CONTEXT
Oral glucose tolerance test (OGTT)-related hypoglycemia is common in pancreatic insufficient cystic fibrosis (PI-CF), but its mechanistic underpinnings are yet to be established.
OBJECTIVE
To delineate the mechanism(s) underlying OGTT-related hypoglycemia.
DESIGN AND SETTING
We performed 180-minute OGTT with frequent blood sampling in adolescents and young adults with PI-CF and compared results to those from a historical healthy control group. Hypoglycemia (Hypo[+]) was defined as plasma glucose <65 mg/dL. We hypothesized that CF-Hypo[+] would demonstrate impaired early-phase insulin secretion and persistent late insulin effect compared to Control-Hypo[+], and explored the contextual counterregulatory response.
MAIN OUTCOME MEASURE
OGTT 1-hour and nadir glucose, insulin, C-peptide, and insulin secretory rate (ISR) incremental areas-under-the-curve (AUC) between 0-30 min (early) and 120-180 min (late), and Δglucagon120-180min and ΔFree Fatty Acids(FFA)120-180min were compared between CF- and Control-Hypo[+].
RESULTS
Hypoglycemia occurred in 15/23 (65%) CF (43% female, age 24.8 [14.6-30.6] years) and 8/15 (55%) controls (33% female, age 26 [21-38] years). CF-Hypo[+] vs Control-Hypo[+] had higher 1-hour glucose (197±49 vs 139±53 mg/dL, p=0.05) and lower nadir glucose (48±7 vs 59±4 mg/dL, p<0.01), while insulin-, C-peptide-,and ISR-AUC0-30 min were lower and insulin- and C-peptide-AUC120-180min were higher (p<0.05). CF-Hypo[+] had lower Δglucagon120-180min and ΔFFA120-180min compared to Control-Hypo[+] (p<0.01).
CONCLUSIONS
OGTT-related hypoglycemia in PI-CF is associated with elevated 1-hour glucose, impaired early-phase insulin secretion, higher late insulin exposure, and less increase in glucagon and FFA. These data suggest that hypoglycemia in CF is a manifestation of islet dysfunction including an impaired counterregulatory response.
Glucose homeostasis is often abnormal in people with pancreatic insufficient cystic fibrosis (PI-CF). This dysfunction is viewed on a continuum from “normal” glucose tolerance to cystic fibrosis-related diabetes (CFRD), and may also include postprandial and oral glucose tolerance test (OGTT)-related hypoglycemia. This study aimed to delineate the mechanism(s) underlying OGTT-related hypoglycemia. We compared extended OGTT with frequent blood sampling of glucose and insulin in adolescents and young adults with PI-CF [CF(+)] to historical data from a healthy cohort [CF(-)]. We hypothesized that the subset of CF(+) with hypoglycemia would demonstrate 1-hour glucose ≥ 155 mg/dL and impaired early phase insulin secretion (insulin secretion within first 30 min of OGTT). Hypoglycemia [hypo(+)] was defined as plasma glucose <65 mg/dL and was used to assign subjects to exposure groups. We restricted analyses to 180 minutes given available control data. Glucose and insulin incremental areas under the curve (Glc-AUC; Ins-AUC) for 30-minute intervals were calculated. One-hour glucose, nadir glucose, Glc-AUC0-30, and Ins-AUC0-30 and were compared between CF(+) and CF(-) subjects using Student’s t-test or Wilcoxon Rank Sum depending upon normality. Participants were 60.5% male, age: 25.4±4.8 years, with BMI-Z: 0.06±0.96kg/m2 [no differences for CF(+) vs CF(-)]. FEV1%-predicted for CF(+) was 83±21. 69.6% of CF(+) participants self-reported prior episodes of hypoglycemia, 68.7% of whom reported confirmation via glucometer. Hypoglycemia occurred by 180 minutes [hypo(+)] in 15/23 (65%) CF(+) and 5/15 (33.3%) CF(-) subjects (p=0.028). For hypo(+), nadir glucose occurred on average at 180 minutes for both CF(+) and (-). Hypo(+) CF(+) had higher mean 1-hour glucose (197±49mg/dL vs 134±66mg/dL, p=0.035), lower mean glucose nadir (48±7mg/dL vs 61±4mg/dL, p<0.01), and lower early-phase insulin secretion (Ins-AUC0-30: 263±168 versus 650±275 µU/mL, p<0.01) than hypo(+) CF(-). There was no difference in Glc-AUC0-30 for hypo(+) CF(+) vs CF(-). Hypoglycemia is frequent in CF, and is associated with early glucose dysregulation (elevated 1-hour glucose) and compromised early-phase insulin secretion compared to controls with presumed non-pathologic reactive hypoglycemia. The mechanism of hypoglycemia in CF appears to be different than that seen in healthy individuals, and its association with progression to CFRD warrants further evaluation.
We report on a del(8)(p22) in a severe intrauterine growth retarded newborn with balanced atrioventricular canal defect and prolonged hyperinsulinemic hypoglycemia of infancy. Atrioventricular septal defects are associated with terminal deletions of chromosome 8p. Hyperinsulinism during infancy represents a group of clinically, genetically and morphologically heterogeneous disorders and is also associated with mutations in several genes. However, such 8p deletions are not associated with hyperinsulinemic hypoglycemia of infancy.
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