Rate Of Glucose Appearance Research Articles

352-OR: Combination Therapy with Dapagliflozin plus Exenatide on Endogenous Glucose Production: A Mechanism of Action Study

Aim: To examine the mechanisms with which GLP-1 RA plus SGLT2i improve glycaemia versus each agent as monotherapy. Study Design: 21 T2D patients (Age= 51±2; BMI=31.2±0.7; A1C=7.9±0.2%, FPG= 172±8; mean PG OGTT [0-5h] =249±8) received 5-hour double tracer (3-3H-glucose IV/1-14C-glucose orally) OGTT and then were randomized to dapagliflozin (DAPA) 10 mg/d, exenatide (EXEN) 2 mg/wk, dapagliflozin plus exenatide (DAPA/EXEN) for 4 months. Results: Combination DAPA/EXEN therapy produced a completely additive effect to reduce HbA1c and near additive effect to decrease FPG and mean PG during OGTT. The additive effect of DAPA/EXEN resulted from: (1) decreased basal EGP; (2) increased urinary glucose excretion (UGE); (3) decreased rate of oral glucose appearance (RaO); (4) enhanced insulin secretion; (5) increased tissue glucose clearance. Of note, exenatide could not overcome the impaired suppression of EGP by dapagliflozin. Disclosure M. Alatrach: None. C. Agyin: None. J.M. Adams: None. O. Lavrynenko: None. N. Laichuthai: None. E. Cersosimo: None. C.L. Triplitt: Speaker’s Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Xeris Pharmaceuticals, Inc. A. Gastaldelli: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk Inc. M. Abdul-Ghani: None. R.A. DeFronzo: None.

The counterregulatory response to hypoglycaemia in the pig

The domestic pig is commonly used as animal model in the pharmaceutical development of new therapeutics for treatment of diabetes. Since a formal definition of hypoglycaemia only exists in humans, the purpose of this study was to assess the counterregulatory response in the domestic pig at glucose levels known to induce symptoms of hypoglycaemia in humans. Six pigs were included in hyperinsulinaemic glucose clamps with plasma glucose targets of 2, 3 and 5mmol/L in a cross-over design, and the associated glucose counterregulatory response was assessed by measuring glucose kinetics and levels of glucagon, c-peptide, catecholamines, cortisol and growth hormone. Results showed that the 2 and 3 vs 5mmol/L clamps significantly decreased and increased the secretion of c-peptide and glucagon, respectively (P<.05). This finding was associated with increased rate of glucose appearance (Ra ) and decreased rate of glucose disappearance (Rd ) (P<.001). No marked differences in the catecholamine, growth hormone or cortisol response were observed. Consequently, like humans, pigs respond to hypoglycaemia by decreasing the pancreatic output of insulin while increasing that of glucagon, with increased glucose mobilization and decreased glucose disposal as a result. The hypoglycaemic clamps did not result in a marked secretion of the other counterregulatory hormones.

Insulin sensitivity depends on the route of glucose administration

Aims/hypothesisThe small intestine plays an important role in hepatic and whole-body insulin sensitivity, as shown by bariatric surgery. Our goal was to study whether routes and dose of glucose administration have an acute impact on insulin sensitivity. The primary endpoint of this proof-of-concept study was the difference in insulin-mediated metabolic clearance rate (MCR/I) of glucose between the oral and intravenous routes of glucose administration. Secondary endpoints were differences in insulin effect on proteolysis, ketogenesis, lipolysis and glucagon levels.MethodsIn this parallel cohort study, we administered multiple oral glucose loads to 23 participants (aged between 18 and 65 years) with morbid obesity and with normal or impaired glucose tolerance or type 2 diabetes. In a different session, we administered isoglycaemic intravenous glucose infusions (IGIVI) to match the plasma glucose levels observed during the oral challenges. Glucose rate of appearance (Ra) and disappearance (Rd) and endogenous glucose production (EGP) were calculated by infusing [6,6-2H2]glucose with or without oral [U-13C6]glucose. Plasma small polar metabolites were measured by gas chromatography and time-of-flight mass spectrometry. Lipids were measured by ultra-HPLC and quadrupole mass spectrometry. Glucagon-like peptide-1, insulin, C-peptide and glucagon were also measured. Participants, caregivers, people doing measurements or examinations, and people assessing the outcomes were unblinded to group assignment.ResultsGlucose MCR/I was significantly higher during IGIVI than during oral glucose administration, independently of glycaemic status (12 ± 6 for IGIVI vs 7.4 ± 3 ml min−1 kg−1 per nmol/l for oral, p< 0.001 from paired t test). Insulin secretion was higher during oral administration than during IGIVI (p< 0.001). The disposition index was significantly lower during the oral procedure: 4260 ± 1820 vs 5000 ± 2360 (ml min−1 kg−1 (nmol/l)−1 pmol/min; p = 0.005). Insulin clearance was significantly higher when glucose was infused rather than ingested (2.53 ± 0.82 vs 2.16 ± 0.49 l/min in intravenous and oral procedure, respectively, p = 0.006). The efficacy of insulin in inhibiting lipolysis and proteolysis was decreased after oral glucose loads. A heat map diagram showed a different pattern for the metabolites between the two routes of glucose administration.Conclusions/interpretationOur study shows that insulin sensitivity depends on the route of glucose administration, the oral route leading to increased insulin secretion and compensatory insulin resistance compared with the intravenous route. The efficacy of insulin in blocking lipolysis and protein breakdown is lower after oral glucose loads vs the intravenous route. Our findings suggest that, while the glucose-mediated incretin release is followed by an increase in insulin release, the effect of the released insulin is limited by an increase in insulin resistance.Trial registrationClinicalTrials.gov NCT03223129.Graphical abstract

Dual glucagon-like peptide-1 receptor/glucagon receptor agonist SAR425899 improves beta-cell function in type 2 diabetes.

To evaluate the change in insulin sensitivity, β-cell function and glucose absorption after 28 days of treatment with high and low doses of SAR425899, a novel dual glucagon-like peptide-1 receptor/glucagon receptor agonist, versus placebo. Thirty-six overweight to obese subjects with type 2 diabetes were randomized to receive daily subcutaneous administrations of low-dose SAR425899 (0.03, 0.06 and 0.09 mg) and high-dose SAR425899 (0.06, 0.12 and 0.18 mg) or placebo for 28 days; dose escalation occurred after days 7 and 14. Mixed meal tolerance tests were conducted before treatment (day -1) and on days 1 and 28. Oral glucose and C-peptide minimal models were used to quantify metabolic indices of insulin sensitivity, β-cell responsiveness and glucose absorption. With low-dose SAR425899, high-dose SAR425899 and placebo, β-cell function from day -1 to day 28 increased by 163%, 95% and 23%, respectively. The change in area under the curve for the rate of meal glucose appearance between 0 and 120 minutes was -32%, -20% and 8%, respectively. After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β-cell function and slowing glucose absorption rate.

Effects of Sucralose Ingestion versus Sucralose Taste on Metabolic Responses to an Oral Glucose Tolerance Test in Participants with Normal Weight and Obesity: A Randomized Crossover Trial.

Here, we tested the hypothesis that sucralose differentially affects metabolic responses to labeled oral glucose tolerance tests (OGTTs) in participants with normal weight and obesity. Participants (10 with normal weight and 11 with obesity) without diabetes underwent three dual-tracer OGTTs preceded, in a randomized order, by consuming sucralose or water, or by tasting and expectorating sucralose (e.g., sham-fed; sweetness control). Indices of β-cell function and insulin sensitivity (SI) were estimated using oral minimal models of glucose, insulin, and C-peptide kinetics. Compared with water, sucralose ingested (but not sham-fed) resulted in a 30 ± 10% increased glucose area under the curve in both weight groups. In contrast, the insulin response to sucralose ingestion differed depending on the presence of obesity: decreased within 20–40 min of the OGTT in normal-weight participants but increased within 90–120 min in participants with obesity. Sham-fed sucralose similarly decreased insulin concentrations within 60 min of the OGTT in both weight groups. Sucralose ingested (but not sham-fed) increased SI in normal-weight participants by 52 ± 20% but did not affect SI in participants with obesity. Sucralose did not affect glucose rates of appearance or β-cell function in either weight group. Our data underscore a physiological role for taste perception in postprandial glucose responses, suggesting sweeteners should be consumed in moderation.

Acute hypoxia reduces exogenous glucose oxidation, glucose turnover, and metabolic clearance rate during steady-state aerobic exercise

BackgroundExogenous carbohydrate oxidation is lower during steady-state aerobic exercise in native lowlanders sojourning at high altitude (HA) compared to sea level (SL). However, the underlying mechanism contributing to reduction in exogenous carbohydrate oxidation during steady-state aerobic exercise performed at HA has not been explored. ObjectiveTo determine if alterations in glucose rate of appearance (Ra), disappearance (Rd) and metabolic clearance rate (MCR) at HA provide a mechanism for explaining the observation of lower exogenous carbohydrate oxidation compared to during metabolically-matched, steady-state exercise at SL. MethodsUsing a randomized, crossover design, native lowlanders (n = 8 males, mean ± SD, age: 23 ± 2 yr, body mass: 87 ± 10 kg, and VO2peak: SL 4.3 ± 0.2 L/min and HA 2.9 ± 0.2 L/min) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically-matched (SL: 1.66 ± 0.14 V̇O2 L/min 329 ± 28 kcal, HA: 1.59 ± 0.10 V̇O2 L/min, 320 ± 19 kcal) treadmill exercise in SL (757 mmHg) and HA (460 mmHg) conditions after a 5-h exposure. Substrate oxidation rates (g/min) and glucose turnover (mg/kg/min) during exercise were determined using indirect calorimetry and dual tracer technique (13C-glucose oral ingestion and [6,6-2H2]-glucose primed, continuous infusion). ResultsTotal carbohydrate oxidation was higher (P < 0.05) at HA (2.15 ± 0.32) compared to SL (1.39 ± 0.14). Exogenous glucose oxidation rate was lower (P < 0.05) at HA (0.35 ± 0.07) than SL (0.44 ± 0.05). Muscle glycogen oxidation was higher at HA (1.67 ± 0.26) compared to SL (0.83 ± 0.13). Total glucose Ra was lower (P < 0.05) at HA (12.3 ± 1.5) compared to SL (13.8 ± 2.0). Exogenous glucose Ra was lower (P < 0.05) at HA (8.9 ± 1.3) compared to SL (10.9 ± 2.2). Glucose Rd was lower (P < 0.05) at HA (12.7 ± 1.7) compared to SL (14.3 ± 2.0). MCR was lower (P < 0.05) at HA (9.0 ± 1.8) compared to SL (12.1 ± 2.3). Circulating glucose and insulin concentrations were higher in response carbohydrate intake during exercise at HA compared to SL. ConclusionNovel results from this investigation suggest that reductions in exogenous carbohydrate oxidation at HA may be multifactorial; however, the apparent insensitivity of peripheral tissue to glucose uptake may be a primary determinate.

The Rate of Glucose Appearance Is Related to Postprandial Glucose and Insulin Responses in Adults: A Systematic Review and Meta-analysis of Stable Isotope Studies

It is often assumed that lower postprandial glucose (PPG) and insulin (PPI) responses are induced by slower glucose influx from the gut (e.g., by delayed carbohydrate digestion). However, changes in the rate of appearance of glucose in the peripheral circulation [rate of appearance of exogenous glucose (RaE)] may be accompanied by changes in endogenous glucose production (EGP) and the rate of disappearance of total glucose into tissues (RdT). The quantitative relationships between reductions in RaE and PPG/PPI levels are unclear. The objective was to perform a meta-analysis to quantify the effect of changes in RaE on changes in PPG and PPI levels (primary) and EGP and RdT (secondary). We systematically searched the Scopus, Medline, and Cochrane library databases through 10 January 2019 for randomized, controlled, carbohydrate-rich interventions that aimed to reduce RaE in humans, measured using dual or triple stable isotope methods. The 2-h net incremental AUCs for all variables were extracted or calculated. Relationships between RaE and outcomes were quantified by weighted regression analyses. There were 12 articles, including 17 comparisons, that satisfied the inclusion criteria. The subjects were mainly men (60%), with age and BMI ranges of 18-40 y and 20.0-27.5 kg/m2, respectively. A 10% reduction in RaE was associated with reductions in PPG levels, PPI levels, and the RdT of 7% (95% CI: 2%, 12%; P=0.010), 8% (95% CI: 2%, 13%; P=0.012), and 11% (95% CI: 4%, 17%; P=0.005), respectively, but was not significantly associated with a change in EGP (13%; 95% CI: -7%, 33%; P=0.176). All fluxes together explained 70% and 26% of the variances in PPG and PPI levels, respectively. In adults, reducing glucose RaE by diet is associated with significant reductions in PPG levels, PPI levels, and the rate of glucose disposal. This trial was registered in the PROSPERO database with identifier CRD42018084824.

A novel natural tracer method to measure complex carbohydrate metabolism

While the triple tracer isotope dilution method has enabled accurate estimation of carbohydrate turnover after a mixed meal, use of the simple carbohydrate glucose as the carbohydrate source limits its translational applicability to everyday meals that typically contain complex carbohydrates. Hence, utilizing the natural enrichment of [13C]polysaccharide in commercially available grains, we devised a novel tracer method to measure postprandial complex carbohydrate turnover and indices of insulin action and β-cell function and compared the parameters to those obtained after a simple carbohydrate containing mixed meal. We studied healthy volunteers after either rice (n = 8) or sorghum (n = 8) and glucose (n = 16) containing mixed meals and modified the triple tracer technique to calculate carbohydrate turnover. All meals were matched for calories and macronutrient composition. Rates of meal glucose appearance (2,658 ± 736 vs. 4,487 ± 909 μM·kg-1·2 h-1), endogenous glucose production (-835 ± 283 vs. -1,123 ± 323 μM·kg-1·2 h-1) and glucose disappearance (1,829 ± 807 vs. 3,606 ± 839 μM·kg-1·2 h-1) differed (P < 0.01) between complex and simple carbohydrate containing meals, respectively. Interestingly, there were significant increase in indices of insulin sensitivity (32.5 ± 3.5 vs. 25.6 ± 3.2 10-5 (dl·kg-1·min-2)/pM, P = 0.006) and β-cell responsivity (disposition index: 1,817 ± 234 vs. 1,236 ± 159 10-14 (dl·kg-1·min-2)/pM, P < 0.005) with complex than simple carbohydrate meals. We present a novel triple tracer approach to estimate postprandial turnover of complex carbohydrate containing mixed meals. We also report higher insulin sensitivity and β-cell responsivity with complex than with simple carbohydrates in mixed meals of identical calorie and macronutrient compositions in healthy adults.

A Bayesian Framework to Identify Type 1 Diabetes Physiological Models Using Easily Accessible Patient Data.

Mathematical physiological models of type 1 diabetes (T1D) glucose-insulin dynamics have been of great help in designing and preliminary assessing new algorithm for glucose control. Derivation of models at the individual level is however difficult because of identifiability issues. Recently, fitting these models against data of real patients with T1D has been made possible by both the use of Bayesian estimation techniques and the availability of individual datasets including plasma glucose and insulin concentration samples gathered in clinical protocols. The aim of this work is to make a step further and develop a methodology able to estimate the parameters of T1D physiological models using easily accessible data only, i.e. continuous glucose monitoring (CGM) sensor, carbohydrate intakes (CHO), and exogenous insulin infusion (I) data. The methodology is tested on synthetic data of 100 patients generated by a composite model of glucose-insulin dynamics. To solve identifiability problems, a Bayesian approach numerically implemented by Markov Chain Monte Carlo (MCMC) has been used to obtain point estimates and confidence intervals of model unknown parameters exploiting a priori knowledge available from the literature. Results show goodness of model fit and acceptable precision of parameter estimates. The methodology is also successful in reconstructing of "non-accessible" glucose-insulin fluxes, i.e. glucose rate of appearance and plasma insulin. These preliminary results encourage further development of this framework and its assessment in more challenging setups.

1944-P: Muscle a-Parvin Is Not Necessary for Integrin-Linked Kinase Related Insulin Resistance in Diet-Induced Obese Mice

High fat diet (HFD) causes obesity and expansion of extracellular matrix (ECM) components and causes insulin resistance. Integrins provide for adhesion between cells and the ECM and signal cells information about the local environment. A major component of signaling through the integrin β1 subunit is the integrin-linked kinase (ILK). Previous studies demonstrated mice that do not express ILK in skeletal muscle (SkM) are resistant to HFD-induced muscle insulin resistance. ILK has no catalytic activity but is the scaffold for signaling molecules, including α-parvin which regulates Rho-GTPases which are involved in actin cytoskeleton and vesicular trafficking. To test the hypothesis that ILK-related insulin resistance is mediated through α-parvin in SkM, we generated a mouse model which lacks α-parvin in SkM (mParKO) using a cre-lox system under control of HSA promoter. mParKO mice and non-transgenic littermates (WT) were fed either chow or HFD for 12 weeks after which insulin sensitivity was assessed in vivo using the hyperinsulinemic-euglycemic clamp combined with 3-[3H]glucose and 2-[14C]deoxyglucose tracers to measure glucose fluxes. Body weight was not different between mParKO and WT mice on either diet, nor was fasting blood glucose. In contrast to previous clamp studies of HFD-fed muscle ILK knockout mice, clamp glucose infusion rate, tracer-determined glucose rates of appearance and disappearance, and an index of SkM glucose uptake were not different between mParKO and WT mice on either diet. These results suggest that the α-parvin unit does not mediate the profound ILK-related susceptibility to insulin resistance in HFD fed mice. Disclosure D.A. Cappel: None. A. Pozzi: None. R. Zent: None. D. Wasserman: None. Funding National Institutes of Health (DK59637, DK50277, DK54902); American Heart Association

Sliding-mode disturbance observers for an artificial pancreas without meal announcement

Carbohydrate counting is not only a burden for patients with type 1 diabetes, but estimation errors in meal announcement could also degrade the outcomes of the current hybrid closed-loop systems. Therefore, removing meal announcement is desirable. A novel control system is addressed here to face postprandial control without meal announcement. The proposed system grounds on two applications of the sliding mode observers in dealing with disturbances: first, the equivalent output technique is used to reconstruct the meal rate of glucose appearance via a first order sliding mode observer; second, a super-twisting-based residual generator is used to detect the meals. Subsequently, a bolusing algorithm uses the information of the two observers to trigger a series of boluses based on a proportional-derivative-like strategy. An in silico validation with 30 patients in a 30-day scenario reveals that the meal detector algorithm achieves a low rate of false positives per day (0.1 (0.1), mean (SD)) and a detection time of 28.5(6.2) min. Additionally, the bolusing algorithm fulfills a non-statistically different mean glucose than the hybrid counterpart with bolus misestimation (146.69 (12.20) mg/dL vs. 144.28 (11.01) mg/dL, p>0.05), without increasing hypoglycemia (0.029 (0.077) vs. 0.004 (0.014)%, p > 0,05), although at the expense of a slightly higher time in hyperglycemia (22.51(8.72) % vs. 18.65 (7.89)%, p < 0.05) due to the conservative tuning of the bolusing algorithm for the sake of safety.

OR07-3 Validation of Surrogate Models to Assess Tissue and Whole-Body Insulin Resistance Among High-Risk Adolescent Girls

Polycystic Ovarian Syndrome (PCOS) is a common endocrine disorder which develops in adolescence and affects 6-10% of women. PCOS is associated with insulin resistance (IR), which can occur in multiple tissues, in particular skeletal muscle and liver. Reliable assessment of tissue-specific IR in youth with PCOS is important for development of new therapies. The gold-standard method to assess tissue-IR is the hyper-insulinemic euglycemic clamp, a method which is too intensive for use in routine research. We aimed to validate surrogate indices (the oral minimal model (OMM)-derived whole-body index and the Abdul-Ghani model-derived muscle index and liver index) against their respective clamp measurements in a population of high-IR-risk adolescent girls. 45 adolescent girls (14.6 ± 1.7 years; BMI %ile 23.3%-98.2%) underwent a standard 2-hour oral glucose tolerance test (OGTT) (75g glucose) and a multi-phase hyper-insulinemic euglycemic clamp (10,16 and 80 mU/m2/min) with a glucose isotope tracer. This study was a secondary analysis. OMM total Si was computed using SAAM II software, using 0, 15, 30, 60, 90, 120 min time points and the assumption that glucose rate of appearance (Ra) decays exponentially after 120 min. Abdul-Ghani muscle and liver insulin resistance indices (IRIs) were calculated: liver IRI= AUC0-30min Glucose (mmol L-1 min) x AUC0-30min Insulin (pmol L-1 min); muscle IRI= mean insulin0-120min. Correlation analyses were performed using Spearman’s or Pearson’s correlation, as appropriate. OMM total Si correlated with clamp-measured insulin sensitivity (glucose infusion rate, r=0.65; p<0.0001), whereas muscle IRI did not (p=0.45). Liver IRI correlated moderately with clamp-derived hepatic insulin sensitivity (insulin concentration required to suppress 50% of basal endogenous glucose production; r=0.35; p=0.03). In adolescent girls at high risk of IR, OMM provided a strong surrogate characterization of whole-body IR when evaluated against the clamp. The Abdul-Ghani model indices are simpler to calculate compared to OMM; however, these results suggest that the Abdul-Ghani indices may not be adequate for describing and distinguishing among individuals within a narrower IR range, such as that found in our study population. By contrast, OMM offers an effective, OGTT-based methodology to be used in research studies for characterizing whole-body IR that is less resource-intensive compared to the clamp. Future work is needed to determine if the sensitivity of this model can be further improved with a longer-duration OGTT as obese youth can have an exaggerated and prolonged response to an OGTT. Funding: Thrasher Research Foundation, AHA CRP, Endocrine Society Fellowship in Women's Health, NIDDK K23

Modest changes to glycemic regulation are sufficient to maintain glucose fluxes in healthy young men following overfeeding with a habitual macronutrient composition

Currently, it is unclear whether short-term overfeeding in healthy people significantly affects postprandial glucose regulation, as most human overfeeding studies have utilized induced experimental conditions such as the euglycemic-hyperinsulinemic clamp technique to assess glucoregulation. The aim of this study was to quantify glucose fluxes [rates of meal glucose appearance (Ra), disposal (Rd), and endogenous glucose production (EGP)] in response to 5 and 28 days of overfeeding (+45% energy) while maintaining habitual macronutrient composition (31.0 ± 1.9% fat, 48.6 ± 2.2% carbohydrate, 16.7 ± 1.4% protein) in healthy, lean young men. Meal tolerance testing was combined with the triple-stable isotope glucose tracer approach. Visceral adipose volume increased by ~15% with 5 days of overfeeding, while there was no further change at 28 days. In contrast, body mass (+1.6 kg) and fat mass (+1.3 kg) were significantly increased only after 28 days of overfeeding. Fasting EGP, Rd, and insulin were increased at 5 but unchanged after 28 days. Postprandial glucose and insulin responses were unaltered by 5 days of overfeeding but were modestly increased after 28 days (P < 0.05). However, meal Ra and glucose Rd were significantly increased after both 5 and 28 days of overfeeding (P < 0.05). Despite this, overfeeding did not lead to alterations to postprandial EGP suppression. Thus, in contrast to findings from euglycemic-hyperinsulinemic clamp studies, chronic overfeeding did not affect the ability to suppress EGP or stimulate Rd under postprandial conditions. Rather, glucose flux was appropriately maintained following 28 days of overfeeding through modest increases in postprandial glycemia and insulinemia.

Pattern Recognition Reveals Characteristic Postprandial Glucose Changes: Non-Individualized Meal Detection in Diabetes Mellitus Type 1.

Accurate continuous glucose monitoring (CGM) is essential for fully automated glucose control in diabetes mellitus type 1. State-of-the-art glucose control systems automatically regulate the basal insulin infusion. Users still need to manually announce meals to dose the prandial insulin boluses. An automated meal detection could release the user and improve the glucose regulation. In this study, patterns in the postprandial CGM data are exploited for meal detection. Binary classifiers are trained to recognize the postprandial pattern in horizons of the estimated glucose rate of appearance and in CGM data. The appearance rate is determined by moving horizon estimation based on a simple model. Linear discriminant analysis (LDA) is used for classification. The proposed method is compared to methods that detect meals when thresholds are violated. Diabetes care data from 12 free-living pediatric patients was downloaded during regular screening. Experts identified meals and their start by retrospective evaluation. The classification was tested by cross-validation. Compared to the threshold-based methods, LDA showed higher sensitivity to meals with a low rate of false alarms. Classifying horizons outperformed the other methods also with respect to time of detection. The onset of meals can be detected by pattern recognition based on estimated model states and consecutive CGM measurements. No individual tuning is necessary. This makes the method easily adopted in the clinical practice.

Sparse Reconstruction of Glucose Fluxes Using Continuous Glucose Monitors

A new technique for estimating postprandial glucose flux profiles without the use of glucose tracers is proposed. A sparse vector space representation is first found for the space of plausible glucose flux profiles using sparse encoding. A Lasso formulation is then used to estimate the glucose fluxes that combines (1) known patient model parameters; (2) the vector space of plausible glucose flux profiles; (3) continuous glucose monitor measurements taken during the meal; (4) amount of insulin injected; (5) amount of meal carbohydrates; and (6) an estimate of the initial conditions. Three glucose fluxes are then estimated, namely; glucose rate of appearance from the intestine; endogenous glucose production from the liver; insulin dependent glucose utilization; and other important state variables. The simulation results show that the technique is capable of estimating the glucose fluxes with high accuracy, even for complex meal scenarios. The experimental results indicate that the technique is capable of reproducing the triple tracer measurements for three T1DM undergoing the triple tracer protocol while estimating the missing measurements for a certain model parameter selection.

Postprandial Nutrient Handling and Gastrointestinal Hormone Secretion After Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy

Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) induce substantial weight loss and improve glycemic control in patients with type 2 diabetes, but it is not clear whether these occur via the same mechanisms. We compared absorption rates of glucose and protein, as well as profiles of gastro-entero-pancreatic hormones, in patients who had undergone SG or RYGB vs controls. We performed a cross-sectional study of 12 patients who had undergone sleeve gastrectomy, 12 patients who had undergone RYGB, and 12 individuals who had undergone neither surgery (controls), all in Denmark. Study participants were matched for body mass index, age, sex, and postoperative weight loss, and all had stable weights. They received continuous infusions of stable isotopes of glucose, glycerol, phenylalanine, tyrosine, and urea before and during a mixed meal containing labeled glucose and intrinsically phenylalanine-labeled caseinate. Blood samples were collected for 6 hours, at 10- to 60-minute intervals, and analyzed. The systemic appearance of ingested glucose was faster after RYGB and SG vs controls; the peak glucose appearance rate was 64% higher after RYGB, and 23% higher after SG (both P < .05); the peak phenylalanine appearance rate from ingested casein was 118% higher after RYGB (P < .01), but similar between patients who had undergone SG and controls. Larger, but more transient increases in levels of plasma glucose and amino acids were accompanied by higher secretion of insulin, glucagon-like peptide 1, peptide YY, and cholecystokinin after RYGB, whereas levels of ghrelin were lower after SG, compared with RYGB and controls. Total 6-hour oral recovery of ingested glucose and protein was comparable among groups. Postprandial glucose and protein absorption and gastro-entero-pancreatic hormone secretions differ after SG and RYGB. RYGB was characterized by accelerated absorption of glucose and amino acids, whereas protein metabolism after SG did not differ significantly from controls, suggesting that different mechanisms explain improved glycemic control and weight loss after these surgical procedures. ClinicalTrials.gov ID NCT03046186.

Effect of alcohol ingestion on plasma glucose kinetics after Roux-en-Y gastric bypass surgery

BackgroundRoux-en-Y gastric bypass surgery (RYGB) increases the rate of alcohol absorption so that peak blood alcohol concentration is 2-fold higher after surgery compared with concentrations reached after consuming the same amount presurgery. Because high doses of alcohol can lead to hypoglycemia, patients may be at increased risk of developing hypoglycemia after alcohol ingestion. ObjectivesWe conducted 2 studies to test the hypothesis that the consumption of approximately 2 standard drinks of alcohol would decrease glycemia more after RYGB than before surgery. SettingSingle-center prospective randomized trial. MethodsWe evaluated plasma glucose concentrations and glucose kinetics (assessed by infusing a stable isotopically labelled glucose tracer) after ingestion of a nonalcoholic drink (placebo) or an alcoholic drink in the following groups: (1) 5 women before RYGB (body mass index = 43 ± 5 kg/m2) and 10 ± 2 months after RYGB (body mass index = 31 ± 7 kg/m2; study 1), and (2) 8 women who had undergone RYGB surgery 2.2 ± 1.2 years earlier (body mass index = 30 ± 5 kg/m2; study 2) ResultsCompared with the placebo drink, alcohol ingestion decreased plasma glucose both before and after surgery, but the reduction was greater before (glucose nadir placebo = −.4 ± 1.0 mg/dL versus alcohol = −9.6 ± 1.5 mg/dL) than after (glucose nadir placebo = −1.0 ± 1.6 mg/dL versus alcohol = −5.5 ± 2.6 mg/dL; P < .001) surgery. This difference was primarily due to an alcohol-induced early increase followed by a subsequent decrease in the rate of glucose appearance into systemic circulation. ConclusionRYGB does not increase the risk of hypoglycemia after consumption of a moderate dose of alcohol.

Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance.

ContextGlucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear.ObjectiveTo determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes.DesignRandomized, double-blind, cross-over study.SettingCentre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom.PatientsEight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)].InterventionsTwo metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies.Main Outcome MeasuresStudy one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion.ResultsStudy one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60–480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0–240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0–360min (P = 0.006) were lower with lixisenatide than with placebo.ConclusionsLixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance.

Preexercise breakfast ingestion versus extended overnight fasting increases postprandial glucose flux after exercise in healthy men.

The aim of this study was to characterize postprandial glucose flux after exercise in the fed versus overnight fasted state and to investigate the potential underlying mechanisms. In a randomized order, twelve men underwent breakfast-rest [(BR) 3 h semirecumbent], breakfast-exercise [(BE) 2 h semirecumbent before 60 min of cycling (50% peak power output)], and overnight fasted exercise [(FE) as per BE omitting breakfast] trials. An oral glucose tolerance test (OGTT) was completed after exercise (after rest on BR). Dual stable isotope tracers ([U-13C] glucose ingestion and [6,6-2H2] glucose infusion) and muscle biopsies were combined to assess postprandial plasma glucose kinetics and intramuscular signaling, respectively. Plasma intestinal fatty acid binding (I-FABP) concentrations were determined as a marker of intestinal damage. Breakfast before exercise increased postexercise plasma glucose disposal rates during the OGTT, from 44 g/120 min in FE {35 to 53 g/120 min [mean (normalized 95% confidence interval)] to 73 g/120 min in BE [55 to 90 g/120 min; P = 0.01]}. This higher plasma glucose disposal rate was, however, offset by increased plasma glucose appearance rates (principally OGTT-derived), resulting in a glycemic response that did not differ between BE and FE ( P = 0.11). Plasma I-FABP concentrations during exercise were 264 pg/ml (196 to 332 pg/ml) lower in BE versus FE ( P = 0.01). Breakfast before exercise increases postexercise postprandial plasma glucose disposal, which is offset (primarily) by increased appearance rates of orally ingested glucose. Therefore, metabolic responses to fed-state exercise cannot be readily inferred from studies conducted in a fasted state.

Are heterozygous carriers for hereditary fructose intolerance predisposed to metabolic disturbances when exposed to fructose?

High fructose intake causes hepatic insulin resistance and increases postprandial blood glucose, lactate, triglyceride, and uric acid concentrations. Uric acid may contribute to insulin resistance and dyslipidemia in the general population. In patients with hereditary fructose intolerance, fructose consumption is associated with acute hypoglycemia, renal tubular acidosis, and hyperuricemia. We investigated whether asymptomatic carriers for hereditary fructose intolerance (HFI) would have a higher sensitivity to adverse effects of fructose than would the general population. Eight subjects heterozygous for HFI (hHFI; 4 men, 4 women) and 8 control subjects received a low-fructose diet for 7 d and on the eighth day ingested a test meal, calculated to provide 25% of the basal energy requirement, containing 13C-labeled fructose (0.35 g/kg), glucose (0.35 g/kg), protein (0.21 g/kg), and lipid (0.22 g/kg). Glucose rate of appearance (GRa, calculated with [6,6-2H2]glucose), fructose, net carbohydrate, and lipid oxidation, and plasma triglyceride, uric acid, and lactate concentrations were monitored over 6 h postprandially. Postprandial GRa, fructose, net carbohydrate, and lipid oxidation, and plasma lactate and triglyceride concentrations were not significantly different between the 2 groups. Postprandial plasma uric acid increased by 7.2% compared with fasting values in hHFI subjects (P<0.01), but not in control subjects (-1.1%, ns). Heterozygous carriers of hereditary fructose intolerance had no significant alteration of postprandial fructose metabolism compared with control subjects. They did, however, show a postprandial increase in plasma uric acid concentration that was not observed in control subjects in responses to ingestion of a modest amount of fructose. This trial was registered at the US Clinical Trials Registry as NCT02979106.