Glucose Area Research Articles

Achieving energy balance with a high-fat meal does not enhance skeletal muscle adaptation and impairs glycaemic response in a sleep-low training model.

What is the central question of this study? Does achieving energy balance mainly with ingested fat in a 'sleep-low' model of training with low muscle glycogen affect the early training adaptive response during recovery? What is the main finding and its importance? Replenishing the energy expended during exercise mainly from ingested fat to achieve energy balance in a 'sleep-low' model does not enhance the response of skeletal muscle markers of early adaptation to training and impairs glycaemic control the morning after compared to training with low energy availability. These findings are important for optimizing post-training dietary recommendations in relation to energy balance and macronutrient intake. Training with low carbohydrate availability (LCHO) has been shown to acutely enhance endurance training skeletal muscle response, but the concomitant energy deficit (ED) in LCHO interventions has represented a confounding factor in past research. This study aimed at determining if achieving energy balance with high fat (EB-HF) acutely enhances the adaptive response in LCHO compared to ED with low fat (ED-LF). In a crossover design, nine well-trained males completed a 'sleep-low' protocol: on day1 they cycled to deplete muscle glycogen while reaching a set energy expenditure (30kcal(kg of fat free mass (FFM))-1 ). Post-exercise, low carbohydrate, protein-matched meals completely (EB-HF, 30kcal(kg FFM)-1 ) or partially (ED-LF, 9kcal(kg FFM)-1 ) replaced the energy expended, with the majority of energy derived from fat in EB-HF. In the morning of day2, participants exercised fasted, and skeletal muscle and blood samples were collected and a carbohydrate-protein drink was ingested at 0.5h recovery. Muscle glycogen showed no treatment effect (P<0.001) and decreased from 350±98to 192±94mmol(kg dry mass)-1 between rest and 0.5h recovery. Phosphorylation status of the mechanistic target of rapamycin and AMP-activated protein kinase pathway proteins showed only time effects. mRNA expression of p53 increased after exercise (P=0.005) and was higher in ED-LF at 3.5h compared to EB-HF (P=0.027). Plasma glucose and insulin area under the curve (P<0.04) and peak values (P≤0.05) were higher in EB-HF after the recovery drink. Achieving energy balance with a high-fat meal in a 'train-low' ('sleep-low') model did not enhance markers of skeletal muscle adaptation and impaired glycaemia in response to a recovery drink following training in the morning.

The Effect of Resistance Exercise Intensity on Acute Hyperglycemia in Young Adult Males.

The purpose of this study was to examine the effect of resistance exercise (RE) intensity on acute hyperglycemia, in young adult males. Thirteen males (age 23.43 ± 2.18 years, height 175.16 ± 10.44 cm, weight 77.02 ± 8.91 kg, body fat 20 ± 0.03%) participated in three randomized testing sessions, each separated by 96 h. The three testing conditions were: control (CON; induction of hyperglycemia with no-exercise), high (HI; induction of hyperglycemia followed by high-intensity RE: 5 × 4, 90% 1-repetition maximum (1-RM)), and moderate (MO; induction of hyperglycemia followed by low-intensity RE: 3 × 14, 65% 1-RM). In all three testing conditions, participants orally ingested a D100 (100 g/10 oz) glucose beverage at a dosage of 2 g glucose/kg body weight and capillary blood was obtained for plasma glucose and insulin analysis at 0 (fasting), 30, 60, 90 and 120 min, following glucose ingestion. At 30-min post-ingestion in the HI and MO conditions, participants began the respective RE protocols. Acute hyperglycemia was achieved throughout all three 2-h testing conditions; mean 2-h plasma glucose levels during CON (7.1 ± 1.3 mmol∙L−1), MO (7.5 ± 0.6 mmol∙L−1) and HI (8.2 ± 1.9 mmol∙L−1) were all significantly (p < 0.05) greater than mean fasting plasma glucose (5.6 ± 0.46 mmol∙L−1). Plasma glucose and insulin did not differ (p < 0.05) between treatment conditions at any times points over the 120 min, however, 2-h glucose area under the curve in the HI condition was significantly greater (p < 0.05) than CON and MO. In conclusion, this study indicates that hyperglycemia, induced prior to RE, may be exacerbated by high-intensity RE.

Dysregulated lipid and fatty acid metabolism link perfluoroalkyl substances exposure and impaired glucose metabolism in young adults

BackgroundPer- and polyfluoroalkyl substances (PFASs) exposure is ubiquitous among the US population and has been linked to adverse health outcomes including cardiometabolic diseases, immune dysregulation and endocrine disruption. However, the metabolic mechanism underlying the adverse health effect of PFASs exposure is unknown. ObjectiveThe aim of this project is to investigate the association between PFASs exposure and altered metabolic pathways linked to increased cardiometabolic risk in young adults. MethodsA total of 102 young adults with 82% overweight or obese participants were enrolled from Southern California between 2014 and 2017. Cardiometabolic outcomes were assessed including oral glucose tolerance test (OGTT) measures, body fat and lipid profiles. High-resolution metabolomics was used to quantify plasma exposure levels of three PFAS congeners and intensity profiles of the untargeted metabolome. Fasting concentrations of 45 targeted metabolites involved in fatty acid and lipid metabolism were used to verify untargeted metabolomics findings. Bayesian Kernel Machine Regression (BKMR) was used to examine the associations between PFAS exposure mixture and cardiometabolic outcomes adjusting for covariates. Mummichog pathway enrichment analysis was used to explore PFAS-associated metabolic pathways. Moreover, the effect of PFAS exposure on the metabolic network, including metabolomic profiles and cardiometabolic outcomes, was investigated. ResultsHigher exposure to perfluorooctanoic acid (PFOA) was associated with higher 30-minute glucose levels and glucose area under the curve (AUC) during the OGTT (p < 0.001). PFAS exposure was also associated with altered lipid pathways, which contributed to the metabolic network connecting PFOA and higher glucose levels following the OGTT. Targeted metabolomics analysis indicated that higher PFOA exposure was associated with higher levels of glycerol (p = 0.006), which itself was associated with higher 30-minute glucose (p = 0.006). ConclusionsIncreased lipolysis and fatty acid oxidation could contribute to the biological mechanisms linking PFAS exposure and impaired glucose metabolism among young adults. Findings of this study warrants future experimental studies and epidemiological studies with larger sample size to replicate.

SUPPLEMENTATION OF CULTURE MEDIUM WITH MELATONIN IMPROVES BLASTOCYST DEVELOPMENT AND REVERSES GLUCOSE INTOLERANCE IN IVF MICE

This study aimed to determine if the adverse effects of IVF on blastocyst and offspring could be reversed by supplementation of culture medium with melatonin in mice. A cross-sectional mouse model was utilized, wherein blastocysts were generated by natural mating (control group) or IVF with or without melatonin (10-6M) (mIVF and IVF group respectively) in clinical grade fertilization and culture media. Blastocysts were transferred to pseudo-pregnant ICR females. Cell lineage allocation was assessed for 30-40 blastocysts from each group. Body weight, glucose tolerance, energy expenditure, hepatic gene expression was measured in 6-10 mice from each group. C57BL/6 female mice and DBA2 male mice were used to generate blastocysts by natural mating (control group) or IVF with or without melatonin (10-6M) (mIVF and IVF group respectively) in clinical grade fertilization and culture media. Blastocysts were transferred to pseudo-pregnant recipients. Embryo development was recorded for IVF groups. Cell numbers of inner cell mass (SOX2) or trophectoderm (Cdx2+) were determined by immunohistochemistry. Males were weaned at 3 weeks of age onto a chow diet or a high-fat diet (60% fat) for 8 weeks. Glucose tolerance was assessed by an intraperitoneal glucose tolerance test (2g/Kg). Energy metabolism was examined in metabolic cages. Hepatic gene expression was measured by RNA-Seq and validated by real-time quantitative PCR. Blastocyst rates were similar in the two IVF groups. Reduced inner cell mass, trophectoderm and total cell number were observed in IVF blastocysts, compared with the control group (P<0.05). IVF pups had significantly lower birth weight and body weight before weaning, but exhibited increased body weight and liver weight at 11 weeks of age compared with controls (P<0.05), independently of diet. IVF mice were glucose intolerant shown as an increased glucose area under the curve, and had decreased energy expenditure as well as a large number of differentially expressed genes related to metabolic pathways in the liver tissue compared with the control group (P<0.05), independently of diet. The mIVF group showed intermediate cell numbers in blastocysts, body weight, liver weight and differentially expressed hepatic genes compared with the IVF group and control group, and normalized glucose tolerance and energy expenditure compared with the IVF group (P<0.05), independently of diet. Importantly, there was no significant difference in glucose tolerance and energy expenditure between the mIVF group and the control group. The data suggests that supplementation of culture medium with melatonin improved IVF blastocyst differentiation, reduced excessive weight gain after birth and normalized glucose intolerance in adult male offspring of IVF mice.

β-cell impairment and clinically meaningful alterations in glycemia in obese youth across the glucose tolerance spectrum

Background/aimsIn obese youth, it is not clear what degree of β-cell impairment translates to glucose dysregulation commensurate with shifts from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes. We aimed to investigate the quantitative relationship between β-cell (clamp-measured disposition index [DI]) and OGTT glucose area under the curve (G-AUC) in obese youth across the spectrum of glucose tolerance. MethodsData from 152 youth (58 African-American [AA] and 94 American-White [AW]; 73 NGT, 48 IGT, and 31 type 2 diabetes) who completed a 3-h hyperinsulinemic (80 mu/m2/min)-euglycemic clamp, and a 2-h hyperglycemic (225 mg/dL) clamp synchronized with a 2-h OGTT were examined. ResultsIn IGT vs. NGT, 36% lower DI corresponded to 27% higher G-AUC; in type 2 diabetes vs. IGT, 65% lower DI related to 25% higher G-AUC, and in type 2 diabetes vs. NGT, 78% lower DI paralleled 59% higher G-AUC. Although AA vs. AW youth had larger decrements in DI, from NGT to IGT and from NGT to type 2 diabetes, they displayed comparable increments in G-AUC. ConclusionAt least ~35–50% recovery in β-cell function might be needed to have clinically meaningful improvement in G-AUC commensurate with conversion to better glucose tolerance. Mechanism(s) protective against dysglycemia might be operative in AA vs. AW youth despite greater declines in DI. Treatments aiming to improve β-cell function should focus on degree of change in DI commensurate with clinically meaningful changes in glycemia, reflective of restoration of glucose tolerance.

Modulation of Energy Sensing by Leucine Synergy with Natural Sirtuin Activators: Effects on Health Span.

Sirt1 and 5' adenosine monophosphate-activated protein kinase (AMPK) are energy-sensing systems that work cooperatively and regulate mitochondrial biogenesis and fuel metabolism, and mediate, in part, the salutary effects of caloric restriction on lifespan and healthspan. We have shown that leucine activates Sirt1 and enables synergy with sirtuin co-activators. Resveratrol is a widely recognized activator of Sirt1; however, poor bioavailability and rapid metabolism limit effective clinical translation of promising animal data. However, we found that combining low resveratrol doses with leucine increased skeletal muscle and adipocyte Sirt1 activity, mitochondrial biogenesis and fatty acid oxidation; these effects result in increased lifespan and marked reductions in insulin resistance, inflammatory markers, body weight, and visceral adiposity in preclinical models. To translate these data to humans, we assessed the effects of resveratrol (50 mg)/leucine (1.11 g) on glucose dynamics in a 4-week placebo-controlled trial of 36 prediabetic subjects. Leucine-resveratrol reduced insulin resistance (homeostatic model assessment for insulin resistance) 33% with corresponding reductions in glucose and insulin area under the curve in oral glucose tolerance tests. We extended these concepts in preclinical studies using both direct Sirt1 activators and Sirt1 pathway activators. Low-dose (10 nM) NAD+ precursors (nicotinic acid, nicotinamide mononucleotide, and nicotinamide riboside) synergized with leucine to increase Sirt1 activity in adipocytes, hepatocytes, and muscle cells (30-100%, P < .01) and lifespan in Caenorhabditis elegans (25%, P = .025) and to significantly regress atherosclerotic lesion size and macrophage infiltration in a mouse model of atherosclerosis. Thus, synergistic activation of Sirt1 using leucine and a co-activator exerts pleiotropic effects impacting cardiometabolic endpoints.

Effect of γ-aminobutyric acid-rich yogurt on insulin sensitivity in a mouse model of type 2 diabetes mellitus

This study aimed to investigate the effect of a γ-aminobutyric acid (GABA)-rich yogurt fermented with Streptococcus thermophilus fmb-5 on insulin sensitivity in high-fat and low-dose streptozotocin-induced type 2 diabetes mellitus mice. To study the ability of the yogurt to enhance insulin sensitivity, diabetic mice were treated with 0.5, 1, or 2 g/L of GABA yogurt once a day from wk 1 to 12. Compared with results in untreated diabetic mice, treatment with different dosages of GABA yogurt was associated with increased serum insulin and fat coefficient (fat weight relative to body weight) levels, decreased blood urea nitrogen, kidney coefficient (kidney weight relative to body weight), glucose area under the curve levels, and insulin sensitivity index, but did not alter blood glucose level or body weight. The highest dosage of GABA yogurt had a greater beneficial effect with respect to insulin resistance than the lower dosages. In particular, dietary supplementation of the high dosage of GABA yogurt favorably regulated HOMA-β (homeostasis model assessment of β-cell function), total cholesterol, high-density lipoprotein cholesterol, fat coefficient, and improved islet cells morphology. These results demonstrated that 2 g/L GABA yogurt could ameliorate insulin sensitivity. The GABA-rich yogurts appeared to be responsible for health-beneficial effects in this mouse model of diabetes.

Hypoglycemia and Islet Dysfunction Following Oral Glucose Tolerance Testing in Pancreatic-Insufficient Cystic Fibrosis.

Oral glucose tolerance test (OGTT)-related hypoglycemia is common in pancreatic-insufficient cystic fibrosis (PI-CF), but its mechanistic underpinnings are yet to be established. To delineate the mechanism(s) underlying OGTT-related hypoglycemia. We performed 180-minute OGTTs with frequent blood sampling in adolescents and young adults with PI-CF and compared results with those from a historical healthy control group. Hypoglycemia (Hypo[+]) was defined as plasma glucose <65 mg/dL. We hypothesized that CF-Hypo[+] would demonstrate impaired early phase insulin secretion and persistent late insulin effect compared with control-Hypo[+], and explored the contextual counterregulatory response. OGTT 1-hour and nadir glucose, insulin, C-peptide, and insulin secretory rate (ISR) incremental areas under the curve (AUC) between 0 and 30 minutes (early) and between 120 and 180 minutes (late), and Δglucagon120-180min and Δfree fatty acids (FFAs)120-180min were compared between individuals with CF and control participants with Hypo[+]. Hypoglycemia occurred in 15/23 (65%) patients with CF (43% female, aged 24.8 [14.6-30.6] years) and 8/15 (55%) control participants (33% female, aged 26 [21-38] years). The CF-Hypo[+] group versus the control-Hypo[+] group had higher 1-hour glucose (197 ± 49 vs 139 ± 53 mg/dL; P = 0.05) and lower nadir glucose levels (48 ± 7 vs 59 ± 4 mg/dL; P < 0.01), while insulin, C-peptide, and ISR-AUC0-30 min results were lower and insulin and C-peptide, and AUC120-180min results were higher (P < 0.05). Individuals with CF-Hypo[+] had lower Δglucagon120-180min and ΔFFA120-180min compared with the control-Hypo[+] group (P < 0.01). OGTT-related hypoglycemia in PI-CF is associated with elevated 1-hour glucose, impaired early phase insulin secretion, higher late insulin exposure, and less increase in glucagon and FFAs. These data suggest that hypoglycemia in CF is a manifestation of islet dysfunction including an impaired counterregulatory response.

Comparing The Effects Of Different Modes Of Exercise On Glucose Handling In Young Recreationally Active Men

PURPOSE: The prevalence of type 2 diabetes (T2D) is increasing dramatically and is characterized by insulin resistance (IR). Exercise training is an effective modality to improve IR and acutely can increase post-exercise glucose handling for up to 72 hours. However, there is conflicting evidence as to which mode of exercise elicits the greatest positive effect on glucose handling. The purpose of this study was to compare the effectiveness of different modes of exercise on post-exercise glucose handling in young recreationally active men. METHODS: Twelve (age: 22±3 years) recreationally active men completed 4 separate oral glucose tolerance tests (OGTT) either at rest, or 1.5 hours after moderate-intensity continuous exercise (MICE; 30 min @ 65% VO2peak), low-load high-repetition resistance exercise circuit (LLHR; 20-25 reps/set for 3 sets at 30% 1RM) and high-intensity interval training bout (HIIE; 10x1min at 90% HRmax). Heart rate and blood lactate were taken throughout the exercise bouts. Blood was analyzed for total plasma glucose concentration (mmol/L), c-peptide concentration (ng/mL) and blood insulin concentration (μIU/mL). RESULTS: Average blood glucose concentration during the OGTT was lower following LLHR (6.386 ± 0.261mmol/L, p = 0.03) as compared with MICE (6.839 ± 0.256 mmol/L, p = 0.03) with no differences between baseline (6.625 ± 0.333 mmol/L) and HIIE (6.737 ± 0.267 mmol/L). Glucose area under the curve (AUC) was lower following LLHR (781.76 ± 36.08) as compared to MICE (842.81 ± 35.8; p = 0.033) with no difference compared to baseline glucose AUC (804.61 ± 46.7, p = 0.475). Blood c-peptide concentrations were not significantly different between baseline, MICE, HIIE or LLHR average concentrations. Similar to c-peptide there were no significant differences between blood insulin concentrations post exercise. CONCLUSION: In young, healthy men none of the exercise modes improved glucose handling as compared with baseline. However, LLHR resistance exercise did result in greater glucose clearance than MICE, suggesting that it may be a better modality to improve glucose control. Future work should examine the acute and chronic effects of LLHR resistance exercise on glucose handling in individuals with IR to determine the potential effectiveness of this exercise modality to improve insulin sensitivity.

Effect Of Exercise During Pregnancy And Lactation In Obese Wistar Rats On Offspring Glycemic Control

PURPOSE: To determine the effect of maternal exercise in pregnant and lactating obese Wistar rats on the glycemic control of their offspring at time of weaning. METHODS: Two days following impregnation, 24 obese Wistar rats were separated into 2 groups. One group received 30 minutes of treadmill exercise (E) at 15-20 m/min each day while the other group received no exercise (NE). The groups were maintained after the birth of the offspring (21 days) through lactation (21 days) for a total of 6 weeks. At weaning an oral glucose tolerance test (OGTT) was performed on 12 randomly selected pups from each group. A t-test was utilized to determine differences in total glucose area under the curve (t-AUC) (mean and standard error) between groups (p≤ 0.05). RESULTS: There was an effect of maternal exercise on the glycemic control of the offspring. The ability to dispose of glucose following a glycemic load was significantly greater in the offspring of E dams (513.1 ± 11.7mmol/L) compared to the offspring of NE dams (542.7 ± 7.1mmol/L) (p ≤ 0.05). CONCLUSIONS: Initiating moderate exercise early during the pregnancy of obese rats and maintaining exercise through lactation can positively impact glycemic control in offspring.

Relationship Of Glucose Kinetics With Exercise Capacity, Body Composition, And Mitochondrial Function With Aging

Aging is commonly associated with decreases in aerobic capacity, skeletal muscle mass and function, as well as metabolic dysregulation including insulin resistance. PURPOSE: We sought to investigate relationships between these aforementioned hallmark traits of aging. METHODS: Young healthy adults (24-34 years; n=16; 7F/9M; BMI: 25±3 kg/m2) and older adults (65-79 years; n=39; 20F/19M; BMI: 27±4 kg/m2) were recruited as a part of this investigation. Subjects completed a graded maximal exercise test (VO2peak) on a treadmill, a dual-energy X-ray absorptiometry scan, measurement of single-leg knee extension power, a mixed meal tolerance test upon which blood glucose was monitored throughout the next 5 hours, and a resting vastus lateralis biopsy to measure ATP production from permeabilized muscle fibers. RESULTS: Young had a 38% greater aerobic capacity and 45% greater knee extensor maximal power/lean mass. Fasting plasma glucose was lower (P<0.05) in young (86±7 mg/dL vs. 93±8 mg/dL in young and old, respectively), as well as young had 31% lower plasma glucose area above baseline (AAB) in response to the mixed meal tolerance test compared to old (P<0.05). No differences between young and old were observed in lean body mass, fasting plasma insulin, or maximal mitochondrial ATP production (state III). Interestingly, AAB was not significantly correlated with phenotypic characteristics (BMI or lean body mass), fasting plasma glucose or insulin, or maximal ATP production. However, AAB was significantly (P<0.05) inversely correlated with VO2peak relative to body mass (r = -0.38) and knee extensor power/lean mass (r = -0.47). CONCLUSIONS: These data suggest that glucose tolerance may be a function of skeletal muscle quality rather than total lean mass. However, the inverse relationship with AAB and measurements of whole body functional tests do not appear to be related mitochondrial energy production, suggesting the need for further mechanistic investigations. Supported by NIH grant R01AG054454

Inhibiting Drp1-Mediated Mitochondrial Fission Attenuates High-Fat Diet Induced Skeletal Muscle Insulin Resistance

Dynamin-related protein 1 (Drp1) is a critical mediator of mitochondrial fission. Recent studies have reported increased Drp1 activation in obese skeletal muscle, which is associated with reduced mitochondrial function and insulin sensitivity. PURPOSE: To determine if inhibiting Drp1-mediated mitochondrial fission by a pharmacologic inhibitor attenuates skeletal muscle insulin resistance induced by a high-fat diet (HFD) in mice. METHODS: 6-week old male C57BL/6J mice (n=9/group) were assigned to either a HFD (45% Fat) or low-fat diet (LFD, 10% Fat) group for a total of 5-weeks. A subgroup of HFD-fed mice received intraperitoneal injections of Mitochondrial Division Inhibitor 1 (MDIVI-1) (20 mg/kg) while the other mice received saline every other day for the last week of diet intervention. A glucose tolerance test was performed after 4 hours of fasting. Twenty-four hours after the final injection, quadriceps and gastrocnemius muscles were collected for further analysis. H2O2 levels were detected using Amplex Red Hydrogen Peroxide kit. Insulin signaling and protein markers of mitochondrial dynamics were measured by immunoblot analysis. RESULTS: HFD significantly increased glucose area under the curve (AUC) than LFD mice (19074 ± 2137 vs. 10726 ± 1254; p < 0.05), but MDIVI-1 treatment attenuated glucose AUC in HFD-fed mice (15354 ± 1278). MDIVI-1 treatment reduced Drp1 expression in mitochondrial fraction from HFD-fed mice when compared to the saline-treated counterparts (0.003 ± 0.001 vs. 0.012 ± 0.003; p < 0.05). The mitochondrial fraction Drp1 expression was positively associated with glucose AUC (r = 0.497, p = 0.042). Insulin-stimulated Aktser473 phosphorylation was reduced in insulin-stimulated skeletal muscle from HFD-fed mice compared to mice fed with LFD (0.70 ± 0.22 vs. 2.21 ± 0.39; p < 0.05), but no difference was found between HFD-fed mice treated with MDIVI-1 and LFD-fed mice. HFD had a significant increase in H2O2 than LFD-fed mice (0.351 ± 0.046 ± 0.186 ± 0.043; p < 0.05), while MDIVI-1 treatment reduced H2O2 production.in HFD-fed mice (0.351 ± 0.046 vs. 0.215 ± 0.364; p < 0.05) CONCLUSION: These data suggest that inhibiting Drp1-mediated mitochondrial fission attenuates skeletal muscle insulin resistance and improves whole-body glucose homeostasis in mice fed by HFD.

Contribution of Katsura-uri (Japan's Heirloom Pickling Melon, Cucumis melo var. conomon) at the Completely Ripe Stage to Diabetes Control.

The fruit of Katsura-uri (Japan's heirloom pickling melon, Cucumis melo var. conomon) possesses a fruity aroma and moderate sweetness. The fruit juice has potential to minimize human postprandial blood glucose levels. This study provides information regarding the health benefits of Katsura-uri and its utility in treating diabetes. The study methodology involved measuring the color and firmness of Katsura-uri fruit at five ripening stages, and quantitation of the aroma substances, proximate composition, and sugars. Significant changes were detected in the color, firmness, and level of aroma substances with ripening of Katsura-uri fruit, albeit with no major changes in proximate composition, with the exception of dietary fiber, and sugars. To determine the effects of Katsura-uri juice, the blood glucose levels of ten diabetic volunteers aged 46-75 y were monitored after its consumption, and compared with after consumption of muskmelon juice equivalent to the total weight of Katsura-uri juice. The blood glucose area under the curve level was significantly lower after consumption of Katsura-uri juice (16±5 h • mg/dL) than after consumption of muskmelon juice (55±17 h • mg/dL; p<0.05). The level of the glucose spike was also significantly lower after consumption of Katsura-uri juice (22±5 mg/dL) than after consumption of muskmelon juice (64±6 mg/dL; p<0.05). The completely ripe Katsura-uri fruit provides the best results for diabetic subjects, which is the first case of fruits sweetened with the addition of zero-calorie sweeteners.

Lixisenatide in type 1 diabetes: A randomised control trial of the effect of lixisenatide on post-meal glucose excursions and glucagon in type 1 diabetes patients.

AimsThe GLP1 agonist lixisenatide is glucagonostatic and reduces post‐prandial blood glucose (PPBG) in type 2 diabetes. This study investigates its impact in type 1 diabetes (T1D).MethodsIn a blinded, crossover trial, 25 patients with T1D were randomised to 4 weeks adjunctive treatment with lixisenatide (L) or placebo (P), with a 4‐week washout period. The primary outcome was percentage of 3 hours PPBG in target (4‐10 mmol/L) assessed by CGM before and after treatment. Participants also underwent post‐treatment standardised mixed meal test (MMT, n = 25) and hyperinsulinaemic hypoglycaemic clamp (n = 15).ResultsPPBG CGM readings in target were similar between L vs P (Mean % ± SE, breakfast 45.4 ± 6.0 vs 44.3 ± 6.0, P = .48, lunch 45.5 ± 5.8 vs 50.6 ± 5.3, P = .27 and dinner 43.0 ± 6.7 vs 47.7 ± 5.6, P = .30). HbA1C was similar between L vs P (64.7 ± 1.6 vs 64.1 ± 1.6 mmol/mol, P = .30). Prandial insulin fell after lixisenatide (dose change −0.7 ± 0.6 vs +2.4 ± 0.7 units/d, P = .004), but basal insulin dose was similar between groups. The post‐MMT glucose area under the curve (AUC) was lower with L than P (392.0 ± 167.7 vs 628.1 ± 132.5 mmol/L × min, P < .001), as was the corresponding glucagon AUC (140.0 ± 110.0 vs 304.2 ± 148.2 nmol/L × min, P < .001). Glucagon and counter‐regulatory hormone values at a blood glucose of 2.4 mmol/L during the hypoglycaemic clamp were similar between L and P.ConclusionIn T1D, PPBG values were not altered by adjunctive lixisenatide although prandial insulin dose fell. Glucose and glucagon level during an MMT were significantly lower after lixisenatide, without affecting counter‐regulatory response during hypoglycaemia.

Association of glucagon-like peptide-1 receptor-targeted imaging probe with invivo glucagon-like peptide-1 receptor agonist glucose-lowering effects.

Aims/IntroductionGlucagon‐like peptide‐1 receptor agonists (GLP‐1RA) are used for treatment of type 2 diabetes mellitus worldwide. However, some patients do not respond well to the therapy, and caution must be taken for certain patients, including those with reduced insulin secretory capacity. Thus, it is clinically important to predict the efficacy of GLP‐1RA therapy. GLP‐1R‐targeted imaging has recently emerged to visualize and quantify β‐cells. We investigated whether GLP‐1R‐targeted imaging can predict the efficacy of GLP‐1RA treatment.Materials and MethodsWe developed 111Indium‐labeled exendin‐4 derivative (111In‐Ex4) as a GLP‐1R‐targeting probe. Diabetic mice were selected from NONcNZO10/LtJ male mice that were fed for different durations with 11% fat chow. After 3‐week administration of dulaglutide as GLP‐1RA therapy, mice with non‐fasting blood glucose levels <300 mg/dL and >300 mg/dL were defined as responders and non‐responders, respectively. In addition, ex vivo 111In‐Ex4 pancreatic accumulations (111In‐Ex4 pancreatic values) were examined.ResultsThe non‐fasting blood glucose levels after treatment were 172.5 ± 42.4 mg/dL in responders (n = 4) and 330.8 ± 20.7 mg/dL in non‐responders (n = 5), respectively. Ex vivo 111In‐Ex4 pancreatic values showed significant correlations with post‐treatment glycohemoglobin and glucose area under curve during an oral glucose tolerance test (R 2 = 0.76 and 0.80; P < 0.01 and <0.01, respectively). The receiver operating characteristic area under curve for identifying responders by ex vivo 111In‐Ex4 pancreatic values was 1.00 (P < 0.01).Conclusion Ex vivo 111In‐Ex4 pancreatic values reflected dulaglutide efficacy, suggesting clinical possibilities for expanding GLP‐1R‐targeted imaging applications.

1368-P: Carbohydrate Intake Is Associated with OGTT Levels in Pregnancy

Background: Traditionally, a carbohydrate-rich diet in the days preceding an oral glucose tolerance test (OGTT) has been recommended based on classic studies in non-pregnant individuals showing that carbohydrate restriction elevates post-load glucose levels. Instructions on carbohydrate intake given to pregnant women having an OGTT for gestational diabetes (GDM) diagnosis vary. We tested if self-reported carbohydrate intake in pregnancy is associated with OGTT results. Methods: Pregnant women (N=79) with ≥ 1 risk factor for GDM underwent a fasting 75 g OGTT at 24-30 wks gestation and completed a 24-hr dietary recall using a validated self-administered instrument. We tested for an association between carbohydrate intake in the 24 hrs preceding the OGTT and 1-hour OGTT glucose using linear regression, with adjustment for age, BMI, gestational age, race, and total caloric intake. We also tested for associations with 30-minute and 2-hour OGTT glucose and glucose area under the curve (AUC). Results: Women with lower carbohydrate intake (&amp;lt;median=235g) were slightly older (34 vs. 32 yrs, P=0.03), but otherwise similar to women with higher intake (BMI, history of GDM in a prior pregnancy, race/ethnicity, fasting glucose). We observed a graded linear relationship between carbohydrate intake and 1-hour OGTT glucose. For every 50 g reduction in carbohydrate intake, there was a 6.2 mg/dl increase in 1-hour OGTT glucose (β=6.2 mg/dl, P&amp;lt;0.01); this remained significant in the adjusted model (β=7.7 mg/dl, P=0.03). Lower carbohydrate intake was also associated with higher 30-minute (unadjusted β=4.4 mg/dl, P&amp;lt;0.01; adjusted β=6.7 mg/dl, P=0.02) and 2-hour OGTT glucose (unadjusted β=4.3 mg/dl, P=0.03; adjusted β=6.9 mg/dl, P=0.05) and glucose AUC (unadjusted β=513, P&amp;lt;0.01; adjusted β=683, P=0.03). Results did not change after excluding women with intake &amp;lt;1000 calories or when % carbohydrate intake was used as the predictor variable. Conclusion: Carbohydrate restriction or excess before an OGTT may affect the diagnosis of GDM. Disclosure E. Rosenberg: None. K. James: None. J. Arenas: None. M.J. Callahan: None. M. Cayford: None. S. Nelson: None. S.N. Bernstein: None. R. Thadhani: None. E.W. Seely: None. C.E. Powe: None. Funding National Institutes of Health (K23DK113218); Robert Wood Johnson Foundation; Harold Amos Medical Faculty Development Award (72456)

277-OR: Teplizumab Reverses the Loss of C-Peptide in Relatives at Risk for Type 1 Diabetes (T1D)

We demonstrated that a 2-week course of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) delayed T1D progression by a median of 24 months in high risk relatives of patients with T1D (76 multiple islet autoantibody positive dysglycemic relatives; 912 day median follow-up). Over the study 72% of the placebo-treated and 43% of the teplizumab-treated participants were diagnosed with T1D. We hypothesized that teplizumab treatment would also result in a secondary outcome of improved C-peptide responses to oral glucose tolerance tests (OGTT) compared to placebo. The C-peptide, 1 hr insulin secretory rate (early ISR), and glucose area under the curve (AUC) means were calculated for each study timepoint. Results were modeled using ANCOVA, regressing on treatment group, age and the baseline value of the dependent variable. Teplizumab treatment was associated with a greater on-study C-peptide AUC (teplizumab vs. placebo adjusted means: 1.94 vs. 1.73 nmol/L; p=0.009). For both groups, C-peptide AUC mean slopes over a mean of 7.9 months preceding study entry were similar and significantly less than zero (declining; p=0.03). In the placebo group, this decline continued over the 6 months after study entry. By contrast, the teplizumab-treated group showed an increased C-peptide AUC over this period (p=0.003 relative to study entry). Insulin secretion during the 1st hr of the OGTT also declined in participants treated with placebo, but increased in those treated with teplizumab at 6 months (p=0.007). Increases in C-peptide AUC were correlated with increases in partially exhausted KLRG1+TIGIT+ CD8+ T cells (r=0.403; p=0.018). Although rates of diabetes were reduced in teplizumab-treated participants, OGTTs showed persistent dysglycemia. In conclusion, we found declines in C-peptide responses to OGTTs in high risk individuals prior to study treatment that were abrogated in the 6 month period after immunomodulation with teplizumab. Disclosure E.K. Sims: None. B.N. Bundy: None. K.D. Stier: None. E. Serti: None. N. Lim: None. G.T. Nepom: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. K.C. Herold: Consultant; Self; Provention Bio, Inc. Funding National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF

846-P: Improvement in Glucose Metabolism with Four Weeks of Neuromuscular Electrical Stimulation in Sedentary Adults

Most U.S. adults do not meet minimum exercise recommendations by ACSM. We and others have shown an increase in GLUT4 protein and glucose uptake with electrical stimulation induced muscle contraction using an in vitro cell culture model. However, effectiveness of neuromuscular electrical stimulation (NMES) in humans to improve insulin sensitivity is not clear. Purpose: To determine the effects of four weeks of NMES on insulin sensitivity, substrate utilization, and muscle mass in sedentary humans. Methods: Sedentary overweight/obese subjects (n=10; Age 36.8 ±3.8 yrs; BMI 32.0 ±1.3 kg/m2) were randomized into a control (Con) or NMES group. All participants received bilateral quadriceps stimulation (3x/wk; 30 min/ses) either at low intensity sensory level (Con) or high intensity neuromuscular level (NMES) for 4 weeks (50Hz). Insulin sensitivity was assessed by oral glucose tolerance test (OGTT), substrate utilization by indirect calorimetry, blood lactate by lactate analyzer, and body composition by DXA. Results: Con and NMES groups had comparable fasting blood glucose, glucose tolerance, substrate utilization, and muscle mass (all p&amp;gt;0.05) at baseline. Four weeks of NMES tended to improve glucose tolerance, measured by glucose area under the curve (AUC) (455.6 ±26.1 to 415.4 ±25.9 AU; p=0.07) whereas no change was observed in Con (430.7 ±20.2 to 494.7 ±77.2 AU; p=0.76). Glucose level after 2 hours of glucose consumption during OGTT was significantly lower after 4 weeks of NMES (150.9 ±7.6 to 138.2 ±7.6 mg/dL; p=0.03) whereas no change was observed in Con (151.8 ±6.1 to 173.2 ±34.2 mg/dL; p=0.33).Additionally, lactate AUC assessed during 30 min of NMES, was significantly greater compared to that of Con (p&amp;lt;0.02). There was no change in substrate utilization (p=0.85) or muscle mass (p=0.17) after NMES intervention. Conclusion: NMES is a novel and effective strategy to improve insulin sensitivity and glucose utilization in an at-risk overweight/obese sedentary population. Disclosure S. Bajpeyi: None. M. Galvan: None. M.J. Sanchez: None. J.B. Boyle: None. K. Min: None. F.J. Agullo: None. J.D. Covington: None. Funding University of Texas at El Paso

937-P: Effects of Insulin and Exenatide on Glycemic Control and ß-Cell Function in Newly Diagnosed Type 2 Diabetic Patients with Severe Hyperglycemia

Objective: To assess the efficacy of short-term insulin therapy compared with exenatide treatment on glycemic control, beta-cell function, insulin sensitivity, and long-term glycemic control in newly diagnosed type 2 diabetic patients with severe hyperglycemia. Methods: Newly diagnosed type 2 diabetic patients with HbA1c above 9% were treated with intensive insulin injection for 10-14 days in the hospital or outpatient clinic. The oral glucose tolerance test (OGTT) was performed after intensive insulin treatment. After the OGTT, the patients were randomized to receive either insulin therapy (NPH injection twice daily) or exenatide therapy (exenatide injection twice daily) for further 4 months. The patients started to take oral antidiabetes drugs after 4 months of randomization. The OGTT was repeated 6 months after randomization to evaluateβ-cell function and insulin sensitivity again. The subjects were continually followed up for another 1 year to evaluate long-term glycemic control. Results: We recruited 44 patients and 40 patients were randomized to insulin group (n = 22) and exenatide group (n = 18). The HbA1c level between insulin group and exenatide group at 6th month (6.74 ± 1.12% vs. 6.88 ± 0.76%; P = 0.681) and 18th month (6.60 ± 0.92% vs. 7.13 ± 0.83%; P = 0.093) of the study showed comparable results. The glucose area under the curve, insulinogenic index, and total insulin secretion improved significantly in both groups after 4 months of treatment. Compared with the exenatide group, the homeostasis model assessment of β-cell function index, insulinogenic index, and total insulin secretion were better in the insulin group. Conclusions: A 4-month course of both the insulin and exenatide treatment could achieve good glycemic control in newly diagnosed type 2 diabetes with severe hyperglycemia. However, the insulin treatment could improve more β-cell function than exenatide therapy. Disclosure T. Wu: None. H. Chen: None.

162-LB: Impact of High-Fat Meal on Circulating microRNA in Youth with T1DM

MicroRNA (miRNA) are small non-coding RNAs that impact translation via degrading or repressing mRNA. From animal models, circulation abundance of miRNA is impacted by feeding. The goal of this project was to compare levels of specific circulating miRNAs between youth with T1DM and controls and the impact of a high fat meal on miRNA abundance. Fourteen youth (6 females, 8 males) with T1DM and 29 normal weight control youth (14 females, 15 males) ingested a milkshake with 830 kcal; 36% carbohydrate, 54% fat (31 grams of saturated fat), and 10% protein. Circulating miRNAs (miR-122, 126, and 130b) at baseline and 150 minutes post-ingestion were measured by qPCR. The group with T1DM had a median A1c of 8.4% (7.4, 8.9) with an average duration of 7 years. At baseline, miR-126 tended to be higher in the youth with T1DM (47%, p=0.072). In pooled groups, all three miRNAs decreased at 150 min (miR-122: -21%, p=0.036; miR-126: -37%, p=0.001; and miR-130b: -33%, p=0.023). Within the control group, miR-122 and miR-126 decreased 26% and 28% from baseline (p=0.037 and p=0.035, respectively). Within the T1DM group, miR-126 and miR-130b decreased 49% and 50% from baseline (p=0.007 and p=0.011, respectively). The decrease in miR-122 from baseline was correlated with the total energy expenditure for the meal (r=0.-0.379, p=0.017) and insulin under the curve (r=0.350, p=0.029). The decrease in miR-126 and miR-130b were negatively correlated with glucose area under the curve (r=-0.369 and -0.358, p=0.021 and 0.025, respectively), and the decrease in miR-130b was negatively correlated with baseline NEFA (r= -0.328, p=0.042). miR-122 and 130b both target AMPK, which could alter lipid metabolism, thus explaining the associations with NEFA and energy expenditure. miR-126 is known to target both IRS1 and PI3K in the insulin signaling pathway, potentially explaining the association with glucose. It is clear that the circulating abundance of these miRNAs is reduced following a high fat meal, and that response may be modified by the presence of T1DM. Disclosure J.B. Tryggestad: None. A.M. Teague: None. K.R. Short: None. Funding Harold Hamm Diabetes Center; Ardmore Institute of Health