Diabetes Mellitus Due to Specific Causes: What s New?

Transcription

1 Diabetes Mellitus Due to Specific Causes: What s New? George Grunberger, MD, FACP, FACE Chairman, Grunberger Diabetes Institute Clinical Professor, Internal Medicine and Molecular Medicine & Genetics Wayne State University School of Medicine Professor, Internal Medicine Oakland University William Beaumont School of Medicine Professor First Faculty of Medicine, Charles University, Prague Past President, American Association of Clinical Endocrinologists President Elect, American College of Endocrinology

2 διαβήτης diabainein, meaning "a siphon, first used in 250 BC by the Greek Apollonius of Memphis "mellitus" or "from honey" was added by Thomas Willis in 1600s

3 Outline Monogenic Diabetes Neonatal Diabetes MODY Pancreatogenic Diabetes (Type 3c) Cystic Fibrosis-Related Diabetes Mitochondrial Diabetes Post-transplantation Diabetes

4 It s All About the β Cell

5

6 It s Diabetes Mellitus, Folks

7

8

9

10 What are monogenic forms of diabetes? Result from mutations or changes in a single gene > monogenic Monogenic forms of diabetes ~ 1 to 4% of all cases of diabetes Most mutations reduce ability to produce insulin Neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) are main forms of monogenic diabetes NDM occurs in newborns and young infants MODY is much more common than NDM usually first occurs in adolescence or early adulthood Most cases are incorrectly diagnosed In adulthood, T2DM is often diagnosed instead of monogenic diabetes Some monogenic forms of diabetes can be treated with oral antidiabetes drugs; other forms require insulin Correct diagnosis allows for proper treatment

11 How is monogenic diabetes diagnosed? Genetic testing can diagnose most forms of monogenic diabetes Genetic testing is recommended if: diabetes is diagnosed within the first 6 months of age diabetes is diagnosed in children and young adults, esp. if strong family history of DM, who don t have typical features of T1DM or T2DM stable, mild fasting hyperglycemia, especially if obesity is not present

12

13 What is neonatal diabetes mellitus (NDM)? Monogenic form of diabetes in the first 6 to 12 months of life Rare: 1 in 400,000 infants in the United States Infants with NDM do not produce enough insulin Often mistaken for T1DM Diabetes that occurs in the first 6 months of life almost always has a genetic cause ~50% lifelong: permanent neonatal diabetes mellitus In the rest, transient, disappears during infancy but can reappear later in life: transient neonatal diabetes mellitus Clinical features depend on gene mutations Signs: frequent urination, rapid breathing, and dehydration Diagnosed by elevated levels of glucose in blood or urine Most fetuses with NDM do not grow well in utero Newborns with NDM much smaller - intrauterine growth restriction After birth, some infants fail to gain weight and grow normally

14 US Pharm. 2013;38(10)(Diabetes suppl):3-6.

15

16 Vaxillaire M and Froguel P. Monogenic forms of diabetes mellitus: an update Endocrinol Nutr. 2009;56(Supl 4):26-9

17 What is maturity onset diabetes of the young (MODY)? Monogenic form of diabetes, usually first occurs during adolescence or early adulthood Up to 2% of diabetes in USA in people ages 20 and younger Different gene mutations cause MODY - all limit insulin production Clinical features depend on gene mutations Certain mutations may have slightly elevated glucose and remain stable, have mild or no symptoms of diabetes, and do not develop any long-term complications Other mutations require treatment with insulin or sulfonylureas Typically family history of diabetes in multiple successive generations

18

19 MODY subtypes

20 MODY etiology Mutation of glucokinase gene (MODY 2) > reduction in β-cell glucokinase activity > decreased glucose phosphorylation and glucose-stimulated insulin release at any blood glucose concentration MODY-associated transcription factors hepatocyte nuclear factor (HNF) 4α (MODY 1), HNF-1α (MODY 3), insulin promoter factor 1 (IPF-1 [MODY 4]), HNF-1β (MODY 5), and neurogenic differentiation factor 1 (NeuroD1), or beta-cell E-box transactivator 2 (BETA2 [MODY 6]) function in nucleus of the β-cell and regulate transcription of the insulin gene (either directly, as in the case of HNF-1α, HNF-1β, IPF-1, and NeuroD1 or BETA2, or indirectly, through effects on the expression of other transcription factors, as in the case of HNF-1α); they also regulate transcription of genes encoding enzymes involved in the transport and metabolism of glucose as well as other proteins required for normal β-cell function

21 The UNITED biomarker screening pathway to investigate etiology of diabetes in patients diagnosed at age 30 years or younger. Genetic testing is carried out on all patients who have endogenous insulin (UCPCR 0.2 nmol/mmol) and do not have either GAD or IA2 islet autoantibodies. Patients without endogenous insulin or with GAD and/or IA2 islet autoantibodies are classed as having type 1 diabetes. Beverley M. Shields et al. Dia Care 2017;40: by American Diabetes Association urinary C-peptide/creatinine ratio (UCPCR)

22 Flow chart of patients recruited as part of UNITED. Biomarker screening pathway in 1,376 patients with no known genetic cause for their diabetes in Exeter and Tayside. Beverley M. Shields et al. Dia Care 2017;40: by American Diabetes Association

23 Biomarker screening pathway for monogenic diabetes is a systematic, cheap (U.K. UCPCR cost of and antibodies cost of 20), easily implemented approach to screening all patients with young-onset diabetes Beverley M. Shields et al. Dia Care 2017;40:

24 Monogenic Insulin Resistance (Lipodystrophy, Type A-insulin resistance, etc.)

25 How is monogenic diabetes managed? Depends on specific genetic subtype In certain forms of MODY and NDM can be treated with sulfonylurea Other people may need insulin Some people with MODY may not need medications and are able to manage their diabetes with lifestyle changes All based on the results of genetic testing

26 US Pharm. 2013;38(10)(Diabetes suppl):3-6.

27

28 Pancreatogenic (Type 3c) Diabetes Pancreatogenic diabetes is a form of secondary diabetes, associated with disease of the exocrine pancreas Most common disease of the exocrine pancreas associated with the development of diabetes is chronic pancreatitis also, due to pancreatic cancer post-pancreatectomy diabetes diabetes is due to impairment in pancreatic endocrine function related to pancreatic exocrine damage due to acute, relapsing and chronic pancreatitis (of any etiology), cystic fibrosis, hemochromatosis, pancreatic cancer, and pancreatectomy, and other, such as neonatal diabetes due to pancreatic agenesis Rickels MR, Bellin M, Toledo FGS, Robertson RP, Andersen DK, Chari ST, et al. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis:. Recommendations from PancreasFest Pancreatology 13: , Gudipathy L, Rickels MR. Pancreatogenic (Type 3c) Diabetes, Version 1.0, September 1, 2015 [DOI: /panc ]

29

30 Pancreatogenic (Type 3c) Diabetes Clinical Presentation Exocrine insufficiency usually pre-dates endocrine insufficiency in chronic pancreatitis > most patients with T3cDM have history of pancreatitis with abdominal pain, steatorrhea or maldigestion with nutritional deficiencies and glucose intolerance May also present with maldigestion and/or abdominal pain without a prior diagnosis of chronic pancreatitis, or even may be asymptomatic except for glucose intolerance or diabetes

31 Pancreatogenic (Type 3c) Diabetes Pathology and Pathogenesis The pathogenesis of T3cDM is due to decreased insulin secretion caused by reduction in islet number and their functional capacity because of extensive fibrosis and sclerosis Mechanism by which scarring of pancreatic tissue induces insulin deficiency is explained by anatomical and functional interplay between pancreatic islets and acinar tissue

32 Pancreatogenic (Type 3c) Diabetes Management Control of hyperglycemia to achieve and maintain the HbA1c <7% for the management of T3cDM, as with T1DM and T2DM, to minimize the risk of micro- and possibility macrovascular complications. Lifestyle modifications Anti-hyperglycemic oral agents Insulin Since the principal endocrine defect is insulin deficiency, insulin therapy is the preferred treatment for most patients

33 Cystic Fibrosis-Related Diabetes Pathophysiology complex primary defect: insulin insufficiency in essentially all CF patients related to collateral damage to the islets as exocrine tissue is destroyed not all CF patients develop diabetes metabolic outcome is influenced by severity of inflammation and infection, genetic susceptibility, malnutrition, and? CF chloride channel defect

34 Cystic Fibrosis-Related Diabetes Pancreatic pathology Abnormal chloride channel function results in thick viscous secretions and obstructive damage to the exocrine pancreas with progressive fibrosis and fatty infiltration > disruption and destruction of islet architecture > loss of endocrine β-, α-, and pancreatic polypeptide cells β-cell destruction not related to autoimmune disease

35 Cystic Fibrosis-Related Diabetes The role of insulin insufficiency Primary defect: severe but not absolute insulin insufficiency Virtually all exocrine insufficient patients with CF have β-cell dysfunction Fasting insulin and C-peptide initially normal Delay and blunting of peak insulin secretion during OGTT Delayed insulin secretion related to loss of first phase insulin secretion Found even in CF patients with normal glucose tolerance Glucagon secretion is also impaired in CF because total islets are destroyed The role of insulin resistance In CF patients without diabetes, insulin sensitivity intact Insulin resistance likely related to more severe illness Insulin resistance acutely increased during periods of active infection CF patients with diabetes are modestly insulin resistant, with both decreased peripheral glucose uptake and poor insulin suppression of hepatic glucose production Insulin resistance is not as important as insulin insufficiency in CFRD

36 How is CFRD treated? Keeping blood glucose at normal levels (usually with insulin but oral anti-diabetic drugs can be used) Maintaining an active lifestyle (150 minutes of moderate aerobic exercise per week) Eating healthy foods Insulin improves nutrient absorption in order to maintain healthy body weight and nutritional status Insulin deficiency can worsen malnutrition > protein and lipid catabolism is accelerated in chronic infections Exercise is important to maintaining good lung function and improving the body s response to insulin

37

38 Mitochondrial diabetes

39 Mitochondrial diabetes ~ 1% of all cases of diabetes due to mutations in the mitochondrial DNA Commonest mutation is the m.3243a>g, associated with the maternally inherited diabetes and deafness (MIDD) Often misclassified as T1 or T2DM Presence of diabetes, deafness and a family history of the above in maternal relatives > suspicion of MIDD Genetic testing should be pursued Treated initially with oral hypoglycemics, but early use of insulin is commonly needed due to insulin deficiency

40 Mitochondrial Diabetes Pathogenesis Mitochondrial DNA is only inherited from mother (due to the degradation of mitochondria in the spermatic cells upon fertilization) m.3243a>g mutation can only be transmitted via mother Both sexes can have mutation and manifestations of the disease Possible explanations for the diabetogenic effect of the m.3243a>g mutation? Mutation affects tertiary structure of the mitochondrial trnaleu > abnormal function of complex 1 and 4 of mitochondrial respiratory chain Metabolically active organs (pancreatic islets, cochlea, retina, muscles, kidneys, heart, brain) affected Impaired insulin secretion in carriers of m.3243a>g mutation Attenuated production of ATP from ADP by mutant mitochondria in β-cells might affect closure of the KATP channel and release of insulin

41 Mitochondrial Diabetes Other clinical features in MIDD Sensorineural deafness Due to cochlear involvement In about 75% of diabetic patients Commonly precedes the diagnosis of diabetes More common and more severe and rapidly progressive in men Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) m.3243a>g mutation results in continuum of clinical manifestations from diabetes or deafness only to MIDD and MELAS Psychiatric disorders severe depression, schizophrenia and various phobias Macular retinal dystrophy Commonest ophthalmic manifestation of the m.3243a>g mutation (>80% of MIDD) Both pigmented retinal lesions and atrophy of either the choroid or the retinal epithelium reported Muscular involvement Proximal, exercise-induced muscle cramps or weakness (~40% of MIDD patients) Cardiac involvement Premature cardiac death Left ventricular hypertrophy, cardiac autonomic neuropathy, various arrhythmias (e.g. Wolff- Parkinson-White syndrome, atrial fibrillation) End-stage renal failure without features of diabetic nephropathy Often develops before diagnosis of diabetes or deafness Presence of deafness occasionally leads to misclassification of these patients as X-linked Alport disease Endocrine manifestations Short stature (deficiency of the Growth Hormone Releasing Hormone from hypothalamus) Low BMI (insulin deficiency, or due to loss of adipose or muscle tissue mass)

42

43

44 Thank You!