Response to Comment on "Minimal and Maximal Models to Quantitate Glucose Metabolism: Tools to Measure, to Simulate and to Run in Silico Clinical Trials"

We thank Eichenlaub and coworkers for their interesting letter to the editor entitled Comment on “Minimal and Maximal Models to Quantitate Glucose Metabolism: Tools to Measure, to Simulate and to Run in Silico Clinical Trials.”1 When developing the original model,2 we acknowledged that the need of fixing SG (fractional glucose effectiveness) to a population value was an important limitation of the method. To test the implication of this assumption on the model-derived insulin sensitivity, SI , we performed an extensive validation work against independent techniques, including glucose clamp3 and multiple tracer experiment,4 and we were able to prove that SI is well correlated with model-independent indices. Eichenlaub and coworkers’ overlook the SI validation studies3,4 that fully address their concerns: the correlation was 0.81 P < .001 with clamp in 10 normal and 11 impaired glucose tolerant subjects3 and 0.86, P < .0001 with the multiple tracer experiment in 88 healthy individuals.4 Therefore, their critiques cannot be sustained in the face of such a large body of validation evidence. [...

Interstitial fluid glucose is not just a shifted-in-time but a distorted mirror of blood glucose: Insight from an in Silico study

Glucose sensors measure glucose concentration in the interstitial fluid (ISF), remote from blood. ISF glucose is well known to be "delayed" with respect to blood glucose (BG). However, ISF glucose is not simply a shifted-in-time version of BG but exhibits a more complex pattern. METHODS: To gain insight into this problem, one can use linear systems theory. However, this may lose a more clinical readership, thus we use simulation and two case studies to convey our thinking in an easier way. In particular, we consider BG concentration measured after meal and exercise in 12 healthy volunteers, whereas ISF glucose is simulated using a well-accepted model of blood-ISF glucose kinetics, which permits calculation of the equilibration time, a parameter characterizing the system. Two metrics are defined: blood and ISF glucose difference at each time point and time to reach the same glucose value in blood and ISF. RESULTS: The simulation performed and the two metrics show that the relationship between blood-ISF glucose profiles is more complex than a pure shift in time and that the pattern depends on both equilibration time and BG. CONCLUSIONS: In this in silico study, we have illustrated, with simple case studies, the meaning of the of ISF glucose with respect to BG. Understanding that ISF glucose is not just a shifted-in-time version but a distorted mirror of BG is important for a correct use of continuous glucose monitoring for diabetes management

Clinical evaluation of a decision support system for glucose infusion in hypoglycaemic clamp experiments.

AIM To provide a preliminary evaluation of the accuracy and safety of Gluclas decision support system suggestions in a hypoglycaemic clamp study. METHODS This analysis was performed using data from 32 participants (four groups with different glucose-insulin regulation: post Roux-en-Y gastric bypass with and without postprandial hypoglycaemia syndrome, postsleeve gastrectomy and non-operated controls) undergoing Gluclas-assisted hypoglycaemic clamps (target: 2.5 mmol/L for 20 minutes at 150 minutes after oral glucose ingestion). Gluclas provided glucose infusion rate suggestions upon manual entry of blood glucose values (every 5 minutes), which were either followed or overruled by investigators after critical review. Accuracy and safety were evaluated by mean absolute error (MAE), mean absolute percentage error (MAPE), average glucose level, coefficient of variation (CV) and minimal glucose level during the 20-minute hypoglycaemic period. RESULTS Investigators accepted 84% of suggestions, with a mean deviation of 30.33 mg/min. During the hypoglycaemic period, the MAE was 0.16 (0.12-0.24) (median [interquartile range]) mmol/L and the MAPE was 6.12% (4.80%-9.29%). CV was 4.90% (3.58%-7.27%), with 5% considered the threshold for sufficient quality. The minimal glucose level was 2.40 (2.30-2.50) mmol/L. CONCLUSIONS Gluclas achieved sufficiently high accuracy with minimal safety risks in a population with differences in glucose-insulin dynamics, underscoring its applicability to various patient groups

Prediction of Postprandial Glycemic Exposure Utility of fasting and 2-h glucose measurements alone and in combination with assessment of body composition, fitness, and strength

OBJECTIVE —To determine the best predictors of total postprandial glycemic exposure and peak glucose concentrations in nondiabetic humans. RESEARCH DESIGN AND METHODS —Data from 203 nondiabetic volunteers who ingested a carbohydrate-containing mixed meal were analyzed. RESULTS —Fasting glucose and insulin concentrations were poor predictors of postprandial glucose area above basal ( R 2 = ∼0.07, P < 0.001). The correlation was stronger for 2-h glucose concentration ( R 2 = 0.55, P < 0.001) and improved slightly but significantly ( P < 0.001) with the addition of fasting glucose, insulin, age, sex, and body weight to the model ( r 2 = 0.58). The 2-h glucose concentration also predicted the peak glucose concentration ( R 2 = 0.37, P < 0.001) with strength of the prediction increasing ( P < 0.001) modestly with the addition of fasting glucose, insulin, age, sex, and body weight to the model ( R 2 = 0.48, P < 0.001). On the other hand, addition of measures of body function and composition did not improve prediction of total glycemic exposure or peak glucose concentration. CONCLUSIONS —Isolated measures of fasting or 2-h glucose concentrations alone or in combination with more complex measures of body composition and function are poor predictors of postprandial glycemic exposure or peak glucose concentration. This may explain, at least in part, the weak and at times inconsistent relationship between these parameters and cardiovascular risk

Liver triacylglycerol content and gestational diabetes: effects of moderate energy restriction

Aims/hypothesis Women with a history of gestational diabetes mellitus (GDM) have raised liver triacylglycerol. Restriction of energy intake in type 2 diabetes can normalise glucose control and liver triacylglycerol concentration but it is not known whether similar benefits could be achieved in GDM. The aim of this work was to examine liver triacylglycerol accumulation in women with GDM and the effect of modest energy restriction. Methods Sixteen women with GDM followed a 4 week diet (5 MJ [1200 kcal]/day). Liver triacylglycerol, before and after diet and postpartum, was measured by magnetic resonance. Insulin secretion and sensitivity were assessed before and after diet. Twenty-six women who underwent standard antenatal care for GDM (matched for age, BMI, parity and ethnicity) were used as a comparator group. Results Fourteen women, who completed the study, achieved a weight loss of 1.6 ± 1.7 kg over the 4 week dietary period. Mean weight change was −0.4 kg/week in the study group vs +0.3 kg/week in the comparator group (p = 0.002). Liver triacylglycerol level was normal but decreased following diet (3.7% [interquartile range, IQR 1.2–6.1%] vs 1.8% [IQR 0.7–3.1%], p = 0.004). There was no change in insulin sensitivity or production. Insulin was required in six comparator women vs none in the study group (eight vs two required metformin). Blood glucose control was similar for both groups. The hypo-energetic diet was well accepted. Conclusions/interpretation Liver triacylglycerol in women with GDM was not elevated, unlike observations in non-pregnant women with a history of GDM. A 4 week hypo-energetic diet resulted in weight loss, reduced liver triacylglycerol and minimised pharmacotherapy. The underlying pathophysiology of glucose metabolism appeared unchanged

Effects of Roux-en-Y gastric bypass and sleeve gastrectomy on β-cell function at one year after surgery: a systematic review.

Bariatric surgery is a highly effective obesity treatment resulting in substantial weight loss and improved glucose metabolism. We hereby aimed to summarize available evidence of the effect of the two most common bariatric surgery procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), on dynamic measures of β-cell function (BCF). A systematic search of the literature was conducted in 3 bibliographic databases for studies reporting effects of RYGB and/or SG on BCF assessed using dynamic metabolic perturbation (oral or intravenous bolus stimulation), performed before and 1 year (± 3 months) after surgery. Twenty-seven unique studies (6 randomized controlled trials and 21 observational studies), involving a total of 1,856 obese adults were included for final analysis. 25 and 9 studies report effects of RYGB and SG on BCF respectively (7 studies compared the two procedures). 7 studies report results according to pre-surgical diabetic status. Owing to variable testing procedures and BCF indices reported, no meta-analysis was feasible, and data were summarized qualitatively. For both surgical procedures, most studies suggest an increase in BCF and disposition index, particularly when using oral stimulation, with a more pronounced increase in diabetic than non-diabetic individuals. Additionally, limited indications for greater effects after RYGB and SG was found. The quality of the included studies was in general satisfactory. The considerable heterogeneity of test protocols and outcome measures underscores the need for a harmonization of BCF testing in future research

Unraveling, contributing factors to the severity of postprandial hypoglycemia after gastric bypass surgery.

BACKGROUND Despite the increasing prevalence of postbariatric hypoglycemia (PBH), a late metabolic complication of bariatric surgery, our understanding of its diverse manifestations remains incomplete. OBJECTIVES To contrast parameters of glucose-insulin homeostasis in 2 distinct phenotypes of PBH (mild versus moderate hypoglycemia) based on nadir plasma glucose. SETTING University Hospital (Bern, Switzerland). METHODS Twenty-five subjects with PBH following gastric bypass surgery (age, 41 ± 12 years; body mass index, 28.1 ± 6.1kg/m2) received 75g of glucose with frequent blood sampling for glucose, insulin, C-peptide, and glucagon-like peptide 1 (GLP)-1. Based on nadir plasma glucose (</≥50mg/dL), subjects were grouped into level 1 (L1) and level 2 (L2) PBH groups. Beta-cell function (BCF), GLP-1 exposure (λ), beta-cell sensitivity to GLP-1 (π), potentiation of insulin secretion by GLP-1 (PI), first-pass hepatic insulin extraction (HE), insulin sensitivity (SI), and rate of glucose appearance (Ra) were calculated using an oral model of GLP-1 action coupled with the oral minimal model. RESULTS Nadir glucose was 43.3 ± 6.0mg/dL (mean ± standard deviation) and 60.1 ± 9.1mg/dL in L2- and L1-PBH, respectively. Insulin exposure was significantly higher in L2 versus L1 (P = .004). Mathematical modeling revealed higher BCF in L2 versus L1 (34.3 versus 18.8 10-9∗min-1; P = .003). Despite an increased GLP-1 exposure in L2 compared to L1 PBH (50.7 versus 31.9pmol∗L-1∗min∗102; P = .021), no significant difference in PI was observed (P = .204). No significant differences were observed for HE, Ra, and SI. CONCLUSIONS Our results suggest that higher insulin exposure in PBH patients with lower postprandial nadir glucose values mainly relate to a higher responsiveness to glucose, rather than GLP-1

Study protocol for a randomised, double-blind, placebo-controlled crossover trial assessing the impact of the SGLT2 inhibitor empagliflozin on postprandial hypoglycaemia after gastric bypass.

INTRODUCTION Postprandial hypoglycaemia after gastric bypass surgery (also known as postbariatric hypoglycaemia or PBH) is an increasingly encountered clinical problem. PBH is characterised by meal-induced rapid spikes and consequent falls in glycaemia, resulting in both hypoglycaemia burden and high glycaemic variability. Despite its frequency, there is currently no approved pharmacotherapy. The purpose of this investigation is to evaluate efficacy and safety of empagliflozin 25 mg, a sodium-glucose cotransporter 2-inhibitor, to reduce glucose excursions and hypoglycaemia burden in patients with PBH after gastric bypass surgery. METHODS AND ANALYSIS In a prospective, single-centre, randomised, double-blind, placebo-controlled, crossover trial, we plan to enrol 22 adults (≥18 years) with PBH after Roux-en-Y gastric bypass surgery (plasma or sensor glucose <3.0 mmol/L). Eligible patients will be randomised to receive empagliflozin 25 mg and placebo once daily, each for 20 days, in random order. Study periods will be separated by a 2-6 weeks wash-out period. The primary efficacy outcome will be the amplitude of plasma glucose excursion (peak to nadir) during a mixed meal tolerance test. Results will be presented as paired-differences±SD plus 95% CIs with p values and hypothesis testing for primary and secondary outcomes according to intention-to-treat. Secondary outcomes include continuous glucose monitoring-based outcomes, further metabolic measures and safety. ETHICS AND DISSEMINATION The DEEP-EMPA trial (original protocol title: Randomized, double-blind, placebo-controlled crossover trialassessing the impact of the SGLT2 inhibitor empagliflozin onpostprandial hypoglycaemia after gastric bypass) was approved by the Bern Ethics Committee (ID 2021-01187) and Swissmedic (Ref. Number: 102663190) in October and November 2021, respectively. First results are expected in the first quarter of 2023 and will be disseminated via peer-reviewed publications and presented at national and international conferences. The acronym DEEP was derived from an overarching project title (DEciphering the Enigma of Postprandial Hyperinsulinaemic Hypoglycaemia after Bariatric Surgery), the term EMPA stands for the drug empagliflozin. TRIAL REGISTRATION NUMBER NCT05057819

Alterations in Postprandial Hepatic Glycogen Metabolism in Type 2 Diabetes

Decreased skeletal muscle glucose disposal and increased endogenous glucose production (EGP) contribute to postprandial hyperglycemia in type 2 diabetes, but the contribution of hepatic glycogen metabolism remains uncertain. Hepatic glycogen metabolism and EGP were monitored in type 2 diabetic patients and nondiabetic volunteer control subjects (CON) after mixed meal ingestion and during hyperglycemic-hyperinsulinemic-somatostatin clamps applying 13C nuclear magnetic resonance spectroscopy (NMRS) and variable infusion dual-tracer technique. Hepatocellular lipid (HCL) content was quantified by 1H NMRS. Before dinner, hepatic glycogen was lower in type 2 diabetic patients (227 ± 6 vs. CON: 275 ± 10 mmol/l liver, P &lt; 0.001). After meal ingestion, net synthetic rates were 0.76 ± 0.16 (type 2 diabetic patients) and 1.36 ± 0.15 mg · kg−1 · min−1 (CON, P &lt; 0.02), resulting in peak concentrations of 283 ± 15 and 360 ± 11 mmol/l liver. Postprandial rates of EGP were ∼0.3 mg · kg−1 · min−1 (30–170 min; P &lt; 0.05 vs. CON) higher in type 2 diabetic patients. Under clamp conditions, type 2 diabetic patients featured ∼54% lower (P &lt; 0.03) net hepatic glycogen synthesis and ∼0.5 mg · kg−1 · min−1 higher (P &lt; 0.02) EGP. Hepatic glucose storage negatively correlated with HCL content (R = −0.602, P &lt; 0.05). Type 2 diabetic patients exhibit 1) reduction of postprandial hepatic glycogen synthesis, 2) temporarily impaired suppression of EGP, and 3) no normalization of these defects by controlled hyperglycemic hyperinsulinemia. Thus, impaired insulin sensitivity and/or chronic glucolipotoxicity in addition to the effects of an altered insulin-to-glucagon ratio or increased free fatty acids accounts for defective hepatic glycogen metabolism in type 2 diabetic patients

Diabetes-Associated Common Genetic Variation and Its Association With GLP-1 Concentrations and Response to Exogenous GLP-1

The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1–induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp and GLP-1 infusion. In addition, we measured active and total GLP-1 in response to an oral challenge in nondiabetic subjects. After genotyping the relevant single nucleotide polymorphisms, generalized linear regression models and repeated-measures ANCOVA models incorporating potential confounders, such as age and BMI, were used to assess the associations, if any, of response with genotype. These variants did not alter GLP-1 concentrations in response to oral intake. No effects on β-cell responsiveness to hyperglycemia and GLP-1 infusion were apparent. Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02). In nondiabetic subjects, diabetes-associated genetic variation does not alter GLP-1 concentrations after an oral challenge or its effect on insulin secretion