Genetics of diabetes

From Ganfyd

Polygenetic diabetes mellitus

There are multiple associations of Type 1 and Type 2 diabetes mellitus with particular genotypes. These associations only predispose to the respective condition and are not predictive nor have any known therapeutic implications. They are consistent with Type 1 diabetes being an autoimmune disease and Type 2 diabetes being a polygenetic condition like essential hypertension.

Type 1 diabetes associations

• HLA DQ haplotypes show strongest association.
• Other major histocompatibility complex (MHC)associations
  • HLA DR haplotypes
  • Major histocompatibility complex I related gene A (MIC-A) gene
• Genes outside MHC
  • Lymphoid protein tyrosine phosphatase (PTPN22) gene
  • Cytotoxic T lymphocyte-associated antigen-4 CTLA4 gene
  • Insulin INS gene.

Type 2 diabetes associations

There are multiple weak but proven associations^[1].Attempts to use the multiple known genetic loci associated with risk of type 2 diabetes to predict diabetes are little more successful than using classic clinical risk factors^[2].

The reproducible associations to date include:

• KCNJ11 E23K polymorphism^[3]
  • Present in 40% of population increases risk of diabetes by a fifth.
• TCF7L2^{[3] [4]}
• PPARG^[3]
• CDKAL1^[4]
• IGF2BP2^[4]
• JAZF1^{[5] [4]}
• CDC123^[5]
• CAMK1D^[5]
• TSPAN8/lGR5^[5]
• THADA^[5]
• ADAMTS9^[5][4]
• NOTCH2^[5]
• Region on chromosome 9

Monogenetic diabetes mellitus

Up to two per cent (probably less, but the papers will be biased towards tertiary centres) of those with diabetes mellitus actually have monogenetic diabetes. This can have very important therapeutic and prognostic implications if diagnosed. To date 6 different genes have been associated with maturity-onset diabetes of the young (MODY)^[6].

Maturity-onset Diabetes of the Young (MODY)

• Glycolytic enzyme glucokinase
  • Onset at birth
  • Stable hyperglycaemia
  • Complications rare
  • Treat by diet
• Beta cell transcription factors (complications frequent)
  • HNF1α MODY (hepatic nuclear factor-1α maturity-onset diabetes of the young) is most common
    • Incidence 1:20,000 in Uk
    • Age of onset results in misdiagnosis typically as Type 1 (younger patients) or Type 2 (older patients)
    • Autosomial dominant
    • Little risk microvascular complications
    • Extremely sensitive to sulphonylureas(four times as sensitive as type 2 diabetics)
      1. Insulin may not be required
         • Unnecessary risk hypos
         • Quality of life on sulphonylureas much better
      2. Metformin as typically now recommended in guidelines the wrong drug to use -major loss glycaemic control!
  • HNF4α monogenetic diabetes
    • Also respond to sulphonylureas
  • HNF1β monogenetic diabetes
  • Insulin promoter factor 1 monogenetic diabetes
  • NeuroD1 monogenetic diabetes

Neonatal Diabetes Mellitus

• Multiple rare genetic causes
• Commonest is of Kir6.2 subunit of beta cell K⁺_ATP channel
  • Often a spontaneous mutation
  • Half of permanent neonatal diabetes mellitus (PNDM)
  • Beta cell remains in hyperpolarised state so can not secrete insulin
  • Many mutations respond to high dose sulphonylureas ( Act on the sulphonylurea receptor 1 (SUR1) subunit of K⁺_ATP channel)^[7]
  • Presentation
    • Low birth weight
    • At diagnosis (can be up to 6 months) marked hyperglycaemia or even ketoacidosis
    • No pancreatic autoantibodies
    • Rarely in context of DEND syndrome
      • Developmental delay
      • Epilepsy
      • Neonatal Diabetes
        • One variety, the V59M mutation responds specifically to glibenclamide with improved muscle strength and concentration as predicted by glibenclamide actions on the SUR2 receptor on nerve and muscle cells)

References