Hypoglycemia and islet dysfunction following oral glucose tolerance testing in pancreatic-insufficient cystic fibrosis

Marissa J. Kilberg, Clea Harris, Saba Sheikh, Darko Stefanovski, Marina Cuchel, Christina Kubrak, Denis Hadjiliadis, Ronald C. Rubenstein, Michael R. Rickels, Andrea Kelly

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 OGTTs with frequent blood sampling in adolescents and young adults with PI-CF and compared results with 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 with 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 and 30 minutes (early) and between 120 and 180 minutes (late), and Δglucagon120-180min and Δfree fatty acids (FFAs)120-180min were compared between individuals with CF and control participants with Hypo[+]. Results: Hypoglycemia occurred in 15/23 (65%) patients with CF (43% female, aged 24.8 [14.6-30.6] years) and 8/15 (55%) control participants (33% female, aged 26 [21-38] years). The CF-Hypo[+] group versus the control-Hypo[+] group had higher 1-hour glucose (197 ± 49 vs 139 ± 53 mg/dL; P = 0.05) and lower nadir glucose levels (48 ± 7 vs 59 ± 4 mg/dL; P < 0.01), while insulin, C-peptide, and ISR-AUC0-30 min results were lower and insulin and C-peptide, and AUC120-180min results were higher (P < 0.05). Individuals with CF-Hypo[+] had lower Δglucagon120-180min and ΔFFA120-180min compared with the control-Hypo[+] group (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 FFAs. These data suggest that hypoglycemia in CF is a manifestation of islet dysfunction including an impaired counterregulatory response. (J Clin Endocrinol Metab 105: 1–11, 2020)

Original languageEnglish
Pages (from-to)3179-3189
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Volume105
Issue number10
DOIs
StatePublished - Oct 1 2020

Keywords

  • Cystic fibrosis
  • Glucose counterregulation
  • Glucose tolerance
  • Hypoglycemia
  • Insulin secretion
  • Pancreatic insufficiency

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