Glucose Kinetics Research Articles

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.

Multi-Task Disentangled Autoencoder for Time-Series Data in Glucose Dynamics.

The objective of this study is to propose MD-VAE: a multi-task disentangled variational autoencoders (VAE) for exploring characteristics of latent representations (LR) and exploiting LR for diverse tasks including glucose forecasting, event detection, and temporal clustering. We applied MD-VAE to one virtual continuous glucose monitoring (CGM) data from an FDA-approved Type 1 Diabetes Mellitus simulator (T1DMS) and one publicly available CGM data of real patients for glucose dynamics of Type 1 Diabetes Mellitus. LR captured meaningful information to be exploited for diverse tasks, and was able to differentiate characteristics of sequences with clinical parameters. LR and generative models have received relatively little attention for analyzing CGM data so far. However, as proposed in our study, VAE has the potential to integrate not only current but also future information on glucose dynamics and unexpected events including interactions of devices in the data-driven manner. We expect that our model can provide complementary views on the analysis of CGM data.

Essential amino acid profile of supplemental metabolizable protein affects mammary gland metabolism and whole-body glucose kinetics in dairy cattle.

This study investigated mammary gland metabolism and whole-body (WB) rate of appearance (Ra) of glucose in dairy cattle in response to a constant supplemental level of metabolizable protein (MP) composed of different essential AA (EAA) profiles. Five multiparous rumen-fistulated Holstein-Friesian dairy cows (2.8 ± 0.4 lactations; 81 ± 11 d in milk; mean ± standard deviation) were abomasally infused according to a 5 × 5 Latin square design with saline (SAL) or 562 g/d of EAA delivered in different profiles where individual AA content corresponded to their relative content in casein. The profiles consisted of (1) a complete EAA mixture (EAAC), (2) Ile, Leu, and Val (ILV), (3) His, Ile, Leu, Met, Phe, Trp, Val (GR1+ILV), and (4) Arg, His, Lys, Met, Phe, Thr, Trp (GR1+ALT). A total mixed ration (58% corn silage, 16% alfalfa hay, and 26% concentrate on a dry matter basis) was formulated to meet 100 and 83% of net energy and MP requirements, respectively, and was fed at 90% of ad libitum intake on an individual cow basis. Each experimental period consisted of 5 d of continuous abomasal infusion followed by 2 d of no infusion. Arterial and venous blood samples were collected on d 4 of each period for determination of mammary gland AA and glucose metabolism. On d 5 of each period, D-[U-13C]glucose (13 mmol priming dose; continuous 3.5 mmol/h for 520 min) was infused into a jugular vein and arterial blood samples were collected before and during infusion to determine WB Ra of glucose. Milk protein yield did not differ between EAAC, GR1+ILV, and GR1+ALT, or between SAL and ILV, and increased over SAL and ILV with EAAC and GR1+ILV. Mammary plasma flow increased with ILV infusion compared with EAAC and GR1+ILV. Infusion of EAAC tended to increase mammary gland net uptake of total EAA and decreased the mammary uptake to milk protein output ratio (U:O) of non-EAA compared with SAL. Infusion of ILV increased mammary net uptake and U:O of Ile, Leu, and Val markedly over all treatments. The U:O of total Ile, Leu, and Val increased numerically (25%) with GR1+ILV infusion compared with EAAC, and the U:O of total Arg, Lys, and Thr tended to decrease, primarily from decreased U:O of Lys. During GR1+ALT infusion, U:O of total Arg, Lys, and Thr was greater than that during EAAC infusion, whereas U:O of Ile, Leu, and Val did not differ from EAAC. Glucose WB Ra increased 16% with GR1+ALT over SAL, and increased numerically 8 and 12% over SAL with EAAC and GR1+ILV, respectively. The average proportion of lactose yield relative to glucose WB Ra did not differ across treatments and averaged 0.53. On average, 28% of milk galactose arose from nonglucose precursors, regardless of treatment. In conclusion, intramammary catabolism of group 2 AA increased to support milk component synthesis when the EAA profile of MP was incomplete with respect to casein. Further, WB and mammary gland glucose metabolism was flexible in support of milk component synthesis, regardless of absorptive EAA profile.

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.

Contrasting dose-dependent effects of acute intravenous methamphetamine on lateral hypothalamic extracellular glucose dynamics in male and female rats.

Glucose is the brain's primary energetic resource. The brain's use of glucose is dynamic, balancing delivery from the neurovasculature with local metabolism. Although glucose metabolism is known to differ in humans with and without methamphetamine use disorder (MUD), it is unknown how central glucose regulation changes with acute methamphetamine experience. Here, we determined how intravenous methamphetamine regulates extracellular glucose levels in a brain region implicated in MUD-like behavior, the lateral hypothalamus (LH). We measured extracellular LH glucose in awake adult male and female drug-naive Wistar rats using enzyme-linked amperometric glucose biosensors. Changes in LH glucose were monitored during a single session after: 1) natural nondrug stimuli (novel object presentation and a tail-touch), 2) increasing cumulative doses of intravenous methamphetamine (0.025, 0.05, 0.1, and 0.2 mg/kg), and 3) an injection of 60 mg of glucose. We found second-scale fluctuations in LH glucose in response to natural stimuli that differed by both stimulus type and sex. Although rapid, second-scale changes in LH glucose during methamphetamine injections were variable, slow, minute-scale changes following most injections were robust and resulted in a reduction in LH glucose levels. Dose and sex differences at this timescale indicated that female rats may be more sensitive to the impact of methamphetamine on central glucose regulation. These findings suggest that the effects of MUD on healthy brain function may be linked to how methamphetamine alters extracellular glucose regulation in the LH and point to possible mechanisms by which methamphetamine influences central glucose metabolism more broadly.NEW & NOTEWORTHY Enzyme-linked glucose biosensors were used to monitor lateral hypothalamic (LH) extracellular fluctuations during nondrug stimuli and intravenous methamphetamine injections in drug-naive awake male and female rats. Second-scale glucose changes occurred after nondrug stimuli, differing by modality and sex. Robust minute-scale decreases followed most methamphetamine injections. Sex differences at the minute-scale indicate female central glucose regulation is more sensitive to methamphetamine effects. We discuss likely mechanisms underlying these fluctuations, and their implications in methamphetamine use disorder.

WWOX inhibition by Zfra1-31 restores mitochondrial homeostasis and viability of neuronal cells exposed to high glucose.

Diabetes has been associated with an increased risk of cognitive decline and dementia. However, the mechanisms underlying this association remain unclear and no effective therapeutic interventions exist. Accumulating evidence demonstrates that mitochondrial defects are a key feature of diabetes contributing to neurodegenerative events. It has also been demonstrated that the putative tumor suppressor WW domain-containing oxidoreductase 1 (WWOX) can interact with mitochondria in several pathological conditions. However, its role in diabetes-associated neurodegeneration remains unknown. So, this study aimed to evaluate the role of WWOX activation in high glucose-induced neuronal damage and death. Our experiments were mainly performed in differentiated SH-SY5Y neuroblastoma cells exposed to high glucose and treated (or not) with Zfra1-31, the specific inhibitor of WWOX. Several parameters were analyzed namely cell viability, WWOX activation (tyrosine 33 residue phosphorylation), mitochondrial function, reactive oxygen species (ROS) production, biogenesis, and dynamics, autophagy and oxidative stress/damage. The levels of the neurotoxic proteins amyloid β (Aβ) and phosphorylated Tau (pTau) and of synaptic integrity markers were also evaluated. We observed that high glucose increased the levels of activated WWOX. Interestingly, brain cortical and hippocampal homogenates from young (6-month old) diabetic GK rats showed increased levels of activated WWOX compared to older GK rats (12-month old) suggesting that WWOX plays an early role in the diabetic brain. In neuronal cells, high glucose impaired mitochondrial respiration, dynamics and biogenesis, increased mitochondrial ROS production and decreased mitochondrial membrane potential and ATP production. More, high glucose augmented oxidative stress/damage and the levels of Aβ and pTau proteins and affected autophagy, contributing to the loss of synaptic integrity and cell death. Of note, the activation of WWOX preceded mitochondrial dysfunction and cell death. Importantly, the inhibition of WWOX with Zfra1-31 reversed, totally or partially, the alterations promoted by high glucose. Altogether our observations demonstrate that under high glucose conditions WWOX activation contributes to mitochondrial anomalies and neuronal damage and death, which suggests that WWOX is a potential therapeutic target for early interventions. Our findings also support the efficacy of Zfra1-31 in treating hyperglycemia/diabetes-associated neurodegeneration.

Technical Difficulties in the Implementation of the Continuous Glucose Monitoring System

The continuous glucose monitoring system (CGMS) has been clinically applied to monitor the dynamic change of the subcutaneous interstitial glucose concentration which is a function of the blood glucose level by glucose sensors. It can track blood glucose levels all day along, and thus provide comprehensive and reliable information about blood glucose dynamics. The clinical application of CGMS enables monitoring of blood glucose fluctuations and the discovery of hidden hyperglycemia and hypoglycemia that are difficult to be detected by traditional methods. As a CGMS needs to work subcutaneously for a long time, a series of factors such as biocompatibility, enzyme inactivation, oxygen deficiency, foreign body reaction, implant size, electrode flexibility, error correction, comfort, device toxicity, electrical safety, et al. should be considered beforehand. The study focused on the difficulties in the technology, and compared the products of Abbott, Medtronic and DexCom, then summarized their cutting-edge. Finally, this study expounded some key technologies in dynamic blood glucose monitoring and therefore can be utilized as a reference for the development of CGMS.

The Effect of Enhanced External Counterpulsation on the Vascular State, Indicators of Glycemic Control and Quality of Life in Patients with Coronary Artery Disease and Type 2 Diabetes Mellitus

Aim. To study the effect of enhanced external counterpulsation (EECP) on the functional status, quality of life, structural and functional state of the vascular bed, and markers of glycemic control in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM).Material and methods. A pilot prospective randomized study included 30 patients with CAD and DM. Using a random number generator, patients were randomized into 2 groups: EECP (n=15) and a comparison group (n=15). All patients (n=30) received optimal medical therapy (OMT) during 3 months of follow-up. Patients in the EECP group underwent a course of EECP (35 hours, cuff pressure: 220-280 mmHg) during the first 7 weeks of the study. At baseline and after 3 months of follow-up, patients in both groups underwent an assessment of clinical status, quality of life (based on the SF-36 questionnaire), as well as a 6-minute walk test to assess exercise tolerance. The dynamics of fasting glucose, postprandial glucose, insulin resistance index (HOMA-IR) and glycated hemoglobin were assessed. Photoplethysmography and applanation tonometry were performed to assess the state of the vascular bed.Results. In the EECP group, after 3 months, there was a decrease in the frequency of angina attacks and an improvement in the functional class of angina according to the Canadian Cardiovascular Society (CCS) classification. A significant improvement in exercise tolerance was revealed [an increase in the 6-minute walking distance by 51 (35; 65) m, p&lt;0.05], as well as an improvement in the physical and mental components of health according to the SF-36 questionnaire. A positive dynamics was shown in relation to the indicators of the state of both large vessels and the microvasculature (p&gt;0.05), with the exception of the reflection index and the stiffness index (p&lt;0.05). There was also a significant decrease in the HOMA-IR [-9.9% (-26.5; -4.0) vs 7.7% (-7.9; 13.8), p=0.004], as well as in the levels of fasting glucose [-10.5% (-15.8; -4.0) vs -2.7 (-8.3; 5.9), p=0.012] in the EECP group, compared with the OMT group.Conclusion. EECP course therapy in addition to OMT has a positive effect on the functional status and quality of life of patients with CAD and DM. After 3 months of observation, there was noted a positive dynamics of the vascular state, as well as markers of glycemic control, and these changes were more pronounced in the EECP group. The results obtained may indicate the effectiveness of EECP as an add-on treatment for this group of patients.

Lipid-induced glucose intolerance is driven by impaired glucose kinetics and insulin metabolism in healthy individuals

AimsHypertriglyceridemia is associated with an increased risk of type 2 diabetes. We aimed to comprehensively examine the effects of hypertriglyceridemia on major glucose homeostatic mechanisms involved in diabetes progression. MethodsIn this randomized, cross-over, single-blinded study, two dual-labeled, 3-hour oral glucose tolerance tests were performed during 5-hour intravenous infusions of either 20 % Intralipid or saline in 12 healthy subjects (age 27.9 ± 2.6 years, 11 men, BMI 22.6 ± 1.4 kg/m2) to evaluate lipid-induced changes in insulin metabolism and glucose kinetics. Insulin sensitivity, β cell secretory function, and insulin clearance were assessed by modeling glucose, insulin and C-peptide data. Intestinal glucose absorption, endogenous glucose production, and glucose clearance were assessed from glucose tracers. The effect of triglycerides on β-cell secretory function was examined in perifusion experiments in murine pseudoislets and human pancreatic islets. ResultsMild acute hypertriglyceridemia impaired oral glucose tolerance (mean glucose: +0.9 [0.3, 1.5] mmol/L, p = 0.008) and whole-body insulin sensitivity (Matsuda index: −1.67 [−0.50, −2.84], p = 0.009). Post-glucose hyperinsulinemia (mean insulin: +99 [17, 182] pmol/L, p = 0.009) resulted from reduced insulin clearance (−0.16 [−0.32, −0.01] L min−1 m−2, p = 0.04) and enhanced hyperglycemia-induced total insulin secretion (+11.9 [1.1, 22.8] nmol/m2, p = 0.02), which occurred despite a decline in model-derived β cell glucose sensitivity (−41[−74, −7] pmol min−1 m−2 mmol−1 L, p = 0.04). The analysis of tracer-derived glucose metabolic fluxes during lipid infusion revealed lower glucose clearance (−96 [−152, −41] mL/kgFFM, p = 0.005), increased 2-hour oral glucose absorption (+380 [42, 718] μmol/kgFFM, p = 0.04) and suppressed endogenous glucose production (−448 [−573, −123] μmol/kgFFM, p = 0.005). High-physiologic triglyceride levels increased acute basal insulin secretion in murine pseudoislets (+11 [3, 19] pg/aliquot, p = 0.02) and human pancreatic islets (+286 [59, 512] pg/islet, p = 0.02). ConclusionOur findings support a critical role for hypertriglyceridemia in the pathogenesis of type 2 diabetes in otherwise healthy individuals and dissect the glucose homeostatic mechanisms involved, encompassing insulin sensitivity, β cell function and oral glucose absorption.

Comparative Study of the Results of Operations in Patients with Tumor and Non-Tumor Obstructive Jaundice Who Received and Did Not Receive Antioxidant Therapy for the Correction of Endotoxemia, Glycolysis, and Oxidative Stress.

Purpose: To compare the results of surgical treatment and changes in biomarkers of cholestasis, endotoxicosis, cytolysis, lipid peroxidation, glycolysis disorders, and inflammation in patients with benign and malignant obstructive jaundice (OJ) in patients receiving and not receiving antioxidant pharmacotherapy (AOT). Patients and methods: The study included 113 patients (aged 21–90 years; 47 males and 66 females) who received surgical intervention for OJ due to non-malignant (71%) or malignant tumor (29%) etiologies. Patients were divided into two groups: Group I (n = 61) who did not receive AOT and Group II (n = 51) who received AOT (succinate-containing drug Reamberin) as part of detoxification infusion therapy. The surgical approach and scope of interventions in both groups were identical. Dynamic indicators of endotoxicosis, cholestasis, and cytolysis (total, direct, and indirect bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [AP] and gamma-glutamyltransferase [GGT]), kidney function (urea), lipid peroxidation (malonic dialdehyde, MDA), inflammation (leukocytosis), and glycolysis disorders (lactate dehydrogenase (LDH), glucose) were evaluated. Results: Tumor jaundice, unlike non-tumor jaundice, persisted and was characterized by a more severe course, a higher level of hyperbilirubinemia, and lipid peroxidation. The prognostic value of the direct (and total) bilirubin, MDA, glycemia, and leukocytosis levels on the day of hospitalization, which increased significantly in severe jaundice and, especially, in deceased patients, was established. Decompression interventions significantly reduced levels of markers of liver failure, cytolysis, cholestasis, and lipid peroxidation on day 3 after decompression by 1.5–3 times from initial levels; this is better achieved in non-tumor OJ. However, 8 days after decompression, most patients did not normalize the parameters studied in both groups. AOT favorably influenced the dynamics (on day 8 after decompression) of total and direct bilirubin, ALT, AST, MDA, and leukocytosis in non-tumor jaundice, as well as the dynamics of direct bilirubin, AST, MDA, glucose, and LDH in tumor jaundice. Clinically, in the AOT group, a two-fold reduction in the operative and non-operative complications was recorded (from 23% to 11.5%), a reduction in the duration of biliary drainage by 30%, the length of stay in intensive care units was reduced by 5 days, and even hospital mortality decreased, especially in malignancy-induced OJ. Conclusion: A mechanism for the development of liver failure in OJ is oxidative stress with the appearance of enhanced lipid peroxidation and accompanied by hepatocyte necrosis. Inclusion of AOT in perioperative treatment in these patients improves treatment outcomes.

The effect of glucose dynamics on plasma copeptin levels upon glucagon, arginine, and macimorelin stimulation in healthy adults

PurposeNon-osmotic stimulation tests using glucagon, arginine, or macimorelin were recently evaluated for their ability to assess posterior pituitary function. Glucagon and arginine, but not macimorelin, stimulated copeptin secretion (a surrogate marker of vasopressin) and, therefore, provide novel tests to assess the posterior pituitary. The exact underlying mechanism behind their stimulatory effect remains elusive.MethodsThis analysis combined data from three diagnostic studies conducted at the University Hospital Basel, Switzerland. In total, 80 healthy adults underwent the glucagon (n = 22), arginine (n = 30), or macimorelin (n = 28) stimulation tests. The primary objective was to investigate glucose course upon glucagon, arginine, and macimorelin stimulation tests and its effect on plasma copeptin release.ResultsUpon glucagon stimulation, the median [IQR] glucose level at baseline was 5.0 [4.6, 5.2] mmol/l, peaked at 8.1 [7.2, 9.4] mmol/l after 30 min and decreased to a minimum of 3.8 [3.5, 4.5] mmol/l after 120 min. The median copeptin increase upon glucagon stimulation was 7.7 [2.6, 28.0] pmol/l. Upon arginine, the glucose level at baseline was 4.9 [4.8, 5.5] mmol/l, peaked at 6.0 [5.2, 6.4] mmol/l after 30 min and decreased to a minimum of 4.3 [3.8, 4.8] mmol/l after 60 min. The median copeptin increase upon arginine stimulation was 4.5 [2.9, 7.5] pmol/l. Upon macimorelin, glucose levels showed no notable dynamics over the 120 min, and no major change in copeptin was observed.In the pooled dataset, a decrease in glucose levels was significantly correlated with copeptin increase (ρ = 0.53, p < 0.01).ConclusionA similar course in plasma glucose was observed in the copeptin-stimulating test, i.e., after glucagon and arginine, while macimorelin had no effect on glucose and copeptin levels. We hypothesize that a drop in glucose levels observed upon glucagon and arginine might stimulate copeptin.

The rs10830963 Polymorphism of the MTNR1B Gene: Association With Abnormal Glucose, Insulin and C-peptide Kinetics.

BackgroundThe MTNR1B gene encodes a receptor for melatonin, a hormone regulating biorhythms. Disruptions in biorhythms contribute to the development of type 2 diabetes mellitus (T2DM). Genetic studies suggest that variability in the MTNR1B gene affects T2DM development. Our aim was to compare the distribution of the genetic variant rs10830963 between persons differing in glucose tolerance in a sample of the Czech population (N=1206). We also evaluated possible associations of the polymorphism with insulin sensitivity, beta cell function, with the shape of glucose, insulin and C-peptide trajectories measured 7 times during a 3-hour oral glucose tolerance test (OGTT) and with glucagon response. In a subgroup of 268 volunteers we also evaluated sleep patterns and biorhythm.Results13 persons were diagnosed with T2DM, 119 had impaired fasting blood glucose (IFG) and/or impaired glucose tolerance (IGT). 1074 participants showed normal results and formed a control group. A higher frequency of minor allele G was found in the IFG/IGT group in comparison with controls. The GG constellation was present in 23% of diabetics, in 17% of IFG/IGT probands and in 11% of controls. Compared to CC and CG genotypes, GG homozygotes showed higher stimulated glycemia levels during the OGTT. Homozygous as well as heterozygous carriers of the G allele showed lower very early phase of insulin and C-peptide secretion with unchanged insulin sensitivity. These differences remained significant after excluding diabetics and the IFG/IGT group from the analysis. No associations of the genotype with the shape of OGTT-based trajectories, with glucagon or with chronobiological patterns were observed. However, the shape of the trajectories differed significantly between men and women.ConclusionIn a representative sample of the Czech population, the G allele of the rs10830963 polymorphism is associated with impaired early phase of beta cell function, and this is evident even in healthy individuals.

1343-P: The Acute Effects of Glucagon on Glucose Dynamics Are Not Impaired in Individuals with Nonalcoholic Fatty Liver Disease

Glucagon is essential for glucose control and increased levels of glucagon (hyperglucagonemia) observed in patients with type 2 diabetes contribute to their hyperglycemia. Recently, hyperglucagonemia has also been found in individuals with non-alcoholic fatty liver disease (NAFLD) as well as impaired actions of glucagon on amino acid catabolism. Whether glucagon actions on hepatic glucose production are impaired is unknown. We investigated the acute effects of a single bolus of glucagon (0.2mg) on glucose dynamics in 18 normoglycemic individuals (age: 51±3 years, BMI; 31± 0.8kg/m2, hepatic fat content: 20±2%, fasting glucose: 5.5±0.1mM) with magnetic resonance imaging verified NAFLD and 22 controls (age: 38±3 years, BMI; 24± 0.8kg/m2, hepatic fat content: 4±0.1%, fasting glucose: 5.0±0.1mM) . On a separate day, a mixture of amino acids (14 g/L; 331 mg/min/kg body weight) was infused intravenously for 45min to evaluate the actions of endogenous glucagon on glucose dynamics. Glucose levels (see figure) were significantly increased in individuals with NAFLD 60min after the glucagon bolus and during the amino acid infusion with a maximal difference of 0.5mM 30min into the infusion. These data suggest that the actions of glucagon on hepatic glucose production are not impaired by NAFLD. Therefore, the hyperglucagonemia in patients with NAFLD may constitute a diabetogenic risk factor. Disclosure S.Kjeldsen: None. H.Vilstrup: None. F.V.Schiødt: Advisory Panel; Novo Nordisk. A.Møller: None. E.B.Rashu: None. L.Gluud: Advisory Panel; Novo Nordisk, Consultant; Pfizer Inc., Research Support; Alexion Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk, Sobi. S.B.Haugaard: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. J.Rungby: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Speaker’s Bureau; AstraZeneca, Bayer AG, Novo Nordisk, Pfizer Inc. N.J.Wewer albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc., Speaker’s Bureau; Merck &amp; Co., Inc., Mercodia AB. N.J.Jensen: None. M.Nilsson: None. N.Heinz: None. J.D.Nybing: None. F.H.Linden: None. E.Høgh-schmidt: n/a. M.P.Boesen: None. S.Madsbad: None. Funding NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude.

106-OR: Fetal Sex Influences Maternal Insulin and Glucose Metabolism in Pregnancy

Aims and Hypothesis: Women carrying a male fetus are suggested to have altered maternal glucose and insulin dynamics and increased rates of GDM, but current literature remains inconclusive. We aimed to determine the relationship between fetal sex and maternal glucose and insulin metabolism and assess whether inclusion of fetal sex improves prediction of IADPSG GDM. Methods: Using blinded data from five Hyperglycaemia and Adverse Pregnancy Outcome study centres, we examined maternal metabolic data at mean gestational week 28 in 6337 untreated women. Stratifying women by either male (n = 3273) or female fetus (n = 3064) we analysed data from the 75g OGTT, estimates of insulin secretion (Stumvoll first phase) and sensitivity (Matsuda index) and their product (oral Disposition index) using multiple linear regression analysis. To assess the relationship and predictive ability of fetal sex and GDM we utilised multiple logistic regression and receiver operating characteristic curve analysis. Results: Women carrying a male fetus were found to have a modest increase in fasting plasma glucose (4.52 vs. 4.44 mmol/L; P=0.008) and 1 h glucose (7.57 vs. 7.46 mmol/L; P=0.015) during OGTT which translated into an overall increase in the OGTT z score (0.vs. 0.02; P=0.005) . The Matsuda (β: -0.06; 95% CI [-0.10, -0.02]; P=0.008) and oral Disposition index (β: -0.07; 95% CI [-0.11, -0.02]; P=0.005) were significantly reduced in women carrying a male fetus after correction for established maternal clinical risk factors. Women carrying a male fetus were not at higher odds of developing GDM in adjusted (aOR: 1.04; 95% CI [0.9, 1.19]; P=0.6) or unadjusted (OR: 1.09; 95% CI [0.96, 1.25]; P=0.16) models. Conclusion/interpretation: The male fetus is associated with increased maternal fasting and postprandial glucose with concomitant decreased insulin sensitivity and β-cell compensation. The alterations in maternal glucose and insulin dynamics associated with having a male fetus does not translate into a clinical diagnosis of GDM. Disclosure T.P.Mullins: None. K.S.Gibbons: None. L.R.Madsen: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. W.H.Tam: None. P.Catalano: None. D.A.Sacks: None. H.L.Barrett: None. D.Mcintyre: None.

61-OR: Machine Learning Framework Predicts Metabolic Subphenotypes Using Glucose Dynamics during Oral Glucose Tolerance Test

Type 2 diabetes (T2D) is classically defined by measures of glycemia which do not take into account its physiologic basis, which differs between individuals. Defining the relative contribution of fundamental physiologic processes to glucose dysregulation would facilitate targeted treatment approaches for diabetes prevention and treatment. We propose that muscle insulin resistance, beta cell dysfunction, incretin defect, and hepatic insulin resistance are present to varying degrees in individuals predisposed to T2D, who can be thus classified according to their metabolic subphenotype. While this transformative approach to T2D is appealing, traditional metabolic tests are invasive and unavailable outside research units. We tested the ability of the shape of the glucose response curve during an oral glucose tolerance test (OGTT) to identify metabolic subphenotypes. 32 participants underwent gold-standard metabolic tests including frequently-sampled 3-hour OGTT, isoglycemic intravenous glucose infusion for quantification of incretin effect, steady-state plasma glucose measurement of insulin resistance, and calculated hepatic insulin resistance. We developed a machine learning framework to predict metabolic subphenotypes of an individual using dynamic features of the glucose time series during the OGTT. Metabolic testing revealed extensive inter-individual heterogeneity and the existence of four major metabolic subphenotypes. The features of the glucose time series identified insulin resistance, beta cell deficiency, and incretin deficiency with auROCs of 94%, 76%, and 75%, respectively. These were superior to standard clinical and laboratory measures of metabolic phenotypes. We suggest that identification of distinct metabolic subphenotypes using features of the glucose time series during OGTT may both enhance early identification of at-risk individuals as well as inform targeted therapeutic approaches to prevent and treat T2D. Disclosure A.A.Metwally: None. D.Perelman: None. H.Park: None. A.L.Gloyn: Other Relationship; Genentech, Inc., Roche Pharmaceuticals. T.Mclaughlin: Board Member; January, Inc., Research Support; Merck &amp; Co., Inc., Novo Nordisk, Stock/Shareholder; Eiger BioPharmaceuticals. M.Snyder: Stock/Shareholder; January, Inc. Funding National Institutes of Health (R01DK110186-01) National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK105535; U01-DK085545, UM1DK126185)

55-LB: Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2DM and NGT Subjects

We previously have shown that both acute and chronic SGLT-2 inhibition increases endogenous glucose production (EGP) . However, the organ - liver versus kidney - responsible for the increase in EGP has not been identified. We assessed the effect of a single dose of Dapagliflozin or Placebo on renal glucose production in 13 T2DM (age=57.5±1.8 yrs, BMI = 30±1.4 kg/m2) and 9 NGT (age 42±2 3 yrs, BMI = 30±1.1 kg/m2) subjects. Renal glucose production was measured using arteriovenous balance technique across the kidney combined with [3-3H] glucose infusion and PAH infusion (for determination of renal blood flow) before and 4 hours after administration of Dapagliflozin (10 mg) and Placebo; thus, each subject served as their own control. EGP increased following DAPA in both T2DM (2.00±0.11 to 2.43±0.15, P&amp;lt;0.05) and NGT (1.72±0.11 to 2.1±0.16, p&amp;lt;0.05) , while it decreased after placebo in T2DM (2.02±0.12 vs. 1.15±0.06) and NGT (2.10±0.2 vs. 2.05±0.1) (both p&amp;lt;0.01, DAPA vs. placebo) . The fractional renal extraction of glucose (0.02± 0.004 vs. 2.99 ± 1.0, p=0.001 in T2DM, and 0.02± 0.004 vs. 1.62± 1.4 in NGT, p=NS) and renal glucose uptake (0.067 ± 0.02 vs. 0.347 ± 0.06 in T2DM and 0.08 ± 0.02 vs. 0.27 ± 0.08 mg/kg.min in NGT) were higher following DAPA vs. placebo (p&amp;lt;0.05) and were entirely explained by the increase in glucosuria. There was a small, non-significant increase (0.065 &amp; 0.032 mg/kg.min, respectively) in renal glucose production (RGP) following dapagliflozin in T2DM and NGT compared to the 0.45 mg/kg.min increase in total body EGP. Conclusion: A single dose of Dapagliflozin significantly increases EGP which primarily is explained by an increase in hepatic glucose production. Disclosure X. Chen: None. C. Solis-herrera: Speaker’s Bureau; Novo Nordisk. D. Tripathy: None. A. A. Hansis-diarte: None. R. Chilton: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Nova Biomedical. E. Cersosimo: Research Support; AstraZeneca. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck &amp; Co., Inc., Speaker’s Bureau; AstraZeneca. Funding Astra Zeneca

91-OR: Association between Complexity of Glucose Time Series and All-Cause Mortality in Patients with Type 2 Diabetes Mellitus: A Prospective Cohort study

Background: Continuous glucose monitoring (CGM) can comprehensively reflect the dynamic changes of blood glucose varying with time. CGM data with more patterns of change represents glucose time series with higher complexity. However, the relationship between complexity of glucose dynamics and clinical outcomes of diabetes remains unknown. Objective: To investigate the association between complexity of glucose time series, quantified by multiscale entropy (MSE) analysis, and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) in a prospective cohort study. Methods: Data of 6,001 adult inpatients with T2DM included from January 2005 to December 2015 in a single center was analyzed. Complexity of glucose index (CGI) of glucose time series from CGM was measured by MSE analysis at baseline. Participants were stratified by the tertiles of CGI: &amp;lt; 2.15,2.15∼2.99, and ≥ 3.00. Cox proportional hazards regression models were used to estimate the association between different levels of CGI and the risks of all-cause mortality. Results: During a median follow-up of 6.8 years, 799 deaths were identified. Multivariate Cox regression analysis revealed that the increase of CGI was associated with a lower risk of all-cause mortality (P for trend = 0.021) . The multivariable-adjusted HRs for all-cause mortality at different CGI levels [&amp;lt; 2.15 (reference group) , 2.15∼2.99, and ≥ 3.00] were 1.00, 0.49 (95%CI 0.30-0.79) , and 0.56 (95%CI 0.36-0.87) in patients with HbA1c &amp;lt; 7.0% (P for trend = 0.015) , while the association was nonsignificant in those with HbA1c ≥ 7.0%. And a significant interaction between HbA1c and CGI (P for interaction = 0.032) was noted in the study. Conclusion: Lower CGI is associated with an increased risk of all-cause mortality in T2DM achieving HbA1c target, which suggests that the improvement of CGI may further reduce the risk of long-term adverse outcomes in T2DM at an early stage or with good glycemic control. Disclosure J.Cai: None. J.Lu: None. Y.Shen: None. W.Lu: None. W.Zhu: None. J.Zhou: None. Funding The Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20161430)

240-OR: Quantifying Glucose Utilization and Endogenous Glucose Production during Resistance Exercise in People with Type 1 Diabetes (T1D)

Glucose dynamics during and after resistance exercise in people with T1D is not well understood. We recruited 25 people with T1D to perform 3 separate sessions of in-clinic resistance exercise under low (basal) , medium (1.5x basal) , or high (3.0x basal) insulin infusion levels. Blood glucose was clamped by intravenous dextrose infusion 3 hours prior to, and 4 hours after a 45-minute session of strength training. Glucose tracer was infused to match the rate of endogenous glucose production (EGP) . Glucose and tracer data were used to fit a two-compartment model and quantify the rate of glucose disposal (Rd) and EGP. For 58 sessions across 25 participants, blood glucose levels remained constant during and after resistance exercise. The mean change in area under the curve (AUC) for Rd was not higher during resistance exercise compared to baseline (+1.2 mM, p=0.69) , but increased during previously published aerobic exercise (+12.5 mM, p&amp;lt;0.01) . Mean AUC for EGP rose during resistance exercise (+6.5 mM, p&amp;lt;0.01) primarily due to non-insulin mediated factors and the increase was higher than during aerobic exercise (+2.mM, p&amp;lt;0.01) . Resistance exercise is characterized by a strong rise in EGP that is predominantly driven by non-insulin mediated effects. This may mitigate drops in blood glucose caused by increased glucose utilization in peripheral tissues during anaerobic activity. Disclosure G.Young: None. M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Consultant; Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. J.El youssef: None. P.G.Jacobs: Other Relationship; Pacific Diabetes Technologies, Research Support; Dexcom, Inc. N.S.Tyler: None. T.P.Nguyen: None. J.R.Castle: Advisory Panel; Insulet Corporation, Novo Nordisk, Zealand Pharma A/S, Stock/Shareholder; Pacific Diabetes Technologies. L.M.Wilson: n/a. D.Branigan: None. V.Gabo: None. F.H.Guillot: Stock/Shareholder; Pacific Diabetes Technologies. Funding National Institutes of Health (5R01DK110175, 1F30DK128914)

Effects of Bromocriptine on Glucose and Insulin Dynamics in Normal and Insulin Dysregulated Horses.

The objectives of the study were to study the effects of the synthetic ergot alkaloid (EA), bromocriptine, on glucose and lipid metabolism in insulin dysregulated (ID, n = 7) and non-ID (n = 8) mares. Horses were individually housed and fed timothy grass hay and two daily concentrate meals so that the total diet provided 120% of daily DE requirements for maintenance. All horses were given intramuscular bromocriptine injections (0.1 mg/kg BW) every 3 days for 14 days. Before and after 14 days of treatment horses underwent a combined glucose-insulin tolerance test (CGIT) to assess insulin sensitivity and a feed challenge (1 g starch/kg BW from whole oats) to evaluate postprandial glycemic and insulinemic responses. ID horses had higher basal plasma concentrations of insulin (P = 0.01) and triglycerides (P = 0.02), and lower concentrations of adiponectin (P = 0.05) compared with non-ID horses. The CGIT response curve showed that ID horses had slower glucose clearance rates (P = 0.02) resulting in a longer time in positive phase (P = 0.03) and had higher insulin concentrations at 75 min (P = 0.0002) compared with non-ID horses. Glucose (P = 0.02) and insulin (P = 0.04) responses to the feeding challenge were lower in non-ID compared to ID horses. Regardless of insulin status, bromocriptine administration increased hay intake (P = 0.03) and decreased grain (P < 0.0001) and total DE (P = 0.0002) intake. Bromocriptine treatment decreased plasma prolactin (P = 0.0002) and cholesterol (P = 0.10) and increased (P = 0.02) adiponectin concentrations in all horses. Moreover, in both groups of horses, bromocriptine decreased glucose clearance rates (P = 0.02), increased time in positive phase (P = 0.04) of the CGIT and increased insulin concentrations at 75 min (P = 0.001). The postprandial glycemic (P = 0.01) and insulinemic (P = 0.001) response following the oats meal was lower after bromocriptine treatment in all horses. In conclusion, in contrast to data in humans and rodents, bromocriptine treatment reduced insulin sensitivity in all horses, regardless of their insulin status. These results indicate that the physiological effects of EA might be different in horses compared to other species. Moreover, because bromocriptine shares a high degree of homology with natural EA, further investigation is warranted in horses grazing endophyte-infected grasses.

Evolution of the diagnostic value of "the sugar of the blood": hitting the sweet spot to identify alterations in glucose dynamics.

In this paper, we provide an overview of the evolution of the definition of hyperglycemia during the past century and the alterations in glucose dynamics that cause fasting and postprandial hyperglycemia. We discuss how extensive mechanistic, physiological research into the factors and pathways that regulate the appearance of glucose in the circulation and its uptake and metabolism by tissues and organs has contributed knowledge that has advanced our understanding of different types of hyperglycemia, namely prediabetes and diabetes and their subtypes (impaired fasting plasma glucose, impaired glucose tolerance, combined impaired fasting plasma glucose, impaired glucose tolerance, type 1 diabetes, type 2 diabetes, gestational diabetes mellitus), their relationships with medical complications, and how to prevent and treat hyperglycemia.