Type 2 Diabetes: Pathophysiology, Diagnosis, HbA1c & Treatment

Q: Does metformin cause hypoglycaemia?

No - as monotherapy it reduces hepatic gluconeogenesis without stimulating insulin release, so hypoglycaemia is rare unless combined with insulin or sulfonylureas.

Q: Which agents give proven cardiorenal benefit?

GLP-1 receptor agonists (semaglutide, liraglutide, tirzepatide) and SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) - both reduce MACE and slow CKD progression.

Q: When is insulin needed in T2DM?

Severe hyperglycaemia at diagnosis (A1c >10%, glucose >16.7 mmol/L), symptoms of catabolism, pregnancy, or failure of oral/GLP-1 combinations.

Pathophysiology

Adipose-driven inflammation and ectopic lipid deposition impair insulin receptor signalling (IRS-1/PI3K/Akt pathway), reducing GLUT4 translocation in muscle and failing to suppress hepatic gluconeogenesis. Beta-cells initially hypersecrete but eventually fail due to glucolipotoxicity and amyloid deposition.

Sources: ADA Standards of Care in Diabetes 2026 (Diabetes Care 2026;49:S1); ADA/EASD Consensus on Hyperglycaemia in T2DM (Diabetologia 2022;65:1925); KDIGO Diabetes in CKD Guideline (Kidney Int 2022;102:S1)

Clinical presentation

Often asymptomatic for years; polyuria, polydipsia, blurred vision, recurrent candidiasis, acanthosis nigricans, or discovered on screening. Presenting complication may be MI, stroke, foot ulcer, or hyperosmolar hyperglycaemic state (HHS).

Diagnosis (ADA 2026)

Any one, confirmed on repeat: HbA1c >=6.5%, fasting plasma glucose >=7.0 mmol/L (126 mg/dL), 2-h OGTT >=11.1 mmol/L (200 mg/dL), or random glucose >=11.1 mmol/L with classic symptoms. Pre-diabetes: HbA1c 5.7-6.4%.

Management

Lifestyle plus metformin remain first-line for most. Add GLP-1 receptor agonists (semaglutide, tirzepatide) or SGLT2 inhibitors (empagliflozin, dapagliflozin) early - both give cardiorenal benefit independent of A1c. Target A1c <7% in most adults, individualised. Statin for ASCVD risk, ACEi/ARB if albuminuria.

Complications

Microvascular: retinopathy (leading cause of adult blindness), nephropathy (leading cause of ESRD), neuropathy (distal symmetric). Macrovascular: 2-4x MI/stroke risk. Diabetic foot ulcers, gastroparesis, and increased infection susceptibility.

Sample USMLE-style MCQs

Try 5 questions on this topic. Practice hundreds more free with a trial.

Question 1

Which HbA1c value confirms diabetes mellitus?

Question 2

A 58-year-old man with T2DM and CKD stage 3 needs additional therapy. Which class has proven renal benefit?

Question 3

Which agent carries the highest risk of hypoglycaemia?

Question 4

A T2DM patient presents with glucose 42 mmol/L, osmolality 340 mOsm/kg, no ketones, altered mental state. Diagnosis?

Question 5

What is the mechanism of metformin?

Frequently asked

Does metformin cause hypoglycaemia?

No - as monotherapy it reduces hepatic gluconeogenesis without stimulating insulin release, so hypoglycaemia is rare unless combined with insulin or sulfonylureas.

Which agents give proven cardiorenal benefit?

GLP-1 receptor agonists (semaglutide, liraglutide, tirzepatide) and SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) - both reduce MACE and slow CKD progression.

When is insulin needed in T2DM?

Severe hyperglycaemia at diagnosis (A1c >10%, glucose >16.7 mmol/L), symptoms of catabolism, pregnancy, or failure of oral/GLP-1 combinations.

What is HHS?

Hyperosmolar hyperglycaemic state - profound hyperglycaemia (>33 mmol/L), high osmolality, minimal ketosis, altered mental status; typical of decompensated T2DM.

Type 2 Diabetes Mellitus

Pathophysiology

Clinical presentation

Diagnosis (ADA 2026)

Management

Complications

Sample USMLE-style MCQs

References

Frequently asked

Related conditions

More in Endocrinology

Studied alongside Type 2 Diabetes Mellitus

Ready to master this topic?