Glucose Concentration-time Curve Research Articles

Efficacy and safety of cotadutide, a dual glucagon‐like peptide‐1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease

AimTo assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease.Materials and MethodsIn this phase 2a study (NCT03550378), patients with body mass index 25‐45 kg/m2, estimated glomerular filtration rate 30‐59 ml/min/1.73 m2 and type 2 diabetes [glycated haemoglobin 6.5‐10.5% (48‐91 mmol/mol)] controlled with insulin and/or oral therapy combination, were randomized 1:1 to once‐daily subcutaneous cotadutide (50‐300 μg) or placebo for 32 days. The primary endpoint was plasma glucose concentration assessed using a mixed‐meal tolerance test.ResultsParticipants receiving cotadutide (n = 21) had significant reductions in the mixed‐meal tolerance test area under the glucose concentration‐time curve (–26.71% vs. +3.68%, p < .001), more time in target glucose range on continuous glucose monitoring (+14.79% vs. –21.23%, p = .001) and significant reductions in absolute bodyweight (–3.41 kg vs. –0.13 kg, p < .001) versus placebo (n = 20). In patients with baseline micro‐ or macroalbuminuria (n = 18), urinary albumin‐to‐creatinine ratios decreased by 51% at day 32 with cotadutide versus placebo (p = .0504). No statistically significant difference was observed in mean change in estimated glomerular filtration rate between treatments. Mild/moderate adverse events occurred in 71.4% of participants receiving cotadutide and 35.0% receiving placebo.ConclusionsWe established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albumin‐to‐creatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longer‐term clinical trials.

Blood glucose response after oral lactulose intake in type 2 diabetic individuals.

BACKGROUNDLactulose is approved for the symptomatic treatment of constipation, a gastrointestinal (GI) complication common in individuals with diabetes. Lactulose products contain carbohydrate impurities (e.g., lactose, fructose, galactose), which occur during the lactulose manufacturing process. These impurities may affect the blood glucose levels of individuals with type 2 diabetes mellitus (T2DM) using lactulose for the treatment of mild constipation. A previous study in healthy subjects revealed no increase in blood glucose levels after oral lactulose intake. However, it is still unclear whether the intake of lactulose increases blood glucose levels in individuals with diabetes.AIMTo evaluate the blood glucose profile after oral lactulose intake in mildly constipated, non-insulin-dependent subjects with T2DM in an outpatient setting.METHODSThis prospective, double-blind, randomized, controlled, single-center trial was conducted at the Clinical Research Center at the Medical University of Graz, Austria, in 24 adult Caucasian mildly constipated, non-insulin-dependent subjects with T2DM. Eligible subjects were randomized and assigned to one of six treatment sequences, each consisting of four treatments stratified by sex using an incomplete block design. Subjects received a single dose of 20 g or 30 g lactulose (crystal and liquid formulation), water as negative control or 30 g glucose as positive control. Capillary blood glucose concentrations were measured over a period of 180 min post dose. The primary endpoint was the baseline-corrected area under the curve of blood glucose concentrations over the complete assessment period [AUCbaseline_c (0-180 min)]. Quantitative comparisons were performed for both lactulose doses and formulations vs water for the equal lactulose dose vs glucose, as well as for liquid lactulose vs crystal lactulose. Safety parameters included GI tolerability, which was assessed at 180 min and 24 h post dose, and adverse events occurring up to 24 h post dose.RESULTSIn 24 randomized and analyzed subjects blood glucose concentration-time curves after intake of 20 g and 30 g lactulose were almost identical to those after water intake for both lactulose formulations despite the different amounts of carbohydrate impurities (≤ 3.0% for crystals and approx. 30% for liquid). The primary endpoint [AUCbaseline_c (0-180 min)] was not significantly different between lactulose and water regardless of lactulose dose and formulation. Also with regard to all secondary endpoints lactulose formulations showed comparable results to water with one exception concerning maximum glucose level. A minor increase in maximum blood glucose was observed after the 30 g dose, liquid lactulose, in comparison to water with a mean treatment difference of 0.63 mmol/L (95% confidence intervals: 0.19, 1.07). Intake of 30 g glucose significantly increased all blood glucose endpoints vs 30 g liquid and crystal lactulose, respectively (all P < 0.0001). No differences in blood glucose response were observed between the different lactulose formulations. As expected, lactulose increased the number of bowel movements and was generally well tolerated. Subjects experienced only mild to moderate GI symptoms due to the laxative action of lactulose.CONCLUSIONBlood glucose AUCbaseline_c (0-180 min) levels in mildly constipated, non-insulin dependent subjects with T2DM are not affected by the carbohydrate impurities contained in 20 g and 30 g crystal or liquid lactulose formulations.

Bioequivalence and Evaluation Parameters Based on the Pharmacodynamics of Miglitol in Healthy Volunteers

The aim of this study was to explore the bioequivalence of miglitol based on pharmacodynamic properties. The study was performed as a single-dose, randomized, open-label, 3-period, 3-way crossover trial over a 7-day washout period. Forty-eight subjects were randomly assigned into 3 groups: (1) miglitol test formulation/sucrose coadministration, (2) miglitol reference formulation/sucrose coadministration, and (3) sucrose administration alone. Serum glucose concentrations were measured by the hexokinase detection method. The peak serum glucose concentration (Cmax ) and the area under the serum glucose concentration-time curve through 4 hours (AUC0-4h ) were used as the main pharmacodynamic parameters to evaluate bioequivalence. The 90% confidence intervals for the geometric mean ratios of Cmax and AUC0-4h were 94.81%-101.07% and 98.82%-100.72%, respectively, which were all within the bioequivalence range of 80.00%-125.00%. The test and reference formulations of miglitol were pharmacodynamically bioequivalent during the trial.

Blood glucose response after oral intake of lactulose in healthy volunteers: A randomized, controlled, cross-over study.

AIMTo investigate possible changes of blood glucose levels after oral intake of lactulose in healthy subjects.METHODSThe study was performed as prospective, randomized, two-part study with 4-way cross-over design with n = 12 in each study arm. Capillary blood glucose levels were determined over a time period of 180 min after intake of a single dose of 10 g or 20 g lactulose provided as crystal or liquid formulation. During the manufacturing process of lactulose, impurities with sugars (e.g., lactose, fructose, galactose) occur. Water and 20 g glucose were used as control and reference. Because lactulose is used as a functional food ingredient, it may also be consumed by people with impaired glucose tolerance, including diabetics. Therefore, it is of interest to determine whether the described carbohydrate impurities may increase blood glucose levels after ingestion.RESULTSThe blood glucose concentration-time curves after intake of 10 g lactulose, 20 g lactulose, and water were almost identical. None of the three applications showed any changes in blood glucose levels. After intake of 20 g glucose, blood glucose concentration increased by approximately 3 mmol/L (mean Cmax = 8.3 mmol/L), reaching maximum levels after approximately 30 min and returning to baseline within approximately 90 min, which was significantly different to the corresponding 20 g lactulose formulations (P < 0.0001). Comparing the two lactulose formulations, crystals and liquid, in the dosage of 10 g and 20 g, there was no difference in the blood glucose profile and calculated pharmacokinetic parameters despite the different amounts of carbohydrate impurities (1.5% for crystals and 26.45% for liquid). Anyhow, the absolute amount of single sugars was low with 0.3 g in crystals and 5.29 g in liquid formulation in the 20 g dosages. Lactulose was well tolerated by most volunteers, and only some reported mild to moderate mainly gastrointestinal side effects.CONCLUSIONThe unchanged blood glucose levels after lactulose intake in healthy subjects suggest its safe use in subjects with impaired glucose tolerance.

Effect of Food Thickener on the Inhibitory Effect of Mitiglinide Tablets on Post-prandial Elevation of Blood Glucose Levels.

The aim of this study was to examine the effect of food thickener on the pharmacodynamics of mitiglinide (MGN), a drug belonging to a class of rapid-acting insulin secretagogues. First, MGN tablets were coated by immersion in a xanthan gum-based food-thickening agent. This treatment was shown to delay disintegration rates of MGN tablets in vitro. The pharmacodynamics of MGN after ingestion of a single oral dose of an MGN tablet, with or without food thickener immersion, were then examined in an open-label crossover study comprising 5 healthy participants. It was observed that after administration of 75g of oral glucose, the area under the blood glucose concentration-time curve was larger for treatment with MGN tablets that had been immersed in the food thickener than for nonimmersed tablets. The maximum blood glucose level was also higher in treatments with MGN tablets that had been immersed in food thickener. The extended time of higher glucose levels associated with thickener-immersed MGN tablets given to human volunteers may be associated with the reduced disintegration rates of immersed MGN tablets as observed in the in vitro experiment. Overall, our study suggests that commercially available food thickeners influence the pharmacodynamics of MGN and that their use should therefore be carefully assessed and monitored in certain clinical situations.

Intake of kale suppresses postprandial increases in plasma glucose: A randomized, double-blind, placebo-controlled, crossover study.

Kale (Brassica oleracea var. acephala), a vegetable in the family Brassicaceae, has beneficial effects on health, including hypoglycemic effects. In our previous study with a limited number of subjects, intake of kale-containing food at a dose of 14 g decreased postprandial plasma glucose levels. In the present study, the effective dose of kale-containing food was investigated in a randomized, double-blind, placebo-controlled, crossover trial. The trial was conducted on 42 Japanese subjects aged 21-64 years with fasting plasma glucose levels of ≤125 mg/dl and 30-min postprandial plasma glucose levels of 140-187 mg/dl. The subjects consumed placebo or kale-containing food [7 or 14 g; low-dose (active-L) or high-dose (active-H) kale, respectively] together with a high-carbohydrate meal. At 30-120 min after the test meal intake, the plasma levels of glucose and insulin were determined. The postprandial plasma glucose levels in subjects with intake of active-L or active-H were significantly lower than those in subjects with intake of placebo, with the maximum plasma concentration (Cmax; 163±24 mg/dl for active-L and 162±23 mg/dl for active-H compared with 176±26 mg/dl for placebo [values presented as means ± standard deviation (SD); P<0.01]. The area under the plasma glucose concentration-time curve for 0-2 h (AUC0-2 h) values (means ± SD) were significantly lower for active-L (268±43 mg/h/dl) and active-H (266±42 mg/h/dl) than for the placebo (284±43 mg/h/dl; P<0.05). No significant differences were identified in the postprandial plasma insulin levels between the three conditions. No adverse events associated with intake of either dose of kale were observed. Our findings suggest that intake of kale suppresses postprandial increases in plasma glucose levels at a single dose of 7 g, and that a dose as high as 14 g is safe.

Effect of Methanolic Extract of Passiflora foetida on Glucose Kinetics in Alloxan-induced Diabetic Mice

Background: This study investigated the hypoglycemic potential of methanolic extract of Passiflora foetida (PF) in alloxan-induced diabetic albino mice. Diabetes is a metabolic disease characterized with high blood sugar levels over a prolonged period. Discovery of a new drug will greatly reduce the mortality and morbidity associated with the disease. Methods: Diabetes was induced in albino mice by administration of 150 mg/kg body weight (b.w.) alloxan. Different concentrations of the methanolic extract of PF was prepared and administered orally to groups of alloxan-induced diabetic mice. Blood glucose was determined at different time points over 4 hrs. Results: The extract reduced blood glucose levels in diabetic mice significantly (P<0.001) and the kinetic parameters such as, area under glucose concentration time curve (AUC 0-4hG ) (P<0.05), glucose mean residence time (MRT G), glucose t 1/2G were significantly lower (<0.05) in PF treated groups when compared with the control groups. The rate of glucose clearance (CL G) was high in the group treated with the extract. Conclusion: The results of this study indicate presence of hypoglycemic constituent in the plant. Original Research Article

Effect of Acarbose on Glycemic Variability in Patients with Poorly Controlled Type 2 Diabetes Mellitus Receiving Stable Background Therapy: A Placebo-Controlled Trial.

To evaluate the effect of acarbose on glycemic control and glycemic variability, using a continuous glucose-monitoring system, in patients with type 2 diabetes mellitus who were not well controlled on metformin and vildagliptin therapy. Multicenter, randomized, double-blind, placebo-controlled study. Clinical research units at three hospitals in Italy. Fifty-three patients with type 2 diabetes who were taking stable dosages of metformin 850 mg 3 times/day and vildagliptin 50 mg twice/day for at least 3 months and who were not adequately controlled with these therapies. Patients were randomized to either placebo or acarbose 100 mg 3 times/day to be added to their metformin-vildagliptin regimen. Glycemic excursions were assessed by using a continuous glucose-monitoring system for 1 week. Glycemic control was estimated as the mean blood glucose (MBG) level, the area under the glucose concentration-time curve for a glucose level above 70 mg/dl (AUC above 70) or 180 mg/dl (AUC above 180), and the percentage of time that the glucose level was above 70 mg/dl (T above 70) or 180 mg/dl (T above 180). Intraday glycemic variability was assessed by the standard deviation of the blood glucose level, the mean amplitude of glycemic excursions (MAGE), the M value, and continuous overlapping net glycemic action. Day-to-day glycemic variability was assessed as the mean of daily difference (MODD). The MBG level was ~20 mg/dl lower in the acarbose group than in the placebo group (p<0.05), particularly during the postprandial period. The AUC above 70 did not significantly differ between the two groups, whereas the AUC above 180 was ~40% lower in the acarbose group than in the placebo group during the daytime (p<0.01). The T above 180 was significantly higher in the placebo group than in the acarbose group (31% vs 8%, p<0.01. Moreover, the standard deviation and MAGE values were significantly lower in the acarbose group. The MODD value was not significantly changed in either group, and no significant differences were recorded between groups. All adverse events were mild in both groups, with only a significantly greater frequency of flatulence noted in the acarbose group (5% with acarbose vs 0.5% with placebo, p<0.05). The addition of acarbose to metformin and vildagliptin background therapy in patients with inadequately controlled type 2 diabetes decreased intraday glycemic variability, especially postprandial variability, but it was not associated with a significant change in interday glycemic variability.

Insulin resistance and β-cell function influence postprandial blood glucose levels in Japanese patients with gestational diabetes mellitus

Aims/introduction: The aim of this study in patients with gestational diabetes mellitus (GDM) was to evaluate the relationship of insulin resistance and secretion to area-under-the-sensor glucose concentration–time curve from before to 120 min postmeal (CGM-AUC0–120 min) as determined with continuous glucose monitoring (CGM).Materials and methods: Immunoreactive insulin and HbA1c were determined in 22 Japanese patients with GDM undergoing a 75 g oral glucose tolerance test. Patients underwent CGM within 3 weeks of receiving a diagnosis of GDM.Results: HbA1c (NGSP) was 5.5 ± 0.4%, BMI was 24.8 ± 5.3 kg/m2, mean sensor glucose by CGM was 94.2 ± 10.3 mg/dL, standard deviation was 17.5 ± 4.4 mg/dL, and CGM-AUC0–120 min was 204.2 ± 23.8 h mg/dL. The insulin resistance indices the homeostasis model assessment ratio (HOMA-R), quantitative insulin sensitivity check index (QUICKI), and the Matsuda Index were correlated with CGM-AUC0–120 min. The disposition index (DI), which was used to evaluate insulin secretion, was negatively correlated with CGM-AUC0–120 min.Conclusions: Not only insulin resistance but also beta cell dysfunction contributes to postprandial hyperglycemia in Japanese patients with GDM.

Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin.

Metformin, the most widely prescribed antidiabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney, and peripheral tissues. Organic cation transporter 3 (OCT3, SLC22A3), expressed ubiquitously, transports metformin, but its in vivo role in metformin response is not known. Using Oct3 knockout mice, the role of the transporter in metformin pharmacokinetics and pharmacodynamics was determined. After an intravenous dose of metformin, a 2-fold decrease in the apparent volume of distribution and clearance was observed in knockout compared with wild-type mice (P < 0.001), indicating an important role of OCT3 in tissue distribution and elimination of the drug. After oral doses, a significantly lower bioavailability was observed in knockout compared with wild-type mice (0.27 versus 0.58, P < 0.001). Importantly, metformin's effect on the plasma glucose concentration-time curve was reduced in knockout compared with wild-type mice (12 versus 30% reduction, respectively, P < 0.05) along with its accumulation in skeletal muscle and adipose tissue (P < 0.05). Furthermore, the effect of metformin on phosphorylation of AMP activated protein kinase, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3(-/-) mice. Additional analysis revealed that an OCT3 3' untranslated region variant was associated with reduced activity in luciferase assays and reduced response to metformin in 57 healthy volunteers. These findings suggest that OCT3 plays an important role in the absorption and elimination of metformin and that the transporter is a critical determinant of metformin bioavailability, clearance, and pharmacologic action.

Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study.

BackgroundThis study evaluated the effect of empagliflozin on postprandial glucose (PPG) and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus (T2DM).MethodsPatients (N = 60; baseline mean [SD] HbA1c 7.91 [0.80]%; body mass index 24.3 [3.2] kg/m2) were randomized to receive empagliflozin 10 mg (n = 20), empagliflozin 25 mg (n = 19) or placebo (n = 21) once daily as monotherapy for 28 days. A meal tolerance test and continuous glucose monitoring (CGM) for 24 hours were performed at baseline and on days 1 and 28. The primary endpoint was change from baseline in area under the glucose concentration-time curve 3 hours after breakfast (AUC1–4h for PPG) at day 28.ResultsAdjusted mean (95%) differences versus placebo in changes from baseline in AUC1-4h for PPG at day 1 were −97.1 (−126.5, −67.8) mg · h/dl with empagliflozin 10 mg and −91.6 (−120.4, −62.8) mg · h/dl with empagliflozin 25 mg (both p < 0.001 versus placebo) and at day 28 were −85.5 (−126.0, −45.0) mg · h/dl with empagliflozin 10 mg and −104.9 (−144.8, −65.0) mg · h/dl with empagliflozin 25 mg (both p < 0.001 versus placebo). Adjusted mean (95% CI) differences versus placebo in change from baseline in 24-hour mean glucose (CGM) at day 1 were −20.8 (−27.0, −14.7) mg/dl with empagliflozin 10 mg and −23.9 (−30.0, −17.9) mg/dl with empagliflozin 25 mg (both p < 0.001 versus placebo) and at day 28 were −24.5 (−35.4, −13.6) mg/dl with empagliflozin 10 mg and −31.7 (−42.5,-20.9) mg/dl with empagliflozin 25 mg (both p < 0.001 versus placebo). Changes from baseline in mean amplitude of glucose excursions (MAGE; CGM) were not significantly different with either empagliflozin dose versus placebo at either timepoint. Curves of mean glucose (CGM) did not change between baseline and day 1 or 28 with placebo, but shifted downward with empagliflozin. Percentage of time with glucose ≥70 to <180 mg/dl increased from 52.0% at baseline to 77.0% at day 28 with empagliflozin 10 mg and from 55.0% to 81.1% with empagliflozin 25 mg, without increasing time spent with hypoglycemia.ConclusionEmpagliflozin for 28 days reduced PPG from the first day and improved daily blood glucose control in Japanese patients with T2DM.Trial registrationClinicaltrials.gov NCT01947855Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-014-0169-9) contains supplementary material, which is available to authorized users.

Verapamil decreases the glucose-lowering effect of metformin in healthy volunteers.

The organic cation transporter 1 (OCT1) plays a key role in the cellular transport of metformin and its subsequent glucose-lowering effect. A recent non-clinical study reported that metformin uptake into hepatocytes is regulated via OCT1, and that uptake was strongly inhibited by verapamil. Therefore, we investigated the effects of verapamil co-administration on the pharmacokinetics and pharmacodynamics of metformin in humans. We evaluated the pharmacokinetics and the anti-hyperglycaemic effects of metformin using an oral glucose tolerance test (OGTT) in 12 healthy participants, before (day 1) and after metformin treatment (day 2), and again on days 15 and 16 after co-administration with verapamil. Verapamil inhibited the ability of metformin to reduce maximum blood glucose concentrations (ΔGmax ) by 62.5% (P = 0.008) and decreased the area under the glucose concentration-time curve (ΔAUCgluc ) by 238% (P = 0.015). However, verapamil did not significantly alter the Cmax and the AUC of metformin, nor its renal clearance. Our results suggest that verapamil remarkably decreases the glucose-lowering effect of metformin, possibly by acting as a competitive inhibitor of OCT1.

Hypoglyceamic Effect of Methanolic Extract of Pergularia daemia in Alloxan-Induced Diabetic Mice

Objective:&nbsp;The aim of the present study was to investigate the antidiabetic potential of&nbsp;Pergularia daemiamethanolic extract (PD) on alloxan-induced diabetic mice.Methods:&nbsp;Diabetes was induced using alloxan (150mg/kg). Different doses of the methanolic extract of&nbsp;P. daemia&nbsp;were prepared and administered orally. The alloxan-induced diabetic mice were treated with 200, 400 and 1000 mg/kg body weight (b.w.) methanolic extract of&nbsp;Pergularia daemia&nbsp;and the blood glucose levels were measured over 4 hrs.Results:&nbsp;All doses of the extract (200, 400 and 1000 mg/kg b.w) significantly (p&lt;0.0001) lowered fasting blood glucose level after treatment. The hypoglycaemic effect of the methanolic extract was also compared with that of an oral dose of glibenclamide under the same conditions. The extract showed significant (p&lt;0.05) hypoglycemic effect in alloxan-induced diabetic mice. The glucose half-life (t1/2G) (p&lt;0.0001), Mean Glucose Residence Time (MRTG) (p&lt;0.0001), and the area under glucose concentration time curve (AUC0-4hG) (p&lt;0.05) were high in control group compared to the alloxan-induced mice treated with&nbsp;P. daemia&nbsp;extract.Conclusion:&nbsp;The results of this study indicate that methanolic extract of the plant of&nbsp;Pegularia daemiapossess hypoglycaemic activity.

The 5-time point oral glucose tolerance test as a predictor of new-onset diabetes after kidney transplantation

AimsTo evaluate the predictive power of the 5-time point oral glucose tolerance test (OGTT) for new-onset diabetes after kidney transplantation (NODAT). MethodsWe performed a retrospective study of 145 patients without diabetes who received kidney transplantations at our hospital. The 5-time point OGTT was performed before transplantation. The area under a receiver-operating characteristic curve (aROC) was used for evaluating the predictive power of 5-time point OGTT values. ResultsSeventeen patients developed NODAT within 1 year after transplantation. All postload plasma glucose (PPG) levels were higher in patients who developed NODAT than in those who did not; fasting plasma glucose levels were not different. The aROC for the area under the glucose concentration-time curve was significantly greater than that for fasting plasma glucose. Univariate and multivariate analyses showed that each PPG level was an independent risk factor for NODAT. Furthermore, patients with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) could be stratified with a 1-h plasma glucose (1h-PG) cut-off point of 8.4mmol/L. The incidences of NODAT were 23.5%, 16.7%, 9.1%, and 0% for patients with IGT+1h-PG ≥8.4mmol/L,IGT+1h-PG <8.4mmol/L, NGT+1h-PG ≥ 8.4mmol/L, and NGT+1h-PG<8.4mmol/L, respectively. ConclusionsThe area under the glucose concentration-time curve and each PPG concentration during the 5-time point OGTT are strong predictors of NODAT. A 1h-PG cut-off point of 8.4mmol/L plus NGT/IGT can be used to identify patients at intermediate and high risk of developing NODAT.

A Pilot Study to Examine the Tolerability and Device Preference in Type 1 Diabetes of Insulin Aspart Administered by InsuJet Compared with Subcutaneous Injection

Jet injectors allow needle-free insulin delivery. The study objective was to compare the tolerability and device preference of subcutaneous insulin aspart delivery by jet injector (InsuJet™; European Pharma Group, Schiphol-Rijk, The Netherlands) with pen injection in an open-label, randomized, crossover pilot study. Ten participants with type 1 diabetes underwent two meal tolerance tests 1 week apart. Plasma glucose and serum insulin levels were sampled from 10 min preceding to 240 min after insulin aspart administration by InsuJet or FlexPen(®) (Novo Nordisk Pharmaceuticals Pty. Ltd., Baulkham Hills, NSW, Australia). Insulin dose was calculated using participants' insulin-to-carbohydrate ratios. Immediately after insulin administration, participants drank 500 mL of Ensure(®) (Abbott Australasia Pty. Ltd., Botany, NSW, Australia) (providing 2,240 kJ of energy, 18.6 g of protein, 96 g of carbohydrate, and 3 g of fat). In this small pilot study, the devices were similar in glucose excursion (median [quartile 1, quartile 3], InsuJet vs. FlexPen, 9.4 [4.8, 12.8] vs. 8.1 [5.4, 10.6] mmol/L; P=0.43), in the area under the glucose concentration-time curve for 0-240 min corrected for baseline glucose level (InsuJet vs. FlexPen, 1,230 [623, 2,012] vs. 1,175 [91, 1,774] mmol · min/L; P=0.4), and in insulin absorption over the 240-min period. Devices were similar for participant preference and relative injection pain. Subcutaneous jet injection of aspart insulin was well tolerated.

The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects

Gastro-esophageal reflux disease is common in patients with type 2 diabetes. A common treatment is the co-administration of proton-pump inhibitors (PPIs) and metformin. To date, however, the effects of co-administration of PPIs, which inhibit organic cation transporter (OCT) activity, on the action of metformin (a well-known substrate of OCTs) have not been clearly demonstrated. This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 20) received metformin (single dose 1,000 mg on day 1 and single dose 750 mg on day 2, with a 12-h interval) co-administered with placebo or with lansoprazole (30 mg). Plasma concentrations of metformin were measured up to 24 h after the second dose. The glucose-lowering effects of metformin were evaluated by the oral glucose tolerance test before and after each single dose of metformin within the 2-day period. Lansoprazole increased the mean metformin maximum plasma concentration and area under the plasma concentration-time curve from zero to 24 h after the second dosing by 15 and 17 %, respectively (P < 0.05). Moreover, lansoprazole prolonged the metformin elimination half-life from 3.9 to 4.5 h and decreased its renal clearance by 13 % (P < 0.05). However, lansoprazole had no effect on the maximum glucose level and the area under the serum glucose concentration-time curve of metformin. Collectively, we found a modest pharmacokinetic drug interaction between lansoprazole and metformin, which suggests that the concomitant use of these drugs should be appropriately monitored. Further studies are warranted to assess changes in metformin pharmacokinetics in patients with diabetes receiving long-term lansoprazole therapy.

A Placebo-Controlled, Single and Multiple Dose Study to Investigate the Appropriate Parameters for Evaluation of Pharmacodynamic Equivalence of Voglibose in Healthy Korean Volunteers

Background: Voglibose is an α-glucosidase inhibitor. The purpose of this study was to evaluate the pharmacodynamic characteristics of voglibose for determining the appropriate study design and parameters for a pharmacodynamic equivalence study of voglibose. Methods: This study consisted of two studies. The single dose study had an open and single sequence design. Nineteen subjects received placebo and then one tablet of voglibose on two consecutive days with sucrose. The multiple dose study was performed with the similar design, except that it was a multiple dose of the single dose study. Nine subjects who showed an effective response in the single dose study received placebo three times and then voglibose 4 times on two consecutive days. Serial blood samples for pharmacodynamic parameters were taken until 180 mins after each administration. The baseline adjusted maximum serum glucose level (Gmax) and area under the serum glucose level-time profiles were determined and compared. Results: In the single dose study, the difference in Gmax was -10.6 ± 28.7 mg/dL. The area under the serum glucose concentration-time curve (AUGC0-1h) of placebo and voglibose were 7825.0 ± 1145.3 mg? min/dL, 7907.5 ± 917.2 mg?min/dL, respectively. In the multiple dose study, the difference in Gmax was 46.6 ± 16.1 mg/dL. The AUGC0-1h of placebo and voglibose were 8138.6 ± 721.9 mg?min/dL and 6499.7 ± 447.2 mg?min/dL, respectively. The Gmax and AUGC0-1h of the multiple dose study was significantly different between placebo and voglibose in paired t-test. Conclusion: The differences in Gmax and AUGC0-1h are suitable for pharmacodynamic parameters to evaluate bioequivalence of voglibose.

Effectiveness of sensor-augmented pump therapy in children and adolescents with type 1 diabetes in the STAR 3 study

Maintenance of appropriate A1C values and minimization of hyperglycemic excursions are difficult for many pediatric patients with type 1 diabetes. Continuous glucose monitoring (CGM) sensor-augmented pump (SAP) therapy is an alternative to multiple daily injection (MDI) therapy in this population. Sensor-augmented pump therapy for A1C reduction (STAR 3) was a 1-yr trial that included 82 children (aged 7-12) and 74 adolescents (aged 13-18) with A1C values ranging from 7.4 to 9.5% who were randomized to either SAP or MDI therapy. Quarterly A1C values were obtained from all subjects. CGM studies were carried out at baseline, 6 months, and 12 months to quantify glycemic excursions [calculated as area under the glucose concentration-time curve (AUC)] and variability. In the SAP group, sensor compliance was recorded. Baseline A1C values were similar in subjects randomized to the SAP (8.26 ± 0.55%) and MDI groups (8.30 ± 0.53%). All subsequent A1C values showed significant (p < 0.05) treatment group differences favoring SAP therapy. Compared with the MDI group, subjects in the SAP group were more likely to meet age-specific A1C targets and had lower AUC values for hyperglycemia with no increased risk of hypoglycemia. Glucose variability improved in the SAP group compared to the MDI group. Children wore CGM sensors more often and were more likely to reach age-specific A1C targets than adolescents. SAP therapy allows both children and adolescents with marginally or inadequately controlled type 1 diabetes to reduce A1C values, hyperglycemic excursions, and glycemic variability in a rapid, sustainable, and safe manner.

Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart prior to a standard meal in obese subjects with type 2 diabetes

Aims: A multinational, randomized, double-blind, two-way crossover trial to compare the pharmacokinetic and pharmacodynamic properties of bolus, subcutaneously administered insulin glulisine (glulisine) and insulin aspart (aspart) in insulin-naÏve, obese subjects with type 2 diabetes.Methods: Thirty subjects [9/21 females/males; mean ± SD age: 60.7 ± 7.7 years; body mass index (BMI): 33.5 ± 3.3 kg/m2; duration of diabetes: 6.8 ± 4.6 years; HbA1c: 7.1 ± 0.8%] were included in the analysis. They fasted overnight and then received a 0.2 U/kg subcutaneous dose of glulisine or aspart 2 min before starting a standardized test meal, 7 days apart, according to a randomization schedule. Blood samples were taken every 15 min, starting 20 min before the meal and ending 6 h postprandially.Results: The area under the absolute glucose concentration–time curve between 0 and 1 h after insulin injection and maximal glucose concentration was significantly lower with glulisine than with aspart (p = 0.0455 and 0.0337, respectively). However, for the total study period, plasma glucose concentration was similar for glulisine and aspart. Peak insulin concentration was significantly higher for glulisine than for insulin aspart (p < 0.0001). Hypoglycaemic events (≤ 70 mg/dl with or without symptoms) occurred in 13 and 16 subjects treated with glulisine and aspart, respectively, but there were no cases of severe hypoglycaemia requiring intervention.Conclusions: Glulisine was associated with lower glucose levels during the first hour after a standard meal; the remaining glucose profiles were otherwise equivalent, with higher insulin levels observed throughout the study period.

Amyloglucosidase enzymatic reactivity inside lipid vesicles

Efficient functioning of enzymes inside liposomes would open new avenues for applications in biocatalysis and bioanalytical tools. In this study, the entrapment of amyloglucosidase (AMG) (EC 3.2.1.3) from Aspergillus niger into dipalmitoylphosphatidylcholine (DPPC) multilamellar vesicles (MLVs) and large unilamellar vesicles (LUVs) was investigated. Negative-stain, freeze-fracture, and cryo-transmission electron microscopy images verified vesicle formation in the presence of AMG. Vesicles with entrapped AMG were isolated from the solution by centrifugation, and vesicle lamellarity was identified using fluorescence laser confocal microscopy. The kinetics of starch hydrolysis by AMG was modeled for two different systems, free enzyme in aqueous solution and entrapped enzyme within vesicles in aqueous suspension. For the free enzyme system, intrinsic kinetics were described by a Michaelis-Menten kinetic model with product inhibition. The kinetic constants, Vmax and Km, were determined by initial velocity measurements, and Ki was obtained by fitting the model to experimental data of glucose concentration-time curves. Predicted concentration-time curves using these kinetic constants were in good agreement with experimental measurements. In the case of the vesicles, the time-dependence of product (glucose) formation was experimentally determined and simulated by considering the kinetic behavior of the enzyme and the permeation of substrate into the vesicle. Experimental results demonstrated that entrapped enzymes were much more stable than free enyzme. The entrapped enzyme could be recycled with retention of 60% activity after 3 cycles. These methodologies can be useful in evaluating other liposomal catalysis operations.