Type 2 Diabetes Mellitus

Background and Epidemiology

• Similarly, characterised by persistently high circulating blood glucose but instead due to resistance to the activity of insulin.
• Most common form of diabetes (90%)
• Prevalence increases with age (1/20 people >65 and 1/5 people >85)
• Estimated incidence of around 1.7 in 1000 people / year
• Diagnosis of exclusion (should rule out T1DM, and other types of DM prior to diagnosis)

Aetiology/Pathogenesis

• Age
• Weight/Obesity (central obesity > peripheral) and lack of physical activity
• Family History
• Hypertension and hypercholesterolaemia
• PCOS
• Insulin resistance is the underlying pathogenic process, although the exact mechanisms of this are not fully understood.
  • In early/pre-diabetic disease, the pancreas may compensate by producing more insulin
  • If the problem persists, the pancreas eventually can no longer keep up with blood sugar and may begin to become damaged (glycotoxicity)
  • This process is generally slower than that seen in T1DM

Presentation

• Because relatively small amounts of insulin are required to suppress lipolysis, this does not tend to occur in T2DM (cf T1DM) (neither does proteolysis). => NO weight loss/ketoacidosis
• Many patients are asymptomatic because the degree of hyperglycaemia is usually mild.  Non-specific symptoms e.g. fatigue and malaise are most common
  • Diagnosis is commonly incidental after blood tests (e.g. abnormal LFTs suggestive of NAFLD/check for diabetes)
• Patients with T2DM are typically obese/overweight (often central), will often have other cardiovascular risk factors e.g. Hypertension

Investigations

• See investigations for T1DM
• Check cholesterol levels

Management

1. Dietary and lifestyle advice
2. Metformin
   1. Or sulfonylurea if the patient is not overweight or if particularly high glucose levels
3. If HbA1c remains >48mmol/mol (6.5%); try metformin + sulfonylurea
   1. If hypoglycaemia is a problem on sulfonylurea, consider thiozolidinedione
   2. A rapid acting secretagogue (meglitinides e.g. repaglinide) may be considered for people with non-routine daily lifestyle (rare)
4. If HbA1c persists and rises to ≥59mmol/mol (7.5%), add thiozolidinedione or insulin
   1. Exenatide may be considered when body weight is a problem or if insulin is not an option
5. If HbA1c remains above 59mmol/mol (7.5%), insulin + metformin +sulfonylurea

Diabetic Medications

• Metformin
  • Indication- first line oral antihyperglycaemic in patient with T2DM who are overweight
  • Mechanism: Decrease Hepatic glucose output and increase peripheral glucose uptake by enhancing insulin action via AMPK pathways
    • Usually decreases blood glucose (HbA1c by 11-15mmol/l or 1-1.5%) by 1.6-2mmol/l (BM)
  • Contraindications: severe renal failure (totally metabolised/excreted by kidney)
    • NB Cimetidine increases the action of metformin by up to 50%
  • Advantages
    • Effective; no hypoglycaemia risk; possible weight loss (no gain); possible CVS benefit; can be used well in conjunction with insulin; low cost
  • Disadvantage
    • Common side effects (GI- dose related; can also cause B12 anaemia); should not be used in patients with a risk of lactic acidosis (i.e. severe major organ dysfunction; alcoholism)
• Sulfonylureas (e.g. Gliclazide)
  • Indication: Second line oral antihyperglycaemic (first line if normal/underweight patients)
  • Mechanism: Increase insulin secretion (both basal and prandial)- effect on blood sugar is similar to metformin
    • NB due to effect on insulin- there is a risk of hypoglycaemia
    • Metabolised by the liver (CYP450 system– be weary of enzyme inhibitors/inducers)
      • e.g. Clarithromycin (increase activity); Fluconazole (increase activity); Rifampicin (decrease activity)
  • Advantages
    • Effective; well tolerated; ok in renal insufficiency; once only dosing; low cost
  • Disadvantages
    • Hypoglycaemia risk; weight gain; efficacy can decline with time (insulin resistance increases)
• Thiazolidinediones
  • Indication: Mainly used as a substitute for sulfonylureas in patients at risk of hypoglycaemia or are intolerant of sulfonylureas (NB DPP-4 inhibitors and GLP analogues are becoming more widely used as 3rd line agents over TZDs)
  • Mechanism: Increase peripheral glucose uptake by enhancing insulin action and decreases hepatic glucose output via action of PPAR-γ receptors
    • Again, similar effect on blood glucose
    • Also metabolised by CYP450
  • AVOID IN HEART FAILURE
  • Advantages:
    • Effective; more durable glycaemic control than sulfonylureas; no hypoglycaemia risk; generally well tolerated and once daily dosing possible
  • Disadvantages:
    • Slow onset of maximal effect (8-12 weeks); Weight gain; Risk of fracture, MI and bladder cancer; Should not be used in:
      • Fluid retention/oedema
      • Risk of worsening heart failure (contraindication)
• DPP-4 Inhibitor (Gliptin)
  • Indication: May be preferable to a TZD if body weight is a problem or there are contraindications/intolerability of TZDs
  • Mechanism: Inhibits the action of DPP-4 receptors which are important in controlling gastric enzymes including GLP-1.  Actions include increasing insulin activity and secretion (prominently prandial secretion) and decrease glucagon secretion.
    • Occur only with raised blood sugar i.e. effect is minimal/none in a normal individual
    • Has a milder effect on blood glucose than other drugs above (half the reduction)
  • Advantages:
    • No hypoglycaemia; weight neutral; well tolerated; once daily (anytime) dosing
  • Disadvantages:
    • Not as efficient; Avoid in patients with features of damaged pancreas (pancreatitis, alcoholism, high triglycerides etc); expensive
• GLP-1 Agonists (exenatide)
  • Indication: generally used third line as an add-on therapy to MET+SUL when there is persistently high blood glucose
  • Mechanism: GLP1 is a gastric hormone responsible, in part, for regulating blood glucose and insulin action- same actions as DPP4 inhibitors
    • More effective, however, than DPP-4 inhibitors (similar to metformin)
    • Contraindicated in renal failure (uncertain of effect)
  • Advantages
    • Efficacy; No hypoglycaemia; Dose-related weight loss
  • Disadvantages
    • Long term effects uncertain (?thyroid cancer); avoid in pancreatitis like pictures; must be injected; Expensive

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