A Potential Role for Endogenous Glucagon in Preventing Post-Bariatric Hypoglycemia

Abstract

Obesity and obesity-related diseases are major public health concerns that have been exponentially growing in the last decades. Bariatric surgery is an effective long-term treatment to achieve weight loss and obesity comorbidity remission. Post-bariatric hypoglycemia (PBH) is a late complication of bariatric surgery most commonly reported after Roux-en-Y gastric bypass (RYGB). PBH is the end result of postprandial hyperinsulinemia but additional endocrine mechanisms involved are still under debate. Our aim was to characterize entero-pancreatic hormone dynamics associated with postprandial hypoglycemia after RYGB. Individuals previously submitted to RYGB (N=23) in a single tertiary hospital presenting PBH symptoms (Sym, n=14) and asymptomatic weight-matched controls (Asy, n=9) were enrolled. Participants underwent a mixed-meal tolerance test (MMTT) to assess glucose, total amino acids (total AA), insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and neurotensin (NT). We found that hypoglycemia during the MMTT was equally frequent in Sym and Asy groups (p=1.000). Re-grouped according to glucose nadir during the MMTT (Hypo n=11 vs NoHypo n=12; nadir <3.05 mmol/l vs ≥3.05 mmol/l), subjects presented no differences in anthropometric (BMI: p=0.527) or metabolic features (HbA1c: p=0.358), yet distinct meal-elicited hormone dynamics were identified. Postprandial glucose excursion and peak glucose levels were similar (p>0.05), despite distinct late glycemic outcomes (t=60 min and t=90 min: p<0.01), with overall greater glycemic variability in Hypo group (minimum-to-maximum glucose ratio: p<0.001). Hypo group meal-triggered hormone profile was characterized by lower early glucagon (t=15 min: p<0.01) and higher insulin (t=30 min: p<0.05, t=45 min: p<0.001), C-peptide (t=30 min: p<0.01, t=45 min: p<0.001, t=60 min: p<0.05), and GLP-1 (t=45 min: p<0.05) levels. Hyperinsulinemia was an independent risk factor for hypoglycemia (p<0.05). After adjusting for hyperinsulinemia, early glucagon correlated with glycemic nadir (p<0.01), and prevented postprandial hypoglycemia (p<0.05). A higher insulin to glucagon balance in Hypo was observed (p<0.05). No differences were observed in total AA, GIP or NT excursions (p>0.05). In sum, after RYGB, postprandial hyperinsulinemia is key in triggering PBH, but a parallel and earlier rise in endogenous glucagon might sustain the inter-individual variability in glycemic outcome beyond the effect of hyperinsulinism, advocating a potential pivotal role for glucagon in preventing hyperinsulinemic hypoglycemia.

Counter-regulatory responses to postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia vs surgical and non-surgical control individuals

“…Against our hypothesis and indications from previous work using provocative tests [ 46 ], counter-regulatory responses to hypoglycaemia did not differ significantly between the PBH and the RYGB control group. Although attenuated counter-regulation may predispose to PBH, these response patterns may be rather characteristic of the altered post-bariatric surgery physiology (sustained weight loss and lower nadir glucose levels) rather than a root cause of PBH.…”

The Association of Postprandial Triglyceride Variability with Renal Dysfunction and Microalbuminuria in Patients with Type 2 Diabetic Mellitus: A Retrospective and Observational Study

“…Previous papers on “variability” have used various indices to evaluate their variability. SD has been used to evaluate the glycemic, blood pressure, and fasting TG variability ( 19 , 20 , 32 , 33 ) ( 34 , 35 ); the Adj-SD has also been used to evaluate the glycemic and fasting TG variability with adjusting for the number of measurements ( 19 , 21 , 22 , 36 ); and the MMD has been used to evaluate the glycemic and blood pressure variability ( 23 , 24 , 37 , 38 ). Our study suggested that the SD and Adj-SD might be more reliable than MMD, but MMD is calculated more easily than the other two.…”

“…Three indices of postprandial TG variability were calculated; the standard deviation (SD), SD adjusted (Adj-SD) for the number of measurements, and maximum minus minimum difference (MMD) of postprandial TG during the first three years of follow-up ( 19 – 22 ) ( 23 , 24 ). To minimize the effect of different numbers of TG measurements on the calculated values, the Adj-SD was defined according to the following formula: Adj − SD = SD/√[ n /( n − 1)].…”

The Association of Postprandial Triglyceride Variability with Renal Dysfunction and Microalbuminuria in Patients with Type 2 Diabetic Mellitus A Retrospective and Observational Study.

“…A total number of participants accounted for 527 patients, including 42 patients who dropped out from 5.5 to 7.5 years follow-up (Figure 1). Three indices of postprandial TG variability were calculated, including standard deviation (SD), SD adjusted (Adj-SD) for the number of measurements, and maximum minus minimum difference (MMD) of postprandial TG during the rst 3-year follow up (19) (20) (21) (22) (23) (24). To minimize any effect of different numbers of TG measurements on the calculated values, an Adj-SD was de ned according to the formula: Adj-SD = SD/√[n/(n−1)].…”