priori algorithm for treatment. The successful treatment of LADA will require a personalized medicine approach that takes into account the intrinsic characteristics of each patient (antibody titer, onset age…). Fulminant T1DM should be suspected in newly diagnosed DKA with HbA1c less than 8.5%. The evidence of simultaneous exocrine pancreatic destruction can be observed. Double diabetes should be considered in patients with T1DM accompanied by several features including high total daily insulin dose, family Hx of T2DM, central adiposity, low HDL-C, and increased hepatic fat. autoAb 있는 group 섞여 있음

Thank You for Careful Listening.