Hypoglycemia and Islet Dysfunction Following Oral Glucose Tolerance Testing in Pancreatic-Insufficient Cystic Fibrosis

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 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.

Islet Function in the Pathogenesis of Cystic Fibrosis-Related Diabetes Mellitus

“… 28 At the same time, glucagon release in response to low glucose is impaired in T1D and long lasting T2D increasing the risk of hypoglycemic episodes. 29 Along the same lines, Kilberg et al 21 showed that reduced glucagon secretion hours after a meal can lead to hypoglycemic events in CF patients diagnosed with pancreatic insufficiency. The dysregulation of glucagon secretion, with impaired high secretion in the early post-prandial phase 20 , 24 followed by a failed counter-regulatory response in the later phase 20 , 30 is not well understood.…”

“… 8 , 17 , 18 Insulin levels are lower in the first phase during an oral glucose tolerance test (OGTT) in CF and CFRD patients. 18 – 21 Also, there is an elevated secretion of proinsulin in both CFRD patients and CF patients with impaired glucose tolerance (IGT). 22 , 23 Failure to supress initial glucagon secretion following an OGTT correlates with decreased glucose tolerance among CF patients.…”

“… 26 Rather, the only established secretion abnormality is failed counter-regulatory secretion of glucagon in late phases of OGTT trials, even though there may be some aberrant increased secretion in the early phase. 20 , 21 , 30 …”

Spontaneous and iatrogenic hypoglycemia in cystic fibrosis

“…Hypoglycemia rates are higher during extended (3 or 4 hr) compared to standard (2 hr) OGTT. Postprandial hypoglycemia in CF patients has been reported as 6–15% on 2-hr OGTT [17] , 45–79% on 3-hr OGTT [17] , [20] , [21] , and 26% on mixed meal tolerance test (MMTT) [22] . In a study of youth with CF (mean age ∼ 14 years), Chan et al reported that rates of hypoglycemia on CGM, defined as time < 70 mg/dL and < 60 mg/dL, were not significantly different in subjects with CF (stratified according to glucose tolerance) compared to healthy controls [23] .…”

The Variation and Correlation of Serum Adiponectin, Nesfatin-1, IL-6 and TNF-α Levels in Prediabetes

“…Some studies believed that β cell dysfunction started even before the impaired glucose tolerance [3,4] . It has been proved that in ammation in islet of T2DM patient is due to immune cell in ltration [5] , amyloid deposition [6] , cell death [7] and brosis [8,9] . Tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) as proin ammatory factors secreted by M1 macrophage [10] could impair insulin secretion through degrading insulin receptor substrate [11] .…”