Effects of a single 10mg dose of empagliflozin on postprandial insulin kinetics in patients with postbariatric hypoglycaemia

Introduction: Postbariatric hypoglycaemia (PBH) is an increasingly recognized late metabolic complication of Roux-en-Y gastric bypass (GB) surgery. PBH typically manifests with a fact occurring post-meal hyperglycaemic peak, followed by a disproportionately exaggerated insulin response leading to low glucose levels. On this basis, we evaluated the effect of a single dose of empagliflozin 10mg vs. placebo on parameters of insulin kinetics. Materials and methods: Insulin secretion, hepatic insulin extraction and total insulin clearance were evaluated after a single of empagliflozin 10mg vs. placebo followed by a standardized liquid mixed meal were evaluated in 11 subjects with confirmed PBH after GB over 3h. Parameters of interest were calculated using established mathematical models. Indices were compared between the groups using the Wilcoxon signed-rank test. Results Total beta-cell responsiveness tends to be lower with empagliflozin vs. placebo (24.83±11.00 vs. 27.15±9.68 [10-9 min-1], p=0.150). Total first-pass hepatic insulin extraction increased after empagliflozin compared to placebo (49.6±14.2 vs. 39.7±12.1 %, p=0.006), while no significant effect of empaglizflozin on basal first-pass hepatic insulin extraction was observed (79.7±7.1 vs. 81.1±6.6 %, p=0.521). Total insulin clearance resulted to be significantly lower after empagliflozin compared to placebo (3.91±1.58 vs. 3.00±1.27 l/min, p=0.002). Conclusion The present analysis suggests that the hypoglycaemia-attenuating effect of SGLT2-inhibition in patients with PBH is mainly mediated by an increment in insulin clearance, with also a tendency to a reduction in insulin secretion.

Reply to Landry et al. Findings from Diet Comparison Difficult to Interpret in the Absence of Adherence Assessment. Comment on “Tricò et al. Effects of Low-Carbohydrate versus Mediterranean Diets on Weight Loss, Glucose Metabolism, Insulin Kinetics and β-Cell Function in Morbidly Obese Individuals. Nutrients 2021, 13, 1345”

We thank Dr. Landry and colleagues [...]

Findings from Diet Comparison Difficult to Interpret in the Absence of Adherence Assessment. Comment on Tricò et al. Effects of Low-Carbohydrate versus Mediterranean Diets on Weight Loss, Glucose Metabolism, Insulin Kinetics and β-Cell Function in Morbidly Obese Individuals. Nutrients 2021, 13, 1345

We read, with interest, the recent publication by Tricò et al. [...]

Modeling Intraperitoneal Insulin Absorption in Patients with Type 1 Diabetes

Standard insulin therapy to treat type 1 diabetes (T1D) consists of exogenous insulin administration through the subcutaneous (SC) tissue. Despite recent advances in insulin formulations, the SC route still suffers from delays and large inter/intra-subject variability that limiting optimal glucose control. Intraperitoneal (IP) insulin administration, despite its higher invasiveness, was shown to represent a valid alternative to the SC one. To date, no mathematical model describing the absorption and distribution of insulin after IP administration is available. Here, we aim to fill this gap by using data from eight patients with T1D, treated by implanted IP pump, studied in a hospitalized setting, with frequent measurements of plasma insulin and glucose concentration. A battery of models describing insulin kinetics after IP administration were tested. Model comparison and selection were performed based on model ability to predict the data, precision of parameters and parsimony criteria. The selected model assumed that the insulin absorption from the IP space was described by a linear, two-compartment model, coupled with a two-compartment model of whole-body insulin kinetics with hepatic insulin extraction controlled by hepatic insulin. Future developments include model incorporation into the UVa/Padova T1D Simulator for testing open- and closed-loop therapies with IP insulin administration.

The Impact of Exogenous Insulin Input on Calculating Hepatic Clearance Parameters

Objective: Model-based metabolic tests require accurate identification of subject-specific parameters from measured assays. Insulin assays are used to identify insulin kinetics parameters, such as general and first-pass hepatic clearances. This study assesses the impact of intravenous insulin boluses on parameter identification precision. Method: Insulin and C-peptide data from two intravenous glucose tolerance test (IVGTT) trials of healthy adults ( N = 10 × 2; denoted A and B), with (A) and without (B) insulin modification, were used to identify insulin kinetics parameters using a grid search. Monte Carlo analysis ( N = 1000) quantifies variation in simulation error for insulin assay errors of 5%. A region of parameter values around the optimum was identified whose errors are within variation due to assay error. A smaller optimal region indicates more precise practical identifiability. Trial results were compared to assess identifiability and precision. Results: Trial B, without insulin modification, has optimal parameter regions 4.7 times larger on average than Trial A, with 1-U insulin bolus modification. Ranges of optimal parameter values between trials A and B increase from 0.04 to 0.12 min-1 for hepatic clearance and from 0.07 to 0.14 for first-pass clearance on average. Trial B’s optimal values frequently lie outside physiological ranges, further indicating lack of distinct identifiability. Conclusions: A small 1-U insulin bolus improves identification of hepatic clearance parameters by providing a smaller region of optimal parameter values. Adding an insulin bolus in metabolic tests can significantly improve identifiability and outcome test precision. Assay errors necessitate insulin modification in clinical tests to ensure identifiability and precision.

The Impact of Amino Acids on Postprandial Glucose and Insulin Kinetics in Humans: A Quantitative Overview

Different amino acids (AAs) may exert distinct effects on postprandial glucose and insulin concentrations. A quantitative comparison of the effects of AAs on glucose and insulin kinetics in humans is currently lacking. PubMed was queried to identify intervention studies reporting glucose and insulin concentrations after acute ingestion and/or intravenous infusion of AAs in healthy adults and those living with obesity and/or type 2 diabetes (T2DM). The systematic literature search identified 55 studies that examined the effects of l-leucine, l-isoleucine, l-alanine, l-glutamine, l-arginine, l-lysine, glycine, l-proline, l-phenylalanine, l-glutamate, branched-chain AAs (i.e., l-leucine, l-isoleucine, and l-valine), and multiple individual l-AAs on glucose and insulin concentrations. Oral ingestion of most individual AAs induced an insulin response, but did not alter glucose concentrations in healthy participants. Specific AAs (i.e., leucine and isoleucine) co-ingested with glucose exerted a synergistic effect on the postprandial insulin response and attenuated the glucose response compared to glucose intake alone in healthy participants. Oral AA ingestion as well as intravenous AA infusion was able to stimulate an insulin response and decrease glucose concentrations in T2DM and obese individuals. The extracted information is publicly available and can serve multiple purposes such as computational modeling.

Obesity is associated with increased basal and postprandial β-cell insulin secretion even in the absence of insulin resistance

We tested the hypothesis that obesity, independent of insulin resistance, is associated with increased insulin secretion. We compared insulin kinetics before and after glucose ingestion in lean healthy people and people with obesity who were matched on multi-organ insulin sensitivity (inhibition of adipose tissue lipolysis and glucose production and stimulation of muscle glucose uptake), assessed by using a two-stage hyperinsulinemic-euglycemic pancreatic clamp procedure in conjunction with glucose and palmitate tracer infusions and positron emission tomography. We also evaluated the effect of diet-induced weight loss on insulin secretion in people with obesity who did not improve insulin sensitivity despite marked (~20%) weight loss. Basal and postprandial insulin secretion rates were more than 50% greater in people with obesity than lean people even though insulin sensitivity was not different between groups. Weight loss in people with obesity decreased insulin secretion by 35% even though insulin sensitivity did not change. These results demonstrate that increased insulin secretion in people with obesity is associated with excess adiposity itself and is not simply a compensatory response to insulin resistance. These findings have important implications regarding the pathogenesis of diabetes, because hyperinsulinemia causes insulin resistance and insulin hypersecretion is an independent risk factor for developing diabetes.