What are the causes of post‑prandial (reactive) hypoglycaemia?

Causes of Post-Prandial Hypoglycemia

Post-prandial hypoglycemia occurs through two primary mechanisms: post-bariatric surgery hyperinsulinemic hypoglycemia (most common in surgical patients) and idiopathic reactive hypoglycemia in non-surgical patients, both driven by exaggerated insulin responses to rapid carbohydrate absorption.

Post-Bariatric Surgery Hypoglycemia (Most Common Surgical Cause)

This is the predominant cause in patients with altered gastric anatomy and occurs in up to 34% of patients after Roux-en-Y gastric bypass or sleeve gastrectomy. 1, 2

Pathophysiology

• Rapid delivery of undigested carbohydrates to the small intestine triggers excessive GLP-1 and other incretin hormone secretion, causing hyperinsulinemic overstimulation and subsequent hypoglycemia 1-3 hours after high-carbohydrate meals 1
• The exaggerated endogenous GLP-1 response is the key mediator of this hyperinsulinemic effect, with studies showing a 10-fold increase in insulin concentrations compared to normal glucose absorption 1, 3
• Altered gastric emptying from surgical modification of gastric anatomy (RYGB, sleeve gastrectomy, esophagectomy, vagotomy with pyloroplasty) eliminates normal pyloric barrier function 1, 4
• This typically presents more than 1 year post-surgery, distinguishing it from early dumping syndrome which occurs within 10-30 minutes of eating 1, 2

Clinical Context

• Affects 25-40% of post-bariatric surgery patients, with approximately one-third reporting postprandial hypoglycemia symptoms 4, 2
• Symptoms range from sweating, tremor, tachycardia to impaired cognition, loss of consciousness, and seizures 1
• Can severely impact quality of life and may lead to significant weight loss from food avoidance 2

Idiopathic Reactive Hypoglycemia (Non-Surgical)

This occurs in patients without surgical history and represents the most common cause in the general population, though it remains controversial and often overdiagnosed. 5

Pathophysiological Mechanisms

Exaggerated insulin response with insulin resistance: 6, 7

• Decreased first-phase insulin response causes initial blood glucose rise after meals, triggering late but excessive second-phase insulin secretion
• This leads to late reactive hypoglycemia at 4-5 hours post-meal 6
• Down-regulation of insulin post-receptors on muscle and fat cells decreases insulin sensitivity 6

High insulin sensitivity (most frequent cause, 50-70% of cases): 7

• Occurs in very lean individuals, after massive weight reduction, or in women with moderate lower body overweight 7
• Not adequately compensated by hypoinsulinemia and cannot be measured by standard insulin sensitivity indices 7

Increased GLP-1 secretion: 7, 3

• Exaggerated GLP-1 response to nutrients can cause reactive hypoglycemia even without surgical history 7, 3
• Studies reproducing patient glucose and hormone profiles show GLP-1 infusion causes nadir glucose of 2.4 mmol/L compared to 4.5 mmol/L with glucose alone 3

Other mechanisms: 7, 5

• Renal glycosuria 7
• Defects in glucagon counter-regulatory response 7
• Dysinsulinism or hyperinsulinism in diabetes mellitus patients 5

Clinical Timing Patterns

• Idiopathic RH: occurs at 180 minutes (3 hours) post-meal 6
• Alimentary RH: occurs within 120 minutes (2 hours) 6
• Late RH: occurs at 240-300 minutes (4-5 hours), associated with increased diabetes risk 6

Alimentary (Gastrointestinal) Causes

Gastrointestinal dysfunction from non-bariatric surgeries or conditions causing accelerated gastric emptying leads to reactive hypoglycemia through similar incretin-mediated mechanisms. 5, 3

• Patients with accelerated gastric emptying show exaggerated GLP-1 response to nutrients, responsible for high incidence of postprandial reactive hypoglycemia 3
• This category includes patients with gastrointestinal dysfunction who have not undergone bariatric surgery but have altered gastric motility 5

Hormonal Deficiency States

Hormonal reactive hypoglycemia occurs in patients with endocrine deficiencies affecting counter-regulatory hormone responses. 5

• Characterized by inadequate glucagon, cortisol, or growth hormone responses to hypoglycemia 5
• Less disputed than idiopathic reactive hypoglycemia but less common than post-surgical causes 5

Diabetes-Related Reactive Hypoglycemia

Patients with diabetes mellitus can develop reactive hypoglycemia due to characteristic alterations in insulin secretion patterns. 5

• Dysinsulinism or hyperinsulinism accounts for hypoglycemia in these patients 5
• Often related to insulin resistance and delayed insulin response patterns 6

Critical Diagnostic Distinctions

Key differentiating features to identify the underlying cause:

• Timing: Post-bariatric hypoglycemia occurs 1-3 hours post-meal and presents >1 year after surgery, while early dumping occurs 10-30 minutes post-meal and improves over time 1, 4
• Surgical history: Presence of RYGB, sleeve gastrectomy, esophagectomy, or vagotomy strongly suggests post-surgical etiology 4
• Late hypoglycemia (4-5 hours): Suggests prediabetes risk, especially with family history of diabetes and obesity 6
• Exclude insulinoma: Fasting hypoglycemia versus postprandial timing distinguishes insulinoma from reactive causes 4

Common Pitfalls

• The oral glucose tolerance test produces false positives for reactive hypoglycemia diagnosis and should not be used; ambulatory glucose monitoring or hyperglucidic breakfast test are preferred 7
• Many patients self-diagnosed with reactive hypoglycemia actually have neuropsychiatric disease with similar adrenergic symptoms 5
• Patients with reactive hypoglycemia often have excessive refined carbohydrate intake, which perpetuates the condition 5
• Post-bariatric hypoglycemia patients may develop hypoglycemia unawareness from recurrent episodes, making diagnosis more difficult 1