Effects of Fructose or Glucose on Circulating ApoCIII and Triglyceride and Cholesterol Content of Lipoprotein Subfractions in Humans.

ApoCIII and triglyceride (TG)-rich lipoproteins (TRL), particularly, large TG-rich lipoproteins particles, have been described as important mediators of cardiovascular disease (CVD) risk. The effects of sustained consumption of dietary fructose compared with those of sustained glucose consumption on circulating apoCIII and large TRL particles have not been reported. We measured apoCIII concentrations and the TG and cholesterol content of lipoprotein subfractions separated by size in fasting and postprandial plasma collected from men and women (age: 54 ± 8 years) before and after they consumed glucose- or fructose-sweetened beverages for 10 weeks. The subjects consuming fructose exhibited higher fasting and postprandial plasma apoCIII concentrations than the subjects consuming glucose (p < 0.05 for both). They also had higher concentrations of postprandial TG in all TRL subfractions (p < 0.05, effect of sugar), with the highest increases occurring in the largest TRL particles (p < 0.0001 for fructose linear trend). Compared to glucose consumption, fructose consumption increased postprandial TG in low-density lipoprotein (LDL) particles (p < 0.05, effect of sugar), especially in the smaller particles (p < 0.0001 for fructose linear trend). The increases of both postprandial apoCIII and TG in large TRL subfractions were associated with fructose-induced increases of fasting cholesterol in the smaller LDL particles. In conclusion, 10 weeks of fructose consumption increased the circulating apoCIII and postprandial concentrations of large TRL particles compared with glucose consumption.

Interaction Between the Sodium-Glucose-Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects.

BACKGROUND: Dapagliflozin inhibits the sodium-glucose-linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium-glucose-linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide. METHODS AND RESULTS: Healthy subjects (n=42) receiving a fixed diet with ≈110 mmol·d-1 of Na+ were randomized to bumetanide (1 mg·d-1), dapagliflozin (10 mg·d-1), or both for 7 days, followed by 7 days of both. There were no meaningful pharmacokinetic interactions. Na+ excretion increased modestly with the first dose of dapagliflozin (22±6 mmol·d-1; P<0.005) but by more (P<0.005) with the first dose of bumetanide (74±7 mmol·d-1; P<0.005), which was not significantly different from both diuretics together (80±5 mmol·d-1; P<0.005). However, Na+ excretion with dapagliflozin was 190% greater (P<0.005) when added after 1 week of bumetanide (64±6 mmol·d-1), and Na+ excretion with bumetanide was 36% greater (P<0.005) when added after 1 week of dapagliflozin (101±8 mmol·d-1). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy (P<0.05). CONCLUSIONS: First-dose Na+ excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na+ excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide-induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00930865.

Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial.

BACKGROUND: Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. METHODS: DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18-75 years and had inadequately controlled type 1 diabetes (HbA1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. FINDINGS: Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1c was 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA1c compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was -0·42% [95% CI -0·56 to -0·28; p<0·0001] and for dapagliflozin 10 mg vs placebo was -0·45% [-0·58 to -0·31; p<0·0001]). Among patients in the dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260) groups, the most common adverse events were nasopharyngitis (38 [14%] vs 36 [12%] vs 39 [15%]), urinary tract infection (19 [7%] vs 11 [4%] vs 13 [5%]), upper respiratory tract infection (15 [5%] vs 15 [5%] vs 11 [4%]), and headache (12 [4%] vs 17 [6%] vs 11 [4%]). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the dapagliflozin 5 mg group, five (2%) in the dapagliflozin 10 mg group, and three (1%) in the placebo group. INTERPRETATION: Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes. FUNDING: AstraZeneca and Bristol-Myers Squibb.

Bioequivalence and food effect of heat-stressed and non-heat-stressed dapagliflozin 2.5- and 10-mg tablets.

Physical storage of formulations may result in physical composition changes that affect pharmacokinetics. Dapagliflozin, an oral sodium-glucose cotransporter 2 inhibitor used for type 2 diabetes mellitus, stored under prolonged exposure to heat converts crystalline dapagliflozin to an amorphous form. Bioequivalence of the amorphous to crystalline form and food effects of each form in the 2.5-mg formulation are unknown. Two open-label, crossover, single-dose studies in healthy participants assessed pharmacokinetics for heat-stressed (HS) and non-heat-stressed (NH) dapagliflozin 10-mg (study 1, N=29, fasted+HS food effect) and 2.5-mg (study 2, N=28, fasted+HS and NH food effect) tablets. The 90% confidence intervals for geometric mean ratios of area under the concentration-time curve (AUC) and peak concentration (Cmax) for HS 2.5- and 10-mg tablets were within 80-125%, indicating bioequivalence. In the fed vs. fasted state for 2.5-mg and 10-mg HS tablets, AUCs were similar, time to Cmax was prolonged by 1.25h, and Cmax decreased by approximately 50%. No serious adverse events were reported. Given that dapagliflozin's efficacy is dependent upon AUC, it was concluded that HS and NH dapagliflozin tablets are bioequivalent in 2.5- and 10-mg doses with no clinically meaningful food effect for either form.

Outcome Measures for Artificial Pancreas Clinical Trials: A Consensus Report.

Research on and commercial development of the artificial pancreas (AP) continue to progress rapidly, and the AP promises to become a part of clinical care. In this report, members of the JDRF Artificial Pancreas Project Consortium in collaboration with the wider AP community 1) advocate for the use of continuous glucose monitoring glucose metrics as outcome measures in AP trials, in addition to HbA1c, and 2) identify a short set of basic, easily interpreted outcome measures to be reported in AP studies whenever feasible. Consensus on a broader range of measures remains challenging; therefore, reporting of additional metrics is encouraged as appropriate for individual AP studies or study groups. Greater consistency in reporting of basic outcome measures may facilitate the interpretation of study results by investigators, regulatory bodies, health care providers, payers, and patients themselves, thereby accelerating the widespread adoption of AP technology to improve the lives of people with type 1 diabetes.

Fed and Fasted Single-dose Assessment of Bioequivalence of Dapagliflozin and Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects.

PURPOSE: In patients with type 2 diabetes mellitus, fixed-dose combinations (FDCs) of antihyperglycemic medications may provide complementary efficacy while reducing tablet burden and improving compliance. The aim of this study was to assess the bioequivalence and tolerability of 2 FDCs of dapagliflozin and metformin extended-release (XR) versus their individual component (IC) tablets. METHODS: An open-label, balanced, randomized, 2-way crossover, 4-arm study was conducted in 129 healthy Brazilian subjects (aged 18-55 years). Two oral doses of the FDCs (5 mg dapagliflozin and 500 mg metformin XR, and 10 mg dapagliflozin and 1000 mg metformin XR) were evaluated in fed and fasted states. FINDINGS: Under fed and fasted conditions the 5 mg dapagliflozin and 500 mg metformin XR FDC showed bioequivalence to its ICs. The 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent to its ICs in fed subjects. Although AUC for the 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent in fasted subjects, the Cmax for metformin was not bioequivalent to its ICs in fasted subjects (upper 90% CI was 127.5%, and thus outside the 80%-125% bioequivalence interval). The small increase in the fasted state is not considered clinically meaningful due to the small magnitude of the difference (9.2%), the lack of metformin Cmax being associated with efficacy or tolerability concerns, and the fasted state not being the recommended state for dosing of metformin XR. The safety profile and tolerability of the FDCs were similar to those of their ICs and no deaths or serious adverse events were reported. IMPLICATIONS: Both FDCs of dapagliflozin and metformin XR were bioequivalent to their ICs in fed and fasted subjects, except for the metformin Cmax from the 10 mg dapagliflozin and 1000 mg metformin XR FDC in fasted subjects. These data support the use of a dapagliflozin and metformin XR FDC in patients with type 2 diabetes mellitus.

Bioequivalence, Food Effect, and Steady-State Assessment of Dapagliflozin/Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects.

PURPOSE: Simplification of therapeutic regimens for patients with type 2 diabetes mellitus can provide convenience that leads to improved compliance. Dapagliflozin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the convenience of once-daily dosing. Two pharmacokinetic (PK) studies were conducted to establish bioequivalence for 2 doses of dapagliflozin/metformin XR FDC versus the same dosage of the individual component (IC) tablets in healthy adults. METHODS: Two open-label, randomized, 4-period, 4-arm crossover studies were conducted to assess the bioequivalence and PK properties of dapagliflozin and metformin FDCs in healthy subjects under fed and fasting conditions. Participants received single oral doses or once-daily dosing of dapagliflozin/metformin XR (5 mg/500 mg [study 1] or 10 mg/1000 mg [study 2]) for 4 days in an FDC formulation or corresponding strengths of IC tablets. FINDINGS: For both of the studies, dapagliflozin and metformin 5 mg/500 mg or 10 mg/1000 mg FDC tablets were bioequivalent to the respective IC tablets. The 90% CIs of the ratio of the adjusted geometric means for all key PK parameters (Cmax, AUC0-T, and AUC0-∞) were contained within the predefined 0.80 to 1.25 range to conclude bioequivalence for both dapagliflozin and metformin. Once-daily dosing to steady state of each FDC tablet had no effect on the PK properties of dapagliflozin or metformin. When the FDCs were administered with a light-fat meal, there was no effect on metformin PK values and only a modest, nonclinically meaningful effect on dapagliflozin PK values. There were no safety or tolerability concerns. IMPLICATIONS: Bioequivalence of the FDCs of dapagliflozin/metformin XR and the ICs was established, and no safety issues of clinical concern were raised.

Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study.

OBJECTIVE: Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters. RESEARCH DESIGN AND METHODS: A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA1c 7-10%), who were receiving treatment with stable doses of insulin, to one of four dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons. RESULTS: Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0-92.3%); one major event of hypoglycemia occurred with dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with dapagliflozin 10 mg and decreased by -21.5 g/24 h (95% CI -53.9 to 11.0) with placebo. Changes from baseline with dapagliflozin 10 mg by day 7 were as follows: -2.29 mmol/L (95% CI -3.71 to -0.87 [-41.3 mg/dL; 95% CI -66.9 to -15.7]) for 24-h daily average blood glucose; -3.77 mmol/L (95% CI -6.09 to -1.45 [-63.1 mg/dL; 95% CI -111.5 to -14.8]) for mean amplitude of glycemic excursion; and -16.2% (95% CI -29.4 to -0.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: -1.13 mmol/L (95% CI -3.63 to 1.37), -0.45 mmol/L (95% CI -4.98 to 4.08), and 1.7% (95% CI -22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all dapagliflozin doses overlapped those for placebo. CONCLUSIONS: This exploratory study of dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the dapagliflozin groups, dose-related reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes.

Use of systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans.

In the kidney, glucose in glomerular filtrate is reabsorbed primarily by sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) along the proximal tubules. SGLT2 has been characterized as a high capacity, low affinity pathway responsible for reabsorption of the majority of filtered glucose in the early part of proximal tubules, and SGLT1 reabsorbs the residual glucose in the distal part. Inhibition of SGLT2 is a viable mechanism for removing glucose from the body and improving glycemic control in patients with diabetes. Despite demonstrating high levels (in excess of 80%) of inhibition of glucose transport by SGLT2 in vitro, potent SGLT2 inhibitors, e.g., dapagliflozin and canagliflozin, inhibit renal glucose reabsorption by only 30-50% in clinical studies. Hypotheses for this apparent paradox are mostly focused on the compensatory effect of SGLT1. The paradox has been explained and the role of SGLT1 demonstrated in the mouse, but direct data in humans are lacking. To further explore the roles of SGLT1/2 in renal glucose reabsorption in humans, we developed a systems pharmacology model with emphasis on SGLT1/2 mediated glucose reabsorption and the effects of SGLT2 inhibition. The model was calibrated using robust clinical data in the absence or presence of dapagliflozin (DeFronzo et al., 2013), and evaluated against clinical data from the literature (Mogensen, 1971; Wolf et al., 2009; Polidori et al., 2013). The model adequately described all four data sets. Simulations using the model clarified the operating characteristics of SGLT1/2 in humans in the healthy and diabetic state with or without SGLT2 inhibition. The modeling and simulations support our proposition that the apparent moderate, 30-50% inhibition of renal glucose reabsorption observed with potent SGLT2 inhibitors is a combined result of two physiological determinants: SGLT1 compensation and residual SGLT2 activity. This model will enable in silico inferences and predictions related to SGLT1/2 modulation.

Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2.

Sodium-glucose co-transporter 2 (SGLT2) is predominantly expressed in the S1 segment of the proximal tubule of the kidney and is the major transporter responsible for mediating renal glucose reabsorption. Dapagliflozin is an orally active, highly selective SGLT2 inhibitor that improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption leading to urinary glucose excretion (glucuresis). Orally administered dapagliflozin is rapidly absorbed generally achieving peak plasma concentrations within 2 h. Dose-proportional systemic exposure to dapagliflozin has been observed over a wide dose range (0.1-500 mg) with an oral bioavailability of 78 %. Dapagliflozin has extensive extravascular distribution (mean volume of distribution of 118 L). Dapagliflozin metabolism occurs predominantly in the liver and kidneys by uridine diphosphate-glucuronosyltransferase-1A9 to the major metabolite dapagliflozin 3-O-glucuronide (this metabolite is not an SGLT2 inhibitor at clinically relevant exposures). Dapagliflozin is not appreciably cleared by renal excretion (<2 % of dose is recovered in urine as parent). Dapagliflozin 3-O-glucuronide elimination occurs mainly via renal excretion, with 61 % of a dapagliflozin dose being recovered as this metabolite in urine. The half-life for orally administered dapagliflozin 10 mg was 12.9 h. Maximal increases in urinary glucose excretion were seen at doses ≥20 mg/day in patients with T2DM. No clinically relevant differences were observed in dapagliflozin exposure with respect to age, race, sex, body weight, food, or presence of T2DM. Pharmacodynamic changes are dependent on plasma glucose and renal function, and decreases in urinary glucose excretion were observed due to the lower filtered load (plasma glucose × glomerular filtration rate) in healthy volunteers compared to subjects with T2DM. After multiple doses of dapagliflozin, urinary glucose excretion was associated with dose-related decreases in plasma glucose parameters in subjects with T2DM. Patients with severe renal or hepatic impairment show higher systemic exposure to dapagliflozin. No clinically relevant drug interactions were observed that would necessitate dose adjustment of dapagliflozin when administered with other antidiabetic or cardiovascular medications, as well as drugs that could potentially influence dapagliflozin metabolism.

Pharmacokinetic and pharmacodynamic properties of single- and multiple-dose of dapagliflozin, a selective inhibitor of SGLT2, in healthy Chinese subjects.

BACKGROUND: Dapagliflozin, a selective, orally active, renal sodium glucose cotransporter 2 (SGLT2) 2 inhibitor, is under investigation as a treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin reduces hyperglycemia by inhibiting renal glucose reabsorption and dose-dependently increasing urinary glucose excretion, independent of insulin secretion or action. OBJECTIVES: These studies assessed the single- and multiple-dose pharmacokinetic and pharmaco dynamic properties of dapagliflozin and its major inactive metabolite, dapagliflozin 3-O-glucuronide (D3OG), in healthy subjects residing in China. METHODS: In 2 identically designed, open-label, single- and multiple-dose studies (n = 14 for both studies), healthy Chinese subjects were administered oral dapagliflozin 5 or 10 mg. In both studies, subjects received a single dose on day 1 (single-dose administration period) followed by 6 once-daily doses on days 5 to 10 (multiple-dose administration period). Pharmacokinetic parameters (plasma and urinary dapagliflozin and D3OG), pharmacodynamic response (urinary glucose excretion), and tolerability were assessed. RESULTS: Fourteen subjects completed the dapagliflozin 5-mg study, and 13 completed the dapagliflozin 10-mg study. Baseline characteristics were balanced across the two studies: 9 versus 10 men; mean age, 27.1 versus 28.9 years; mean weight, 62.8 versus 62.2 kg; and mean body mass index, 23.0 versus 22.2 kg/m(2) in the dapagliflozin 5- and 10-mg studies, respectively. In both doses, dapagliflozin was rapidly absorbed (T(max), ≤1.5 h), accumulation (defined as the geometric mean ratio of AUC(τ) at day 10 to AUC(τ) at day 1) after multiple dosing was minimal (<1.13 fold), and elimination half-life was 10 to 12 h. D3OG showed a slightly longer median Tmax (≤2 h) but a similar plasma concentration-time profile and half-life compared with dapagliflozin. The majority of D3OG (up to 69.7% of the dapagliflozin dose) was excreted in urine, while ≤1.9% of dapagliflozin was excreted unchanged in urine. Over a 24-hour period and at steady state (day 10), urinary glucose excretion values were 28.1 and 41.1 g with dapagliflozin 5 and 10 mg, respectively. Dapagliflozin was generally well tolerated; one dapagliflozin 10 mg-treated subject discontinued the study because of a serious adverse event (bronchitis) considered by the investigator as unrelated to dapagliflozin dosing. CONCLUSIONS: Pharmacokinetic and pharmacodynamic characteristics following single- and multiple-dose dapagliflozin 5 and 10 mg oral administration in healthy Chinese subjects were as predicted from previous studies and were similar to findings observed in non-Chinese healthy subjects. Dapagliflozin dosing was well tolerated. The clinically recommended dapagliflozin dose of 10 mg once daily is expected to be appropriate in patients of Chinese ethnicity; results from an efficacy and tolerability study in Chinese patients with T2DM are awaited.

Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes.

OBJECTIVE: To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. RESEARCH DESIGN AND METHODS: Subjects with type 2 diabetes (n=12) and matched healthy subjects (n=12) underwent pancreatic/SHC (plasma glucose range 5.5-30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves. RESULTS: At baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects. CONCLUSIONS: The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.

Effects of sugar-sweetened beverages on plasma acylation stimulating protein, leptin and adiponectin: relationships with metabolic outcomes.

OBJECTIVE: The effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity were determined. DESIGN AND METHODS: Thirty two overweight/obese adults consumed glucose- or fructose-sweetened beverages (25% energy requirement) with their ad libitum diets for 8 weeks, followed by sweetened beverage consumption for 2 weeks with a standardized, energy-balanced diet. Plasma variables were measured at baseline, 2, 8, and 10 weeks, and body adiposity and insulin sensitivity at baseline and 10 weeks. RESULTS: Fasting and postprandial ASP concentrations increased at 2 and/or 8 weeks. ASP increases correlated with changes in late-evening triglyceride concentrations. At 10 weeks, fasting adiponectin levels decreased in both groups, and decreases were inversely associated with baseline intra-abdominal fat volume. Sugar consumption increased fasting leptin concentrations; increases were associated with body weight changes. The 24-h leptin profiles increased during glucose consumption and decreased during fructose consumption. These changes correlated with changes of 24-h insulin levels. CONCLUSIONS: The consumption of fructose and glucose beverages induced changes in plasma concentrations of ASP, adiponectin, and leptin. Further study is required to determine if these changes contribute to the metabolic dysfunction observed during fructose consumption.

Consumption of fructose- but not glucose-sweetened beverages for 10 weeks increases circulating concentrations of uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese humans.

BACKGROUND: Prospective studies in humans examining the effects of fructose consumption on biological markers associated with the development of metabolic syndrome are lacking. Therefore we investigated the relative effects of 10 wks of fructose or glucose consumption on plasma uric acid and RBP-4 concentrations, as well as liver enzyme (AST, ALT, and GGT) activities in men and women. METHODS: As part of a parallel arm study, older (age 40-72), overweight and obese male and female subjects (BMI 25-35 kg/m2) consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 wks. Fasting and 24-h blood collections were performed at baseline and following 10 wks of intervention and plasma concentrations of uric acid, RBP-4 and liver enzyme activities were measured. RESULTS: Consumption of fructose, but not glucose, led to significant increases of 24-h uric acid profiles (P < 0.0001) and RBP-4 concentrations (P = 0.012), as well as plasma GGT activity (P = 0.04). Fasting plasma uric acid concentrations increased in both groups; however, the response was significantly greater in subjects consuming fructose (P = 0.002 for effect of sugar). Within the fructose group male subjects exhibited larger increases of RBP-4 levels than women (P = 0.024). CONCLUSIONS: These findings suggest that consumption of fructose at 25% of energy requirements for 10 wks, compared with isocaloric consumption of glucose, may contribute to the development of components of the metabolic syndrome by increasing circulating uric acid, GGT activity, suggesting alteration of hepatic function, and the production of RBP-4.

Lack of pharmacokinetic interactions between dapagliflozin and simvastatin, valsartan, warfarin, or digoxin.

INTRODUCTION: Coronary heart disease, stroke, and peripheral vascular disease are the most common causes of mortality in patients with type 2 diabetes mellitus (T2DM). The aim of these studies was to assess the potential for pharmacokinetic interaction between dapagliflozin, a sodium glucose co-transporter-2 inhibitor being developed for the treatment of T2DM, and four medications commonly prescribed in patients with T2DM and cardiovascular disease: simvastatin, valsartan, warfarin, and digoxin. METHODS: Potential pharmacokinetic interactions between 20 mg dapagliflozin, 40 mg simvastatin, or 320 mg valsartan were assessed in an open-label, randomized, five-period, five-treatment, unbalanced crossover study in 24 healthy subjects. In a second study, the effects of steady-state dapagliflozin on the pharmacokinetics of 25 mg warfarin or 0.25 mg digoxin were assessed in an open-label, randomized, two-period, two-treatment crossover study in 30 healthy subjects divided into two cohorts. The potential pharmacodynamic interaction between dapagliflozin and warfarin was also evaluated. RESULTS: All treatments were well tolerated. Neither simvastatin nor valsartan had any clinically meaningful effect on the pharmacokinetics of dapagliflozin. Dapagliflozin increased the area under the curve for simvastatin, simvastatin acid, and valsartan by approximately 19%, 30%, and 6%, respectively, and decreased the maximum observed plasma concentration of valsartan by approximately 6%. These effects were not considered clinically meaningful. In addition, dapagliflozin had no effect on the pharmacokinetics of either digoxin or warfarin. The pharmacodynamics of warfarin were also unaffected by dapagliflozin. CONCLUSION: In these studies the co-administration of dapagliflozin and simvastatin, valsartan, warfarin, or digoxin was well tolerated without clinically meaningful drug-drug interaction.

Circulating concentrations of monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and soluble leukocyte adhesion molecule-1 in overweight/obese men and women consuming fructose- or glucose-sweetened beverages for 10 weeks.

CONTEXT: Results from animal studies suggest that consumption of large amounts of fructose can promote inflammation and impair fibrinolysis. Data describing the effects of fructose consumption on circulating levels of proinflammatory and prothrombotic markers in humans are unavailable. OBJECTIVE: Our objective was to determine the effects of 10 wk of dietary fructose or glucose consumption on plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), E-selectin, intercellular adhesion molecule-1, C-reactive protein, and IL-6. DESIGN AND SETTING: This was a parallel-arm study with two inpatient phases (2 wk baseline, final 2 wk intervention), conducted in a clinical research facility, and an outpatient phase (8 wk) during which subjects resided at home. PARTICIPANTS: Participants were older (40-72 yr), overweight/obese (body mass index = 25-35 kg/m(2)) men (n = 16) and women (n = 15). INTERVENTIONS: Participants consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 wk. Blood samples were collected at baseline and during the 10th week of intervention. MAIN OUTCOME MEASURES: Fasting concentrations of MCP-1 (P = 0.009), PAI-1 (P = 0.002), and E-selectin (P = 0.048) as well as postprandial concentrations of PAI-1 (P < 0.0001) increased in subjects consuming fructose but not in those consuming glucose. Fasting levels of C-reactive protein, IL-6, and intercellular adhesion molecule-1 were not changed in either group. CONCLUSIONS: Consumption of fructose for 10 wk leads to increases of MCP-1, PAI-1, and E-selectin. These findings suggest the possibility that fructose may contribute to the development of the metabolic syndrome via effects on proinflammatory and prothrombotic mediators.

Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-h glucose and insulin excursions.

BACKGROUND: Consumption of sugar-sweetened beverages has been shown to be associated with dyslipidemia, insulin resistance, fatty liver, diabetes, and cardiovascular disease. It has been proposed that adverse metabolic effects of chronic consumption of sugar-sweetened beverages are a consequence of increased circulating glucose and insulin excursions, ie, dietary glycemic index (GI). OBJECTIVE: We determined whether the greater adverse effects of fructose than of glucose consumption were associated with glucose and insulin exposures. DESIGN: The subjects were studied in a metabolic facility and consumed energy-balanced diets containing 55% of energy as complex carbohydrate for 2 wk (GI = 64). The subjects then consumed 25% of energy requirements as fructose- or glucose-sweetened beverages along with their usual ad libitum diets for 8 wk at home and then as part of energy-balanced diets for 2 wk at the metabolic facility (fructose GI = 38, glucose GI = 83). The 24-h glucose and insulin profiles and fasting plasma glycated albumin and fructosamine concentrations were measured 0, 2, 8, and 10 wk after beverage consumption. RESULTS: Consumption of fructose-sweetened beverages lowered glucose and insulin postmeal peaks and the 23-h area under the curve compared with the baseline diet and with the consumption of glucose-sweetened beverages (all P < 0.001, effect of sugar). Plasma glycated albumin concentrations were lower 10 wk after fructose than after glucose consumption (P < 0.01, effect of sugar), whereas fructosamine concentrations did not differ between groups. CONCLUSION: The results suggest that the specific effects of fructose, but not of glucose and insulin excursions, contribute to the adverse effects of consuming sugar-sweetened beverages on lipids and insulin sensitivity. This study is registered at clinicaltrials.gov as NCT01165853.

Supplementation with EPA or fish oil for 11 months lowers circulating lipids, but does not delay the onset of diabetes in UC Davis-type 2 diabetes mellitus rats.

EPA or fish oil supplementation has been suggested as treatments for the prevention of type 2 diabetes mellitus (T2DM) due to their lipid-lowering and potential insulin-sensitising effects. We investigated the effects of supplementation with EPA (1 g/kg body weight per d) or fish oil (3 g/kg body weight per d) on the age of onset of T2DM and circulating glucose, insulin, lipids, leptin and adiponectin in UC Davis (UCD)-T2DM rats. Animals were divided into three groups starting at 1 month of age: control, EPA and fish oil. All the animals were followed until diabetes onset or for up to 12 months of age. Monthly fasting blood samples were collected for the measurement of glucose, lipids, hormones and C-reactive protein (CRP). Neither EPA nor fish oil delayed the onset of T2DM or altered fasting plasma glucose, insulin, CRP, adiponectin or leptin concentrations. The groups did not differ in energy intake or body weight. Fish oil treatment lowered fasting plasma TAG concentrations by 39 (sd 7) % (P < 0.001) and EPA lowered fasting plasma NEFA concentrations by 23 (sd 5) % (P < 0.05) at 4 months of age compared with the control group. EPA and fish oil lowered fasting plasma cholesterol concentrations at 4 months of age by 19 (sd 4) and 22 (sd 4) % compared with the control group, respectively (both P < 0.01). In conclusion, EPA and fish oil supplementation lowers circulating lipid concentrations, but does not delay the onset of T2DM in UCD-T2DM rats.

Chronic administration of the glucagon-like peptide-1 analog, liraglutide, delays the onset of diabetes and lowers triglycerides in UCD-T2DM rats.

OBJECTIVE: The efficacy of liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, to prevent or delay diabetes in UCD-T2DM rats, a model of polygenic obese type 2 diabetes, was investigated. RESEARCH DESIGN AND METHODS: At 2 months of age, male rats were divided into three groups: control, food-restricted, and liraglutide. Animals received liraglutide (0.2 mg/kg s.c.) or vehicle injections twice daily. Restricted rats were food restricted to equalize body weights to liraglutide-treated rats. Half of the animals were followed until diabetes onset, whereas the other half of the animals were killed at 6.5 months of age for tissue collection. RESULTS: Before diabetes onset energy intake, body weight, adiposity, and liver triglyceride content were higher in control animals compared with restricted and liraglutide-treated rats. Energy-restricted animals had lower food intake than liraglutide-treated animals to maintain the same body weights, suggesting that liraglutide increases energy expenditure. Liraglutide treatment delayed diabetes onset by 4.1 ± 0.8 months compared with control (P < 0.0001) and by 1.3 ± 0.8 months compared with restricted animals (P < 0.05). Up to 6 months of age, energy restriction and liraglutide treatment lowered fasting plasma glucose and A1C concentrations compared with control animals. In contrast, liraglutide-treated animals exhibited lower fasting plasma insulin, glucagon, and triglycerides compared with both control and restricted animals. Furthermore, energy-restricted and liraglutide-treated animals exhibited more normal islet morphology. CONCLUSIONS: Liraglutide treatment delays the development of diabetes in UCD-T2DM rats by reducing energy intake and body weight, and by improving insulin sensitivity, improving lipid profiles, and maintaining islet morphology.

Dietary fructose accelerates the development of diabetes in UCD-T2DM rats: amelioration by the antioxidant, alpha-lipoic acid.

Sustained fructose consumption has been shown to induce insulin resistance and glucose intolerance, in part, by promoting oxidative stress. Alpha-lipoic acid (LA) is an antioxidant with insulin-sensitizing activity. The effect of sustained fructose consumption (20% of energy) on the development of T2DM and the effects of daily LA supplementation in fructose-fed University of California, Davis-Type 2 diabetes mellitus (UCD-T2DM) rats, a model of polygenic obese T2DM, was investigated. At 2 mo of age, animals were divided into three groups: control, fructose, and fructose + LA (80 mg LA.kg body wt(-1).day(-1)). One subset was followed until diabetes onset, while another subset was euthanized at 4 mo of age for tissue collection. Monthly fasted blood samples were collected, and an intravenous glucose tolerance test (IVGTT) was performed. Fructose feeding accelerated diabetes onset by 2.6 +/- 0.5 mo compared with control (P < 0.01), without affecting body weight. LA supplementation delayed diabetes onset in fructose-fed animals by 1.0 +/- 0.7 mo (P < 0.05). Fructose consumption lowered the GSH/GSSG ratio, while LA attenuated the fructose-induced decrease of oxidative capacity. Insulin sensitivity, as assessed by IVGTT, decreased in both fructose-fed and fructose + LA-supplemented rats. However, glucose excursions in fructose-fed LA-supplemented animals were normalized to those of control via increased glucose-stimulated insulin secretion. Fasting plasma triglycerides were twofold higher in fructose-fed compared with control animals at 4 mo, and triglyceride exposure during IVGTT was increased in both the fructose and fructose + LA groups compared with control. In conclusion, dietary fructose accelerates the onset of T2DM in UCD-T2DM rats, and LA ameliorates the effects of fructose by improving glucose homeostasis, possibly by preserving beta-cell function.