What Causes Impaired Fasting Glucose
Impaired fasting glucose (IFG) is primarily caused by defective basal insulin secretion from pancreatic β-cells combined with hepatic insulin resistance, specifically resistance of the liver to insulin's suppression of glucose production. 1
Primary Pathophysiological Mechanisms
Defective Insulin Secretion
- IFG results from approximately 35% reduction in first-phase insulin secretion and impaired basal insulin release, while second-phase insulin secretion remains relatively preserved. 1
- The underlying mechanism involves a selective deficit in insulin pulse mass, with approximately 50% reduction in basal insulin pulse mass and up to 80% reduction in glucose-stimulated insulin pulse mass. 2
- This defect in insulin secretion appears to be an intrinsic β-cell dysfunction that may be exacerbated by glucotoxicity and lipotoxicity over time. 3
Hepatic Insulin Resistance
- IFG is characterized by preferential resistance of hepatic glucose production to suppression by insulin, resulting in fasting hyperglycemia despite normal or even elevated plasma insulin concentrations. 1
- HOMA-IR (homeostasis model assessment of insulin resistance) is increased approximately 30% in IFG patients, reflecting this hepatic insulin resistance pattern. 1
- Importantly, peripheral (muscle) insulin sensitivity measured by hyperinsulinemic-euglycemic clamp remains normal in isolated IFG, distinguishing it from impaired glucose tolerance (IGT). 1
Underlying Causes of β-Cell Dysfunction
Reduced β-Cell Mass
- Approximately 50% deficit in β-cell mass can recapitulate the metabolic abnormalities seen in IFG, as demonstrated in partial pancreatectomy studies. 2
- This reduction in β-cell mass leads to decreased insulin secretion through selective deficits in insulin pulse mass rather than pulse frequency. 2
Compensatory Mechanisms
- Decreased hepatic insulin clearance partially compensates for reduced insulin secretion, helping maintain some degree of glucose homeostasis. 2
- However, this compensation is insufficient to prevent fasting hyperglycemia when β-cell function is impaired. 2
Risk Factors and Contributing Conditions
Obesity and Metabolic Factors
- Obesity, particularly abdominal/visceral fat distribution, promotes insulin resistance that can contribute to IFG development. 4
- Excess weight causes adipocyte hypertrophy, oxidative stress, inflammation, and ectopic fat accumulation in liver and muscle. 5
Genetic Factors
- Genetic defects in insulin action, such as insulin receptor mutations, can cause hyperinsulinemia with modest hyperglycemia progressing to IFG. 5
- Specific genetic syndromes affecting β-cell function may predispose to IFG. 4
Endocrine Disorders
- Hormone excess states including acromegaly, Cushing's syndrome, glucagonoma, and pheochromocytoma can cause IFG by antagonizing insulin action. 5
Medications
- Certain drugs including corticosteroids, thiazide diuretics, beta-blockers, and antidepressants can induce or exacerbate IFG. 4
Key Distinction from IGT
The pathophysiology of IFG differs fundamentally from IGT: IFG involves primarily basal insulin secretion defects and hepatic insulin resistance, while IGT results from reduced second-phase insulin release and peripheral (muscle) insulin resistance. 1, 6
- IFG patients have approximately 40% lower HOMA-β (β-cell function) but approximately 50% greater second-phase insulin responses compared to IGT patients. 1
- Factor analysis demonstrates that in IFG, the insulin resistance factor explains 28.4% of variance, whereas in IGT, the insulin secretion factor dominates at 31.1%. 6
Clinical Implications
Common pitfall: Assuming IFG and IGT have identical pathophysiology—they do not, and this distinction may be important for targeted prevention strategies. 6