Why does insulin further cause depletion of intravascular volume in an older adult with type 2 diabetes (T2D) and impaired renal function, particularly in Hyperosmolar Hyperglycemic State (HHS)?

Why Insulin Causes Intravascular Volume Depletion in HHS

Insulin drives glucose from the extracellular space into cells, which reduces serum osmolality and causes water to follow glucose intracellularly, thereby further depleting the already severely contracted intravascular volume in patients with Hyperosmolar Hyperglycemic State. 1, 2

The Core Pathophysiologic Mechanism

The mechanism by which insulin worsens intravascular depletion in HHS involves a critical osmotic shift that occurs when insulin is administered:

• Hyperglycemia in HHS creates severe hyperosmolality (≥320 mOsm/kg), which maintains water in the extracellular/intravascular compartment through osmotic forces 1, 3
• When insulin is given, glucose rapidly moves from blood into cells, causing a precipitous drop in serum osmolality 4, 5
• Water follows glucose intracellularly along the osmotic gradient, shifting fluid from the already depleted intravascular space into the intracellular compartment 5, 6
• This osmotic shift can further compromise intravascular volume in patients who already have profound dehydration (fluid losses of 100-220 ml/kg) 3, 7

Why This Is Particularly Dangerous in Older Adults with Impaired Renal Function

Elderly patients with type 2 diabetes and renal impairment face compounded risk:

• Aging reduces glomerular filtration rate and increases renal threshold for glucose, which prevents correction of hyperglycemia through osmotic diuresis and allows more severe hyperglycemia to develop 1, 8
• Impaired renal function causes prerenal azotemia from the osmotic diuresis that precedes HHS, with elevated BUN/creatinine ratio indicating volume depletion 9, 2
• Elderly patients have impaired thirst mechanisms and often cannot adequately replace fluid losses during the prolonged osmotic diuresis phase 1, 8
• Reduced renal gluconeogenesis in renal insufficiency further impairs the body's ability to maintain glucose homeostasis 1

The Critical Treatment Sequence to Prevent This Complication

The cornerstone principle: fluid replacement MUST precede insulin therapy in HHS to prevent catastrophic intravascular volume depletion. 3, 5

Phase 1: Aggressive Fluid Resuscitation First (0-60 minutes)

• Administer 0.9% sodium chloride intravenously to restore circulating volume before starting insulin 1, 3
• Initial fluid therapy has first priority over insulin administration in HHS 1, 5
• Goal: restore intravascular volume and stabilize vital signs before addressing hyperglycemia 5, 6

Phase 2: Delayed Insulin Initiation (After Volume Restoration)

• Fixed rate intravenous insulin infusion should be commenced ONLY once osmolality stops falling with fluid replacement alone, unless significant ketonaemia is present 3
• If ketonaemia is present (mixed DKA/HHS), insulin must be started simultaneously with fluids 3, 6
• Starting dose: 10-15 units regular insulin bolus followed by 0.1 U/kg/h continuous infusion 5

Phase 3: Monitoring the Osmotic Shift

• Target gradual decline in osmolality of 3.0-8.0 mOsm/kg/h to minimize risk of neurological complications from rapid fluid shifts 3
• Blood glucose should fall to 10-15 mmol/L (180-270 mg/dL) in the first 24 hours, not faster 3
• Once glucose approaches 13.9-16.7 mmol/L (250-300 mg/dL), add 5% dextrose to IV fluids and reduce insulin infusion rate 5

Additional Mechanisms of Insulin-Related Volume Depletion

Beyond the osmotic shift, insulin causes other fluid and electrolyte disturbances:

• Insulin stimulates potassium movement into cells, potentially causing life-threatening hypokalemia that can lead to respiratory paralysis and ventricular arrhythmia 4
• Hypokalemia must be monitored closely when insulin is administered intravenously due to rapid onset of action 4
• Potassium replacement should be initiated according to serum levels during insulin therapy 3

Common Pitfalls to Avoid

• Never start insulin before adequate fluid resuscitation in pure HHS (without significant ketoacidosis) 3, 5
• Avoid rapid correction of hyperglycemia and hyperosmolality, which can precipitate cerebral edema and osmotic demyelination syndrome 3, 7
• Do not use hypotonic fluids initially in hemodynamically unstable patients; start with 0.9% NaCl until vital signs stabilize 5
• Exercise extreme caution in elderly patients with heart failure or cerebral stroke, as aggressive fluid replacement may be difficult to balance with their underlying conditions 8
• Monitor for cardiovascular complications, acute renal failure, and thrombotic events, which are the most serious complications of HHS 7

Special Considerations for Renal Impairment

• Decreased renal degradation and excretion of insulin in renal insufficiency prolongs insulin action and increases hypoglycemia risk 1
• Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment 4
• The elevated BUN/creatinine ratio in these patients reflects prerenal azotemia from volume depletion, which should improve with fluid resuscitation 9