Carbohydrate Metabolism and Insulin Resistance in Critically Ill Patients: Implications for the Management of Insulin and Medical Nutrition Therapy

Dr Neeraj Manikath , claude.ai

Abstract

Critical illness profoundly alters glucose homeostasis through a complex interplay of neuroendocrine stress responses, inflammatory mediators, and iatrogenic factors. This review synthesizes current evidence on the pathophysiology of stress hyperglycemia and insulin resistance in the intensive care unit (ICU), explores bedside assessment strategies, and provides practical guidance on insulin therapy and medical nutrition therapy. Understanding these metabolic derangements is essential for optimizing patient outcomes in contemporary critical care practice.

Keywords: Critical illness, stress hyperglycemia, insulin resistance, glycemic control, medical nutrition therapy, intensive care

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Introduction

The metabolic response to critical illness represents one of the most dramatic physiological adaptations observed in clinical medicine. Since the landmark work by Claude Bernard in the 19th century describing stress-induced hyperglycemia, our understanding has evolved considerably. Today, we recognize that hyperglycemia affects 50-90% of critically ill patients, regardless of pre-existing diabetes, and is independently associated with increased morbidity and mortality across diverse ICU populations.¹

The critical care physician faces a paradox: while stress hyperglycemia appears to be an adaptive response providing glucose to insulin-independent tissues during crisis, sustained hyperglycemia contributes to adverse outcomes including infection, organ dysfunction, and death.² This review addresses the fundamental question: how can we assess and manage carbohydrate metabolism at the bedside to optimize patient care?

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Pathophysiology of Altered Glucose Homeostasis in Critical Illness

The Stress Response: A Double-Edged Sword

Critical illness triggers a coordinated neuroendocrine response orchestrated by the hypothalamic-pituitary-adrenal axis, sympathetic nervous system, and inflammatory cytokines. This response fundamentally reprograms glucose metabolism.

Key pathophysiological mechanisms include:

Increased hepatic glucose production: Cortisol and catecholamines stimulate gluconeogenesis and glycogenolysis, increasing endogenous glucose production by 2-3 fold. Growth hormone and glucagon further amplify this effect. In severe sepsis, hepatic glucose output can reach 4-5 mg/kg/min, double the normal rate.³

Peripheral insulin resistance: Inflammatory cytokines (TNF-α, IL-1, IL-6) impair insulin signaling at multiple levels. Post-receptor defects in the insulin signaling cascade, particularly involving IRS-1 phosphorylation and PI3K activation, reduce glucose uptake in skeletal muscle and adipose tissue. This resistance can be profound, with insulin sensitivity decreasing to 20-30% of normal values.⁴

Relative insulin deficiency: Despite elevated glucose levels, absolute insulin concentrations may be inappropriately low due to direct β-cell suppression by inflammatory mediators and catecholamines. The normal tight coupling between glucose levels and insulin secretion becomes dysregulated.⁵

Impaired insulin clearance: Hepatic and renal insulin clearance decreases during critical illness, paradoxically elevating circulating insulin levels while tissues remain insulin-resistant.

The Mitochondrial Connection

Recent research highlights mitochondrial dysfunction as a central player in critical illness metabolism. Oxidative stress, cytokine-mediated damage, and substrate overload impair mitochondrial glucose oxidation, creating a "metabolic traffic jam" where glucose enters cells but cannot be efficiently utilized. This mechanism partially explains why aggressive glucose control doesn't always translate to improved outcomes.⁶

Pearl #1: The magnitude of stress hyperglycemia correlates with illness severity. A patient with glucose >180 mg/dL without diabetes should prompt consideration of occult sepsis, myocardial infarction, or other serious pathology beyond the apparent diagnosis.

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Bedside Assessment of Carbohydrate Metabolism

Clinical Recognition of Stress Hyperglycemia

The astute clinician recognizes that not all hyperglycemia in the ICU is equivalent. Three distinct patterns emerge:

1. Pre-existing diabetes with decompensation
2. Stress-induced hyperglycemia in previously normoglycemic patients
3. Steroid-induced hyperglycemia (increasingly common with widespread glucocorticoid use)

Bedside Assessment Strategy:

Begin with a focused history (when possible): previous glucose levels, diabetes diagnosis, recent steroid use, and baseline HbA1c if available. Physical examination may reveal signs of diabetes complications (retinopathy, neuropathy, nephropathy) suggesting chronic hyperglycemia versus acute stress response.

Point-of-Care Glucose Monitoring

Practical considerations:

Capillary glucose monitoring using glucometers remains the standard bedside tool, but critical illness introduces significant limitations. Peripheral vasoconstriction, edema, and use of vasopressors can cause discrepancies between capillary and arterial glucose of 10-20%.⁷

Hack #1: In patients on high-dose vasopressors or with severe peripheral hypoperfusion, obtain arterial blood gas with co-oximetry glucose measurement rather than relying solely on fingerstick values. The arterial measurement provides more accurate central glucose levels.

Optimal testing frequency remains debated, but current evidence supports checking glucose every 1-2 hours during insulin infusion titration, then every 4 hours once stable.⁸

Advanced Metabolic Assessment

HbA1c in the ICU: Obtaining HbA1c on admission provides invaluable context. An elevated HbA1c (>6.5%) indicates pre-existing diabetes, while normal HbA1c with marked hyperglycemia confirms stress-induced hyperglycemia. This distinction influences both acute management and discharge planning.

Fructosamine and glycated albumin: These markers reflect 2-3 week glycemic control and may help differentiate acute from chronic hyperglycemia, though their utility in critical care remains limited by altered protein metabolism.⁹

C-peptide levels: Rarely used but potentially valuable in distinguishing type 1 from type 2 diabetes in patients with unclear history. Low or undetectable C-peptide suggests absolute insulin deficiency.

Insulin Resistance Assessment

While hyperinsulinemic-euglycemic clamp studies remain the gold standard for quantifying insulin resistance, they are impractical in the ICU. Surrogate markers include:

• Insulin requirements: >1 unit/hour continuous infusion or >100 units/day suggests significant insulin resistance
• HOMA-IR calculation: Limited applicability due to dynamic insulin and glucose changes
• Clinical response: Poor glycemic response to standard insulin doses indicates resistance

Pearl #2: Insulin resistance varies throughout critical illness. Early sepsis (first 24-48 hours) demonstrates profound resistance, which may improve during recovery. Don't assume that today's insulin requirements predict tomorrow's needs—frequent reassessment prevents hypoglycemia.

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Glycemic Targets: Evolution of Evidence

The pendulum of glycemic control targets has swung dramatically over the past two decades. The Van den Berghe trial (2001) suggested intensive insulin therapy targeting 80-110 mg/dL reduced mortality in surgical ICU patients.¹⁰ This sparked widespread adoption of tight glycemic control protocols.

However, the subsequent NICE-SUGAR trial (2009), the largest randomized controlled trial involving 6,104 patients, demonstrated that intensive glucose control (81-108 mg/dL) increased mortality compared to conventional control (≤180 mg/dL), primarily due to increased severe hypoglycemia.¹¹

Current Evidence-Based Targets:

Major international guidelines now recommend:

• Initiating insulin when glucose persistently exceeds 180 mg/dL
• Target range of 140-180 mg/dL for most critically ill patients
• Avoiding glucose <110 mg/dL to minimize hypoglycemia risk¹²

Oyster #1: Certain populations may benefit from tighter control (130-150 mg/dL), including postcardiac surgery patients and those with acute brain injury where hyperglycemia independently worsens neurological outcomes.¹³ Conversely, patients with chronic poorly controlled diabetes (HbA1c >9%) may tolerate higher targets (180-200 mg/dL) initially to avoid relative hypoglycemia and counterregulatory stress.

The Hypoglycemia Problem

Hypoglycemia (<70 mg/dL) occurs in 5-15% of ICU patients receiving insulin, and severe hypoglycemia (<40 mg/dL) carries independent mortality risk.¹⁴ Risk factors include:

• Renal or hepatic dysfunction (impaired gluconeogenesis and insulin clearance)
• Nutritional interruptions (NPO for procedures, feeding intolerance)
• Resolution of acute stress (improving insulin sensitivity)
• Excessive insulin dosing during transition periods

Hack #2: Implement a "hypoglycemia prevention bundle" including: (1) reducing insulin infusion by 50% if nutrition is held, (2) never discontinuing insulin and nutrition simultaneously, (3) mandatory glucose check 30-60 minutes after stopping nutrition, and (4) available dextrose 10% for immediate treatment.

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Insulin Therapy: Practical Management

Intravenous Insulin Infusion

Continuous intravenous insulin remains the gold standard for managing hyperglycemia in hemodynamically unstable or critically ill patients requiring precise glycemic control.

Advantages:

• Rapid onset and offset (half-life ~5-15 minutes)
• Predictable pharmacokinetics
• Easily titrated to changing insulin requirements
• Independent of subcutaneous absorption

Practical Implementation:

Use regular human insulin diluted in normal saline (typical concentration: 100 units in 100 mL = 1 unit/mL). Avoid dextrose-containing solutions which can cause insulin degradation.

Starting doses: Base initial infusion rate on current glucose and illness severity. A common approach:

• Glucose 150-200 mg/dL: Start 0.5-1 units/hour
• Glucose 200-300 mg/dL: Start 1-2 units/hour
• Glucose >300 mg/dL: Start 2-4 units/hour

Titration strategies: Numerous protocols exist; choose one and standardize across your ICU. Key principles include:

1. Check glucose hourly during active titration
2. Increase insulin by 1-2 units/hour if glucose remains >180 mg/dL for 2 consecutive checks
3. Decrease insulin by 50% if glucose drops below 110 mg/dL
4. Hold insulin and give dextrose if glucose <70 mg/dL

Pearl #3: The "rule of 100s" for estimating insulin sensitivity: if a patient requires >100 units/day or infusion rates >4 units/hour, they are significantly insulin-resistant. Consider adjunctive measures including optimizing nutrition, treating infection, and reducing steroid doses if possible.

Subcutaneous Insulin Regimens

Transition to subcutaneous insulin when patients are hemodynamically stable, tolerating enteral nutrition, and have predictable insulin requirements.

Basal-bolus approach: Provides physiologic insulin coverage with long-acting basal insulin (glargine, detemir) plus rapid-acting prandial insulin (lispro, aspart) and correction doses. This mimics normal pancreatic function.

Sliding scale insulin: Widely used but suboptimal as monotherapy. Reactive rather than proactive, often leading to glycemic excursions. Should be combined with basal insulin.

Conversion from IV to subcutaneous: Calculate total IV insulin used in preceding 6-12 hours, multiply by 4 to estimate 24-hour requirement, then provide 50% as basal insulin and 50% distributed as prandial/correction doses. Give first subcutaneous dose 2-4 hours before discontinuing IV infusion to prevent rebound hyperglycemia.¹⁵

Hack #3: For patients receiving continuous enteral nutrition, use basal insulin (glargine) dosed every 12 hours rather than once daily. This provides better coverage and allows easier dose adjustment if feeds are interrupted. Give 50% of the total daily basal dose every 12 hours.

Special Populations

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS): Require specialized protocols with insulin infusion rates of 0.05-0.1 units/kg/hour, aggressive fluid resuscitation, and electrolyte monitoring. Glucose should decrease by 50-75 mg/dL/hour; faster correction risks cerebral edema.¹⁶

Corticosteroid-induced hyperglycemia: Steroids primarily affect afternoon and evening glucose due to their effect on hepatic gluconeogenesis. Consider NPH insulin or increased afternoon basal insulin dosing to match this pattern.

Continuous renal replacement therapy (CRRT): Both increases insulin clearance and removes glucose via dialysate, creating unpredictable insulin requirements. Check glucose every 2 hours and anticipate frequent adjustments.

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Medical Nutrition Therapy in Critical Illness

Nutrition and glycemic control are inextricably linked in the ICU. The metabolic stress response creates a catabolic state with accelerated protein breakdown, lipolysis, and hypermetabolism.

Nutritional Assessment

Energy requirements: Indirect calorimetry (measuring oxygen consumption and carbon dioxide production) provides the most accurate assessment but is not universally available. Predictive equations (Penn State, Mifflin-St Jeor) estimate resting energy expenditure, typically 25-30 kcal/kg/day in critically ill patients.¹⁷

Protein requirements: Increased to 1.2-2.0 g/kg/day to minimize muscle catabolism. Higher requirements in burns, trauma, and sepsis.

Oyster #2: Overfeeding increases hyperglycemia, hepatic steatosis, and carbon dioxide production (problematic in ventilated patients). The dogma of "feeding to achieve positive caloric balance" has been challenged—permissive underfeeding or trophic feeding in the first week may improve outcomes in some populations, particularly obese patients.¹⁸

Enteral vs. Parenteral Nutrition

Enteral nutrition remains preferred when the gut is functional, maintaining intestinal integrity, reducing infection risk, and better matching physiologic substrate delivery. Start within 24-48 hours if hemodynamically stable.

Parenteral nutrition (PN): Reserved for patients with contraindications to enteral feeding (ileus, bowel obstruction, severe hemodynamic instability). PN-associated hyperglycemia is more pronounced due to high dextrose loads and continuous substrate delivery.

Glucose management strategies for PN:

• Limit dextrose to 150-200 g/day initially (3-4 mg/kg/min)
• Consider reducing dextrose and increasing lipid calories if hyperglycemia proves refractory
• Add regular insulin directly to PN solution (improves glycemic control and anabolism)
• Typical starting dose: 0.1 units per gram of dextrose, adjust based on response¹⁹

Glycemic Variability

Beyond mean glucose levels, glycemic variability (fluctuations between high and low values) independently predicts poor outcomes. Mechanisms include oxidative stress, endothelial dysfunction, and immunosuppression.²⁰

Strategies to reduce variability:

• Consistent nutrition delivery (minimize interruptions)
• Appropriate insulin dosing (avoid overcorrection)
• Protocols that account for nutritional status
• Continuous glucose monitoring (emerging technology)

Pearl #4: When feeds are held for procedures or intolerance, proactively adjust insulin (reduce by 50%) and provide dextrose 5% or 10% infusion at maintenance rates to prevent hypoglycemia and maintain insulin delivery for its anabolic and anti-inflammatory effects.

Specific Nutritional Considerations

Carbohydrate type: Standard polymeric formulas contain 45-55% calories from carbohydrates. Diabetes-specific formulas (modified carbohydrate, higher fat, fiber-enriched) may reduce postprandial hyperglycemia but haven't demonstrated outcome benefits in critical care settings.²¹

Immunonutrition: Formulas enriched with arginine, glutamine, omega-3 fatty acids, and nucleotides modulate immune function. Some evidence supports use in specific populations (surgical, trauma) but remains controversial in sepsis due to concerns about immunostimulation.

Micronutrients: Critical illness depletes thiamine, vitamin C, vitamin D, selenium, and zinc—all important for glucose metabolism and immune function. Routine supplementation is reasonable, though optimal dosing remains unclear.

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Emerging Concepts and Future Directions

Continuous Glucose Monitoring (CGM)

Real-time CGM technology, widely used in outpatient diabetes management, is being adapted for the ICU. Potential advantages include detecting trends, reducing hypoglycemia, and decreasing nursing burden. Current limitations involve accuracy concerns during hemodynamic instability and regulatory approval challenges.²² Expect increasing adoption as technology improves.

Incretin-Based Therapies

GLP-1 receptor agonists and DPP-4 inhibitors modulate glucose-dependent insulin secretion and reduce glucagon. Small studies suggest potential in critical care, particularly for reducing glycemic variability with low hypoglycemia risk, but large trials are lacking.²³ Currently, these agents should be discontinued on ICU admission and insulin used instead.

Precision Medicine Approaches

Genetic polymorphisms in glucose transporters, insulin signaling molecules, and inflammatory mediators influence individual responses to critical illness and insulin therapy. Future personalized approaches may tailor glycemic targets and nutritional prescriptions to individual genetic and metabolic profiles.²⁴

The Vitamin D Connection

Vitamin D deficiency is ubiquitous in critically ill patients and correlates with insulin resistance and hyperglycemia. Supplementation studies show inconsistent results, but correction of severe deficiency (<20 ng/mL) is reasonable given pleiotropic benefits beyond glucose metabolism.²⁵

Hack #4: Order 25-hydroxyvitamin D levels on ICU admission and repllete if deficient. A practical regimen: 50,000 IU weekly for 8 weeks if <20 ng/mL, or 2,000-4,000 IU daily for maintenance. Though effects on glycemia are modest, broader benefits on muscle function, immunity, and bone health justify this intervention.

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Practical Clinical Algorithm

Bedside approach to the hyperglycemic critically ill patient:

1. Assess severity and context

   • Check HbA1c to differentiate pre-existing vs. stress hyperglycemia
   • Review medications (especially steroids)
   • Identify and treat underlying critical illness

2. Initiate monitoring

   • Glucose checks every 1-4 hours based on stability
   • Use arterial samples if on vasopressors
   • Monitor for hypoglycemia risk factors

3. Start insulin therapy if glucose >180 mg/dL

   • IV infusion for unstable patients or NPO status
   • Subcutaneous basal-bolus for stable patients on nutrition
   • Target 140-180 mg/dL for most patients

4. Optimize nutrition

   • Start enteral feeding within 24-48 hours
   • Calculate energy needs (25-30 kcal/kg/day)
   • Provide adequate protein (1.2-2.0 g/kg/day)
   • Avoid overfeeding

5. Reassess frequently

   • Adjust insulin for changing requirements
   • Coordinate insulin with nutritional changes
   • Watch for improving insulin sensitivity during recovery

6. Prevent hypoglycemia

   • Reduce insulin when nutrition held
   • Check glucose after feed interruptions
   • Maintain dextrose infusion if prolonged NPO

7. Plan transition

   • Convert IV to subcutaneous when stable
   • Educate patient about new/modified diabetes diagnosis
   • Arrange endocrine follow-up for stress hyperglycemia patients

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Conclusion

Managing carbohydrate metabolism in critical illness requires understanding complex pathophysiology, employing bedside assessment skills, and implementing evidence-based protocols for insulin and nutrition therapy. The goal is not perfect normoglycemia but rather thoughtful management that balances the risks of hyperglycemia against the very real dangers of hypoglycemia and glycemic variability.

Key takeaways for clinical practice include: (1) target glucose 140-180 mg/dL for most patients, (2) use continuous IV insulin for unstable patients with frequent reassessment, (3) coordinate insulin management with nutritional delivery, (4) implement systematic hypoglycemia prevention strategies, and (5) recognize that insulin requirements change dynamically throughout critical illness.

As our understanding deepens and technology advances, increasingly sophisticated approaches will emerge. However, the fundamental principle remains unchanged: thoughtful, individualized care guided by pathophysiologic principles and delivered through rigorous bedside assessment will continue to serve our patients best.

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References

1. Egi M, Bellomo R, Stachowski E, et al. Blood glucose concentration and outcome of critical illness: the impact of diabetes. Crit Care Med. 2008;36(8):2249-2255.

2. Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycaemia. Lancet. 2009;373(9677):1798-1807.

3. Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab. 2001;15(4):533-551.

4. Marik PE, Raghavan M. Stress-hyperglycemia, insulin and immunomodulation in sepsis. Intensive Care Med. 2004;30(5):748-756.

5. Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? J Clin Invest. 2004;114(9):1187-1195.

6. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002;360(9328):219-223.

7. Kanji S, Buffie J, Hutton B, et al. Reliability of point-of-care testing for glucose measurement in critically ill adults. Crit Care Med. 2005;33(12):2778-2785.

8. Jacobi J, Bircher N, Krinsley J, et al. Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. Crit Care Med. 2012;40(12):3251-3276.

9. Krinsley JS, Preiser JC. Is it time to abandon glucose control in critically ill adult patients? Curr Opin Crit Care. 2019;25(4):299-306.

10. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367.

11. NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297.

12. American Diabetes Association. 15. Diabetes care in the hospital: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021;44(Suppl 1):S211-S220.

13. Oddo M, Schmidt JM, Carrera E, et al. Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study. Crit Care Med. 2008;36(12):3233-3238.

14. Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med. 2007;35(10):2262-2267.

15. Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care. 2011;34(2):256-261.

16. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343.

17. Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48-79.

18. Arabi YM, Aldawood AS, Haddad SH, et al. Permissive underfeeding or standard enteral feeding in critically ill adults. N Engl J Med. 2015;372(25):2398-2408.

19. Korytkowski MT, Salata RJ, Koerbel GL, et al. Insulin therapy and glycemic control in hospitalized patients with diabetes during enteral nutrition therapy: a randomized controlled clinical trial. Diabetes Care. 2009;32(4):594-596.

20. Egi M, Bellomo R, Stachowski E, et al. Variability of blood glucose concentration and short-term mortality in critically ill patients. Anesthesiology. 2006;105(2):244-252.

21. Mesejo A, Acosta JA, Ortega C, et al. Comparison of a high-protein disease-specific enteral formula with a high-protein enteral formula in hyperglycemic critically ill patients. Clin Nutr. 2003;22(3):295-305.

22. Boom DT, Sechterberger MK, Rijkenberg S, et al. Insulin treatment guided by subcutaneous continuous glucose monitoring compared to frequent point-of-care measurement in critically ill patients: a randomized controlled trial. Crit Care. 2014;18(4):453.

23. Uyttendaele V, Dickson JL, Shaw GM, Desaive T, Chase JG. Untangling glycaemia and mortality in critical care. Crit Care. 2017;21(1):152.

24. Mesotten D, Preiser JC, Kosiborod M. Glucose management in critically ill patients: the lingering question of glycemic control. Curr Opin Crit Care. 2015;21(4):299-304.

25. Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520-1530.

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Author's Note: This review synthesizes current evidence and clinical experience to provide practical guidance for managing this complex aspect of critical care medicine. Readers are encouraged to adapt these principles to their local practice patterns and patient populations while maintaining vigilance for evolving evidence in this dynamic field.