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Home , Insulitis, MODY 6, Myotonic dystrophy

Beyond Type 1 and Type 2 ; Why Correct Diabetes Classification is Important

Gabriel I. Uwaifo, MD, FACP, FTOS, FACE. Dept of , 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 “”. He is on basal bolus 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; Other types of Diabetes; a) Including monogenetic dysfunctional syndromes; MODYs b) Genetic defects of insulin action including type A and B sydnromes, leprauchanism, Rabson Mendenhall syndrome, lipoatrophic and lipodystrophic diabetes etc. c) Exocrine pancreatopathies including pancreatitis, trauma, , 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 , Porphyria, Prada Will syndrome etc. What does this comprehensive classification however miss?

“Type 3 diabetes”; with obesity and insulin resistance “Type 1.5 diabetes”; LADA; latent autoimmune diabetes of Aging syndromes Type 2 diabetes with islet Post transplant diabetes (multifactorial etiology including transplant surgery, perioperative and post transplant immunomodulatory , 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 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 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 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 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 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 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 considerations in the classification and phenotyping of diabetes including adiposity, risk, ASCVD risk, microvascular disease risk, genetics and heritability

The Evolution of Diabetes Classification

The future of diabetes classification will include clinical cluster phenotyping, GWAS characterisation and genotyping So why is indepth diabetes sub - classification important? To the Clinician; Provides proper understanding of anticipated clinical course, best treatment options and expected prognosis for the individual patient. To the Epidemiologist; It enables better understanding of secular and historical trends in diabetes. To the basic scientist; It enables better understanding of the underlying pathophysiology and pathogenesis of various diabetes subtypes. To the geneticist; It provides better understanding of various diabetes types as well as better appreciation of the prevalence and treatment options of monogenic as opposed to polygenic diabetes variants. To the pharmacologist and drug developer; It provides better understanding of possible molecular markers to target for new drug development as well as enabling better fitting of treatment options to specific diabetes sub types. To the individual patient; It provides better understanding of the cause of the diabetes, the prognosis for achieving remission, and developing complications likely familial risk and best treatment options To public health policy; It provides higher quality data regarding current and evolving trends in diabetes prevalence and incidence which influence public health policy and resources for prevention and management strategies to be applied in community based interventions. Case vignette conclusions Patient DL; the 56 yr old AA with BMI of 24 on basal bolus therapy and progressive neurologic symptoms. Further history reveals prior attempts at use of oral agents were unsuccessful and he has no family history of diabetes. Examination revealed spastic ataxic gaite. Auto antibody testing showed GAD titers in the 500-750range on repeated measures; Patient with autoimmune type 1 diabetes and the Stiffman syndrome. Switched from basal bolus to insulin pump therapy + Symlin and referral to for consideration of IVIG and other related therapy.

Patient CY; the 21 yr old Caucasian lady with BMI of 28 and strong family of diabetes and current HBA1c of 6.4. Patient is on low dose metformin and wonders if she even has diabetes. Close family history reveals 3 generations of family relatives all with diabetes and all managed on oral agents and most normal weight. No history of any major microangiopathic complications. CGMS reveals 74% of glucose values normal, 24 % in hyperglycemic range but peak glucose of 178. confirmed MODY 2 with Glucokinase mutation. Patient switched to low dose glimperide along with nutritional therapy.

Patient DR; the 54yr old Asian lady with BMI of 36 and poor glycemic control on multiple oral agents. Clinical examination shows marked fat depletion with thin gaunt face and temporal wasting as well as thin upper chest area but with abdominal distension and obesity, significant acanthosis nigricans and +ve popeyes sign of upper limbs with significant hip adiposity. Further evaluation reveals transaminitis, NAFLD, marked hyperinsulinemia and proteinuria with current HBA1c of 9.3 on 3 oral agents (metformin, glyburide and Januvia). DEXA for body composition showed striking regional disparity in adipose tissue depots in head, neck and chest compared to abdomen, hips, thighs and legs. Presumptive diagnosis of acquired partial lipodystrophy (Barraquer-Simons syndrome). Therapy changed to max dose metformin, actos and bydureon with basal insulin; Tresiba. 6 months later HBA1c 6.7. Diabetes classification and characterization for the primary care provider The most important strategy for proper diabetes classification for the clinician is a careful, thorough history and an equally thorough clinical examination. Need to ignore what the chart says. Take with healthy skepticism what the patient says regarding the type of diabetes they are said to have. Important historical elements to capture; age of onset, circumstances of onset, DKA history if any, thorough family history, weight history, , surgical and other procedure related history, treatment history including insulin dependence. Important clinical examination elements; full vital signs, presence of cutaneous signs of insulin resistance including acanthosis nigricans, skin tags, acneiform eruptions, hirsutism and presence of acromegaloid features. Fat distribution, anthropometric measures etc. Diabetes classification and characterization for the diabetologist/endocrinologist

Careful review of past records; healthy skepticism of what the records and referral notes say regarding stated diabetes type.

Laboratory tests; measures of insulin resistance (HOMA-IR easiest to obtain and quite well validated) Measures of endogenous beta cell secretory capacity (C-peptide easiest to obtain and well studied)

Full islet autoantibody profiling.

Other specialized testing based on clinical history and examination findings

HLA subtyping.

Body Composition testing including bioelectric impedance, DEXA, Bodpod testing etc.

Specific genetic testing on a case by case study for possible monogenic diabetes and other unusual diabetic syndromes.

For large research study samples; GWAS and other genetic screening studies. Summary points and Conclusions

Diabetes classification has evolved considerably since the NDDG era of insulin independent and insulin dependent subtypes.

Better understanding of the causes and pathogenesis of various diabetes types have revealed the huge heterogeneity of diabetes. Etiologic, pathogenetic, phenotypic and genotypic based classification methods are the most commonly used conventions presently.

Careful history and examination remain the cornerstones for proper diabetes characterization and classification.

Addition of beta cell function indices and islet autoantibody profiling have added valuable information to diabetes classification conventions.

Large cohort cluster analyses and GWAS studies have added another dimension to diabetes classification of large populations and identification of distinct clinical subtypes within the population of so called type 2 diabetes.

Careful accurate classification of diabetes subtypes in the individual patient and populations is very important to inform clinical treatment, prognostication and public health trends and policy decision making. Bibliography and references

Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab 2011; 96:3313. Tsoukas MA, Mantzoros CS. Lipodystrophy Syndromes. In: Endocrinology Adult and Pediatric, 7th, Jameson JL, DeGroot LJ (Eds), Saunders, In Press . Pardini VC, Victória IM, Rocha SM, et al. Leptin levels, beta-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatropic diabetes. J Clin Endocrinol Metab 1998; 83:503. Umpierrez GE, Smiley D, Kitabchi AE. Narrative review: ketosis-prone type 2 diabetes mellitus. Ann Intern Med 2006; 144:350. Balasubramanyam A, Nalini R, Hampe CS, Maldonado M. Syndromes of ketosis-prone diabetes mellitus. Endocr Rev 2008; 29:292. Naik RG, Palmer JP. Latent autoimmune diabetes in adults (LADA). Rev Endocr Metab Disord 2003; 4:233. Banerji MA, Dham S. A comparison of classification schemes for ketosis-prone diabetes. Nat Clin Pract Endocrinol Metab 2007; 3:506. Gat-Yablonski G, Shalitin S, Phillip M. Maturity onset diabetes of the young--review. Pediatr Endocrinol Rev 2006; 3 Suppl 3:514. Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes of the young (MODY). BMJ 2011; 343:d6044. Dussoix P, Vaxillaire M, Iynedjian PB, et al. Diagnostic heterogeneity of diabetes in lean young adults: classification based on immunological and genetic parameters. Diabetes 1997; 46:622. Thanks so very much for your attention

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