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  • 1. 1 SUMMER UNIVERSITY ON DIABETES, DUBROVNIK 2000 CROATIA - CEEPUS GENETIC ASPECTS OF DIABETES Eliška Marklová  Introduction  Classification - Terminology - 4 Groups  Genetic background of Type 1, Type 2, Other SpecificTypes  Genetic diseases associated with diabetes Almost every aspect of human biology - influenced by genetic constitution: colour of skin, hair and eyes, body weight, susceptibility to diseases or their complications, response to therapies, person reactions to environmental factors. In the last 50 years - > 500 inborn errors of metabolism (inherited metabolic diseases) identified - monogenic - affecting anabolic, catabolic, transport or structural functions. One of the most difficult challenges for researchers is to find genes involved in diseases that have a complex pattern of inheritance, such as those that contribute to asthma, cancer, cardiovascular diseases, mental illness or diabetes: • no one gene has the yes / no power • more than one mutation required - disease is manifest • a number of genes may each make a subtle contribution to a person's susceptibility to a disease
  • 2. 2 GENETIC ASPECTS OF DIABETES There doesn't exist perfect classification in human medicine. Both the American Diabetes Association (ADA) and the World Health Organisation (WHO) working groups met separately to discuss and, in general, similar conclusions were reached in 1999 - Congress - strategic plan for 21 Century. THE NEW CLASSIFICATION OF DIABETES MELLITUS (DM) include: • Type 1, autoimmune + non-autoimmune, β-cell destruction • Type 2, varying degree of insulin resistance + hyposecretion • Gestational DM • Other Specific Types (the cause is better defined) Regardless of underlying cause, DM is subdivided into: 1) insulin requiring for survival (to prevent ketoacidosis, coma and death); 2) insulin requiring for metabolic control, rather than survival (insufficient endogenous insulin secretion for normoglycaemia) and 3) not insulin requiring (non- pharmacological control or drugs other than insulin used). All types of DM have some genetic determinants. These "diabetogenic genes (alleles)" make some individuals • more susceptible to developing diabetes than others, • more susceptible to complications, • they influence diabetes-associated phenotypes as obesity and hyperlipidemia. Knowledge of the genetic defects may help to identify individuals at risk and targets for specific treatment, it may help in prevention.
  • 3. 3 GENETIC ASPECTS OF DIABETES ROLE OF GENETICS IN TYPE 1 DM Type 1: Insulin-Dependent Diabetes Mellitus (IDDM) • Clinical • Onset: Usually < 45 years • Body weight: Usually lean • Genetics: < 10% of 1st degree relatives affected • Immune: Increased incidence of associated autoimmune phenomena (Hashimoto´s thyroiditis, Addison´s disease) • Metabolism: Ketosis prone; plasma C-peptide low or undetectable • Treatment: Insulin • Pathology • β-cell destruction • Usually leads to absolute insulin deficiency • Etiologies: Immune-mediated; Genetic; Idiopathic; Environmental (twins) • Associated with antibodies to IA-2 glutamate decarboxylase65; Insulin; β-cells (in 85-90% of individuals with Type I) • 3 main susceptibility haplotypes in Caucasians (95%) • HLA-DQ • HLA-DR3, Commonly also X-linked • HLA-DR4 • Genetic predisposition chromosome loci: IDDM # 1 (6p21.3) 6 (18q12-q21) 11 (14q24.3-q31) 2 (11p15.5) 7 (2q31) 12 (2q33) 3 (15q26) 8 (6q25-q27) 13 (2q34) 4 (11q13) 10 (10p11-q11) 15 (6q21) 5 (6q24-q27) GENETIC ASPECTS OF DIABETES
  • 4. 4 Type 1 DM - strongly influenced by genes controling the immune system MHC (Major Histocompatibility Complex) proteins = HLA (Human Leucocytes Antigens or transplantation antigens) - number of sequence variations (alleles) = kind of cellular signature - determined by genes - assure that only foreign substances will be recognised and destroyed In people susceptible to Type 1 DM this recognition system fails - the own insulin-producing beta cells are seen as foreign. chrom 6 Rate of β-cells destruction - variable: rapid or slow Still healthy people with particular HLA types in danger. Although genes for particular HLA DQ, DR3 and DR4 types on chromosome 6 clearly play a role, studies indicate that many other chromosome loci have some influence on susceptibility. Insulin gene on chromosome 11 and cytotoxic T-lymphocyte antigen gene on chromosome 2 + other mutations may contribute. LADA Type 1 -Latent (Late-onset) Autoimmune Diabetes in Adults, rare type with a very slowly progressive form of autoimmune process (in 10 -15 % of the Type 2) usually adipose, not over 40 y function of the β-cells initially only low-grade degraded, lately a rapid waste of the insulin secretion Differencies: from Type 1 - still remainder secretion of insulin from Type 2 - anti-bodies present Type 1 "idiopathic" - in some subjects (African and Asian origin) - permanent insulinopenia, no autoimmunity A genetic predisposition to autoimmune destruction of beta cells is also related to enviromental factors that are still poorly defined. Type I DM - multifactorial disease.
  • 5. 5 GENETIC ASPECTS OF DIABETES GENES CONTRIBUTING TO THE DEVELOPMENT OF TYPE 2 DM Type 2 - the most common form of diabetes - confusing entity; enlistment - limited value for pathophysiology and treatment not requiring insulin treatment for survival wide variety of phenotypes Genetic factors play a critical role in the development of Type 2 DM and may be even more important than in Type 1 disease - genes controlling synthesis of the proteins involved ♦ in insulin action ♦ or insulin secretion basic defect in Type 2 remains uncertain; defining the genetic influences - means ↑ understanding of this disease, new, more effective therapy, prevention programs Type 2: Non Insulin-Dependent Diabetes Mellitus (NIDDM) • Onset: Usually > 30 years • Genetics: > 20% of 1st degree relatives affected • Immune: No associated autoimmune phenomena • Body weight: Usually obese • Metabolism: Ketosis resistant • Treatment: Weight loss ± Oral agent or Insulin • Subtype spectrum • Predominantly insulin resistant with relative deficiency • Predominant insulin secretory defect with insulin resistance • Predisposing factors: General • Age > 45 years • Positive family history • Race: Native- Asian- African American; Hispanic • Features: Obese; hypertensive; Dyslipidemic; h/o Gestational DM GENETIC ASPECTS OF DIABETES
  • 6. 6 Type 2 diabetes is strongly associated with many other important genetically influenced traits, including obesity (abdominal - pear type) OBS gene ⇒ 7 dyslipidemia, accelerated atherosclerosis, hypertension (which together form the Metabolic Syndrome), and even polycystic ovarian disease. Prognosis of Type 2 DM: The severity can either • regress (e.g. with weight reduction) • progress (e.g. with weight gain) • stay the same. GENETIC ASPECTS OF DIABETES
  • 7. 7 Specific genetic subtype of Type 2 DM, usually autosomal dominant, monogenic def. < 25 y, impaired insulin secretion, called MODY (Maturity-Onset Diabetes in Youth) 1-5 • MODY 1 Hepatocyte nuclear factor-4-α; Chromos. 20q12-q13.1 • Insulin secretory defect; 2o insulin resistance • Clinical DM Type: NIDDM • Severe diabetes • Onset: Post pubertal • Complications: Frequent • Frequency: Rare • MODY 2 Glucokinase; Chromos. 7p15-p13; 46 different mutations Pancreas: Impaired insulin secretion   Liver: ↓ processing of glucose to glycogen *** • DM types: MODY; NIDDM; Gestational • Mild diabetes • Onset: Childhood • Complications: Rare • Frequency: Common (1 % of Type 2 DM); Worldwide • MODY 3 Hepatic transcription factor 1 (TCF1) 12q24.2; 40 mut • Insulin secretory defect; No insulin resistance • Severe diabetes • Onset: Post-pubertal • Complications: Frequent • Frequency: Common; U.S., Europe, Japan • MODY 4 Insulin promoter factor (IPF1); Chromos 13q12.1 Pancreatic agenesis & Neonatal DM • MODY 5 Hepatic transcription factor-2 (TCF2) 17cen-q21.3 • Mild diabetes + Renal disease: Non-diabetic GENETIC ASPECTS OF DIABETES
  • 8. 8 **** glycolytic enzyme glucokinase - "glucose sensor" in the insulin-secreting β-cell; mutations ⇒ loss-of-function of enzyme ⇒ ↓ sensitivity of the β-cell to glucose ⇒ ↑ blood glucose levels required to stimulate insulin secretion; other enzymes - breakdown or formation of glucose - might contribute GENETIC ASPECTS OF DIABETES Other subtypes of Type 2 DM
  • 9. 9 • NIDDM Predisposition factors in Mexican Americans from Starr County, Texas: gene termed NIDDM, Chromosomes 2q & 15q21.1 + other 13 mutations • NIDDM Insulin receptor substrate (IRS) 1 Chromosome 2q36; involved in binding other molecules to insulin receptor impaired receptor binding Mediates insulin action: Prominent role in skeletal muscle Clinical DM Type: NIDDM • NIDDM Solute carrier family 2, member 2 (SLC2A2): Glucose transporter 2 (GLUT2) Chromosome 3q26.1-q26.3 Genetics: Mutation: Val197Ile GLUT2 Protein - Function: Low-affinity glucose transporter • NIDDM Neurogenic differentiation factor Chromosome 2q32  Onset: 30 to 59 years • NIDDM Mitogen-activated protein kinase 8-interacting protein 1 (MAPK8IP1) Chromosome 11p12-p11.2 • Mitochondrial  Clinical DM type: NIDDM & Deafness;  Point mutations in mitochondrial DNA; identical lesion occurs in the MELAS syndrome (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like syndrome) - different phenotypic expressions of the same genetic lesion • Hyperproinsulinemia Chromosome 11p15.1-p15.5  Clinical DM type: NIDDM; MODY;  inability to convert proinsulin to insulin GENETIC ASPECTS OF DIABETES OTHER SPECIFIC TYPES of DM include various forms.
  • 10. 10  Genetic defects of • beta-cell function: B-cells agenesis with neonatal DM • insulin action: ♦ impaired β-cell differentiation: Chromosome 6 (MHC - 5-cM portion) - congenital absence of β-cells - normal- appearance of pancreatic islets, early death, autosomal recess ♦ impaired insulin receptor Insulin receptor DM, Insulin resistant DM  Associated with Acanthosis Nigricans (hyperpigmentosis and skin keratosis) former Type A insulin resistance, Chromosome 19p13.2; hyperinsulinaemia + modest hyperglycaemia - or symtomatic diabetes; virilization + polycystic ovaries  Leprechaunism (characteristic facial features) and Rabson-Mendenhall syndrome (abnormalities of teeth and nails + pineal hyperplasia) - two paediatric syndromes - ⇒ extreme insulin resistance, caused by: decreased insulin binding, reduced affinity, reduced phosphorylation or number of receptors • Peroxisome proliferator-activated receptor γ (PPARG 1-3); Chromosome 3p25; members of the nuclear hormone receptor subfamily of transcription factors. PPAR-gamma is believed to be involved in adipocyte differentiation.  Diabetes mellitus, insulin-resistant, + Acanthosis nigricans & Hypertension • Transient neonatal; chromoseme 6q22-6q24; neonatal DM very rare (1 : 400,000); in 50 % - transient, resolves at 3 months, often type II diabetes reappears GENETIC ASPECTS OF DIABETES
  • 11. 11 The insulin receptor - tetramer of 2 alpha and 2 beta subunits, both coded by a single gene and are joined by disulfide bonds, a mechanism parallel to that of the ligand, insulin. Mutation in either the structural gene or some of the processing steps may lead to insulin resistance. • Hyperproinsulinemia Chromosome 11p15.1-p15.5  Clinical DM type: NIDDM; MODY; inability to convert proinsulin to insulin PROINSULIN INSULIN OTHER SPECIFIC TYPES of DM - continue  Diseases of the exocrine pancreas (e.g. pancreatitis, cystic fibrosis Pancreatic agenesis: Insulin promoter factor 1)  Endocrinopathies (e.g. acromegaly);  Drug- or chemical induced Infections  Uncommon forms of immune-mediated diabetes
  • 12. 12 GENETIC ASPECTS OF DIABETES OTHER GENETIC SYNDROMES ASSOCIATED WITH DM Many genetic syndromes are accompanied by an increased incidence of DM. These include the chromosomal abnormalities of Down´s syndrome, Klinefelter´s syndrome, Turner´s syndrome and other syndromes. Down's syndrome one of the most common genetic birth defects Frequency: 1: 800 - 1000 Caused by an extra chromosome 21 in each cell = trisomy 21, or the extra 21, attached to another chromosome (translocation), or rare mosaic Down syndrome - normal number///extra 21 Symptoms:mental retardation, facial features, heart, visual, hearing defects Turner's syndrome rare chromosomal disorder of females (normal 46, XX) Frequency 1: 2 500, Caused by an error during the division (meiosis) of a parent's sex cells 1) genetic defect of one X chromosome (46,XX), 2) reduced number (45,X) with some Y chromosomal material attached, or 3) 45,X/46,XX mosaicism Symptoms: short stature, no sexual development, heart and hearing defects Klinefelter syndrome in males (normal men 46, XY) Frequency 1:500-1000 live male births Caused by an extra X chromosome (47,XXY) possible variants XY/XXY mosaic or XXXY, XXXXY, XXYY Symptoms: tall, small testes or hypogonadism, sparse facial and body hair, incomplete masculinization, emotional, and mental disorders Therapy: luteinizing hormone (pituitary gland) and testosterone
  • 13. 13 GENETIC ASPECTS OF DIABETES Barth syndrome X-linked (distal Xq28) disorder; no evidence for genetic heterogeneity characterised by cardioskeletal myopathy in males usually fatal in childhood Friedreich's Ataxia Most common inherited ataxia (instability), onset before age 25 Frequency: 1 : 50 000 Genetics: autosomal recessive, FRDA gene on chromosome 9q13, 9q13 (or two point mutations L106X and I154F) encodes the conserve mitochondrial protein frataxin; expression in liver and skeletal muscle Symptoms: progressive gait and limbs ataxia + central and peripheral nervous systems and heart affection + diabetes mellitus / impaired glucose tolerance (30%)., optic atrophy, deafness, wheelchair before 25 years, death There is great clinical resemblance to mitochondrial encephalopathies as well as reduced respiratory enzyme activities. Schmidt syndrome - association of diabetes mellitus, Addison disease and myxedema, may be due to unusual susceptibility to immunologic derangement particular immune-response gene linked to HLA on chromosome 6 Wolfram syndrome rare autosomal recessive disorder called DIDMOAD (Diabetes Insipidus and Mellitus with Optic Atrophy and Deafness), paranoid delusions, severe dementia, hallucinations, depression and violent behaviour - additional symptoms Cystic fibrosis autosomal recessive disorder, chromosome 7q31-q32 Frequency: 1 : 3 000 Onset: newborn, infant Symptoms: growth retardation, infections, impaired glucose tolerance, pancreas and respiratory insufficiency, liver cirrhosis or fibrosis, Therapy: mucolytics, antimicrobials, heart / lung / pancreas / liver transplantation
  • 14. 14 GENETIC ASPECTS OF DIABETES GESTATIONAL DIABETES OF PREGNANT Individuals at high risk for gestational DM includes women of higher age (frequent gene mutations), from certain high-risk ethnic groups, those with previous history of ♦ glucose intolerance or ♦ with a history of large for gestational age babies. Forty years ago, the structure of DNA had just been solved and the precise number of human chromosomes was still under debate. We now know that there are 46 human chromosomes, which between them house 3000 million base pairs of DNA and encode about 30,000 to 120,000 proteins. These coding regions make up only about 2% of the genome (the function of the remaining 98% is unknown) and some chromosomes have a higher density of genes than others. Quite recent advances in molecular biology and genetic research connected with the human genome sequencing (significance compared with the atom splitting) might revolutionized medical research. The physical map has assisted directly in identifying about 100 disease-causing genes. Let us hope that today's diabetic patients will soon profit from this great achievement.