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G protein-coupled receptor 119 agonist DS-8500a effects on pancreatic β-cells in Japanese type 2 diabetes mellitus patients.
Watada, H, Shiramoto, M, Irie, S, Terauchi, Y, Yamada, Y, Shiosakai, K, Myobatake, Y, Taguchi, T
Journal of diabetes investigation. 2019;(1):84-93
Abstract
AIMS/INTRODUCTION Pancreatic β-cell dysfunction contributes to type 2 diabetes mellitus progression. Drugs that improve insulin secretion might be a valuable treatment approach. The present study aimed to evaluate the effect of the G protein-coupled receptor 119 agonist DS-8500a on insulin secretory capacity in Japanese type 2 diabetes mellitus patients. MATERIALS AND METHODS This single-center, 4-week, randomized, double-blind, cross-over study enrolled 21 Japanese drug-naïve type 2 diabetes mellitus patients aged ≥20 years with glycated hemoglobin ≥7.0 and <9.0% (NCT02669732, JapicCTI 163126). Patients received 75 mg of DS-8500a or a placebo orally daily for 4 weeks in a random order. A combined euglycemic-hyperinsulinemic and hyperglycemic clamp test was carried out to assess insulin secretion and insulin sensitivity before and after each 4-week treatment period. Primary end-points were first-phase insulin secretion (insulin area under the curve [AUC]180-190 min and C-peptide AUC180-190 min during the clamp test) and second-phase insulin secretion (insulin AUC190-300 min and C-peptide AUC190-300 min ). Insulin sensitivity (M and M/I values), disposition index and changes in lipid profile were also assessed. RESULTS DS-8500a significantly increased first- and second-phase insulin AUC (P = 0.0011, P = 0.0112) and C-peptide AUC (P = 0.0012, P < 0.0001) compared with the placebo. At day 28, M and M/I values were comparable with those of the placebo, whereas the disposition index for insulin and C-peptide was significantly increased (P = 0.0108, P = 0.0002). Total cholesterol, low-density lipoprotein cholesterol and triglyceride concentrations were significantly reduced, and high-density lipoprotein cholesterol concentrations were significantly increased compared with the placebo. No significant treatment-emergent adverse events occurred. CONCLUSION DS-8500a enhanced insulin secretory capacity, but not insulin sensitivity.
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A low-fat diet up-regulates expression of fatty acid taste receptor gene FFAR4 in fungiform papillae in humans: a co-twin randomised controlled trial.
Costanzo, A, Liu, D, Nowson, C, Duesing, K, Archer, N, Bowe, S, Keast, R
The British journal of nutrition. 2019;(11):1212-1220
Abstract
Fatty acid taste (FAT) perception is involved in the regulation of dietary fat intake, where impaired FAT is associated with increased fatty food intake. There are a number of FAT receptors identified on human taste cells that are potentially responsible for FAT perception. Manipulating dietary fat intake, and in turn FAT perception, would elucidate the receptors that are associated with long-term regulation of FAT perception. The present study aimed to assess associations between diet-mediated changes to FAT receptors and FAT perception in humans. A co-twin randomised controlled trial was conducted, where each matching twin within a pair were randomly allocated to either an 8-week low-fat (LF; <20 % energy fat) or an 8-week high-fat (HF; >35 % energy fat) diet. At baseline and week 8, fungiform papillae were biopsied in the fasted state and FAT receptor gene expressions (cluster of differentiation 36 (CD36), free fatty acid receptor 2 (FFAR2), FFAR4, G protein-coupled receptor 84 (GPR84) and a delayed rectifying K+ channel (K+ voltage-gated channel subfamily A member 2; KCNA2)) were measured using RT-PCR; and FAT threshold (FATT) was assessed using three-alternate forced choice methodology. Linear mixed models were fitted, adjusting for correlation between co-twins. Intake was compliant with the study design, with the LF and HF groups consuming 14·8 and 39·9 % energy from fat, respectively. Expression of FFAR4 increased by 38 % in the LF group (P = 0·023; time-diet interaction P = 0·063). ΔFFAR4 (Δ, week 8-baseline) was associated with Δfat intake (g) ( = -159·4; P < 0·001) and ΔFATT ( = -8·8; P = 0·016). In summary, FFAR4 is involved in long-term diet-mediated changes to FAT perception. Manipulating dietary fat intake, and therefore FFAR4 expression, might aid in reducing taste-mediated passive overconsumption of fatty foods.
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Efficacy and safety of the G protein-coupled receptor 119 agonist DS-8500a in Japanese type 2 diabetes mellitus patients with inadequate glycemic control on sitagliptin: A phase 2 randomized placebo-controlled study.
Terauchi, Y, Yamada, Y, Watada, H, Nakatsuka, Y, Shiosakai, K, Washio, T, Taguchi, T
Journal of diabetes investigation. 2018;(6):1333-1341
Abstract
INTRODUCTION We evaluated the efficacy and safety of DS-8500a as add-on therapy to sitagliptin in Japanese type 2 diabetes mellitus patients. MATERIALS AND METHODS This multicenter, randomized, double-blind, placebo-controlled, phase 2 trial randomized patients aged ≥20 years with hemoglobin A1c ≥7.0% and <9.0%, and inadequate glycemic control with sitagliptin 50-mg monotherapy to receive 25 or 75 mg DS-8500a, or a placebo, orally. The primary end-point was change from baseline to day 28 in 24-h weighted mean glucose. Secondary end-points included change from baseline in fasting plasma glucose, 2-h postprandial plasma glucose and lipid profiles. RESULTS Overall, 29, 28 and 27 patients in the placebo, 25- and 75-mg groups, respectively, were analyzed. A significant dose-dependent reduction was observed in 24-h weighted mean glucose (linear: P = 0.0006, saturated at 25 mg: P = 0.0003, responded from 75 mg: P = 0.0176) when compared with the placebo (25 mg: -13.19 mg/dL [-0.73 mmol/L], P = 0.0044 vs placebo and 75 mg: -16.12 mg/dL [-0.89 mmol/L], P = 0.0006 vs placebo). A significant reduction in fasting plasma glucose at 75 mg vs placebo was observed (P < 0.001). At 25 and 75 mg, significant reductions of 2-h postprandial plasma glucose (after breakfast), total cholesterol, low-cholesterol and triglycerides were observed (all P < 0.05), with a (non-significant) trend towards increased high-density lipoprotein cholesterol. Both doses of DS-8500a were well tolerated. There were no significant treatment-emergent adverse events leading to discontinuation during the study. CONCLUSIONS DS-8500a was well tolerated, and showed significant glycemic benefits and favorable changes in lipid profile in Japanese type 2 diabetes mellitus patients with inadequate glycemic control with sitagliptin therapy.
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Genetic coding variants in the niacin receptor, hydroxyl-carboxylic acid receptor 2, and response to niacin therapy.
Tuteja, S, Wang, L, Dunbar, RL, Chen, J, DerOhannessian, S, Marcovina, SM, Elam, M, Lader, E, Rader, DJ
Pharmacogenetics and genomics. 2017;(8):285-293
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OBJECTIVE Niacin has been used for seven decades to modulate plasma lipids, but its mechanism of action is still unclear. We sought to determine whether variants in the niacin receptor gene, hydroxyl-carboxylic receptor 2 (HCAR2), are associated with lipid response to treatment. PARTICIPANTS AND METHODS Coding variants, rs7314976 (p.R311C) and rs2454727 (p.M317I), were genotyped in 2067 participants from the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial. AIM-HIGH was a randomized, placebo-controlled trial that was conducted to assess the effect of extended-release niacin in patients with cardiovascular disease aggressively treated with low-density lipoprotein cholesterol-lowering therapy. RESULTS There was no association of p.R311C or p.M317I with changes in low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol at 1 year in groups receiving placebo or extended-release niacin. In White patients, the reduction in lipoprotein (a) [Lp(a)] in response to niacin was greater in homozygous carriers of the major 317M allele (-22.7%; P=0.005) compared with minor allele carriers (-15.3%). This was directionally consistent in the Black participants. Upon combining both groups, the reduction in Lp(a) in response to niacin was significantly greater in the homozygous major allele carriers (-23.0%; P=0.003) compared with minor allele carriers (-15.2%). CONCLUSION Understanding the genetic contribution toward variation in response to niacin therapy, including Lp(a) reduction, could uncover mechanisms by which niacin decreases Lp(a), an important independent risk factor for cardiovascular disease.
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Bile Acids Increase Independently From Hypocaloric Restriction After Bariatric Surgery.
Jahansouz, C, Xu, H, Hertzel, AV, Serrot, FJ, Kvalheim, N, Cole, A, Abraham, A, Luthra, G, Ewing, K, Leslie, DB, et al
Annals of surgery. 2016;(6):1022-1028
Abstract
OBJECTIVES To measure changes in the composition of serum bile acids (BA) and the expression of Takeda G-protein-coupled receptor 5 (TGR5) acutely after bariatric surgery or caloric restriction. SUMMARY BACKGROUND DATA Metabolic improvement after bariatric surgery occurs before substantial weight loss. BA are important metabolic regulators acting through the farnesoid X receptor and TGR5 receptor. The acute effects of surgery on BA and the TGR5 receptor in subcutaneous white adipose tissue (WAT) are unknown. METHODS A total of 27 obese patients with type 2 diabetes mellitus were randomized to Roux-en-Y gastric bypass (RYGB) or to hypocaloric diet (HC diet) restriction (NCT 1882036). A cohort of obese patients with and without type 2 diabetes mellitus undergoing vertical sleeve gastrectomy was also recruited (n = 12) as a comparison. RESULTS After vertical sleeve gastrectomy, the level of BA increased [total: 1.17 ± 1.56 μmol/L to 4.42 ± 3.92 μmol/L (P = 0.005); conjugated BA levels increased from 0.99 ± 1.42 μmol/L to 3.59 ± 3.70 μmol/L (P = 0.01) and unconjugated BA levels increased from 0.18 ± 0.24 μmol/L to 0.83 ± 0.70 μmol/L (P = 0.009)]. With RYGB, there was a trend toward increased BA [total: 1.37 ± 0.97 μmol/L to 3.26 ± 3.01 μmol/L (P = 0.07); conjugated: 1.06 ± 0.81 μmol/L to 2.99 ± 3.02 μmol/L (P = 0.06)]. After HC diet, the level of unconjugated BA decreased [0.92 ± 0.55 μmol/L to 0.32 ± 0.43 μmol/L (P = 0.05)]. The level of WAT TGR5 gene expression decreased after surgery, but not in HC diet. Protein levels did not change. CONCLUSIONS The levels of serum BA increase after bariatric surgery independently from caloric restriction, whereas the level of WAT TGR5 protein is unaffected.
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Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial.
Kaku, K, Enya, K, Nakaya, R, Ohira, T, Matsuno, R
Diabetes, obesity & metabolism. 2015;(7):675-81
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AIM: To assess the efficacy and safety of fasiglifam 25 and 50 mg in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. METHODS This phase III, double-blind, placebo-controlled, multicentre study included 192 patients randomized to once-daily treatment with fasiglifam 25 mg (n = 63) or 50 mg (n = 62) or placebo (n = 67) for 24 weeks. The primary efficacy endpoint was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS At week 24, both fasiglifam groups had significantly reduced HbA1c levels compared with the placebo group (p < 0.0001). The least squares mean change from baseline in HbA1c was 0.16% with placebo, -0.57% with fasiglifam 25 mg and -0.83% with fasiglifam 50 mg. The percentage of patients who achieved an HbA1c target of <6.9% at week 24 was also significantly higher (p < 0.05) for fasiglifam 25 mg (30.2%) and 50 mg (54.8%) compared with placebo (13.8%). Fasiglifam significantly reduced fasting plasma glucose levels at all assessment points, starting from week 2. The incidence and types of treatment-emergent adverse events in each fasiglifam group were similar to those in the placebo group, and hypoglycaemia was reported in 1 patient receiving fasiglifam 50 mg. There were no clinically meaningful changes in body weight in any treatment group. CONCLUSIONS Fasiglifam significantly improved glycaemic control and was well tolerated, with a low risk of hypoglycaemia in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise; however, in a recent review of data from overall fasiglifam global clinical trials, concerns about liver safety arose and the clinical development of fasiglifam was terminated after this trial was completed.
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Interaction of NPSR1 genotypes and probiotics in the manifestation of atopic eczema in early childhood.
P, K, M, K, K, K, T, L, M, K
Allergologia et immunopathologia. 2014;(6):560-7
Abstract
BACKGROUND Neuropeptide S Receptor (NPSR1) gene has been associated with multiple allergic phenotypes in several patient populations. OBJECTIVE We analysed the effect of the NPSR1 genotypes in the development of asthma, rhinitis, eczema, or food allergy in children randomly receiving either probiotic or placebo treatment. METHODS 796 children born to families at high risk for allergic diseases were examined by a paediatrician at the age of three months, six months, two years, and five years. Asthma, rhinitis, eczema, and food allergy were diagnosed according to international guidelines. Treatment with probiotics (double-blinded and placebo controlled) was begun with mothers at 35 weeks of gestation age and continued after the birth of infants up to the age of six months. Association and additive inheritance models were used in genetic analyses. RESULTS Distribution of the hopo546333 was suggestive in the group of patients with atopic eczema at two years. The hopo546333_G was found more often in those with eczema in the placebo group (p=0.048, after Bonferroni correction) and the hopo546333_A was found more often in those with eczema and probiotics compared to those with eczema and placebo treatment. None of the NPSR1 tagging SNPs was associated with asthma, IgE-mediated asthma, or sensitisation. Allergic disease in both parents doubled the risk for IgE-mediated allergic disease (OR 2.1). CONCLUSIONS The NPSR1 gene SNP hopo546333 showed a suggestive association for high IgE-associated atopic eczema at two years.
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Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure.
Barnes, GD, Alam, S, Carter, G, Pedersen, CM, Lee, KM, Hubbard, TJ, Veitch, S, Jeong, H, White, A, Cruden, NL, et al
Circulation. Heart failure. 2013;(3):482-91
Abstract
BACKGROUND To assess cardiovascular actions of APJ agonism during prolonged (Pyr(1))apelin-13 infusion and renin-angiotensin system activation. METHODS AND RESULTS Forty-eight volunteers and 12 patients with chronic stable heart failure attended a series of randomized placebo-controlled studies. Forearm blood flow, cardiac index, left ventricular dimensions, and mean arterial pressure were measured using bilateral venous occlusion plethysmography, bioimpedance cardiography, transthoracic echocardiography, and sphygmomanometry, respectively, during brief local (0.3-3.0 nmol/min) and systemic (30-300 nmol/min) or prolonged systemic (30 nmol/min) (Pyr(1))apelin-13 infusions in the presence or absence of renin-angiotensin system activation with sodium depletion or angiotensin II coinfusion. During sodium depletion and angiotensin II coinfusion, (Pyr(1))apelin-13-induced vasodilatation was preserved (P<0.02 for both). Systemic intravenous (Pyr(1))apelin-13 infusion increased cardiac index, whereas reducing mean arterial pressure and peripheral vascular resistance index (P<0.001 for all) irrespective of sodium depletion or angiotensin II (0.5 ng/kg per minute) coinfusion (P>0.05 for all). Prolonged 6-hour (Pyr(1))apelin-13 infusion caused a sustained increase in cardiac index with increased left ventricular ejection fraction in patients with chronic heart failure (ANOVA; P<0.001 for all). CONCLUSIONS APJ agonism has sustained cardiovascular effects that are preserved in the presence of renin-angiotensin system activation or heart failure. APJ agonism may hold major promise to complement current optimal medical therapy in patients with chronic heart failure. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00901719, NCT00901888, NCT01049646, NCT01179061.
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Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes.
Kaku, K, Araki, T, Yoshinaka, R
Diabetes care. 2013;(2):245-50
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OBJECTIVE Assessment of the efficacy and safety of TAK-875 (a novel GPR40 agonist) in Japanese patients with type 2 diabetes inadequately controlled by diet/exercise. RESEARCH DESIGN AND METHODS This was a phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week dose-ranging evaluation of TAK-875 (6.25-200 mg once daily) with the primary end point of change in A1C at week 12. A nonblinded group received 1 mg glimepiride once daily as an active control. RESULTS A total of 396 patients were randomized to receive TAK-875 (n = 299), placebo (n = 48), or glimepiride (n = 49). The least square mean changes in A1C at week 12 from baseline were as follows: 0.09% in the placebo group; -0.54, -0.67, -0.88, -1.27, -1.29, and -1.40% in the 6.25-, 12.5-, 25-, 50-, 100-, and 200-mg TAK-875 groups, respectively; and -1.32% in the 1-mg glimepiride group. All TAK-875 groups had statistically significant reductions in A1C compared with placebo (P < 0.0001), and those receiving ≥50 mg TAK-875 achieved reductions in A1C equivalent to those with glimepiride. Results for other glycemic parameters, including improvements during a meal tolerance test, mirrored these positive findings with TAK-875. There were no significant differences in incidence of adverse events among the groups and no dose-dependent changes in tolerability. Hypoglycemic episodes were reported in 0.7% of patients in the TAK-875 groups and in 4.1% of the glimepiride group. CONCLUSIONS TAK-875 produced clinically and statistically significant improvements in glycemic control in patients with type 2 diabetes inadequately controlled by diet and exercise, and it was well tolerated with a lower propensity to cause hypoglycemia.
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Disordered control of intestinal sweet taste receptor expression and glucose absorption in type 2 diabetes.
Young, RL, Chia, B, Isaacs, NJ, Ma, J, Khoo, J, Wu, T, Horowitz, M, Rayner, CK
Diabetes. 2013;(10):3532-41
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We previously established that the intestinal sweet taste receptors (STRs), T1R2 and T1R3, were expressed in distinct epithelial cells in the human proximal intestine and that their transcript levels varied with glycemic status in patients with type 2 diabetes. Here we determined whether STR expression was 1) acutely regulated by changes in luminal and systemic glucose levels, 2) disordered in type 2 diabetes, and 3) linked to glucose absorption. Fourteen healthy subjects and 13 patients with type 2 diabetes were studied twice, at euglycemia (5.2 ± 0.2 mmol/L) or hyperglycemia (12.3 ± 0.2 mmol/L). Endoscopic biopsy specimens were collected from the duodenum at baseline and after a 30-min intraduodenal glucose infusion of 30 g/150 mL water plus 3 g 3-O-methylglucose (3-OMG). STR transcripts were quantified by RT-PCR, and plasma was assayed for 3-OMG concentration. Intestinal STR transcript levels at baseline were unaffected by acute variations in glycemia in healthy subjects and in type 2 diabetic patients. T1R2 transcript levels increased after luminal glucose infusion in both groups during euglycemia (+5.8 × 10(4) and +5.8 × 10(4) copies, respectively) but decreased in healthy subjects during hyperglycemia (-1.4 × 10(4) copies). T1R2 levels increased significantly in type 2 diabetic patients under the same conditions (+6.9 × 10(5) copies). Plasma 3-OMG concentrations were significantly higher in type 2 diabetic patients than in healthy control subjects during acute hyperglycemia. Intestinal T1R2 expression is reciprocally regulated by luminal glucose in health according to glycemic status but is disordered in type 2 diabetes during acute hyperglycemia. This defect may enhance glucose absorption in type 2 diabetic patients and exacerbate postprandial hyperglycemia.