DIABETES MELLITUS

DIABETES MELLITUS

1. A metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydraye, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both

   • excessive urination of sweet urine
   • identification of cause and subsequent treatment development major medical breakthroughs of the 20th century - 3 Nobel Prizes

2. CLASSIFICATION

   • Varied as more information elucidated, described either by treatment or onset: Insulin dependent diabetes mellitus (IDDM) Non-insulin dependent diabetes mellitus (NIDDM) Impaired glucose tolerance Juvenile-onset diabetes (IDDM) Adult-onset diabetes (NIDDM)
     • TYPE 1 DIABETES MELLITUS
       • lack of insulin due to pacnreatic inslet B-cell destruction (prone to ketoacidiosis)
     • TYPE 2 DIABETES MELLITUS
       • defect(s) in insulin secretion and with possible contribution of insulin resistance
     • GESTATIONAL DIABETES MELLITUS
       • hormonal changes in pregnancy
   • other causes include fibrocalculous pancreatopathy, pancreatitis, cystic fibrosis, tumours associated with endocrine glands

3. TYPE 1 DIABETES

   • autoimmne disease - antibodies raised mediating destruction of B- cells in the islets of Langerhans in the pancreas
   • limited number of cases where no antibodies and cause of islets destruction unknown (idiopathic type 1 DM)
   • rapid onset - thirst, polyuria, weight loss, ketoacidiosis, coma
   • CAUSES OF SYMPTOMS
     • POLYURIA
       • increased concentration of glucose in the plasma draws water out of cells by osmosis
       • creates electrolyte gradient (electrolytes in cell > electrolytes outsdie)
       • electrolytes move into extracellular fluid
       • osmotic diluresis - increase in glucose and Na+ and K+ loss
       • loss of fluid causes thirst, loss of ions causes weakness/coma
     • KETOSIS
       • 'starved state' mobilises fat metabolism
       • excess acetyl units covered to acetoacetic acid and B-hydroxybutyrate (ketone bodies/ketoic acids)
       • not required by brain/nervous tissue etc. as sufficient glucose to support these hence accumulates in the plasma (both completely dissociate) and lowers pH - blood buffer capacity overwhelmed
   • GENETICS
     • predominant in north european Caucasians
     • genetic predisposition to the formation of autoantibodies identified - increasing evidence that associated with the human leukocyte antigen (HLA) locus on chromosome 6
     • environmental factors precipate the development
     • not a disease of the young
     • accounts for 10-20% of cases of DM

4. TYPE 2 DIABETES

   • accounts for up to 90% of cases in a population
   • increasing rapidly in 'westernised societies' and developing countries
   • no autoantibodies produced
   • may have accompanying hyperinsulinaemia
   • onset may be slow and unnoticeable in the early stages
   • GENETICS
     • 250+ candidate genes tested for association with or linkage to type 2 DM
       • a few show strong association - majority have been weak (possible polygenic influence)
     • association within families would initially indicate genetic cause but may also be influence of family behaviour

5. GENETIC RISK FACTORS

   • maturity-onset diabetes of the young (MODY) - autosomal dominant inheritance
   • linkage found in 5 chromosomes in genes associated with insulin response and glucose metabolism
   • insulin receptor - 50+ mutations identified in the gene; some cause extreme resistance - severe syndromes vs. limited survival
   • mitochondrial gene defects - throught to account for ~1.5% of diabetics, results in defects in insulin secretion, associated with deafness

6. HYPERGLYCAEMIA

   • causes non-enzymic addition of glucsoe to proteins (especially plasma proteins) - advanced glycation end products (AGEs)
   • glucose added to terminal amino groups, particularly lysine
   • glycosylated proteins deposit increase thickness basement membrane in capillaries
   • cause smooth msucle to proliferate on large vessels (decrease diameter of lumen)
   • glycosylation of lipoproteins leads to ATHEROSCLEROSIS
   • INCREASE IN GLUCOSE CONCENTRATIONS IN CELLS INSENSTIVE TO INSULIN...
     • glucose converted to fructose and sorbitol (increase in osmotic pressure)
     • increase pressure causes nerve damage/eye problems
   • INCREASE IN PRODUCTION OF PLATELETS DERIVED PRODUCTION/GROWTH FACTOR...
     • increases platelet aggregation
     • increases micoemboli
     • increases lesions of vascular tissue

7. TREATMENT

   • TYPE 1 DM
     • insulin and dietary intervention
   • TYPE 2 DM
     • lifestyle
     • range of drugs promoting insulin
     • secretion/resistance/liver metabolsim of glucose/dietary intake of glucose