Beyond Type 1 and Type 2 Diabetes; Why Correct Diabetes Classification is Important Gabriel I. Uwaifo, MD, FACP, FTOS, FACE. Dept of Endocrinology, Diabetes, Metabolism and Weight Management, Ochsner Medical Center Objectives To highlight various classification methods of diabetes To highlight the importance and consequences of appropriate diabetes classification To provide suggested processes for diabetes classification in primary care settings and indices for specialty referral Presentation outline 1. Case presentations 2. Diabetes classification; past present and future 3. Diabetes classification; why is it important? 4. Suggested schemas for diabetes classification 5. Case presentation conclusions 6. Summary points and conclusions 3 Demonstrative cases Patient DL is a 56 yr old AA gentleman with a BMI of 24 referred for management of his “type 2 diabetes”. He is on basal bolus insulin with current HBA1c of 8.3. His greatest concern is on account of recent onset progressive neurologic symptoms and gaite unsteadiness Patient CY is a 21 yr old Caucasian lady with BMI of 28 and strong family history of diabetes referred for management of her “type 2 diabetes”. She is unsure if she even has diabetes as she indicates most of the SMBGs are under 160 and her current HBA1 is 6.4 on low dose metformin. Patient DR is a 54 yr old Asian lady with BMI of 36 and long standing “type 2 diabetes”. She has been referred because of poor diabetes control on multiple oral antidiabetics and persistent severe hypertriglyceridemia. Questions; Do all these patients have type 2 diabetes? How do we classify these patients? What impact if any does this have on treatment strategies and prognosis? ADA Etiologic classification of Diabetes Type 1 diabetes; A; immune mediated, B; Idiopathic Type 2 diabetes; Gestational Diabetes Other types of Diabetes; a) Including monogenetic beta cell dysfunctional syndromes; MODYs b) Genetic defects of insulin action including type A and B insulin resistance sydnromes, leprauchanism, Rabson Mendenhall syndrome, lipoatrophic and lipodystrophic diabetes etc. c) Exocrine pancreatopathies including pancreatitis, trauma, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy etc ADA Etiologic classification of Diabetes continued d) Endocrinopathies including acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, Conns syndrome, etc e) Chemicals and drugs d) Infections including CMV, congenital rubella etc e) Other rare immune mediated diabetes including Stiff man syndrome, IPEX and type 1 autoimmune polyendocrinopathy syndrome, anti insulin receptor antibody syndrome etc. f) Other genetic syndromes associated with diabetes including Down’s syndrome, Klinefelters syndrome, Turner’s syndrome, Wolframs syndrome, Maternal inherited diabetes with deafness (MIDD) Friedrich’s ataxia, Huntington’s Chorea, Laurence Moon Biedl syndrome, Myotonic dystrophy, Porphyria, Prada Will syndrome etc. What does this comprehensive classification however miss? “Type 3 diabetes”; type 1 diabetes with obesity and insulin resistance “Type 1.5 diabetes”; LADA; latent autoimmune diabetes of Aging syndromes Type 2 diabetes with islet autoimmunity Post transplant diabetes (multifactorial etiology including transplant surgery, perioperative and post transplant immunomodulatory medications, genetics etc). Check point inhibitor associated diabetes Neonatal Diabetes syndromes (distinct from the MODYs) The syndromes of ketosis-prone diabetes mellitus The syndromes of so called Malnutrition related diabetes (MRDM) Various combinations of so called “hybrid diabetes”; probably uncommon but exact prevalence unclear Etc etc. The take home point is the wide heterogeneity of diabetes and the fact that it includes very many different diseases with the commonality of chronic hyperglycemia with metabolic derangement and consequent micro nd macrovascular complications The MODYs; Maturity onset diabetes of the young Monogenic causes of diabetes mainly due to various defects of insulin secretion. Heterogenous with variable phenotypes Increasing diversity; currently there are 11 distinct MODY syndromes They are autosomal dominant linked. MODYS 1-6 are the most common and MODY 2 and 3 are by far the most prevalent MODY 1; due to HNF-4 alpha mutation and optimally treated with sulphonylureas MODY 2; due to glucokinase mutations; very mild hyperglycemia; can often be treated with diet alone (15-31% of MODYs). MODY 3; HNF -1 alpha mutations; 52-65% of MODYs and best treated with sulphonylureas MODY 4; insulin promotor 1 mutations; rare and can simulate type 1 b diabetes MODY 5; HNF-1 beta mutations; rare and associated with other anomalies including renal dysplasia, pancreatic atrophy and hypomagnesemia. These are generally insulin dependent. MODY 6; Neurogenic differentiation factor-1 mutation is very rare and the patients also are invariably insulin dependent. The Neonatal Diabetes syndromes • Distinct from but may include some of the MODY variants • Distinctive in the timing of diagnosis within the first year of life and invariably within the first 6mths of life. Can also be referred to as Congenital diabetes mellitus as it is presumed to be present even at birth but there is often delay in firm diagnosis • Relatively rare and often of genetic underlying etiology; prevalence of 1 in 300- 500,000 life births • Two major variants; permanent and transient relapsing variants • Invariably associated with small for gestational age at birth. • Underlying etiology is variable but chromosome 6 Q anomalies are the most common identified cause of the transient relapsing variant. • The genetic defects in the permanent variants are generally mutations of genes involved with beta cell and pancreatic developments as well as transcription factors. • Can be associated with distinct syndromes including the IPEX (immunodeficiency, polyendocrinopathy, enteropathy and X linked), Wolcott Rallison syndrome (bone dysplasia, pancreatic hypoplasia with cardiomegaly, mental retardation, cerebellar dysfunction, renal and hepatic disease with pancreatic exocrine deficiency and insulin dependent diabetes.) and the DEND and iDEND (intermediate DEND) syndromes; Developmental delay, Epilepsy and Neonatal Diabetes. DEND is often due to KCNJ11 or ABCC8 gene mutations which are both beta cell expressed ion channels. These forms of diabetes are much better managed with sulphonylureas than insulin or any other antidiabetics. The LADAs (latent onset diabetes of aging) Highly heterogenous with some presenting like type 1, some like type 2 and some with intermediate phenotypes. Heterogeniety related to the autoantibodies involved and titers (ICA, GAD, Zn transporter protein 8, IA-2, Insulin etc). Heterogeniety related to adiposity and presence of insulin resistance. Heterogeniety related to family history, other autoimmune diseases and HLA subtypes. Distinct from isolated low titers autoantibody positivity in type 2 diabetes patients. Syndromes of ketosis prone diabetes Heterogenous group of entities including so called ketosis prone type 2 diabetes, Flatbrush diabetes and so called atypical diabetes. Among the methods of classification are 1. Modified ADA system that includes an autoimmune variant characterized by islet antibody positivity and among the antibody negative patients an insulin dependent and insulin independent subtype 2. A BMI stratified system with those with BMI <28 presenting often like type 1 diabetes and those with BMI<28 oft presenting akin to type 2 diabetes 3. The A (antibody status) Beta (beta cell secretory status) classification system. This involves a 2 x 2 factorial and thus 4 subtypes; A +ve beta + ve (Antibody + ve with + ve beta cell function) A-ve Beta + ve (Antibody - ve with + ve beta cell function) A +ve Beta – ve (Antibody + ve with - ve beta cell function) A -ve Beta – ve (Antibody - ve with - ve beta cell function) Syndromes of ketosis prone diabetes Copyrights apply The lipodystrophy syndromes Heterogenous group of rare diseases characterized by generalized or localized lack or excess of adipose tissue depots including both subcutaneous and visceral. Can be generalized or partial and can be congenital or acquired. Often associated with multisystemic features of major insulin resistance, hyperglycemia with or without established diabetes and include severe dyslipidemia, NAFLD, proteinuric renal disease etc. Greater genetic and molecular characterization of the underlying defects causing these disorders have led to increasing heterogeneity of the cluster and its classification. Generalized congenital lipodystrophy includes the Berardinelli –Seip syndrome Generalized acquired lipodystrophy includes the Lawrence syndrome Localized congenital lipodystrophy include the Koeberling and Dunnigan syndromes Localized acquired lipodystrophy includes the Barraquer-Simons syndrome The lipodystrophy syndromes The lipodystrophy syndromes Copyrights apply Copyrights apply Copyrights apply Copyrights apply Copyrights apply Copyrights apply Drug induced Hyperglycemia and Diabetes Copyrights apply Check point inhibitors; cause insulitis and a unque form of insulinopenic diabetes akin to type 1a. Childhood onset diabetes; a unique entity Child hood onset diabetes continued Childhood onset diabetes continued Childhood onset diabetes continued The heterogeneity of diabetes in particular lends itself to the need of precision and personalized profiling and management Growing awareness of the need for other