Genetics of Diabetes

• Diabetes


  Greek word meaning "passing through" or "siphon"
• Diabetes Insipidus


  • Characterized by frequent and heavy urination
  • Excessive thirst and an overall feeling of weakness
  • Urine is tasteless (insipid)
  • Defect in the pituitary gland or in the kidney (ADH)
  • Blood glucose levels are normal
• Diabetes Mellitus


  • Mellitus means honey or sweet
  • Metabolic disease
  • Hyperglycaemia - Abnormally high blood glucose levels due to either lack of insulin or failure to respond normally to insulin
• Types of diabetes mellitus

  • Insulin dependent - Type 1 (T1DM)
  • Insulin "independent" - Type 2 (T2DM)
• Type 1 diabetes (T1DM)


  • Rare and onset is almost always during childhood (~0.4% of the population affected)
  • Virtually "curable" by treatment with sophisticated insulin regimes
  • High incidence of renal, retinal, and vascular complications
  • Referred to as IDDM in earlier work
• Type 2 diabetes (T2DM)


  • Very common, predominantly arising in middle age (up to 10% of the population affected)
  • Cause is unknown - poor prognosis - dreadful record of morbidity and mortality
  • Known as NIDDM in early genetics work
• Monogenic


  • Single gene forms of diabetes (1-2% of the population affected) - MODY
  • Single gene mutations cause diabetes
• Gestational diabetes


  Glucose intolerance affecting ~10% of women during pregnancy (usually temporarily)
• Increase in blood glucose concentration (glycemia) in Type 1 diabetes

  1. Subjects are insulin deficient

  2. Insulin promotes the uptake and utilization of glucose by tissues

  3. Autoimmune reaction - T-cell–mediated destruction of the pancreatic insulin-producing β-cells

  4. Arises early in life
• Insulin


  • Protein hormone secreted by b-cells of the pancreas
  • 51 amino acid residues
  • Molecular weight of 5.8 kDa
  • Isolated in 1921 by Sir Frederick Grant Banting & Charles Herbert Best from dog pancreas with help from biochemist James Collip & John Macleod
• Function of insulin


  • Promotes cellular uptake of glucose following a meal - mostly by the liver for storage as glycogen
  • Glycogen is then released gradually between meals to keep blood glucose at 5mM (glucose used mostly by the brain)
• Pancreas


  Releases exocrine hormones that go the liver first
• Type 2 diabetes (T2DM)


  • Hyperglycaemia defines T2DM
  • Too much glucose remains in the blood following a meal
  • Aetiology and cause remain unknown, but it is not due to insulin insufficiency (at least to start with)
  • Chronic hyperglycaemia has detrimental consequences for most tissues and organs - it causes micro and macro-vascular damage
• Assessing T2DM


  1. Need a mechanism/method that defines both its presence and its severity in individuals

  2. T2DM is fundamentally a failure of the mechanism(s) which underlie glucose homeostasis

  3. Need to generate a clear diagnostic protocol for measuring blood glucose in subjects suspected of having diabetes

  4. Protocol should be simple and easily reproducible worldwide
• Clinical diagnostic criteria for T2DM

  • Measure fasting blood glucose:
  • Below 6.1 mM - normal
  • Between 6.2 and 7 mM - suspected Impaired Glucose Tolerance (IGT)
  • Above 7 mM - suspected T2DM
• Oral glucose tolerance test (OGTT) results and interpretation

  • Normal: Fasting glucose < 6.1, 2 Hr post glucose load < 7.8
  • DM: Fasting glucose > 7.0 or 2 Hr post glucose load > 11.1
  • IGT: 2 Hr post glucose load > 7.8 and < 11.1
  • IFG: Fasting glucose > 6.1 and < 7.0
• Type 2 diabetes (T2DM)


  • Global issue - amongst the biggest killers in the developed world
  • Increasing prevalence - predicted to affect 300 Million people by 2025
  • Huge healthcare burden
  • Aetiology still largely unknown
  • GWAS has identified ~240 susceptibility loci
  • No overlap with T1DM loci - different aetiologies
  • Substantial Genetic contribution & Environment-Lifestyle
• Cystic fibrosis


  Predominantly genetic - Nutritional supplements have little effect
• Vitamin D deficiency


  Predominantly environmental - Gene therapy is not a rational starting point
• Diabetes clearly has both genetic & environmental components - multifactorial
• Twins


  • The "concordance" of T2DM diabetes in monozygotic twins (MZ) is almost 70% compared with 20–30% in dizygotic twins (DZ)
  • Higher than T1DM - ~50% MZ & ~12% DZ
• Family history


  • There is an increased risk of developing T2DM of about 40% if one parent has T2DM (slightly greater if the mother has T2DM)
  • 70% if both parents have diabetes
• The strong familial clustering of T2DM established by the 1980s clearly suggested a genetic basis
• Genetics of T2DM


  • In 1985 a WHO study group suggested that T2DM was an autosomal dominant disorder involving a single dominant gene and characterized by a variable penetrance dependent on both obesity and aging
  • In 1992 Froguel et al. demonstrated that mutation of the glucokinase gene caused early onset T2DM in a classic genetic pedigree, for the first time establishing that a monogenetic mutation could cause the disease
  • To date, there are about 30 distinct genes in which mutation can cause monogenic diabetes
• T1DM


  Type 1 Diabetes Mellitus
• T1DM


  • ~50% in monozygotic twins
  • ~12% in dizygotic twins
• Family history


  Increased risk of developing T2DM
• Increased risk of T2DM if


  • One parent has T2DM (40%)
  • Both parents have diabetes (70%)
• The strong familial clustering of T2DM clearly suggests a genetic basis
• WHO study group (1985)

  T2DM is an autosomal dominant disorder involving a single dominant gene with variable penetrance dependent on obesity and aging
• Froguel et al. (1992)


  Mutation of the glucokinase gene caused early onset T2DM in a classic genetic pedigree, establishing that a monogenetic mutation could cause the disease
• Monogenic diabetes (MODY)


  • There are about 30 distinct genes in which mutation can cause monogenic diabetes
• The sum total of monogenic mutations accounts for no more than 5% of existing T2DM
• In the overwhelming majority of cases, no clear genetic cause or aberration has been demonstrated to be responsible even in clear familial pedigrees with T2DM
• This has been clearly established by Genome Wide Association Studies (GWAS) in the past ten years or so
• There is irrefutable evidence that T2D has a strong "genetic" basis
• The concordance in monozygotic twins can be explained by foetal programming and is not such good evidence for genetic aetiology
• Lifetime risk of developing T2DM


  • ~40% in offspring of one parent with T2DM
  • Greater if the mother is affected
  • Nearly 70% if both parents have T2DM
• GWAS tells us that there are no strong genetic candidates for T2DM
• The predictive capacity of knowing a subject's BMI is more powerful than knowing their entire DNA sequence of 3 billion bases even alongside the most powerful computational analysis known