6.1 Diabetes Mellitus & Metabolic Complications
Key Takeaways
- Diabetes mellitus is diagnosed by an HbA1c ≥ 48 mmol/mol (6.5%), fasting plasma glucose ≥ 7.0 mmol/L, or 2-hour post-OGTT glucose ≥ 11.1 mmol/L in symptomatic patients.
- Diabetic Ketoacidosis (DKA) requires the triad of blood glucose > 11.0 mmol/L (or known DM), venous pH < 7.30 or HCO3⁻ < 15.0 mmol/L, and blood ketones ≥ 3.0 mmol/L; managed with fixed-rate IV insulin (0.1 units/kg/h) and 0.9% NaCl.
- Hyperosmolar Hyperglycemic State (HHS) is characterized by glucose > 30.0 mmol/L, serum osmolality > 320 mOsm/kg, and minimal ketosis; management prioritizes cautious 0.9% NaCl fluid replacement to lower osmolality by 3–5 mOsm/kg/h.
- Metformin requires dose reduction at eGFR < 45 mL/min/1.73m² and cessation at eGFR < 30 mL/min/1.73m², whereas SGLT2 inhibitors retain cardiorenal benefits down to an eGFR of 20 mL/min/1.73m².
6.1 Diabetes Mellitus & Metabolic Complications
Diagnostic Criteria & Classification
The diagnosis of diabetes mellitus (DM) relies on standardized biochemical thresholds established by international guidelines. In a symptomatic individual (polyuria, polydipsia, unexplained weight loss), a single abnormal laboratory value is diagnostic; in asymptomatic individuals, two abnormal tests (either from the same sample or on separate days) are required.
Diagnostic Criteria Summary
- HbA1c: ≥ 48 mmol/mol (6.5%)
- Fasting Plasma Glucose (FPG): ≥ 7.0 mmol/L (126 mg/dL) after an 8-hour fast
- 2-Hour Post-OGTT Glucose: ≥ 11.1 mmol/L (200 mg/dL) following a 75 g oral glucose load
- Random Plasma Glucose: ≥ 11.1 mmol/L in the presence of classic hyperosmolar or glycemic symptoms
Differentiating Type 1 vs. Type 2 Diabetes
Differentiating Type 1 DM (T1DM) from Type 2 DM (T2DM) and atypical forms such as Latent Autoimmune Diabetes in Adults (LADA) or Maturity-Onset Diabetes of the Young (MODY) is essential for selecting appropriate therapy. Pancreatic autoantibodies—specifically glutamic acid decarboxylase (anti-GAD65), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8)—are positive in > 90% of newly diagnosed T1DM patients. Fasting or stimulated serum C-peptide provides an index of endogenous insulin secretion; levels < 200 pmol/L confirm absolute insulin deficiency, whereas levels > 600 pmol/L favor T2DM or insulin resistance.
Pharmacological Management of Type 2 Diabetes
Modern management guidelines prioritize organ protection—specifically reducing major adverse cardiovascular events (MACE), heart failure hospitalizations, and chronic kidney disease (CKD) progression—over simple HbA1c lowering.
First-Line & Cardiorenal Protective Agents
- Metformin (Biguanide): Decreases hepatic gluconeogenesis and increases peripheral insulin sensitivity. It is weight-neutral and does not cause hypoglycemia. Common side effects include gastrointestinal distress and Vitamin B12 deficiency. Renal Dosing: Reduce dose by 50% when eGFR is 30–45 mL/min/1.73m²; stop immediately if eGFR drops < 30 mL/min/1.73m² due to the risk of lactic acidosis.
- SGLT2 Inhibitors (Empagliflozin, Dapagliflozin, Canagliflozin): Inhibit sodium-glucose cotransporter 2 in the proximal renal tubule, promoting glucosuria. Mandatory in T2DM with established atherosclerotic cardiovascular disease (ASCVD), heart failure (HFrEF/HFpEF), or diabetic nephropathy (urine ACR > 3 mg/mmol). Benefits persist down to an eGFR of 20 mL/min/1.73m². Exam Pearls: Risks include mycotic genital infections, volume depletion, and euglycemic DKA (blood glucose < 14 mmol/L with severe ketoacidosis).
- GLP-1 Receptor Agonists (Semaglutide, Liraglutide, Dulaglutide): Incretin mimetics that enhance glucose-dependent insulin secretion, suppress glucagon release, and delay gastric emptying. Indicated for T2DM with high ASCVD risk or obesity. Contraindications: Personal or family history of medullary thyroid carcinoma or MEN 2.
- DPP-4 Inhibitors (Sitagliptin, Linagliptin): Prevent degradation of endogenous GLP-1. Weight-neutral with minimal hypoglycemia risk. Note: Do NOT combine DPP-4 inhibitors with GLP-1 receptor agonists.
- Sulfonylureas (Gliclazide, Glimepiride): Stimulate pancreatic beta-cell insulin secretion via ATP-sensitive K+ channel closure. Associated with weight gain and high hypoglycemia risk.
Acute Metabolic Crises: DKA vs. HHS
Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS) represent life-threatening emergencies requiring prompt recognition and structured protocol-driven therapy.
| Clinical Parameter | Diabetic Ketoacidosis (DKA) | Hyperosmolar Hyperglycemic State (HHS) |
|---|---|---|
| Primary Population | Type 1 DM (predominantly young) | Type 2 DM (elderly, frail, comorbid) |
| Onset Timeline | Rapid (< 24–48 hours) | Insidious (days to weeks) |
| Blood Glucose | > 11.0 mmol/L (or known DM) | > 30.0 mmol/L |
| Venous pH | < 7.30 (severe if < 7.00) | > 7.30 |
| Serum Bicarbonate | < 15.0 mmol/L (severe if < 10.0) | > 15.0 mmol/L |
| Blood Ketones | ≥ 3.0 mmol/L (urine ++ or higher) | < 1.5 mmol/L |
| Serum Osmolality | Variable (< 320 mOsm/kg) | > 320 mOsm/kg |
| Primary Treatment | Fixed-Rate IV Insulin (0.1 u/kg/h) + IV 0.9% NaCl | Cautious IV 0.9% NaCl (target ΔOsm 3–5 mOsm/kg/h) |
Step-by-Step DKA Management Protocol
- Fluid Resuscitation: Infuse 0.9% NaCl: 1 L over 1st hour, 1 L over 2 hours, 1 L over 2 hours, 1 L over 4 hours, and 1 L over 8 hours. When blood glucose drops below 14.0 mmol/L, add 5% or 10% IV glucose at 125 mL/h while continuing insulin to prevent hypoglycemia.
- Fixed-Rate Soluble Insulin Infusion (FRIII): Administer 0.1 units/kg/hour. Continue FRIII until blood ketones are < 0.6 mmol/L and venous pH is > 7.30. Do NOT stop insulin based solely on normalized blood glucose.
- Potassium Replacement: Insulin drives potassium intracellularly.
- Serum K+ < 3.5 mmol/L: Hold insulin, administer IV potassium urgently.
- Serum K+ 3.5–5.5 mmol/L: Add 20–30 mmol KCl per liter of IV fluid.
- Serum K+ > 5.5 mmol/L: Omit potassium, recheck hourly.
Step-by-Step HHS Management Protocol
- Gradual Volume Expansion: The central deficit in HHS is extreme dehydration (often 10–22% of total body water). Infuse 0.9% NaCl over 48 hours. Target a reduction in serum osmolality of 3–5 mOsm/kg/hour. Rapid osmolality drop risks cerebral edema and central pontine myelinolysis.
- Low-Dose Fixed Insulin: Initiate fixed-rate IV insulin (0.05 units/kg/hour) ONLY IF blood glucose fails to decline despite adequate 0.9% NaCl fluid replacement or if significant ketonemia is present.
Chronic Microvascular & Macrovascular Complications
- Diabetic Retinopathy: Screen annually. Graded into Background (microaneurysms, dot hemorrhages), Pre-proliferative (cotton wool spots, venous beading), and Proliferative (neovascularization requiring urgent panretinal photocoagulation). Diabetic maculopathy requires anti-VEGF intravitreal injections.
- Diabetic Nephropathy: Screen annually via urine albumin-to-creatinine ratio (ACR). Microalbuminuria is defined as ACR 3–30 mg/mmol; macroalbuminuria as ACR > 30 mg/mmol. Initiate ACE inhibitors or ARBs as first-line therapy regardless of baseline blood pressure, combined with SGLT2 inhibitors.
- Diabetic Neuropathy: Presents as distal symmetric sensorimotor polyneuropathy ("glove-and-stocking"). Autonomic neuropathy presents with gastroparesis, postural hypotension, resting tachycardia, or neurogenic bladder. First-line treatments for painful neuropathy include Duloxetine, Pregabalin, or Amitriptyline.
A 24-year-old woman with type 1 diabetes is admitted with diabetic ketoacidosis (DKA). Initial bloods show glucose 24.2 mmol/L, venous pH 7.18, bicarbonate 11 mmol/L, blood ketones 4.8 mmol/L, and potassium 4.2 mmol/L. Intravenous fluid resuscitation with 0.9% NaCl and fixed-rate IV soluble insulin at 0.1 units/kg/h are commenced. After 4 hours of treatment, her blood glucose drops to 13.5 mmol/L, but her blood ketones remain elevated at 2.4 mmol/L and venous pH is 7.26. What is the most appropriate next step in management?
An 72-year-old man presents with severe lethargy, confusion, and dehydration. Laboratory investigation reveals blood glucose 38.4 mmol/L, serum sodium 149 mmol/L, serum potassium 4.8 mmol/L, venous pH 7.36, serum bicarbonate 18 mmol/L, blood ketones 0.8 mmol/L, and calculated serum osmolality 342 mOsm/kg. What is the cornerstone of initial emergency management for this condition?
A 58-year-old woman with type 2 diabetes mellitus and established ischemic heart failure with reduced ejection fraction (HFrEF) has an HbA1c of 62 mmol/mol (7.8%) while taking metformin 1000 mg twice daily. Her serum creatinine is 110 µmol/L and eGFR is 52 mL/min/1.73m². Which glucose-lowering agent is most strongly indicated as add-on therapy?