Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia

Abstract

Context: Postprandial hypoglycemia, a late complication of gastric bypass (GB) surgery, is associated with an exaggerated insulin response to meal ingestion.

Objective: The purpose of this study was to characterize insulin secretion and other glucoregulatory hormone responses to meal ingestion after GB based on hypoglycemia and clinical symptoms.

Methods: We conducted a cross-sectional analysis of insulin secretion rate and islet and gastrointestinal hormone responses to liquid mixed meal ingestion in 65 subjects with GB and 11 body mass index-matched controls without surgery. The GB subjects were stratified by clinical history for analysis of their responses to the test meal.

Results: The glucose and insulin responses to meal ingestion were shifted upward and to the left after GB, with the largest early insulin response and the lowest nadir glucose levels in patients with a history of hypoglycemia, particularly those with neuroglycopenic symptoms. Hypoglycemic GB subjects had lower postprandial insulin clearance rates and higher insulin secretion rates during the glucose decline after the test meal. Meal-induced glucagon was enhanced in all GB subjects but did not differ between subjects who did and did not develop hypoglycemia. Plasma gastric inhibitory polypeptide and glucagon-like peptide-1 concentrations did not differ between asymptomatic and neuroglycopenic GB subjects.

Conclusion: Among GB subjects with a clinical history of hypoglycemia, hyperinsulinemia is the result of inappropriate insulin secretion and reduced insulin clearance. In subjects with symptoms of postprandial hypoglycemia, insulin secretion is higher in the latter stages of meal glucose clearance, and despite elevated meal-induced glucagon, there is no further response to hypoglycemia. These abnormalities in islet function are most pronounced in subjects who report neuroglycopenic symptoms.

Figure 1.

Plasma glucose (A), islet hormone (B–D), and incretin (E and F) responses to meal ingestion in GB subjects, with (Sym, solid line and closed square, black bar) and without (Asym, dashed line and open square, white bar) previous hypoglycemia, and controls (CON, gray solid line and closed square, gray bar). †, (P < .05) compared to Asym; *, P < .05, and **, P < .01 compared to CON using post hoc analysis.

Figure 2.

Plasma glucose (A), islet hormone (B–D), and incretin (E and F) responses to meal ingestion in postsurgical subjects categorized by previous clinical symptoms. Neuroglycopenic symptoms (SymN, solid line and closed circle, black bar); autonomic symptoms (SymA, gray dashed line and closed circle, gray bar); and asymptomatic (Asym, dashed line and open circle, white bar). †, P < .05, compared to SymA; *, P < .05, and **, P < .01, compared to Asym using post hoc analysis.

Figure 3.

Plasma glucose (A), insulin:glucose ratios (B), and glucagon response (C) in postsurgical subjects stratified by previous clinical symptoms and glycemic response during the MTT. Neuroglycopenic symptoms and hypoglycemia during MTT (SymN-hypoglycemia, solid line and closed circle); neuroglycopenic symptoms and blood glucose ≥2.78 mmol/L during MTT (SymN-euglycemia, dashed line and open circle); asymptomatic and hypoglycemia during MTT (Asym-hypoglycemia, gray solid line and closed square); asymptomatic and blood glucose ≥2.78 mmol/L during MTT (Asym-euglycemia, gray dashed line and open square).

Figure 4.

Relationship between β-cell secretion and blood glucose values during MTT (0–120 min). ISR (A) and C-peptide (B) vs glucose levels in GB subjects with (Sym, solid line and closed square) and without (Asym, dashed line and open square) a history of hypoglycemia, and controls (CON, gray solid line and closed square). ISR (C) and C-peptide (D) vs glucose levels in GB patients with a history of neuroglycopenic (SymN, solid line and closed circle) or autonomic (SymA, gray dashed line and closed circle) hypoglycemic symptoms and asymptomatic surgical subjects (Asym, dashed line and open circle). Each data point represents ISR/glucose or C-peptide/glucose values at 0, 10, 20, 30, 40, 50, 60, 75, 90, and 120 minutes. White arrow shows the initial phase of the MTT, and black arrow the latter phase of the MTT (declining glucose).