Will occur over two separate study visits after screening. Eligible subjects with MetSyn will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.

Will occur over two separate study visits after screening. Eligible male subjects with MetSyn will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.

Will occur over two separate study visits after screening. Eligible control subjects will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.

Will occur over two separate study visits after screening. Eligible male control subjects will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.

Metabolic Syndrome X

NOS inhibition: L - NMMA is a potent non-selective NOS inhibitor used to study vascular physiology. L-NMMA will be infused at 3 mg/kg body weight/hr bolus (over 10min ) followed by a maintenance infusion of 1 mg/kg/hr for the duration of the experiment. Systemic delivery of L - NMMA has been shown to elevate blood pressure ~8-15 mmHg that is within the range observed during exercise.

NOS Inhibition

ET-1 inhibition: Ambrisentan is an antagonist of the ETA receptor. Subjects will receive 10 mg of Ambrisentan in a pill form 90-150 minutes prior to the OGTT. This class of drugs have been used to research ET-1 signaling in diabetes, obesity, and hypertension. ETA receptors are the most likely to mediate excessive constriction in MetSyn patients. Ambrisentan will be taken orally. Systemic delivery of endothelin antagonist have been shown at chronic dosing to decrease systolic blood pressure 4.5±10 mmHg and diastolic 3 ± 7.5 mmHg in hypertensives, and not alter mean arterial pressure in obesity.

ET-1 Inhibition

Saline will be infused at the same rate and quantity as the corresponding drug visit.

NOS Inhibition Placebo

A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits (at baseline and during treatment conditions).

3 Tesla MRI

A blood sampling IV catheter will be used to draw up to 15 mL blood samples at specific time points throughout each study visit to measure concentrations of glucose and insulin as well as for markers of inflammation and oxidative stress.

Intravenous Catheter

The subject will drink distilled deionized water (300ml) containing 75 grams glucose within 5 minutes.

Oral Glucose Tolerance Test

Placebo pill similar in size and shape to Ambrisentan will be used as placebo control.

ET-1 Inhibition Placebo

University of Wisconsin, Madison

Mechanisms of Cerebrovascular Control

Mechanisms of Cerebrovascular Control: Acute Insulin Surges Lead to Brain Hypoperfusion in Human Metabolic Syndrome

A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits.

American Heart Association

American Diabetes Association

2 tablets three times daily, oral for 16 weeks

three times daily, oral for 16 weeks
BTI320: BTI320, also known as SUGARDOWN®, is derived from galactomanan which blocks key enzymes that break down carbohydrate in the gut. BTI320 therefore helps to slow down the absorption of carbohydrates to lower post-meal blood sugar.

BTI320 4 Grams

BTI320 8 Grams

2 tablets three times daily, oral for 16 weeks
BTI320 matching placebo: Placebo

BTI320 Matching Placebo

Total

Sex: Female, Male

Region of Enrollment

Body weight

Body mass index

Waist circumference

Systolic blood pressure

Diastolic blood pressure

Fructosamine

HbA1c

Total cholesterol

Impaired fasting glucose

Impaired glucose tolerance

Impaired fasting glucose and impaired glucose tolerance

Normal glucose tolerance

1-hour post-prandial glucose incremental area under curve on continuous glucose monitoring system

1-hour post-prandial glucose AUC

2-hour post-prandial glucose incremental area under curve on continuous glucose monitoring system

2-hour post-prandial glucose AUC

3-hour post-prandial glucose incremental area under curve on continuous glucose monitoring system

3-hour post-prandial glucose AUC

Area under curve for glucose levels >180 mg/dL on continuous glucose monitoring system

72 hour AUC-180

Mean blood glucose on continuous glucose monitoring system

Mean blood glucose

Mean post-meal maximum glucose on continuous glucose monitoring system

Mean post-meal maximum glucose

Mean amplitude of glucose excursion on continuous glucose monitoring system

Mean amplitude of glucose excursion

Percentage coefficient of variation on continuous glucose monitoring system

Percentage coefficient of variation

Standard deviation on continuous glucose monitoring system

Standard deviation

Change in Serum Fructosamine in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo

Changes in 3-hour post-prandial glucose incremental area under curve on continuous glucose monitoring system from baseline to Week 16.
Note that this is not a pharmacokinetic study and this is not pharmacokinetic data as we are not measuring drug levels. Here we are examining glucose levels after meals as one of the anticipated glycemic outcomes of using glucose-lowering therapy (BTI320 in this case). With data-analysis based on continuous glucose monitoring, it is conventional to present post-prandial (i.e. post-meal) glucose incremental area under curve at up to 3 hours. It is not meaningful to look at post-meal glucose changes at more than 3 hours after meal for the obvious reason that subject might have taken another meal by then.

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Post-prandial Glucose Incremental Area Under Curve on Continuous Glucose Monitoring System

Changes in Subjects Treated With Low Dose BTI320 and High Dose BTI320 Compared With Placebo in Mean Post-meal Maximum Glucose on Continuous Glucose Monitoring System

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Amplitude of Glucose Excursion on Continuous Glucose Monitoring System

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Blood Glucose on Continuous Glucose Monitoring System

Area under curve for glucose levels >180 mg/dL over 72 hours

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Area Under Curve for Glucose Levels >180mg/dL on Continuous Glucose Monitoring System

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Glucose on Continuous Glucose Monitoring System

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation on Continuous Glucose Monitoring System

Changes in HbA1c in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo

Changes in Fructosamine in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo

Changes in area under curve of glucose from 0 minute to 120 minutes from baseline to Week 16

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Area Under Curve of Glucose During Standard Meal Tolerance Test From 0 Minute to 120 Minutes

Changes in area under curve of insulin from 0 minute to 120 minutes from baseline to Week 16

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Area Under Curve of Insulin During Standard Meal Tolerance Test From 0 Minute to 120 Minutes

Changes in area under curve of C-peptide from 0 minute to 120 minutes from baseline to Week 16

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Area Under Curve of C-peptide During Standard Meal Tolerance Test From 0 Minute to 120 Minutes

Changes in area under curve of glucagon-like peptide-1 from 0 minute to 120 minutes from baseline to Week 16

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Glucagon-like Peptide 1 During Standard Meal Tolerance Test From 0 Minute to 120 Minutes

Proportion of subjects with impaired fasting glucose, impaired glucose tolerance, both impaired fasting glucose and impaired glucose tolerance, HbA1c 5.7-6.4%, or type 2 diabetes at 30 days post-treatment

Proportion of Subjects With Impaired Fasting Glucose or Impaired Glucose Tolerance in Low Dose BTI320, High Dose BTI320 and Placebo Group

Changes in systolic blood pressures from baseline to Week 16

Changes in Blood Pressures in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes in Waist Circumference in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes in Body Weight in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes in total cholesterol from baseline to Week 16.

Changes in Lipids in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes in High-sensitivity C-reactive Protein in Subjects Treated With High Dose and Low Dose BTI320 Compared Placebo

Changes in Urate in Subjects Treated With High Dose and Lose Dose BTI320 Compared to Placebo

Changes in WHOQOL-BREF physical health domain score from baseline to Week 16. This is a sub-scale of the WHOQOL-BREF. Possible scores range from minimal of 4 to maximum of 20. Higher score indicate better physical health domain.

Changes in Quality of Life Measures in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes to question of "how full do you feel" in the Appetite Questionnaire adopted from Hill and Blundell from baseline and Week 16. Scale score ranges from minimum of 0 to maximum of 10. 10 being the most full and 0 being the least full.

Changes in Measures of Food Satiety in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes in daily calories intake from baseline to Week 16

Changes in Measures of Nutritional Intake in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes in the number of days per week that the subject spent walking for at least 10 minutes from baseline to Week 16

Changes in Measures of Exercise in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean 1 Hour Post-prandial Glucose Incremental Area Under Curve on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean 2 Hour Post-prandial Glucose Incremental Area Under Curve on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean 3 Hour Post-prandial Glucose Incremental Area Under Curve on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in 1 Hour Post-prandial Mean Blood Glucose on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in 2 Hour Post-prandial Mean Blood Glucose on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in 3 Hour Post-prandial Mean Blood Glucose on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Blood Glucose During 24 Hours on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Post-prandial Maximum Glucose on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Post-prandial Maximum Glucose During 24 Hours on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Blood Glucose During 1 Hour Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Blood Glucose During 2 Hours Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Blood Glucose During 3 Hours Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Blood Glucose Over 24 Hours on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation of Blood Glucose Over 1 Hour Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation of Blood Glucose Over 2 Hours Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation of Blood Glucose Over 3 Hours Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation of Blood Glucose Over 24 Hours on Continuous Glucose Monitoring System Repeated Measures Analysis

Changes in Serum Creatinine in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes in Measures of Liver Function in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Changes in Complete Blood Count in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo

Overall Study

Dr Andrea Luk

Pre-Diabetes

BTI320, also known as SUGARDOWN®, is derived from galactomanan which blocks key enzymes that break down carbohydrate in the gut. BTI320 therefore helps to slow down the absorption of carbohydrates to lower post-meal blood sugar.

BTI320

BTI320 matching placebo

The Chinese University of Hong Kong

BTI320 (SUGARDOWN®) on Post-Prandial Hyperglycaemia in Subjects With Pre-Diabetes

A Study to Evaluate the Effect of BTI320 (SUGARDOWN®) on Post-Prandial Hyperglycaemia in High Risk Chinese Subjects With Pre-Diabetes

Andrea On Yan Luk

Assocoiate Professor

Chinese University of Hong Kong

Sugardown Company Limited

The group who receive spironolactone, the dose employed will be 25 mg each other day and titrated to 25 mg daily according to potassium.

Renal Failure

Spironolactone

Hospital of the Medical School of Botucatu

Effects of Spironolactone in Dialysis

Assessment of the Effects of the Combination of Spironolactone to Conventional Pharmacotherapy in Dialysis Patients

The reduction of left ventricular hypertrophy will be measured by echocardiography, blood pressure monitoring residential and pulse wave velocity.

Measurement of serum potassium and other routine laboratory parameters pertaining to the hemodialysis unit of the Hospital of the Medical School of Botucatu - UNESP.

Greicy Mara Mengue Feniman De Stefano

UPECLIN HC FM Botucatu Unesp

Prebiotic: 8g/day, will be selected on the basis of ability to promote optimal growth and survival of the probiotic (inulin, fructooligosaccharides [FOS], galactooligosaccharides[GOS] and xylooligosaccharides[XOS] will be tested). Probiotic: 10^8 - 10^9 live bacteria/day, bifidobacterium longum bv. infantis CCUG52486.

Influenza

The probiotic strain will be Bifidobacterium longum bv. infantis CCUG 52486 (10^8 - 10^9 live bacteria per day), which was originally isolated from healthy elderly subjects, and which has been demonstrated to have particular ecological fitness and anti-pathogenic effects in vitro. A suitable prebiotic (8g/day) will be selected on the basis of ability to promote optimal growth and survival of this probiotic (inulin, fructooligosaccharides [FOS], galactooligosaccharides[GOS] and xylooligosaccharides[XOS] will be tested).

Prebiotic and probiotic mix

University of Reading

PRIMAGE (Probiotics, Immunity and Ageing)

A Randomised, Controlled, Parallel Study to Determine the Immunomodulatory Effects of Pre- and Probiotics Upon the Immune Response to Influenza Vaccination in Young and Older Volunteers

Serum vaccine-specific antibodies to the 2010-2011 influenza vaccine will be measured by hemagglutination assay.

Blood samples will be subject to density gradient separation of peripheral blood mononuclear cells (PBMC), and cryopreserved for NK cell analysis, cell phenotypes, cytokine production, proliferation, expression of activation markers, expression of toll like receptors and assessment of T cell receptor excision circles (TREC). Serum and plasma will be stored for measurement of chemokines, plasma lipids and glucose. Saliva samples will be used to assess salivary IgA content.

Faecal samples will be processed for later analysis by fluorescence in situ hybridization (FISH) using oligonucleotide 16s rRNA probes targeting dominant and important groups of gut bacteria. Denatured gradient gel electrophoresis (DGGE) will be used to assess changes in faecal bacterial abundance and species diversity. qPCR will be used to identify specific bacterial species, including Bifidobacterium longum. Faecal dry weight and IgA content will be assessed. Faecal content of microbial metabolites such as short chain fatty acids and ammonia will be quantified.

lactose/beroerte

Mechanisms of Cerebrovascular Control

BTI320 (SUGARDOWN®) on Post-Prandial Hyperglycaemia in Subjects With Pre-Diabetes

Effects of Spironolactone in Dialysis

PRIMAGE (Probiotics, Immunity and Ageing)

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