Rate Of Glucose Appearance Research Articles

Rationale and Design of the Study to Investigate the Metabolic Action of Imeglimin on Patients with Type2 Diabetes Mellitus (SISIMAI).

Imeglimin is a first-in-class, novel, oral glucose-lowering agent for the treatment of type2 diabetes mellitus. The efficacy and safety of imeglimin as an antidiabetic agent have been investigated in clinical trials. However, its metabolic effects in humans have not yet been fully elucidated. The Study to InveStIgate the Metabolic Action of Imeglimin on patients with type2 diabetes mellitus (SISIMAI) is a single-arm intervention study. In this study, we have recruited 25 patients with type2 diabetes to receive 2000mg/day imeglimin for 20weeks. We perform a 75-g oral glucose tolerance test (OGTT) with double-glucose tracers, a two-step hyperinsulinemic-euglycemic clamp with glucose tracer, ectopic fat measurement by proton magnetic resonance spectroscopy, visceral/subcutaneous fat area measurement by magnetic resonance imaging, muscle biopsy, and evaluation of fitness level by cycle ergometer before and after imeglimin administration. The primary outcome is the change in area under the curve of glucose levels during the OGTT after 20weeks of imeglimin treatment. We also calculate the endogenous glucose production, rate of oral glucose appearance, and rate of glucose disappearance from the data during the 75-g OGTT and compare them between pre- and post-treatment. Additionally, we will compare other parameters, such as the changes in tissue-specific insulin sensitivity, ectopic fat accumulation, visceral/subcutaneous fat area accumulation, and fitness level between each point. This is the first study to investigate the organ-specific metabolic action of imeglimin in patients with type2 diabetes mellitus using the 75-g OGTT with the double tracer method. The results of this study are expected to provide useful information for drug selection based on the pathophysiology of individual patients with type2 diabetes mellitus. jRCTs031210600.

Pioglitazone does not affect exogenous glucose oxidation or metabolic clearance rate during steady-state aerobic exercise at high altitude

Background: Hypoxia-induced insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR, proxy for peripheral glucose uptake) in native lowlanders exercising during the initial hours of high-altitude (HA) exposure compared sea level. These data suggest that administering an insulin sensitizing drug before HA exposure may increase exogenous glucose oxidation rate by stimulating peripheral glucose uptake. Objective: To compare the effects of pioglitazone (PIO) and placebo (PLA) on exogenous glucose oxidation and MCR during steady-state aerobic exercise at HA. We hypothesized that exogenous glucose oxidation and MCR would be higher with PIO than PLA. Methods: Using a randomized, crossover design, native lowlanders (n = 7 males, mean ± SD, age: 23 ± 6 y, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically-matched (1.43 ± 0.16 VȮ2 L/min) treadmill exercise at HA (460 mmHg) after being administered PIO (15 mg) or PLA (microcrystalline cellulose pill) daily for five days. Substrate oxidation and glucose turnover were determined using indirect calorimetry, oral 13C-glucose and [6,6-2H2]-glucose primed, continuous infusions. Results: Exogenous glucose oxidation rate was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation with PIO (1.65 ± 0.22 g/min) was the same as PLA (1.68 ± 0.32 g/min). There were no treatment effects on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min) disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), and MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Conclusion: These data do not support our hypothesis that exogenous glucose oxidation during exercise at HA can be restored through the short-term administration of PIO. Findings from this study may suggest that hypoxia-induced insulin resistance may be a symptom and not the primary etiology of dysregulated glucose metabolism during acute HA exposure. Supported by MOMRP; authors’ views not offcial US Army or DoD policy. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pioglitazone does not enhance exogenous glucose oxidation or metabolic clearance rate during aerobic exercise in men under acute high-altitude exposure.

Insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR) during aerobic exercise in unacclimatized lowlanders at high altitude (HA). Whether use of an oral insulin sensitizer before acute HA exposure enhances exogenous glucose oxidation is unclear. This study investigated the impact of pioglitazone (PIO) on exogenous glucose oxidation and glucose turnover compared with placebo (PLA) during aerobic exercise at HA. With the use of a randomized crossover design, native lowlanders (n = 7 males, means ± SD, age: 23 ± 6 yr, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80 min of steady-state (1.43 ± 0.16 V̇o2 L/min) treadmill exercise at HA (460 mmHg; [Formula: see text] 96.6 mmHg) following short-term (5 days) use of PIO (15 mg oral dose per day) or PLA (microcrystalline cellulose pill). Substrate oxidation and glucose turnover were determined using indirect calorimetry and stable isotopes ([13C]glucose and 6,6-[2H2]glucose). Exogenous glucose oxidation was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation (PIO: 1.65 ± 0.22 g/min, PLA: 1.68 ± 0.32 g/min) or fat oxidation (PIO: 0.10 ± 0.0.08 g/min, PLA: 0.09 ± 0.07 g/min) was not different between treatments. There was no treatment effect on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min), disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), or MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Results from this study indicate that PIO is not an effective intervention to enhance exogenous glucose oxidation or MCR during acute HA exposure. Lack of effect with PIO suggests that the etiology of glucose metabolism dysregulation during acute HA exposure may not result from insulin resistance in peripheral tissues.NEW & NOTEWORTHY Short-term (5 days) use of the oral insulin sensitizer pioglitazone does not alter circulating glucose or insulin responses to enhance exogenous glucose oxidation during steady-state aerobic exercise in young healthy men under simulated acute (8 h) high-altitude (460 mmHg) conditions. These results indicate that dysregulations in glucose metabolism in native lowlanders sojourning at high altitude may not be due to insulin resistance at peripheral tissue.

The Minimally-Invasive Oral Glucose Minimal Model: Estimation of Gastric Retention, Glucose Rate of Appearance, and Insulin Sensitivity From Type 1 Diabetes Data Collected in Real-Life Conditions.

Modeling the effect of meal composition on glucose excursion would help in designing decision support systems (DSS) for type 1 diabetes (T1D) management. In fact, macronutrients differently affect post-prandial gastric retention (GR), rate of appearance (R[Formula: see text]), and insulin sensitivity (S[Formula: see text]). Such variables can be estimated, in inpatient settings, from plasma glucose (G) and insulin (I) data using the Oral glucose Minimal Model (OMM) coupled with a physiological model of glucose transit through the gastrointestinal tract (reference OMM, R-OMM). Here, we present a model able to estimate those quantities in daily-life conditions, using minimally-invasive (MI) technologies, and validate it against the R-OMM. Forty-seven individuals with T1D (weight =78±13 kg, age =42±10 yr) underwent three 23-hour visits, during which G and I were frequently sampled while wearing continuous glucose monitoring (CGM) and insulin pump (IP). Using a Bayesian Maximum A Posteriori estimator, R-OMM was identified from plasma G and I measurements, and MI-OMM was identified from CGM and IP data. The MI-OMM fitted the CGM data well and provided precise parameter estimates. GR and R[Formula: see text] model parameters were not significantly different using the MI-OMM and R-OMM (p 0.05) and the correlation between the two S[Formula: see text] was satisfactory ( ρ =0.77). The MI-OMM is usable to estimate GR, R[Formula: see text], and S[Formula: see text] from data collected in real-life conditions with minimally-invasive technologies. Applying MI-OMM to datasets where meal compositions are available will allow modeling the effect of each macronutrient on GR, R[Formula: see text], and S[Formula: see text]. DSS could finally exploit this information to improve diabetes management.

The impact of glucagon to support postabsorptive glucose flux and glycemia in healthy rats and its attenuation in male Zucker diabetic fatty rats.

Hyperglucagonemia is a hallmark of type 2 diabetes (T2DM), yet the role of elevated plasma glucagon (P-GCG) to promote excessive postabsorptive glucose production and contribute to hyperglycemia in patients with this disease remains debatable. We investigated the acute action of P-GCG to safeguard/support postabsorptive endogenous glucose production (EGP) and euglycemia in healthy Zucker control lean (ZCL) rats. Using male Zucker diabetic fatty (ZDF) rats that exhibit the typical metabolic disorders of human T2DM, such as excessive EGP, hyperglycemia, hyperinsulinemia, and hyperglucagonemia, we examined the ability of hyperglucagonemia to promote greater rates of postabsorptive EGP and hyperglycemia. Euglycemic or hyperglycemic basal insulin (INS-BC) and glucagon (GCG-BC) clamps were performed in the absence or during an acute setting of glucagon deficiency (GCG-DF, ∼10% of basal), either alone or in combination with insulin deficiency (INS-DF, ∼10% of basal). Glucose appearance, disappearance, and cycling rates were measured using [2-3H] and [3-3H]-glucose. In ZCL rats, GCG-DF reduced the levels of hepatic cyclic AMP, EGP, and plasma glucose (PG) by 50%, 32%, and 50%, respectively. EGP fell in the presence GCG-DF and INS-BC, but under GCG-DF and INS-DF, EGP and PG increased two- and threefold, respectively. GCG-DF revealed the hyperglucagonemia present in ZDF rats lacked the ability to regulate hepatic intracellular cyclic AMP levels and glucose flux, since EGP and PG levels fell by only 10%. We conclude that the liver in T2DM suffers from resistance to all three major regulatory factors, glucagon, insulin, and glucose, thus leading to a loss of metabolic flexibility.NEW & NOTEWORTHY In postabsorptive state, basal plasma insulin (P-INS) and plasma glucose (PG) act dominantly to increase hepatic glucose cycling and reduce endogenous glucose production (EGP) and PG in healthy rats, which is only counteracted by the acute action of basal plasma glucagon (P-GCG) to support EGP and euglycemia. Hyperglucagonemia, a hallmark of type 2 diabetes (T2DM) present in Zucker diabetic fatty (ZDF) rats, is not the primary mediator of hyperglycemia and high EGP as commonly thought; instead, the liver is resistant to glucagon as well as insulin and glucose.

Impaired plasma glucose clearance is a key determinant of fasting hyperglycemia in people with obesity.

The objective of this study was to evaluate the relative importance of the basal rate of glucose appearance (Ra) in the circulation and the basal rate of plasma glucose clearance in determining fasting plasma glucose concentration in people with obesity and different fasting glycemic statuses. The authors evaluated basal glucose kinetics in 33 lean people with normal fasting glucose (<100 mg/dL; Lean < 100 group) and 206 people with obesity and normal fasting glucose (Ob < 100 group, n = 118), impaired fasting glucose (100-125 mg/dL; Ob 100-125 group, n = 66), or fasting glucose diagnostic of diabetes (≥126 mg/dL; Ob ≥ 126 group, n = 22). Although there was a large (up to three-fold) range in glucose Ra within each group, the ranges in glucose concentration in the Lean < 100, Ob < 100, and Ob 100-125 groups were small because of a close relationship between glucose Ra and clearance rate. However, the glucose clearance rate at any Ra value was lower in the hyperglycemic than the normoglycemic groups. In the Ob ≥ 126 group, plasma glucose concentration was primarily determined by glucose Ra, because glucose clearance was markedly attenuated. Fasting hyperglycemia in people with obesity represents a disruption of the precisely regulated integration of glucose production and clearance rates.

Estimation and Prediction of Glucose Appearance Rate for Use in a Fully Closed-Loop Dual-Hormone Intraperitoneal Artificial Pancreas.

A fully automated artificial pancreas requires a meal estimator and predictions of blood glucose levels (BGL) to handle disturbances during meal times, all without relying on manual meal announcements and user interventions. This study introduces a technique for estimating the glucose appearance rate (GAR) and predicting BGL in people with type 1 diabetes and insulin and glucagon administration. It is demonstrated for intraperitoneal insulin and glucagon delivery but may be adapted to other delivery sites. The estimator is designed based on the moving horizon estimation (MHE) approach, where the underlying cost function incorporates prior statistical information on the GAR in subjects over the course of a day. The proposed prediction scheme is developed to predict GAR using estimated states and an intestinal model, which is then used to predict BGL with the help of an animal glucose metabolic model. The intraperitoneal dual-hormone estimator was evaluated on three anesthetized animals, achieving a 21.8% mean absolute percentage error (MAPE) for GAR estimation and a 10.0% MAPE for BGL prediction when the future GAR is known. For a 120-minute prediction horizon, the proposed predictor achieved an 18.0% MAPE for GAR and a 28.4% MAPE for BGL. The findings demonstrate the effectiveness and reliability of the proposed estimator and its potential for use in a fully automated artificial pancreas and reducing user interventions. This study represents advancements toward the development of a fully automated artificial pancreas, ultimately enhancing the quality of life for people with type 1 diabetes.

Modelling Rate of Exogenous Glucose Appearance for Biomedical Applications Using Conditional Generative Models

The assessment of oral carbohydrate intake and its rate of exogenous glucose appearance is crucial for monitoring blood glucose in patients who suffer from diabetes and also for healthy individuals, as it is one of the major factors involved in human metabolism. Its accurate modelling is necessary when developing methodologies to mimic the physiological processes within the human body. Considering the recent advancements in data-driven methods that demand non-deterministic solutions to simulate real-life scenarios, this study proposes a novel approach based on conditional generative adversarial models to introduce realistic variability to the models in the state of the art, which are incapable of representing the full variety of scenarios due to their deterministic nature.

Increased Insulin Secretion and Glucose Effectiveness in Obese Patients with Type 2 Diabetes following Bariatric Surgery.

β-cell dysfunction and insulin resistance are the main mechanisms causing glucose intolerance in type 2 diabetes (T2D). Bariatric surgeries, i.e., sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), are procedures both known to induce weight loss, increase insulin action, and enhance β-cell function, but hepatic insulin extraction and glucose effectiveness may also play a role. To determine the contribution of these regulators on glucose tolerance after bariatric surgery, an oral glucose tolerance test (OGTT) was performed before and 2 months after surgery in 9 RYGB and 7 SG subjects. Eight healthy subjects served as metabolic controls. Plasma glucose, insulin, C-peptide, GLP-1, and GIP were measured during each OGTT. Insulin sensitivity and secretion, glucose effectiveness, and glucose rate of appearance were determined via oral minimal models. RYGB and SG resulted in similar weight reductions (13%, RYGB (p < 0.01); 14%, SG (p < 0.05)). Two months after surgery, insulin secretion (p < 0.05) and glucose effectiveness both improved equally in the two groups (11%, RYGB (p < 0.01); 8%, SG (p > 0.05)), whereas insulin sensitivity remained virtually unaltered. Bariatric surgery resulted in a comparable increase in the GLP-1 response during the OGTT, whereas GIP concentrations remained unaltered. Following surgery, oral glucose intake resulted in a comparable increase in hepatic insulin extraction, the response in both RYGB and SG patients significantly exceeding the response observed in the control subjects. These results demonstrate that the early improvement in glucose tolerance in obese T2D after RYGB and SG surgeries is attributable mainly to increased insulin secretion and glucose effectiveness, while insulin sensitivity seems to play only a minor role. This trial is registered with NCT02713555.

OR18-03 Peripheral But Not Hepatic Insulin Resistance Associates With Adverse Vascular And Metabolic Health In Type 1 Diabetes: A Possible Target For Adjunctive Therapy

Abstract Disclosure: J.R. Snaith: None. N. Olsen: None. G. Kowalski: None. C. Bruce: None. J. Holmes-Walker: None. J.R. Greenfield: None. Insulin resistance in type 1 diabetes (T1D) is a cardiometabolic risk factor that is potentially targetable with adjunctive therapy. Prior studies of metformin in T1D have yielded mixed results. Whether liver and/or muscle insulin resistance is a prerequisite for metformin’s action in adults with T1D is unknown. The INTIMET study recruited 40 adults with T1D (age 37.4±8.8 years, HbA1c 7.5±0.9%, diabetes duration 22.9±8.8 years, BMI 26.4±0.9 kg/m2) and 20 age- and BMI-matched controls without diabetes. Subjects with T1D were randomized to metformin extended-release 1500mg daily or placebo for 26 weeks. Two-step hyperinsulinemic euglycemic clamps (low-dose 20 mU/m2/min, high-dose 60 mU/m2/min insulin) using 6,6-2H2-glucose tracers assessed liver (basal glucose rate of appearance [B-Ra] and low-dose endogenous glucose production [L-EGP]; primary outcomes) and muscle (high-dose glucose infusion rate [GIR]; secondary outcome) insulin resistance at t=0 in all subjects and at t=26 weeks in T1D. Dual-energy x-ray absorptiometry was used to measure fat free mass and visceral adipose tissue (VAT). Applanation tonometry was used to measure arterial stiffness (AIx, augmentation index). Adults with T1D and controls had similar B-Ra (18.2±5.1 vs 18.3±2.2 mmol/kgFFM/min; p=0.87). However, T1D were insulin-resistant at the liver (L-EGP 5.9±2.2 vs 3.6±1.7 mmol/kgFFM/min; p&amp;lt;0.001) and at muscle (GIR 62±20 vs 88±18 µmol/min·kgFFM; p&amp;lt;0.001). Despite these differences, VAT was comparable. In all subjects, baseline GIR correlated with L-EGP (r=-0.343; p=0.008), VAT (r=-0.269; p=0.039) and BMI (r=-0.304; p=0.019). In contrast, baseline L-EGP did not relate to VAT (r=0.060; p=0.653) or BMI (r=0.173; p=0.189). Adults with T1D had borderline higher AIx than controls (11.2±11.4 vs 4.7±13.1%, p=0.05). In the whole group, GIR was associated with LogAIx (r=-0.258, p=0.048), but L-EGP was not (r=0.154; p=0.246). In T1D, HbA1c correlated with GIR (r=-0.329; p=0.041) but L-EGP did not (r=0.307; p=0.057). After 26 weeks, there was no difference between metformin vs placebo-treated T1D subjects in HbA1c and weight, or B-Ra, L-EGP or GIR using generalised linear regression adjusted for age and baseline B-Ra, L-EGP and GIR. In these models, baseline GIR inversely predicted L-EGP (p=0.027) and directly predicted GIR (p&amp;lt;0.001) at 26 weeks. Adults with T1D exhibited greater liver and muscle insulin resistance, and higher arterial stiffness, which was not improved with metformin. Muscle but not liver insulin resistance related to BMI, VAT, HbA1c and AIx. Baseline muscle insulin resistance predicted muscle and hepatic insulin resistance at 26 weeks, irrespective of metformin treatment. This study highlights 1) the importance of muscle but not liver insulin resistance in T1D and 2) the need to identify muscle insulin resistant T1D individuals to enable interventions that improve vascular and metabolic outcomes. Presentation: Saturday, June 17, 2023

Active Labeling Correction of Mealtimes and the Appearance of Types of Carbohydrates in Type 1 Diabetes Information Records

People with type 1 diabetes are required to adhere to their treatment rigorously to ensure maximum benefits. Diabetes tracking tools have played an important role in this regard. Type 1 diabetes monitoring has evolved and matured with the advent of blood glucose monitor sensors, insulin pens, and insulin pump automation. However, carbohydrate monitoring has seen little progress despite carbohydrates representing a major potential disruption. Relying on the modeling of carbohydrate intake using the rate of exogenous glucose appearance, we first present a methodology capable of identifying the type of carbohydrates ingested by classifying them into fast and non-fast carbohydrates. Second, we test the ability of the methodology to identify the correct synchrony between the actual mealtime and the time labeled as such in diabetes records. A deep neural network is trained with processed input data that consist of different values to estimate the parameters in a series of experiments in which, firstly, we vary the response of ingested carbohydrates for subsequent identification and, secondly, we shift the learned carbohydrate absorption curves in time to estimate when the meals were administered to virtual patients. This study validates that the identification of different carbohydrate classes in the meal records of people with type 1 diabetes could become a valuable source of information, as it demonstrates the potential to identify inaccuracies in the recorded meal records of these patients, suggesting the potential abilities of the next generation of type 1 diabetes management tools.

Role of prior feeding status in mediating the effects of exercise on blood glucose kinetics.

Changes in blood glucose concentrations are underpinned by blood glucose kinetics (endogenous and exogenous glucose appearance rates and glucose disappearance rates). Exercise potently alters blood glucose kinetics and can thereby be used as a tool to control blood glucose concentration. However, most studies of exercise-induced changes in glucose kinetics are conducted in a fasted state, and therefore less is known about the effects of exercise on glucose kinetics when exercise is conducted in a postprandial state. Emerging evidence suggests that food intake prior to exercise can increase postprandial blood glucose flux compared with when meals are consumed after exercise, whereby both glucose appearance rates and disappearance rates are increased. The mechanisms underlying the mediating effect of exercise conducted in the fed versus the fasted state are yet to be fully elucidated. Current evidence demonstrates that exercise in the postprandial state increased glucose appearance rates due to both increased exogenous and endogenous appearance and may be due to changes in splanchnic blood flow, intestinal permeability, and/or hepatic glucose extraction. On the other hand, increased glucose disappearance rates after exercise in the fed state have been shown to be associated with increased intramuscular AMPK signaling via a mismatch between carbohydrate utilization and delivery. Due to differences in blood glucose kinetics and other physiological differences, studies conducted in the fasted state cannot be immediately translated to the fed state. Therefore, conducting studies in the fed state could improve the external validity of data pertaining to glucose kinetics and intramuscular signaling in response to nutrition and exercise.

Acute Statin Withdrawal Does not Interfere With the Improvements of a Session of Exercise in Postprandial Metabolism.

The risk for atherogenic plaque formation is high after ingestion of meals in individuals with high blood lipid levels (ie, dyslipidemia). Statins and exercise reduce the rise of blood triglyceride concentrations after a meal, but the effect of their combination is unclear. In a randomized crossover design, 11 individuals with dyslipidemia and metabolic syndrome treated with statins underwent a mixed-meal (970 ± 111 kcal, 24% fat, and 34% carbohydrate) tolerance test. Plasma lipid concentrations, fat oxidation, glucose, and glycerol kinetics were monitored immediately prior and during the meal test. Trials were conducted with participants under their habitual statin treatment and 96 hours after blinded statin withdrawal. Trials were duplicated after a prolonged bout of low-intensity exercise (75 minutes at 53 ± 4% maximal oxygen consumption) to study the interactions between exercise and statins. Statins reduced postprandial plasma triglycerides from 3.03 ± 0.85 to 2.52 ± 0.86 mmol·L-1 (17%; P = .015) and plasma glycerol concentrations (ie, surrogate of whole-body lipolysis) without reducing plasma free fatty acid concentration or fat oxidation. Prior exercise increased postprandial plasma glycerol levels (P = .029) and fat oxidation rates (P = .024). Exercise decreased postprandial plasma insulin levels (241 ± 116 vs 301 ± 172 ρmol·L-1; P = .026) but not enough to increase insulin sensitivity (P = .614). Neither statins nor exercise affected plasma glucose appearance rates from exogenous or endogenous sources. In dyslipidemic individuals, statins reduce blood triglyceride concentrations after a meal, but without limiting fat oxidation. Statins do not interfere with exercise lowering the postprandial insulin that likely promotes fat oxidation. Last, statins do not restrict the rates of plasma incorporation or oxidation of the ingested glucose.

254-OR: Effects of Roux-en-Y Gastric Bypass on Postprandial Glucose Turnover Assessed through the Single-Tracer Oral Minimal Model

Rearrangements of gastrointestinal anatomy after Roux-en-Y gastric bypass (RYGB) surgery alter postprandial glucose metabolism. However, the impact on different components of glucose homeostasis remain incompletely understood. Here, we aim to evaluate the effects of RYGB on postprandial glucose turnover, production (P) and disposal (D) glucose effectiveness (GEP, GED) and production and disposal sensitivity to insulin (SIP, SID). Ten RYGB (2M, age=39.2±3.1 y, BMI=28±1 kg/m2- mean±SE) subjects and 10 healthy controls (5M, age=36.4±3.2 y, BMI=26±1 kg/m2) ingested 60g of glucose (G) labelled with [6,6-2H2]-glucose. Plasma samples were frequently drawn to measure G, insulin (I) and tracer concentrations in the following 180 min. The Single-Tracer Oral Minimal Model was used to estimate meal glucose rate of appearance (Ra), endogenous glucose production (EGP), glucose disposal (Rd), GEP, GED, SIP and SID. Incremental area under the G curve (iAUC(G)) was not different in the two groups, while iAUC(I) was significantly higher in RYGB (8346±803 vs. 5451±602 μU/mL*min, p=0.011); iAUC(Ra) normalized to the G dose was significantly higher in the first 60 min after the meal (0.72±0.04 vs. 0.28±0.03, p&amp;lt;0.001) while, throughout the experiment, EGP suppression (EGPs) normalized to basal (EGPb) was significantly lower (0.31±0.06 vs. 0.55±0.05, p=0.006) and iAUC(Rd) normalized to basal (Rdb) was higher (3.46±0.10 vs. 2.82±0.08, p&amp;lt;0.001) in RYGB than controls. Model predicted SIP was significantly lower in RYGB than controls (2.0±0.5 vs. 5.1±1.2 10-4 dL/kg/min per μU/mL, p=0.033) while no differences were observed in GEP, GED and SID. We concluded that the abnormally high I concentration in RYGB was responsible for the higher iAUC(Rd) in the operated individuals, while the reduced SIP likely works as a protective mechanism against postprandial hypoglycaemia by reducing EGPs despite the high circulating I. Disclosure A.Brunasso: None. C.Dalla man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. D.Herzig: None. L.Bally: Research Support; Dexcom, Inc., Ypsomed AG. M.Schiavon: None. Funding Italian Minister for Education (Law 232/2016); Swiss National Science Foundation (PCEGP3_186978)

Estimation of glucose rate of appearance in portal vein circulation using a phenomenological-based model.

The joint work of the stomach and the small intestine plays a fundamental role in human digestion. In the stomach, food is turned into a semi-fluid mixture that is slowly released into the small intestine, where most enzymatic reactions occur, and nutrients are absorbed as they become available. This whole process is closely related to glucose homeostasis, mainly because of the appearance of glucose in the portal system and the energetic expenditure of the process itself. The current phenomenological-based model describes such effects of the digestive process on blood glucose concentration. It considers enzymatic and mechanical transformations, energetic expenditure, and the impact of macro-nutrients, fiber, and water on overall digestion and glucose absorption. The model estimates the rate of glucose appearance in the portal vein and is intended to be further integrated into existing models for other human organs and used in model-based systems such as an artificial pancreas with automated insulin delivery.

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

Despite the increasing prevalence of postbariatric hypoglycemia (PBH), a late metabolic complication of bariatric surgery, our understanding of its diverse manifestations remains incomplete. To contrast parameters of glucose-insulin homeostasis in 2 distinct phenotypes of PBH (mild versus moderate hypoglycemia) based on nadir plasma glucose. University Hospital (Bern, Switzerland). 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. 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. 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.

Ketone Monoester Plus Carbohydrate Supplementation Does Not Alter Exogenous and Plasma Glucose Oxidation or Metabolic Clearance Rate During Exercise in Men Compared with Carbohydrate Alone

BackgroundIncreasing β-hydroxybutyrate (βHB) availability through ketone monoester (KE) plus carbohydrate supplementation is suggested to enhance physical performance by sparing glucose use during exercise. However, no studies have examined the effect of ketone supplementation on glucose kinetics during exercise. ObjectivesThis exploratory study primarily aimed to determine the effect of KE plus carbohydrate supplementation on glucose oxidation during steady-state exercise and physical performance compared with carbohydrate alone. MethodsUsing a randomly assigned, crossover design, 12 men consumed 573 mg KE/kg body mass plus 110 g glucose (KE+CHO) or 110 g glucose (CHO) before and during 90 min of steady-state treadmill exercise [54 ± 3% peak oxygen uptake (V˙O2peak)] wearing a weighted vest (30% body mass; 25 ± 3 kg). Glucose oxidation and turnover were determined using indirect calorimetry and stable isotopes. Participants performed an unweighted time to exhaustion (TTE; 85% V˙O2peak) after steady-state exercise and a weighted (25 ± 3 kg) 6.4 km time trial (TT) the next day after consuming a bolus of KE+CHO or CHO. Data were analyzed by paired t-tests and mixed model ANOVA. ResultsβHB concentrations were higher (P < 0.05) after exercise [2.1 mM (95% CI: 1.6, .6)] and the TT [2.6 mM (2.1, 3.1)] in KE+CHO compared with CHO. TTE was lower [−104 s (−201, −8)], and TT performance was slower [141 s (19,262)] in KE+CHO than in CHO (P < 0.05). Exogenous [−0.01 g/min (−0.07, 0.04)] and plasma [−0.02 g/min (−0.08, 0.04)] glucose oxidation and metabolic clearance rate {MCR [0.38 mg·kg−1·min−1 (−0.79, 1.54)]} were not different, and glucose rate of appearance [−0.51 mg·kg−1·min−1 (−0.97, −0.04)], and disappearance [−0.50 mg·kg−1·min−1 (−0.96, −0.04)] were lower (P < 0.05) in KE+CHO compared with CHO during steady-state exercise. ConclusionsIn the current study, rates of exogenous and plasma glucose oxidation and MCR were not different between treatments during steady-state exercise, suggesting blood glucose utilization is similar between KE+CHO and CHO. KE+CHO supplementation also results in lower physical performance compared with CHO alone.This trial was registered at www.clinicaltrials.gov as NCT04737694.

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

Aims/hypothesisPost-bariatric hypoglycaemia is an increasingly recognised complication of bariatric surgery, manifesting particularly after Roux-en-Y gastric bypass. While hyperinsulinaemia is an established pathophysiological feature, the role of counter-regulation remains unclear. We aimed to assess counter-regulatory hormones and glucose fluxes during insulin-induced postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia after Roux-en-Y gastric bypass vs surgical and non-surgical control individuals.MethodsIn this case–control study, 32 adults belonging to four groups with comparable age, sex and BMI (patients with post-bariatric hypoglycaemia, Roux-en-Y gastric bypass, sleeve gastrectomy and non-surgical control individuals) underwent a postprandial hypoglycaemic clamp in our clinical research unit to reach the glycaemic target of 2.5 mmol/l 150–170 min after ingesting 15 g of glucose. Glucose fluxes were assessed during the postprandial and hypoglycaemic period using a dual-tracer approach. The primary outcome was the incremental AUC of glucagon during hypoglycaemia. Catecholamines, cortisol, growth hormone, pancreatic polypeptide and endogenous glucose production were also analysed during hypoglycaemia.ResultsThe rate of glucose appearance after oral administration, as well as the rates of total glucose appearance and glucose disappearance, were higher in both Roux-en-Y gastric bypass groups vs the non-surgical control group in the early postprandial period (all p<0.05). During hypoglycaemia, glucagon exposure was significantly lower in all surgical groups vs the non-surgical control group (all p<0.01). Pancreatic polypeptide levels were significantly lower in patients with post-bariatric hypoglycaemia vs the non-surgical control group (median [IQR]: 24.7 [10.9, 38.7] pmol/l vs 238.7 [186.3, 288.9] pmol/l) (p=0.005). Other hormonal responses to hypoglycaemia and endogenous glucose production did not significantly differ between the groups.Conclusions/interpretationThe glucagon response to insulin-induced postprandial hypoglycaemia is lower in post-bariatric surgery individuals compared with non-surgical control individuals, irrespective of the surgical modality. No significant differences were found between patients with post-bariatric hypoglycaemia and surgical control individuals, suggesting that impaired counter-regulation is not a root cause of post-bariatric hypoglycaemia.Trial registrationClinicalTrials.gov NCT04334161Graphical abstract

EFFECTS OF STATINS ON SUBSTRATE UTILIZATION DURING EXERCISE

PURPOSE: Statin is the most prescribed medicine worldwide to lower cardiovascular risk. Its blood triglyceride lowering effect, may limit fat mobilization/oxidation during exercise. METHODS: Nine individuals with metabolic syndrome, chronically treated with statins to correct their dyslipidemia exercised at three increasing intensities (40, 70, and 85% VO2 MAX) while taking statins or placebo using a randomized double-blind crossover design. Indirect calorimetry and stable isotope tracer techniques were combined to assess plasma substrate kinetic and oxidation. RESULTS: As expected, statin use lowered resting plasma triglyceride concentration (i.e., PLAC 1.4±0.7 vs STAT 1.1±0.5 mmol·L-1, p = 0.003), and also plasma triglyceride concentration during exercise (i.e., PLAC 1.7±0.8 vs STAT 1.2±0.5 mmol·L-1; p < 0.001). Ra glycerol (i.e., index of whole-body lipolysis) increased along with exercise intensity but the increase was attenuated by statins (p < 0.014) at the 85% VO2 MAX exercise intensity (i.e., PLAC 7.4±1.9 vs STAT 5.8±2.2 mM·kg·min-1; p = 0.046). This 21% lower lipolysis during STAT did not limit fat oxidation that was similarly low in PLAC and STAT (i.e., PLAC 0.7±2.1 vs STAT 0.8±2.2 mM·kg·min-1; p = 0.459). STAT increased resting plasma glucose concentration (i.e., PLAC 6.6±1.6 vs STAT 6.8±1.6 mmol·L-1, p = 0.036) but did not affect exercise glucose or insulin plasma. Rates of glucose appearance (i.e., Ra glucose, index of liver glucose output) were similar during PLAC and STAT at rest and during exercise. Glucose disappearance rates increased during the first two exercise intensities (i.e., 40 and 70% VO2 MAX), but decreased in both groups at 85% VO2 explaining the ensuing hyperglycaemia at this intensity. CONCLUSIONS: Statin reduces exercise lipolysis during high intensity exercise, without affecting the already low rates of fat oxidation at that intensity. However, statin use does not affect plasma glucose kinetics or carbohydrate oxidation during exercise in a wide range of intensities in individuals chronically medicated with this drug.

Ketone Ester Plus Carbohydrate Supplementation Impairs Physical Performance And Decreases Glucose Turnover Versus Carbohydrate Alone

BACKGROUND: Ketone esters combined with carbohydrate have been reported to enhance physical performance compared to carbohydrate alone. Improvements in physical performance are suggested to result from sparing of glucose for fuel use during exercise; however, no studies have examined the effect of ketone supplementation on glucose kinetics. PURPOSE: Determine the effect of ketone ester plus carbohydrate (KE + CHO) supplementation on physical performance and glucose kinetics during steady-state aerobic exercise. METHODS: Twelve men (mean ± SD; 29 ± 5 y, 26 ± 3 kg/m2) completed this randomized, double-blind, crossover study. After controlling exercise and diet for 48 h, participants consumed a KE + CHO (KE: 573 mg KE/kg body mass, CHO: 110 g glucose) or CHO (110 g glucose) drink before and during 90 min of steady-state treadmill exercise (54 ± 3 % VO2peak) with a weighted vest (30% body mass; 25 ± 3 kg). Glucose kinetics during exercise were determined using indirect calorimetry and tracer techniques ([6,6-2H2] glucose and 13C glucose). Participants performed an unweighted time to exhaustion test (TTE; 85 % VO2peak) following steady-state exercise. After 24 h of controlled feeding, participants consumed a bolus of KE + CHO or CHO and completed a weighted 4-mile time trial (TT; 25 ± 3 kg). RESULTS: β-hydroxybutyrate concentrations were higher (P < 0.05) after exercise (2.3 ± 0.8 vs. 0.1 ± 0.1 mM) and the TT (2.7 ± 0.8 vs. 0.1 ± 0.1 mM) in KE + CHO than CHO. TTE was lower (761 ± 429 vs. 865 ± 458 sec) and TT performance was slower (55.0 ± 7.4 vs. 52.9 ± 6.6 min) in KE + CHO than CHO (P < 0.05). Exogenous (0.5 ± 0.1 vs. 0.5 ± 0.1 g/min) and plasma (0.6 ± 0.1 vs. 0.6 ± 0.1 g/min) glucose oxidation rates in the last 40 min of steady-state exercise were the same between KE + CHO and CHO (P > 0.05). Glucose rate of appearance (6.5 ± 1.4 vs. 7.0 ± 1.6 mg/kg/min) and disappearance (6.7 ± 1.3 vs. 7.2 ± 1.6 mg/kg/min) during steady-state exercise was lower (P < 0.05) in KE + CHO than CHO, and metabolic clearance rate (MCR) did not differ between treatments (10.5 ± 3.0 vs. 10.1 ± 3.4 mL/kg/min; P > 0.05). CONCLUSION: KE + CHO impaired TT and TTE performance compared to CHO alone. Though glucose turnover was lower, similar rates of exogenous glucose oxidation and MCR during steady-state exercise in KE + CHO and CHO suggests performance decrements occur independent of glucose kinetics.