What can cause hyperinsulinemia and hypoglycemia, and is obesity a contributing factor?

Causes of Hyperinsulinemia and Hypoglycemia

Hyperinsulinemia with hypoglycemia is most commonly caused by exogenous insulin or sulfonylurea medications, but can also result from insulinoma, non-insulinoma pancreatogenous hypoglycemia (NIPH), or rarely from surreptitious drug administration. 1, 2, 3

Iatrogenic (Medication-Related) Causes

Insulin therapy is the single most common cause of hypoglycemia in patients with diabetes, accounting for the majority of cases. 1 The mechanism involves:

• Absolute insulin excess from inappropriate dosing, timing, or failure to adjust for reduced food intake 1, 4
• Relative insulin excess when meals are delayed, carbohydrate content is reduced, or physical activity increases 1
• Impaired insulin clearance in renal insufficiency, where decreased renal degradation and excretion of insulin leads to prolonged insulin action 1

Sulfonylureas are the second most important cause, producing endogenous hyperinsulinemia by stimulating pancreatic beta-cell insulin secretion. 1, 2 Risk is particularly elevated with:

• Renal failure (decreased drug clearance)
• Malnutrition (lack of gluconeogenic substrates)
• Alcohol consumption 2

Metformin rarely causes hypoglycemia by itself, but significantly enhances hypoglycemic effects when combined with insulin or sulfonylureas. 5, 2

Endogenous Hyperinsulinism

Insulinoma produces autonomous insulin secretion independent of glucose levels, causing fasting hypoglycemia with inappropriately elevated insulin levels. 1, 3

Non-insulinoma pancreatogenous hypoglycemia (NIPH) is a newly recognized disorder causing endogenous hyperinsulinism without a discrete tumor. 3

Surreptitious sulfonylurea administration can mimic insulinoma or NIPH, and the calcium stimulation test may show uniformly positive insulin responses, alerting physicians to possible felonious drug administration. 3

Pathophysiological Mechanisms Leading to Hypoglycemia

Compromised glucose counterregulation is the critical factor that converts hyperinsulinemia into clinically significant hypoglycemia. 4 This involves:

• Absent glucagon response to falling glucose (universal in type 1 diabetes after 5 years duration) 4
• Deficient epinephrine response when glucagon is absent 4
• Reduced release of counterregulatory hormones (glucagon, epinephrine, growth hormone, cortisol) in elderly patients and those with autonomic neuropathy 1, 2

Hypoglycemia-associated autonomic failure creates a vicious cycle where recent hypoglycemia shifts glycemic thresholds lower, causing both defective glucose counterregulation and hypoglycemia unawareness, leading to recurrent episodes. 4

Risk Factors That Amplify Hypoglycemia Risk

Renal failure is a major predictor of hypoglycemia through multiple mechanisms: 1

• Decreased renal gluconeogenesis (normally 20-40% of total glucose production)
• Impaired insulin degradation and excretion
• Reduced counterregulatory hormone responses

Sepsis and severe illness predict hypoglycemia, though mortality may be higher with spontaneous hypoglycemia rather than iatrogenic insulin-induced hypoglycemia. 1

Low albumin levels independently predict hypoglycemia in hospitalized patients. 1

Alcohol potentiates metformin's effect on lactate metabolism and independently causes hypoglycemia by inhibiting gluconeogenesis. 5, 2

Elderly patients experience failure of regulatory mechanisms including reduced glucagon and epinephrine release, plus inability to perceive neuroglycopenic and autonomic symptoms. 1

Obesity and Hyperinsulinemia

Obesity does NOT typically cause hyperinsulinemia with hypoglycemia—it causes hyperinsulinemia with hyperglycemia. 6, 7 The distinction is critical:

• Obesity-related hyperinsulinemia is compensatory, attempting to overcome insulin resistance, and is associated with elevated (not low) glucose levels 6, 7
• This represents syndrome X (metabolic syndrome) with hyperinsulinemia, insulin resistance, hyperlipidemia, and atherosclerotic disease 7
• Hyperinsulinemia itself can drive insulin resistance, creating a self-perpetuating cycle, but this manifests as hyperglycemia, not hypoglycemia 6

In type 1 diabetes with obesity, insulin resistance develops despite insulin deficiency, creating a unique phenotype where exogenous insulin requirements increase but hypoglycemia risk also rises due to impaired counterregulation. 1

Clinical Pitfalls to Avoid

Do not assume all hypoglycemia in diabetic patients is iatrogenic—always exclude insulinoma, NIPH, and surreptitious drug use, particularly when insulin requirements seem excessive or hypoglycemia patterns are atypical. 3

Do not overlook renal function—even mild renal insufficiency dramatically increases hypoglycemia risk by impairing both insulin clearance and glucose production. 1

Do not ignore the temporal relationship—hypoglycemia occurring 7-15 hours after insulin administration suggests excessive basal insulin, while hypoglycemia 1-3 hours post-meal suggests excessive bolus insulin or sulfonylurea effect. 1

Recognize that hyperinsulinemia from obesity causes hyperglycemia, not hypoglycemia—if an obese patient presents with hyperinsulinemia and hypoglycemia, investigate for insulinoma, exogenous insulin, or sulfonylurea exposure. 6, 3, 7