Plasma Glucose Area Under The Curve Research Articles

0003 Sleep and Circadian Disruption Induced by Simulated Night Shift Work Impair Cardiometabolic Outcomes in Healthy Adults

Abstract Introduction People who work evening, night or rotating shifts make up 20% of the US workforce and have a heightened risk for Type 2 diabetes (T2D) and cardiovascular disease (CVD) compared to people who work days, possibly due to repeated bouts of sleep and circadian disruption. However, the mechanism(s) by which sleep and circadian disruption impair cardiometabolic health are unclear. We therefore investigated the impact of acute circadian misalignment on factors related to cardiometabolic health including interstitial glucose concentration, glucose tolerance, resting systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). Methods Ten healthy adults (6F, 25.0±4.5y, BMI: 22.0±2.2kg/m2; mean±SD) participated in an ongoing 6d inpatient simulated night shift protocol to induce sleep and circadian disruption. Participants lived at the Sleep and Metabolism Laboratory for 2d to simulate day shift work followed by 2d of simulated night shift work. Continuous interstitial glucose monitoring was conducted throughout the study (FreeStyle Libre Pro; Abbott, Alameda, CA, USA). BP and HR were assessed 30 minutes after waketime (Omron HEM-FL31; Omron Healthcare, Kyoto, JP) followed by an oral glucose tolerance tests (OGTT) conducted 1.5h after waketime in both conditions. Results Simulated night shift work was associated with significantly higher interstitial glucose area under the curve (AUC) in response to an identical first meal after waking (18,299±1412 v 14,606±2035 [mg/dl]*min; p=0.009; mean±SEM) as well as plasma glucose AUC during the OGTT (23,239±2574 v 18,776±1832; p=0.002) compared to simulated day work. Furthermore, simulated night shift work was associated with a significant increase in resting DBP (75±3 v 66±2; p=0.017) compared to day work. No changes were observed in resting SBP (p=0.40) or HR (p=0.11) between conditions. Conclusion Sleep and circadian disruption induced by simulated night shift work appear to impair markers of cardiometabolic health, even in healthy, lean adults. Night shift work is largely unavoidable in modern society, thus is it critical to identify strategies or countermeasures to prevent the impact of circadian misalignment on T2D and CVD risk in a large portion of the population. Support (if any) This project was supported in part by R01DK125653 & F31HL165883.

Pilot Trial on the Effect of 5-Aminolevulinic Acid on Glucose Tolerance in Patients with Maternally Inherited Diabetes and Deafness.

The amino acid 5-aminolevulinic acid (5-ALA) is the first heme biosynthetic precursor. The combination of 5-ALA with sodium ferrous citrate (SFC) enhances heme production, leading to increased adenosine triphosphate (ATP) production in mitochondria. We investigated whether administering 5-ALA/SFC improves glucose tolerance with an increase in insulin secretion in patients with maternally inherited diabetes and deafness (MIDD), which is characterized by an insulin secretory disorder due to impaired mitochondrial ATP production. This was a single-arm, open-label, interventional study. We prospectively administered the oral glucose tolerance test (OGTT) twice in five patients with MIDD who had received intensive insulin therapy: before and 24weeks after an administration of 5-ALA/SFC (200/232mg per day). We measured the concentrations of glucose, insulin, C-peptide, and proinsulin at fasting, and 30, 60, and 120min after glucose load in each OGTT. The primary endpoint was the changes in the area under the curve (AUC) of serum insulin from 0 to 120min during OGTT from baseline to 24weeks. The serum insulin AUC (µU/mL) during the 120-min OGTT tended to increase from baseline to 24weeks but not significantly (17.1 ± 13.7 versus 22.3 ± 13.4, p = 0.077). The plasma glucose AUC (mg/dL) during the 120-min OGTT at 24weeks was not significantly decreased; the late phase of glucose excursion from 60 to 120min was significantly decreased compared with baseline (357 ± 42 versus 391 ± 50, p = 0.041). The mean level of glycated hemoglobin (HbA1c) decreased from 8.3 ± 1.2% at baseline to 7.9 ± 0.3% at 24weeks (p = 0.36) without increasing the daily dose of insulin injections. The 24-week administration of 5-ALA/SFC did not demonstrate a significant improvement in insulin secretion in patients with MIDD. Further investigations with a larger number of patients and a placebo control group are required to clarify the potential efficacy of 5-ALA/SFC for ameliorating mitochondrial dysfunctions in MIDD. UMIN-CTR000040581 and jRCT071200025.

Effects of incretin-based therapies on β-cell function in type 1 diabetes mellitus: a systematic review and meta-analysis.

AimTo assess the effects of incretin-based therapies on β-cell function in patients with type 1 diabetes mellitus (T1DM).MethodsWe searched the PubMed, Cochrane Library, Embase, and Web of Knowledge databases for eligible randomized clinical trials published up to July 2021. The inclusion criteria were patients with T1DM or latent autoimmune diabetes in adults, patients treated with dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists, and outcomes included one of the following: fasting plasma glucose, fasting C-peptide, postprandial C-peptide, C-peptide area under the curve (AUC), homeostasis model assessment for β cell function, and insulin resistance. The effects were analyzed using a random effect model with STATA 11.0.ResultsEight trials including 427 participants were included in the final analysis. A pooled analysis found no significant difference in fasting plasma glucose, fasting C-peptide, postprandial C-peptide, or C-peptide AUC between patients treated with incretin-based therapies and placebo. The two trials that reported changes in 2-hour postprandial C-peptide and two of the four trials that reported changes in C-peptide AUC reported increases after incretin-based therapies.ConclusionThis meta-analysis showed that incretin-based therapies did not preserve β-cell function in patients with T1DM.

Effects of Extruded and Conventional Sorghum Flour on Postprandial Plasma Amino Acid and Glucose Patterns in Adult Men

Sorghum is a nutrient-rich grain shown to improve growth and alleviate malnutrition in clinical studies; however, starch-protein interactions can limit its protein digestibility. Extrusion can help to improve protein availability from some foods. Three probe feeding studies were conducted to assess amino acid availability from extruded sorghum flour using postprandial plasma amino acid concentrations. For each study, a randomized crossover design with a one-week washout period was used to determine responses in healthy men aged 21-34 yr following intake of either extruded (EX) or conventional (CON) sorghum flour. In probe 1 (P1) and probe 2 (P2), men consumed 34 g (n=2) or 68 g (n=3) of flour, with plasma amino acid concentrations determined every 30 min for 180 min. A third probe (P3) provided 68 g (n=4) of flour, and samples for both plasma amino acids and glucose were collected every 15 min for 90 min. Responses were calculated as both the area-under-the-curve (AUC) and the incremental AUC (iAUC). In all three probes, amino acid responses were similar between the flours. The plasma glucose AUC was significantly greater from EX compared to CON, but the iAUCs between them were not significantly different. In these initial probe trials, a small sample size, along with individual variability in responses may explain the lack of differences in patterns of postprandial amino acids. Additional research on extrusion techniques and response measures is warranted.

Hourly 4-s Sprints Prevent Impairment of Postprandial Fat Metabolism from Inactivity.

This study determined if the interruption of prolonged sitting (i.e., 8 h of inactivity) with hourly cycling sprints of only 4-s duration each (i.e., 4 s × 5 per hour × 8 h = 160 s·d SPRINTS) improves PPL. The 4-s sprints used an inertial load ergometer and were followed by 45 s of seated rest. Four men and four women participated in two trials. Interventions consisted of an 8-h period of sitting (SIT), or a trial with equal sitting time interrupted with five SPRINTS every hour. The morning after the interventions, PPL and fat oxidation were measured over a 6-h period. Plasma glucose, insulin, and triglyceride concentrations were measured bihourly and incremental area under the curve (AUC) was calculated. No differences (P > 0.05) between interventions were found for plasma insulin or glucose AUC. However, SPRINTS displayed a 31% (408 ± 119 vs 593 ± 88 mg·dL per 6 h; P = 0.009) decrease in plasma triglyceride incremental AUC and a 43% increase in whole-body fat oxidation (P = 0.001) when compared with SIT. These data indicate that hourly very short bouts (4 s) of maximal intensity cycle sprints interrupting prolonged sitting can significantly lower the next day's postprandial plasma triglyceride response and increase fat oxidation after a high-fat meal in healthy young adults. Given that these improvements were elicited from only 160 s of nonfatiguing exercise per day, it raises the question as to what is the least amount of exercise that can acutely improve fat metabolism and other aspects of health.

The Effect of Exogenous Ketone Monoester Ingestion on Plasma BDNF during an Oral Glucose Tolerance Test

Brain‐derived neurotrophic factor (BDNF) is important for the maintenance of healthy brain function. Plasma BDNF is lower in people with obesity compared to their lean counterparts, potentially due to differences in metabolic control as acute hyperglycemia reduces cerebral output of BDNF in young, healthy adults. Ingestion of a ketone monoester (KME) drink containing beta‐hydroxybutyrate (β‐OHB) attenuates the glycemic response during an oral‐glucose tolerance test (OGTT) in humans, and increases neuronal expression of BDNF in rodents. Whether ingestion of a KME affects plasma BDNF in humans is currently unknown. The purpose of this study was to examine the effect of KME ingestion before an OGTT on plasma BDNF in normal‐weight adults and adults with obesity.MethodsSecondary analyses of two separate studies were performed. Study 1 included lean adults (n=18; Mage=25.3 ± 4.3 years; BMI=22.2 ± 2.3 kg/m2) and Study 2 included adults with obesity (n=12; Mage=48.8 ± 9.5 years; BMI = 33.7 ± 5.0 kg/m2). In both studies, participants ingested 0.45 mL/kg−1 body weight KME or Placebo 30 minutes prior to completing a 75 g OGTT. β‐OHB, and BDNF were measured via blood samples at fasting baseline (BSL) and 120 min post‐OGTT. Plasma glucose was measured at BSL and every 30 minutes during the OGTT. A 2‐factor repeated measures ANOVA was computed to assess β‐OHB and BDNF responses by time and condition. A paired t‐test was computed to compare glucose area under the curve (AUC). An independent sample t‐test was used to compare fasting plasma BDNF between lean and obese participants.ResultsStudy 1KME ingestion significantly increased β‐OHB by 800 ± 454% (p<0.001) and blunted plasma glucose AUC by 15.3 ± 12.7% (p<0.001) compared to Placebo. Plasma BDNF significantly decreased post‐OGTT compared to BSL in the Placebo condition (389.3 ± 595.8 pg/mL vs. 718.6 ± 830.8 pg/mL; p=0.018), whereas it was unchanged in the KME condition (469.2 ± 791.8 pg/mL vs. 560.2 ± 689.6 pg/mL; p=0.28).Study 2KME ingestion significantly increased β‐OHB by 1586 ± 602% (p<0.001) and blunted plasma glucose AUC by 12.3 ± 7.9% (p=0.001) compared to Placebo. In the KME condition, plasma BDNF significantly increased post‐OGTT compared to BSL (188.9 ± 138.2 pg/mL vs. 122.6 ± 129.3 pg/mL; p=0.037), whereas it was unchanged in the Placebo condition (126.4 ± 134.0 pg/mL vs. 143.9 ± 161.9 pg/mL; p=0.18). Fasting plasma BDNF was significantly lower in adults with obesity compared to lean adults (132.8 ± 142.8 pg/mL vs. 639.4 ± 756.8 pg/mL; p=0.002).ConclusionsPlasma BDNF is differentially impacted by acute KME ingestion and an OGTT in adults with obesity compared to lean adults. Our findings suggest that KME ingestion may increase BDNF during an OGTT in adults with obesity, whereas KME may protect against hyperglycemia‐induced reductions in BDNF in lean adults. The difference in basal BDNF between groups may suggest that long‐term differences in metabolism and/or body composition impact BDNF. KME may be a strategy for altering plasma BDNF responses during hyperglycemia.Support or Funding InformationNSERC Discovery

Maternal obesity and degree of glucose intolerance on neonatal hypoglycaemia and birth weight: a retrospective observational cohort study in women with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is an increasing problem worldwide. Postnatal hypoglycaemia and excess foetal growth are known important metabolic complications of neonates born to women with diabetes. This retrospective cohort study aims to determine the influence of obesity and glucose intolerance on neonatal hypoglycaemia and birth weight over the 90th percentile (LGA). Data were abstracted from 303 patient medical records from singleton pregnancies diagnosed with GDM. Data were recorded during routine hospital visits. Demographic data were acquired by facilitated questionnaires and anthropometrics measured at the first antenatal appointment. Blood biochemical indices were recorded. Plasma glucose area under the curve (PG-AUC) was calculated from OGTT results as an index of glucose intolerance. OGTT results of 303 pregnant women aged between 33.6years (29.8-37.7) diagnosed with GDM were described. Neonates of mothers with a BMI of over 30kg/m2 were more likely to experience neonatal hypoglycaemia (24 (9.2%) vs. 23 (8.8%), p = 0.016) with odds ratio for neonatal hypoglycaemia significantly higher at 2.105, 95% CI (1.108, 4.00), p = 0.023. ROC analysis showed poor strength of association (0.587 (95% CI, .487 to .687). Neonatal LGA was neither associated with or predicted by PG-AUC nor obesity; however, multiparous women were 2.8 (95% CI (1.14, 6.78), p = 0.024) times more likely to have a baby born LGA.Conclusion: Maternal obesity but not degree of glucose intolerance increased occurrence of neonatal hypoglycaemia. Multiparous women had greater risk of neonates born LGA.What is Known:•Excess foetal growth in utero has long-term metabolic implications which track into adulthood.•Neonatal hypoglycaemia is detrimental to newborns in the acute phase with potential long-term implications on the central nervous system.What is New:•Maternal obesity but not degree of glucose intolerance in a GDM cohort increased occurrence of neonatal hypoglycaemia.•Multiparous women diagnosed had greater risk of neonates born LGA.

OR14-1 Pharmacodynamics, Safety, Tolerability, and Efficacy of Oral Insulin Formulation (Oshadi Icp) among Young Adults with Type 1 Diabetes: A Summary of Clinical Studies Phases I, Ib, and Ii

Background Replacement of subcutaneous (SC) insulin by oral insulin for Type I diabetes (T1D) could promote patient compliance and minimize hyperinsulinemia. Oshadi Drug Administration Ltd. has developed an oral carrier for proteins delivery, composed of known ingredients, including polysaccharides and nano-silica , and based on quantum theory of biochemical reactions. Objectives To assess the pharmacodynamics of Oshadi oral insulin formulation (Oshadi-I) and the safety, tolerability and glucose-lowering effect of Oshadi oral insulin, proinsulin and c-peptide formulation (Oshadi-Icp) in young patients with T1D. Methods Phase I: a single blinded crossover between Oshadi-I and placebo. Glucose concentration was followed over 13 hours post a single dose. Phase Ib: a crossover open label comparison between 2 sessions of 3 days of Oshadi-Icp or placebo. During both sessions patients stayed at the research unit, provided with identical low carbs diet and minimal doses of SC insulin. Phase II:a prospective 4 weeks open-label follow-up of patients using an insulin pump combined with Oshadi-Icp at home. During Phases Ib and II iinterstitial glucose (IG) was monitored by CGMS, and capillary glucose by finger pricks (CG). Mean IG, mean CG, their area under the curve (AUC), weight adjusted total daily dose (TDD) of SC insulin, BMI, HbA1c, fructosamine, and safety parameters were compared. Results Eight patients, mean age 27.7±4.8 years, 5 males, were included in Phase I study, 10 patients mean age 26.2±4.7 years, 7 males, were included in Phase Ib study, and 16 patients mean age 23.5± 4.6 years, 12 males, were included in Phase II study. Oshadi-Icp was well tolerated, with no adverse events nor clinically relevant changes in vital signs, electrocardiograms, and standard safety laboratory parameters during all study phases. Phase I demonstrated a significantly lower plasma glucose AUC within 7 hours post Oshadi-I compared with placebo: 1116.1mg/dl±107.0 vs. 1345.7mg/dl ±82.0, p <0.01. Phase Ib study demonstrated significantly lower mean post meals GC, AUC-GC and mean insulin TDD at the third day during Oshadi-Icp session compared to placebo: 207.5mg/dl± 6.0 vs. 265.4mg/dl±3.9, p<0.001, 3107.57mg/dl±20.5 vs. 4031.58mg/dl±26.76, p<0.001, 0.14 ±0.04 IU/kg/day vs. 0.18 ±0.06 IU/kg/day, p≤0.01. Four episodes of GC ≤70mg/dL were detected during the Oshadi Icp session and 1 episode of mild DKA was detected during the placebo session. Phase II study demonstrated the ratio of SC insulin dose to carbohydrate intake was significantly lower during Oshasi-Icp month 78-80% for each week compared to baseline 100%. Fructosamine was stable throughout the study, with no episodes of severe hypoglycemia and DKA. Conclusions A substantial safety and glucose lowering effect of Oshadi-Icp formulation were demonstrated. Its clinical potential and beneficial effect for patients with T1D should be further studied.

Effect of Sward Height on Pasture Nonstructural Carbohydrate Concentrations and Blood Glucose/Insulin Profiles in Grazing Horses

Six mature stock-type geldings with maintenance only requirements were used in a randomized cross-over design to determine the effect of sward height on pasture plant nonstructural carbohydrate (NSC) concentrations and blood glucose and insulin concentrations. Horses were randomly assigned to one of two tall fescue (Lolium arundinaceum Schreb cv Max-Q, Pennington Seed, Madison, GA) grazing cells (0.37 ha) having two different sward heights for a period of 7 days: (1) short (approximately 15 cm; n = 3) or tall (between 30 and 40 cm; n = 3). After the first 7-day period, treatment groups were reversed by moving horses to ungrazed cells having similar characteristics to those used in the first 7 days, so that all horses receive all treatments resulting in six observations per treatment. Both short and tall grazing cells were mowed to a height of approximately 15 cm 32 days before the experiment starts. The short grazing cells were removed to approximately 15 cm at 11 days before the start of the first 7-day period and again 1 day before the start of each 7-day period. All horses had access to pasture for 10 h/d beginning at 8 AM and ending at 6 PM. Although not at pasture, all horses were individually housed in 3.7 × 12.2 m partially covered pens containing automatic water troughs and a crushed stone surface. Herbage mass (kg DM/ha) was determined by use of a falling plate meter for each pasture to ensure that both groups of horses had adequate dry matter to provide grazing for at least 7 days. On day 7 of each period, jugular venous blood samples were collected from each horse before being turned out to pasture, and then at 2, 4, 6, and 8 hours after turn-out. Pasture samples were also collected from each grazing cell at the same time blood samples were taken. Serum and plasma from blood samples were harvested and analyzed for insulin and glucose concentrations, respectively. Pasture samples were analyzed for water soluble carbohydrate (WSC), ethanol soluble carbohydrate (ESC), and starch. The sum of WSC and starch were used as an estimate of NSC. Area under the curve (AUC) and peak concentration were calculated for both plasma glucose (PPG) and serum insulin (PSI) concentration and were analyzed using analysis of variance for randomized cross-over designs. Pasture WSC, ESC, starch, and NSC concentrations were analyzed using analysis of variance for randomized complete block design. A P value of < .05 was considered significant. Mean pasture plant NSC, WSC, and ESC concentrations were lower (P < .001) in short as compared with tall. Pasture plant starch concentration was not different between treatments. Mean pregrazing plasma glucose concentrations, PPG concentrations, and plasma glucose AUC were not affected by treatment. Mean pregrazing serum insulin concentrations were not affected by treatment. Mean PSI and insulin AUC were greater (P < .01) when horses grazed tall, as compared with short. In conclusion, decreasing the sward height by mowing pasture decreased NSC, WSC, and ESC concentrations and subsequently decreased the postprandial insulin response of horses grazing the pasture. These findings may be important in developing strategies aimed at preventing insulin resistance in grazing horses.

Effects of Varying Physical Activity Level on Glucose Tolerance Testing

The oral glucose tolerance test (OGTT) is a commonly used method for the diagnosis of insulin resistance. Currently the only level of control prior to an OGTT is an 8-10 hour fast. Physical activity is known to influence glucose uptake kinetics. Thus, our PURPOSE was to determine if varying the level of physical activity, the day prior to an OGTT, influenced the blood glucose and insulin responses to an OGTT. We hypothesized that higher levels of physical activity the day prior to an OGTT would result in attenuated blood glucose and insulin responses to an OGTT. METHODS: Ten healthy adults (6 m/4 f; age = 21.5±0.3y; BMI= 24±5 kg·m-2) participated in three OGTT trials the morning after performing 50%, 100%, or 150% of their habitual physical activity in randomized order. Habitual physical activity as average steps/day (12,318±1310 steps·day-1) was determined using 7-day pedometery. Pedometers were worn for 24 hrs prior to each OGTT trial and used to confirm steps·day-1 for the 50%, 100%, and 150% conditions. Trials were separated by at least one week and subjects were asked to follow a similar diet the day prior to each OGTT trial. For each OGTT trial, plasma glucose and insulin were measured after an overnight fast and at 30 min intervals for two hours following ingestion of the glucose beverage (1-gram glucose·kg-1 body mass). Area under the curve (AUC) for glucose and insulin for each OGTT was calculated using the trapezoidal method. Between trial differences for these variables were analyzed using a general linear model with repeated measures. Significance was set to p< 0.05. RESULTS: Subjects successfully achieved the desired percentage of habitual steps prior to each trial: 52±1%, 98±2%, and 146±3%. Fasting plasma glucose (50%: 95±2 mg·dl-1; 100%: 91±2 mg·dl-1; 150%: 91±2 mg·dl-1), glucose AUC (50%: 12,932±769 mg·min·dl-1; 100%: 13,239±1,008 mg·min·dl-1; 150%: 13,016±471 mg·min·dl-1), and insulin AUC (50%: 5,562±1810 μIU·min·ml-1; 100%: 5181±1839 μIU·min·ml-1; 150%: 4735±1776 μIU·min·ml-1) did not differ between trials. CONCLUSIONS: Our data suggests that varying the physical activity level (from 50 to 150% of habitual activity) the day prior to an oral glucose tolerance test does not influence the blood glucose or insulin responses to this commonly utilized diagnostic test.

Effects of the intake of Undaria pinnatifida (Wakame) and its sporophylls (Mekabu) on postprandial glucose and insulin metabolism.

Long-term suppression of postprandial glucose concentration is an important dietary strategy for the prevention and treatment of type 2 diabetes. Because previous reports have suggested that seaweed may exert anti-diabetic effects in animals, the effects of Wakame or Mekabu intake with 200 g white rice, 50 g boiled soybeans, 60 g potatoes, and 40 g broccoli on postprandial glucose, insulin and free fatty acid levels were investigated in healthy subjects. Plasma glucose levels at 30 min and glucose area under the curve (AUC) at 0-30 min after the Mekabu meal were significantly lower than that after the control meal. Plasma glucose and glucose AUC were not different between the Wakame and control meals. Postprandial serum insulin and its AUC and free fatty acid concentration were not different among the three meals. In addition, fullness, satisfaction, and wellness scores were not different among the three meals. Thus, consumption of 70 g Mekabu with a white rice-based breakfast reduces postprandial glucose concentration.

Impaired glucose regulation is associated with poorer performance on the Stroop Task

BackgroundType 2 diabetes is a risk factor for development of cognitive dysfunction. Impairments in glucose regulation have been associated with poorer performance on tests of executive function and information processing speed. MethodsWe administered the Stroop Color Word Task, where higher interference scores are indicative of decreased selective attention, to 98 non-diabetic volunteers (64m; %fat=37±12; age=36±9yrs, race=41 NA/30 C/13 H/14 AA) on our inpatient unit. After 3d on a weight maintaining diet, % body fat was measured by DXA and a 75g oral glucose tolerance test (OGTT) was administered. Impaired glucose regulation (IGR) was defined as: fasting plasma glucose ≥100 and ≤125mg/dL and/or 2h plasma glucose between ≥140 and ≤199mg/dL (IGR; n=48; NGR; n=50). Total and incremental area under the curve (AUC) for insulin and glucose were calculated. ResultsStroop interference scores were not significantly associated with any measure of adiposity or insulin concentrations. Individuals with IGR had significantly higher interference scores than those with normal glucose regulation (NGR; p=0.003). Higher interference scores were significantly correlated with fasting plasma glucose concentrations (r=0.26, p=0.007) and total glucose AUC (r=0.30, p=0.02) and only trending so for iAUC and 2h plasma glucose (r=0.18, p=0.08; r=0.17, p=0.09 respectively). In separate multivariate linear models, fasting plasma glucose (p=0.002) and total glucose AUC (p=0.0005) remained significant predictors of Stroop interference scores, even after adjustment for age, sex, race, education and %fat. ConclusionsIndividuals with IGR had decreased performance on a test of selective attention. Fasting plasma glucose was more strongly associated with lower performance scores than 2h plasma glucose. Our results indicate that even mild hyperglycemia in the non-diabetic range is associated with attentional processing difficulties in a sample of younger adults. Whether these impairments precede or are induced by impaired glucose regulation is not clear.

Dynamics of plasma active GLP-1 versus insulin and glucose concentrations during GLP-1 infusion in rat model of postprandial hyperglycemia

In vitro studies in isolated pancreas and islets have shown that glucagon-like peptide-1 (GLP-1) promotes insulin release in a typical concentration-dependent manner. In contrast, the relationship between plasma GLP-1 and insulin concentrations in vivo is complicated, because GLP-1-promoted insulin release lowers blood glucose, which influences glucose-dependent insulinotropic ability of GLP-1. GLP-1 also stimulates insulin release via hepatoportal neuronal mechanism. Hence, the dynamic relationship between plasma active GLP-1 vs. insulin and glucose concentrations is obscure. In this study, we aimed to determine in vivo relationships between these parameters in rats. To mimic postprandial state, intraduodenal glucose challenge in anesthetized rats was performed, which can minimize the release of endogenous GLP-1. The glucose challenge induced the 1st phase and 2nd phase insulin release. GLP-1 infusion from jugular vein significantly and concentration-dependently enhanced area under the curve (AUC) of the 1st phase insulin, in which the minimum effective active GLP-1 concentration was 6.6 pmol/l. In contrast, bell-shaped dose responses were observed for both the 2nd phase and total insulin AUCs, in which a significant increase was obtained only with 11 pmol/l of active GLP-1 for total insulin AUC. A statistically significant reduction in the plasma glucose AUC was observed when active GLP-1 concentration was 11 pmol/l and 21 pmol/l. These results indicate that GLP-1 markedly enhances the 1st phase insulin release while less potently the 2nd phase insulin release, possibly due to a negative feedback regulation of β-cells via reduced plasma glucose levels by the enhanced 1st phase insulin release.

Effects of consumption of honey, sucrose and glucose on satiety and postprandial metabolism in healthy subjects

We recently demonstrated that consuming a 240‐kcal portion of honey produces an attenuated glycemic response in healthy adults compared to glucose but not sucrose and that honey reduces food intake compared to sucrose in rats. The purpose of this study was to compare the effects of consuming honey, sucrose and glucose at a greater energy load on satiety and plasma glucose, insulin and ghrelin. In a randomized, crossover design, 14 healthy subjects consumed 400‐kcal solutions containing honey, sucrose or glucose following a 10‐hr fast. Visual analog scales for satiety assessment and fingerprick blood samples were collected over a 2‐hr period. Satiety area under the curve (AUC) and plasma ghrelin area over the curve did not differ significantly among the sweeteners consumed. Intake of honey resulted in lower (p≤.05) plasma glucose and insulin AUCs (mean ± SEM: −33.3±6.1% and −11.1%±1.6%, respectively) than the AUCs induced by glucose consumption (p≤.05). Consumption of honey elicited lower (p≤.05) plasma glucose AUC (−16.4%±6.2%) compared to sucrose but resulted in similar insulin AUCs. These results suggest that at the given energy load, honey promotes a potentially healthier response than sucrose and glucose with regard to postprandial glucose metabolism. However, there appears to be no difference in satiating power among honey, sucrose and glucose.Sponsored by a grant from the American Heart Association

Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross‐over trial in people with Type 1 diabetes

To compare blood glucose control using insulin glargine + insulin lispro with that on NPH insulin + unmodified human insulin in adults with Type 1 diabetes managed with a multiple injection regimen. In this 32-week, five-centre, two-way cross-over study, people with Type 1 diabetes (n = 56, baseline HbA1c 8.0 +/- 0.8%) were randomized to evening insulin glargine + mealtime insulin lispro or to NPH insulin (once- or twice-daily) + mealtime unmodified human insulin. Each 16-week period concluded with a 24-h inpatient plasma glucose profile. HbA1c was lower with glargine + lispro than with NPH + human insulin [7.5 vs. 8.0%, difference -0.5 (95% CI -0.7, -0.3) %, P < 0.001]. This was confirmed by an 8% lower 24-h plasma glucose area under the curve (AUC) (187 vs. 203 mmol l(-1) h(-1), P = 0.037), a 24% reduction in plasma glucose AUC > 7.0 mmol/l1 (47 vs. 62 mmol l(-1) h(-1), P = 0.017) and a 15% lower post-prandial plasma glucose AUC (75 vs. 88 mmol l(-1) h(-1), P = 0.002). There was no reduction in night-time plasma glucose AUC or increase in plasma glucose area < 3.5 mmol/l. Monthly rate of nocturnal hypoglycaemia was reduced by 44% with glargine + lispro (0.66 vs. 1.18 episodes/month, P < 0.001). Compared with NPH insulin + unmodified human insulin, the combination of insulin glargine with a rapid-acting insulin analogue as multiple-injection therapy for Type 1 diabetes improves overall glycaemic control as assessed by HbA1c and 24-h plasma glucose monitoring to a clinically significant degree, together with a reduction in nocturnal hypoglycaemia.

Weight loss‐associated changes in acute effects of nateglinide on insulin secretion after glucose loading: results of glucose loading on 2 consecutive days

The aim of this study was to investigate the influence of changes in insulin resistance and early insulin secretion on the insulin secretagogic effects of nateglinide. Oral glucose tolerance testing (OGTT, 75 g) was performed in obese patients before and after weight loss on 2 consecutive days (first day OGTT without nateglinide, second day OGTT with nateglinide), to compare any weight loss associated changes in the nateglinide-induced insulin response to glucose loading. Reductions in visceral fat, liver fat, skeletal muscle fat and homeostasis model assessment (HOMA)-R due to weight loss were associated with increased Delta insulin 30 min/Delta glucose 30 min (DeltaI30/DeltaG30), and reduced area under the curve (AUC) for plasma glucose as seen in OGTT results. Results from OGTT showed that nateglinide administration was associated with reductions in plasma glucose AUC, both before and after weight loss. Before weight loss, although there was a significant elevation of DeltaI30/DeltaG30 associated with nateglinide treatment, no major change in the insulin-secreting dynamics after glucose loading was observed. After weight loss, nateglinide administration produced a significant increase in DeltaI30/DeltaG30, with insulin secretion peaking more quickly. Insulin response to nateglinide after glucose loading varied greatly in conjunction with weight loss. This may be accounted for not only by the enhancement of early insulin response to nateglinide associated with the improvement of early insulin response with weight loss but also by the reduced visceral fat, which in turn led to reduced levels of free fatty acids in portal blood and hepatic triglycerides, as well as increased hepatic insulin clearance.

Glycemic index of cracked corn, oat groats and rolled barley in horses.

Muscle glycogen synthesis depends on glucose availability. This study was undertaken to determine the glycemic and insulinemic response of horses to equal amounts of hydrolyzable carbohydrates (starch and sugar) in the form of one of three grain meals or intragastric administration of a glucose solution. In a randomized crossover design, seven horses were fed each of three grain meals (cracked corn, steamed oat groats, or rolled barley) or were infused intragastrically with glucose solution at 2 g of hydrolyzable carbohydrate (starch plus sugar) per kilogram of BW. The quantity of hydrolyzable carbohydrate ingested was not different among all treatments (P = 0.70). Plasma glucose concentration peaked in all four treatments by 1.5 to 2 h after feeding. Plasma glucose concentration remained higher than baseline in oat groats or barley-fed horses throughout 8 h, whereas plasma glucose returned to baseline by 5 to 6 h in corn-fed horses or after glucose administration. Meal consumption was slower in oat groats-fed horses than in corn-fed ones, which may confound the glycemic and insulinemic responses observed after grain feeding. Plasma glucose area under the curve (AUC) was 63% both in corn and oat groats and 57% in barley-fed horses compared with that of horses administered glucose (P = 0.13). Serum immunoreactive insulin concentration peaked between 2 and 3 h after feeding or glucose administration, and barley-fed horses had lower serum immunoreactive insulin concentration by 3 to 4 h than corn-fed horses or after glucose administration (P < 0.05). We conclude, in horses, ingestion of oat groats, corn, and barley result in similar plasma glucose AUC and, compared with the glycemic index of 100 as the glucose reference, corn, oat groats, and barley had a glycemic index of approximately 60.

C-peptide and glucagon profiles in minority children with type 2 diabetes mellitus.

The present study was conducted to determine the extent of insulin deficiency and glucagon excess in the hyperglycemia of type 2 diabetes in children. The incidence of type 2 diabetes mellitus in children and adolescents has increased substantially over the past several years. Because insulin and glucagon action both regulate blood glucose concentration, we studied their responses to mixed meals in children with type 2 diabetes. Subjects were 24 patients with type 2 diabetes compared with 24 controls, aged 9--20 yr (predominantly African-Americans), matched for body mass index and sexual maturation. All of those with diabetes were negative for antibodies to glutamic acid decarboxylase. Plasma glucose, glucagon, and serum C-peptide concentrations were measured at 0, 30, 60, 90, and 120 min after a mixed liquid meal (Sustacal) ingestion (7 mL/kg body weight; maximum, 360 mL). The area under the curve (AUC) was calculated by trapezoidal estimation. The incremental C-peptide (Delta CP) in response to the mixed meal was calculated (peak -- fasting C-peptide). The plasma glucose AUC was significantly greater in patients than in controls (mean +/- SEM, 1231 +/- 138 vs. 591 +/- 13 mmol/L x min; P < 0.001). The Delta CP was significantly lower in those with diabetes than in controls (1168 +/- 162 vs. 1814 +/- 222 pmol/L; P < 0.02). Glucagon responses did not differ between the two groups. Hyperglycemia is known to inhibit glucagon secretion. Therefore, our patients with substantial hyperglycemia would be expected to have decreased glucagon responses compared with controls and are thus relatively hyperglucagonemic. Patients were divided into poorly and well controlled subgroups (glycosylated hemoglobin A(1c), > or =7.2% and <7.2%, respectively). There were no significant differences in the Delta CP and glucagon responses between these two subgroups. We next analyzed the data in terms of duration of diabetes (long term, > or =1 yr; short term, <1 yr). The CP was significantly lower in long- vs. short-term patients (768 +/- 232 vs. 1407 +/- 199 pmol/L; P < 0.05). The plasma glucagon AUC was significantly higher in the long- vs. short-term patients (9029 +/- 976 vs. 6074 +/- 291 ng/L x min; P < 0.001). Hemoglobin A(1c) did not differ between long- vs. short-term patients. Our results indicate that relative hypoinsulinemia and hyperglucagonemia represent the pancreatic beta- and alpha-cell dysfunctions in children with type 2 diabetes. The severity of both beta- and alpha-cell dysfunctions appears to be determined by the duration of diabetes.

C-peptide and Glucagon Profiles in Minority Children with Type 2 Diabetes Mellitus

The present study was conducted to determine the extent of insulin deficiency and glucagon excess in the hyperglycemia of type 2 diabetes in children. The incidence of type 2 diabetes mellitus in children and adolescents has increased substantially over the past several years. Because insulin and glucagon action both regulate blood glucose concentration, we studied their responses to mixed meals in children with type 2 diabetes. Subjects were 24 patients with type 2 diabetes compared with 24 controls, aged 9–20 yr (predominantly African-Americans), matched for body mass index and sexual maturation. All of those with diabetes were negative for antibodies to glutamic acid decarboxylase. Plasma glucose, glucagon, and serum C-peptide concentrations were measured at 0, 30, 60, 90, and 120 min after a mixed liquid meal (Sustacal) ingestion (7 mL/kg body weight; maximum, 360 mL). The area under the curve (AUC) was calculated by trapezoidal estimation. The incremental C-peptide (ΔCP) in response to the mixed meal was calculated (peak − fasting C-peptide). The plasma glucose AUC was significantly greater in patients than in controls (mean ± sem, 1231 ± 138 vs. 591 ± 13 mmol/L·min; P < 0.001). The ΔCP was significantly lower in those with diabetes than in controls (1168 ± 162 vs. 1814 ± 222 pmol/L; P < 0.02). Glucagon responses did not differ between the two groups. Hyperglycemia is known to inhibit glucagon secretion. Therefore, our patients with substantial hyperglycemia would be expected to have decreased glucagon responses compared with controls and are thus relatively hyperglucagonemic. Patients were divided into poorly and well controlled subgroups (glycosylated hemoglobin A1c, ≥7.2% and <7.2%, respectively). There were no significant differences in the ΔCP and glucagon responses between these two subgroups. We next analyzed the data in terms of duration of diabetes (long term, ≥1 yr; short term, <1 yr). The ΔCP was significantly lower in long- vs. short-term patients (768 ± 232 vs. 1407 ± 199 pmol/L; P < 0.05). The plasma glucagon AUC was significantly higher in the long- vs. short-term patients (9029 ± 976 vs. 6074 ± 291 ng/L·min; P < 0.001). Hemoglobin A1c did not differ between long- vs. short-term patients. Our results indicate that relative hypoinsulinemia and hyperglucagonemia represent the pancreatic β- and α-cell dysfunctions in children with type 2 diabetes. The severity of bothβ - and α-cell dysfunctions appears to be determined by the duration of diabetes.

The effects of short and long-term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance.

The effects of replacement with biosynthetic human GH on carbohydrate tolerance and lipid metabolism were studied in 40 hypopituitary adults during a randomized double blind, placebo-controlled trial for 6 months, followed by a 12-month open trial. The daily GH dose was 0.04 +/- 0.01 IU/kg. Fasting plasma glucose, serum fructosamine, plasmid lipids, lipoproteins, and plasma C-peptide concentrations were measured, and an oral glucose tolerance test was performed every 6 months. There was no change in fasting triglyceride levels at any stage of the study. There was no significant change in fasting total or LDL cholesterol, total HDL cholesterol, high density lipoprotein2 (HDL2) cholesterol, HDL3 cholesterol, apoprotein-A1, or apoprotein-B during GH or placebo treatment in the placebo-controlled 6-months study. In the open phase of the trial, total and low density lipoprotein cholesterol showed a sustained downward trend during GH therapy. Compared to the pretreatment level, the HDL cholesterol concentration was significantly higher at 18 months. Cholesterol subfractions HDL2 and HDL3 and apoprotein-A1 and -B were not different from the pretreatment levels. The total/HDL cholesterol ratio decreased significantly at 12 and 18 months. During the controlled phase, fasting plasma glucose was similar during GH and placebo administration, but fasting insulin and C-peptide increased during GH therapy, but not during placebo treatment. The mean area under the curve (AUC) for glucose increased by a small, but significant, extent over the 6 months of GH treatment and was higher at 6 months than during placebo treatment. The AUC for insulin also increased during GH treatment. During the open trial, the fasting plasma glucose level increased at 6 and 12 months, and the fasting plasma insulin level increased at 6, 12, and 18 months of GH treatment. The plasma glucose AUC during the oral glucose tolerance test was significantly higher at 6 months, and the plasma insulin AUC was significantly higher at 6, 12, and 18 months of GH therapy. In conclusion, GH therapy has some metabolic effects that are considered beneficial and others that are less desirable.