DM Type- 2

 

• Pathophysiology

  Complex pathophysiology characterised primarily by insulin resistance and, to a lesser extent, impaired insulin secretion.

  Obesity is a key risk factor. Effects may be mediated by:

  • Free fatty acids impairing insulin-stimulated glucose uptake.
  • Altered cytokine release from adipocytes ('adipokines'), including those involved in metabolism (leptin, adiponectin) and inflammation (TNF-alpha, chemokines).

  Part of the metabolic syndrome:

  • Central obesity (↑waist circumference).
  • Hypertension
  • Dyslipidaemia: ↑triglycerides, ↓HDL.
  • ↑Glucose

• Risk factors

  • Obesity
  • Demographic: age, male, Asian.
  • Alcohol use
  • Genetic factors, so family history.
  • PCOS
  • Often preceded by 'pre-diabetes': impaired glucose tolerance (7.8-11 random glucose) or impaired fasting glucose (6.1-6.9 fasting glucose).

• Management

  Lifestyle and monitoring

  Lifestyle:

  • Advise all patients on dietary changes – ↓calories, ↑fibre, ↑low glycaemic-index carbs – and ↑exercise, which improves insulin sensitivity.
  • Very low calorie diets – 400-800 cals/day – can be considered for rapid weight loss before surgery (e.g. knee replacement), but weight is usually regained.

  Monitoring:

  • Check HbA1c every 3-6 months initially, then every 6 months once stable.
  • No need to finger prick for glucose, unless on insulin or there are suspected hypos.

  Medical

  If HbA1c >48 mmol/mol (6.5%) and lifestyle changes ineffective, start oral hypoglycemic agents (OHA):

  1. Initial monotherapy: metformin is 1st line. If not tolerated or contraindicated, consider sulfonylurea, glitazone, DPP4 inhibitor, or SGLT2 inhibitor.
  2. Dual therapy: if HbA1c stays >48 mmol/mol, add sulfonylurea. If high risk of hypos or their consequences (e.g. driver at work), consider glitazone, DPP4 inhibitor, or SGLT2 inhibitor.
  3. Triple therapy or insulin: if HbA1c stays >58 mmol/mol (7.5%) despite 2 drugs, add DPP4 inhibitor, glitazone, or GLP1 agonist (if BMI >35), or alternatively consider insulin, starting with once/twice daily regimen and maybe later switching to MDI. Continue metformin if starting insulin, but review the continued need for other OHAs.

  Other issues:

  • Metformin and glibenclamide are OK in pregnancy.
  • All drivers on insulin must inform the DVLA.
  • Bus or lorry drivers on insulin or OHA must inform the DVLA, even OHAs not known to cause hypoglycaemia. It is now possible to be on insulin and drive a bus or HGV, but strict criteria regarding hypoglycaemia must be met.

  Perioperative management:

  • Major op: variable-rate insulin infusion.
  • Minor op: no OHA in the morning (except metformin and pioglitazone) and fluids only till op. Check capillary blood glucose. Restart OHA after operation with first meal, but avoid metformin if eGFR<30 (use alternative).

  Surgical

  Bariatric surgery:

  • Offer to all patients with a BMI ≥35.
  • Consider for all patients with a BMI ≥30.

• Biguanides

  Metformin is the only biguanide.

  Mechanism

  • ↓Gluconeogenesis.
  • ↑Insulin sensitivity.

  Contranidictions

  • Significant renal impairment.
  • Those at risk of tissue hypoxia: dehydration, sepsis, and acute heart, respiratory, or liver impairment.
  • Iodine-containing radiocontrast: stop metformin day before if needed.

  Side effects

  • GI: nausea, diarrhoea, or vomiting. Minimize by taking with or after food. Start at a low dose then titrate up.
  • Lactic acidosis, hence the contraindication when at risk of tissue hypoxia.

• Sulfonylureas

  Gliclazide, glibenclamide, glimepiride.

  Mechanism

  Binds ATP-sensitive K+-channel of pancreatic β-cell → ↑insulin secretion.

  Dose

  Titrate up until glucose control.

  Side effects

  • Hypoglycaemia
  • ↑Weight
  • SIADH

• Thiazolidinediones (aka glitazones)

  Pioglitazone is the only currently-licensed glitazone.

  Mechanism

  PPARγ agonist → ↓insulin resistance, ↑lipogenesis, ↓lipolysis, ↓plasma fatty acids.

  Side effects and contranidications

  Risk increased by glitazones so contraindicated if present:

  • Heart failure and oedema.
  • ↑LFTs
  • Bladder cancer (current, previous, or suspected).

  Other side effects:

  • ↑Appetite and ↑weight.
  • Fractures

• GLP1 agonists

  Exenatide, liraglutide, lixisenatide.

  Mechanism

  • Mimics glucagon-like peptide-1 (aka incretin), a hormone from GI L-cells that acts on β-cell to secrete insulin.
  • Also ↓glucagon, ↓appetite, ↓weight, slows gastric emptying.

  Route

  Unlike most hypoglycaemic agents for type 2 diabetes, they are given subcut not PO.

  Problems

  • Nausea and vomiting.
  • Contraindicated in kidney failure.
  • Expensive

• DPP4 inhibitors

  Sitagliptin, vildagliptin, alogliptin, linagliptin, saxagliptin.

  Mechanism

  Inhibit dipeptidylpeptidase-4, a GLP1 inactivator (hence work like GLP1 agonists).

  Problems

  • Side effects are uncommon, but include peripheral oedema, GI upset, and URTI.
  • Expensive

• SGLT-2 inhibitors

  Canagliflozin, dapagliflozin, empagliflozin.

  Mechanism

  Inhibit sodium-glucose cotransporter 2 in proximal nephron, blocking renal glucose reabsorption.

  Side effects

  • Urinary frequency and polyuria, leading to thirst.
  • GI: nausea, constipation.
  • DKA, often euglycemic (glucose <14 mmol/L).

• Hyperosmolar hyperglycaemic state (HHS)

  Formerly known as hyperglycaemic hyperosmolar non-ketotic (HONK) coma.

  Pathophysiology

  • ↑↑Glucose → osmotic shift out of cells → intracellular dehydration.
  • No ketoacidosis due to basal insulin which is sufficient to stop ketogenesis, but not to reduce glucose.
  • Usually old patient and first presentation of diabetes.
  • Can be precipitated by illness and dehydration.
  • In rare cases, mixed HHS and DKA states can occur, reflecting some degree of insulin deficiency.

  Signs and symptoms

  • Onset over several days: generalised weakness, leg cramps, visual impairment.
  • Signs of severe hypovolaemia.
  • Signs of underlying infection.
  • Later may develop confusion, lethargy, focal neuro signs, seizures, but only rarely coma (10%).

  Investigations

  Diagnostic criteria:

  1. Glucose >30 mmol/L.
  2. Serum osmolality >320 mOsm/kg.
  3. No significant ketosis: less than +++ on urine or <3 mmol/L.

  Other tests:

  • Bloods: FBC, CRP, U&E.
  • Septic screen if infection suspected.
  • ABG: should be normal.
  • ECG

  Management

  • Rehydrate with normal saline, slower than DKA (older population).
  • Give insulin after 1 hr, at half the rate of DKA as HHS is highly insulin sensitive. Not needed if glucose dropping with fluids alone. Glucose should drop by 3 mmol/L/hr.
  • Monitor fluid balance, glucose, and U&Es. Correct electrolytes if needed.
  • DVT prophylaxis.
  • Treat precipitant.

  Complications

  • Cerebral oedema.
  • PE
  • Ischaemia: MI, stroke.
  • Much higher mortality (>10%) than DKA, in part reflecting patients' underlying poor health.