published_or_final_version / abstract / Surgery / Master / Master of Philosophy

by Lynn Wah Wong Tsang. / Consent form in Chinese. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 127-145). / Declaration --- p.i / Acknowledgments --- p.ii / Table of Contents --- p.iii / List of Tables --- p.vii / List of Figures --- p.x / List of Appendix --- p.xi / Chapter CHAPTER1 --- INTRODUCTION / Chapter 1.1 --- General Introduction --- p.2 / Chapter 1.2 --- Literature Review --- p.6 / Chapter 1.2.1 --- Classifications of Diabetes Mellitus --- p.6 / Chapter 1.2.2 --- Diagnostic Criteria of Diabetes Mellitus --- p.6 / Chapter 1.2.3 --- Characteristics of NIDDM --- p.9 / Chapter 1.2.4 --- Epidemiology of NIDDM --- p.13 / Chapter 1.2.5 --- Pathophysiology of NIDDM --- p.16 / Chapter 1.2.6 --- Determinants and Causes of NIDDM --- p.16 / Chapter 1.2.7 --- Etiology and Risk Factors ofNIDDM --- p.20 / Chapter 1.2.7.1 --- Genetic Factors --- p.20 / Chapter 1.2.7.2 --- Environmental Factors --- p.20 / Chapter 1.2.7.2.1 --- Physical Inactivity --- p.20 / Chapter 1.2.7.3 --- Body Weight and Fat Distribution --- p.21 / Chapter 1.2.7.4 --- Gestational Diabetes Mellitus --- p.22 / Chapter 1.2.7.5 --- Impaired Glucose Tolerance --- p.23 / Chapter 1.2.8 --- Complications --- p.23 / Chapter 1.2.9 --- Oral hypoglycaemic agents --- p.25 / Chapter 1.2.9.1 --- Insulin Secretagogues --- p.25 / Chapter 1.2.9.2 --- Metformin --- p.26 / Chapter 1.2.9.3 --- Apha-Glucosidase Inhibitors --- p.26 / Chapter 1.2.9.4 --- Insulin Sensitizers --- p.27 / Chapter 1.2.10 --- Oral Hypoglycaemic Agent Failure --- p.27 / Chapter 1.2.11 --- Use of Insulin in NIDDM --- p.28 / Chapter 1.2.12 --- Combination Therapy --- p.30 / Chapter CHAPTER2 --- RESEARCH DESIGN AND METHODS / Chapter 2.1 --- Study Protocol --- p.37 / Chapter 2.2 --- Objectives --- p.37 / Chapter 2.3 --- Overall Design --- p.38 / Chapter 2.3.1 --- Selection of Patients --- p.38 / Chapter 2.3.1.1 --- Inclusion Criteria --- p.38 / Chapter 2.3.1.2 --- Exclusion Criteria --- p.40 / Chapter 2.3.2 --- Recruitment Period --- p.40 / Chapter 2.3.2.1 --- Screening Period --- p.40 / Chapter 2.3.2.2 --- Pre-Run-In Period --- p.41 / Chapter 2.3.3 --- Run-in Period --- p.42 / Chapter 2.3.3.1 --- Stabilization --- p.43 / Chapter 2.3.3.2 --- Randomization --- p.44 / Chapter 2.3.3.2.1 --- Combination Group --- p.45 / Chapter 2.3.3.2.2 --- Insulin Group --- p.47 / Chapter 2.3.4 --- Evaluation Periods --- p.48 / Chapter 2.3.5 --- Study Medications --- p.49 / Chapter 2.3.6 --- Clinical Assessments --- p.50 / Chapter 2.4 --- Withdrawals --- p.50 / Chapter 2.5 --- Investigations --- p.51 / Chapter 2.6 --- Analytical Methods --- p.52 / Chapter 2.7 --- Statistical Analysis --- p.53 / Chapter CHAPTER3 --- RESULTS / Chapter 3.1 --- Study Population --- p.56 / Chapter 3.2 --- Randomization --- p.58 / Chapter 3.3 --- Study Results --- p.63 / Chapter 3.3.1 --- Indices of Glycaemic Control and Lipids --- p.63 / Chapter 3.3.1.1 --- Glucose Values --- p.63 / Chapter 3.3.1.2 --- Glucosylated Haemoglobin and Glycated Plasma Protein Concentration --- p.64 / Chapter 3.3.1.2.1 --- Glucosylated Haemoglobin --- p.64 / Chapter 3.3.1.2.2 --- Glycated Plasma Protein Concentration --- p.68 / Chapter 3.3.1.3 --- Plasma Lipid Concentrations --- p.69 / Chapter 3.3.2 --- Clinical Determinants --- p.70 / Chapter 3.3.2.1 --- Blood Pressure Measurements --- p.70 / Chapter 3.3.2.2 --- Body Weight Evaluations --- p.71 / Chapter 3.3.3 --- Insulin Types Used --- p.76 / Chapter 3.3.4 --- Insulin Dosage Requirements --- p.76 / Chapter 3.3.5 --- Subjective Well Being and Acceptability of Insulin Injection --- p.78 / Chapter 3.3.6 --- Hypoglycaemic Events --- p.85 / Chapter 3.3.7 --- Subsequent Study Discontinuation --- p.85 / Chapter 3.3.8 --- Responders versus no Responders --- p.86 / Chapter CHAPTER4 --- GENERAL DISCUSSION / Chapter 4.1 --- Summary of Results --- p.92 / Chapter 4.2 --- Acute and Long Term Effects of --- p.101 / Combination Therapy / APPENDIX --- p.111 / REFERENCES --- p.127 / Chapter 2 --- Abstracts summarized recent data not incorporated in this thesis --- p.147

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010. / Härtill 3 uppsatser.

Plant sterols (PS) are effective in reducing plasma lipid concentrations, however, few studies have examined their cholesterol lowering effects in type 2 diabetics. The objective was to assess whether PS consumption alters blood lipid profile in hypercholesterolemic subjects with and without type 2 diabetes. Fifteen control subjects (age = 55.1 +/- 8.5 yr and BMI = 26.9 +/- 3.0kg/m2) and fourteen diabetic subjects (age = 54.5 +/- 6.7 yr and BMI = 30.2 +/- 3.0kg/m2) participated in a double-blinded, randomized, crossover, placebo-controlled feeding trial. The Western diet included either 1.8g/d of PS or cornstarch placebo each provided over 21 d separated by a 28 d washout period. Subjects consumed only foods prepared in Mary Emily Clinical Nutrition Research Unit of McGill University. Total cholesterol (TC) decreased (p < 0.05) from baseline with PS for control and diabetic subjects by 9.7% and 13.6%, respectively. TC decreased (P < 0.05) from baseline with placebo for control and diabetic subjects by 10.9% and 11.6%, respectively. Non high density lipoprotein cholesterol (non-HDL-C) decreased (p < 0.05) from baseline with PS for diabetic subjects by 18.5%. Low density lipoprotein cholesterol (LDL-C) levels were reduced (p < 0.05) from baseline with PS for control and diabetic subjects by 14.9% and 29.8%, respectively. The reduction of LDL-C due to PS alone is greater with type 2 diabetics. There were no significant changes in HDL-C and TG across diets or treatments. It is thus concluded that PS consumption with diet enhances non-HDL-C and LDL-C reduction compared with diet alone in hypercholesterolemic individuals with and without type 2 diabetes. Demonstration for the first time that PS alone are more efficacious in lowering LDL-C and non-HDL-C in diabetic individuals compared to non-diabetics confirm the beneficial effects of PS to help prevent cardiovascular disease (CVD) for this high risk population.

The objective of this research was to examine the effects of plant sterols and glucomannan on lipid profiles, plasma plant sterol levels and glycemic control in mildly hypercholesterolemic subjects. Thirteen type 2 diabetic and sixteen non-diabetic individuals participated in a randomized crossover trial consisting of 4 phases, of 21 days each. During the study period, subjects were supplemented with plant sterols and/or glucomannan. Overall reductions of total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations were greater after consumption of plant sterols and glucomannan compared to plant sterol or glucomannan supplementation alone. Plasma lathosterol levels, indicators of cholesterol biosynthesis, were decreased after combination treatment. The results suggest that a combination of glucomannan and plant sterols substantially improve plasma lipids by reducing cholesterol absorption and synthesis simultaneously. Supplementation of plant sterols and glucomannan can thus be used as an effective treatment for management of circulating cholesterol levels and prevention of cardiovascular disease.

Type 1 diabetes (T1D) is a metabolic disorder characterized by destruction of the pancreatic beta-islet cells leading to complete loss of insulin production. Gliclazide is used in Type 2 diabetes (T2D) to stimulate insulin production but it also has beneficial extrapancreatic effects which make it potentially useful in T1D. In fact, some T2D patients continue to use gliclazide even after their diabetes progresses to T1D since it provides better glycemic control than insulin alone. About 30% of a gliclazide dose undergoes enterohepatic recirculation which may contribute to the observed high interindividual variability in its pharmacokinetics. This may limit its efficacy in T1D especially since diabetes can disturb the gut microbiota and give rise to changes in bile composition and enterohepatic recirculation. Improving the absorption of gliclazide through the use of bile acids and probiotics may reduce this variability and improve the efficacy of gliclazide in T1D. The aim of this thesis was to investigate the interaction between the semisynthetic bile acid, 12-monoketocholic acid (MKC) and gliclazide in terms of pharmacokinetics and hypoglycemic effects in a rat model of T1D with and without probiotic pretreatment. A parallel ex vivo (Ussing chamber) study was carried out to investigate the mechanism of the interaction. Sensitive LC-MS and HPLC methods (Chapter 2) were developed to determine the concentrations of gliclazide and MKC in Ringer's solution and rat serum. Diabetes was induced in male Wistar rats by intravenous (i.v.) alloxan (30 mg/kg). Rats with blood glucose concentration > 18 mmol/l and serum insulin concentration < 0.04 [mu]g/l, 2-3 days after alloxan injection were considered diabetic. A total of 280 male Wistar rats (Chapter 3) were randomly allocated into 28 groups (n=10) of which 14 were made diabetic. Then 7 groups of healthy and 7 groups of diabetic rats were gavaged with probiotics (10⁸ CFU/mg, 75 mg/kg) every 12 hours for three days after which single doses of gliclazide (20 mg/kg), MKC (4 mg/kg) or the combination were administered either by tail vein injection (i.v.) or by gavage. The other 14 groups (7 healthy and 7 diabetic) were gavaged with saline every 12 hours for three days and then treated in the same way. Blood samples were collected from the tail vein for 10 hours after the dose and analyzed for blood glucose, serum gliclazide & serum MKC concentrations. Serum concentration-time curves for gliclazide and MKC were used to determine pharmacokinetic parameters. In the parallel ex vivo study (Chapter 4), 88 rats were randomly divided into 22 groups (n=4 rats per group, 8 chambers per rat), of which 11 groups were made diabetic. Of the 22 groups, 8 groups (4 healthy and 4 diabetic) were pretreated with probiotics as described above to study their influence on gliclazide and MKC flux, 8 groups (4 healthy and 4 diabetic) were used to investigate the interaction between gliclazide and MKC during transport, and 6 groups (3 healthy and 3 diabetic) were used to study the influence of selective inhibitors of the drug transporters Mrp2, Mrp3 and Mdr1 on gliclazide flux. 10 cm piece of the ileum was removed from each rat, the underlying muscle layer and connective tissue removed and the epithelial sheets mounted into Ussing chambers. Gliclazide, MKC or a combination were added to either the mucosal or serosal side and samples collected from both sides for 3 h to determine mucosal-to-serosal absorptive flux (Jss[MtoS]) and serosal-to-mucosal secretory flux (Jss[StoM]) of gliclazide and MKC as appropriate. In diabetic rats, gliclazide alone had no effect on blood glucose levels (Ch3, exp2) whereas MKC reduced it from 23 � 3 to 18 � 3 mmol/l (Ch3, exp3) and the combination of gliclazide and MKC reduced it even further from 24 � 4 to 16 � 3 mmol/l (Ch3, exp4). In diabetic rats, probiotic treatment reduced blood glucose by 2-fold (Ch3, exp1) and enhanced the hypoglycemic effect of the combination of gliclazide and MKC (blood glucose decreased from 24 � 3 to 10 � 2 mmol/l). The bioavailability of gliclazide was higher in healthy rats (53.2 � 6.2%) than in diabetic rats (39.9 � 6.0%) (Ch3, exp2). In healthy rats, MKC enhanced gliclazide bioavailability (82.7 � 8.2%) but in diabetic rats MKC had no effect on gliclazide bioavailability (Ch3, exp4). In healthy rats, probiotic pretreatment significantly reduced gliclazide and MKC bioavailabilities (p<0.01) while in diabetic rats, probiotic pretreatment significantly increased the low bioavailability of gliclazide to a level similar to that in healthy rats (Ch3, exp2 & 3). MKC showed clear evidence of enterohepatic recycling and probiotics delayed and reduced its systemic absorption (Ch3, exp3). In ileal tissues from healthy rats, Ussing chamber studies showed gliclazide is most likely a substrate of Mrp2 and Mrp3 (Ch4, exp5) and MKC significantly reduced gliclazide Jss[MtoS] probably through Mrp3 inhibition (Ch4, exp1). In ileal tissue from diabetic rats, MKC had no effect on gliclazide Jss[MtoS] and Jss[StoM] (Ch4, exp2) and none of the inhibitors had any effect of gliclazide flux (Ch4, exp6). This suggests that these transporters are dysfunctional in this model of T1D. Probiotics and MKC have hypoglycemic effects that appear to be enhanced by gliclazide and all appear to interact at the level of ileal drug transporters. The combination of probiotic treatment, gliclazide and MKC exerted the greatest hypoglycemic effect in T1D rats. Accordingly, the application of this combination may have potential in improving the treatment of T1D.

Type 1 diabetes (T1D) is a metabolic disorder characterized by destruction of the pancreatic beta-islet cells leading to complete loss of insulin production. Gliclazide is used in Type 2 diabetes (T2D) to stimulate insulin production but it also has beneficial extrapancreatic effects which make it potentially useful in T1D. In fact, some T2D patients continue to use gliclazide even after their diabetes progresses to T1D since it provides better glycemic control than insulin alone. About 30% of a gliclazide dose undergoes enterohepatic recirculation which may contribute to the observed high interindividual variability in its pharmacokinetics. This may limit its efficacy in T1D especially since diabetes can disturb the gut microbiota and give rise to changes in bile composition and enterohepatic recirculation. Improving the absorption of gliclazide through the use of bile acids and probiotics may reduce this variability and improve the efficacy of gliclazide in T1D. The aim of this thesis was to investigate the interaction between the semisynthetic bile acid, 12-monoketocholic acid (MKC) and gliclazide in terms of pharmacokinetics and hypoglycemic effects in a rat model of T1D with and without probiotic pretreatment. A parallel ex vivo (Ussing chamber) study was carried out to investigate the mechanism of the interaction. Sensitive LC-MS and HPLC methods (Chapter 2) were developed to determine the concentrations of gliclazide and MKC in Ringer's solution and rat serum. Diabetes was induced in male Wistar rats by intravenous (i.v.) alloxan (30 mg/kg). Rats with blood glucose concentration > 18 mmol/l and serum insulin concentration < 0.04 [mu]g/l, 2-3 days after alloxan injection were considered diabetic. A total of 280 male Wistar rats (Chapter 3) were randomly allocated into 28 groups (n=10) of which 14 were made diabetic. Then 7 groups of healthy and 7 groups of diabetic rats were gavaged with probiotics (10⁸ CFU/mg, 75 mg/kg) every 12 hours for three days after which single doses of gliclazide (20 mg/kg), MKC (4 mg/kg) or the combination were administered either by tail vein injection (i.v.) or by gavage. The other 14 groups (7 healthy and 7 diabetic) were gavaged with saline every 12 hours for three days and then treated in the same way. Blood samples were collected from the tail vein for 10 hours after the dose and analyzed for blood glucose, serum gliclazide & serum MKC concentrations. Serum concentration-time curves for gliclazide and MKC were used to determine pharmacokinetic parameters. In the parallel ex vivo study (Chapter 4), 88 rats were randomly divided into 22 groups (n=4 rats per group, 8 chambers per rat), of which 11 groups were made diabetic. Of the 22 groups, 8 groups (4 healthy and 4 diabetic) were pretreated with probiotics as described above to study their influence on gliclazide and MKC flux, 8 groups (4 healthy and 4 diabetic) were used to investigate the interaction between gliclazide and MKC during transport, and 6 groups (3 healthy and 3 diabetic) were used to study the influence of selective inhibitors of the drug transporters Mrp2, Mrp3 and Mdr1 on gliclazide flux. 10 cm piece of the ileum was removed from each rat, the underlying muscle layer and connective tissue removed and the epithelial sheets mounted into Ussing chambers. Gliclazide, MKC or a combination were added to either the mucosal or serosal side and samples collected from both sides for 3 h to determine mucosal-to-serosal absorptive flux (Jss[MtoS]) and serosal-to-mucosal secretory flux (Jss[StoM]) of gliclazide and MKC as appropriate. In diabetic rats, gliclazide alone had no effect on blood glucose levels (Ch3, exp2) whereas MKC reduced it from 23 � 3 to 18 � 3 mmol/l (Ch3, exp3) and the combination of gliclazide and MKC reduced it even further from 24 � 4 to 16 � 3 mmol/l (Ch3, exp4). In diabetic rats, probiotic treatment reduced blood glucose by 2-fold (Ch3, exp1) and enhanced the hypoglycemic effect of the combination of gliclazide and MKC (blood glucose decreased from 24 � 3 to 10 � 2 mmol/l). The bioavailability of gliclazide was higher in healthy rats (53.2 � 6.2%) than in diabetic rats (39.9 � 6.0%) (Ch3, exp2). In healthy rats, MKC enhanced gliclazide bioavailability (82.7 � 8.2%) but in diabetic rats MKC had no effect on gliclazide bioavailability (Ch3, exp4). In healthy rats, probiotic pretreatment significantly reduced gliclazide and MKC bioavailabilities (p<0.01) while in diabetic rats, probiotic pretreatment significantly increased the low bioavailability of gliclazide to a level similar to that in healthy rats (Ch3, exp2 & 3). MKC showed clear evidence of enterohepatic recycling and probiotics delayed and reduced its systemic absorption (Ch3, exp3). In ileal tissues from healthy rats, Ussing chamber studies showed gliclazide is most likely a substrate of Mrp2 and Mrp3 (Ch4, exp5) and MKC significantly reduced gliclazide Jss[MtoS] probably through Mrp3 inhibition (Ch4, exp1). In ileal tissue from diabetic rats, MKC had no effect on gliclazide Jss[MtoS] and Jss[StoM] (Ch4, exp2) and none of the inhibitors had any effect of gliclazide flux (Ch4, exp6). This suggests that these transporters are dysfunctional in this model of T1D. Probiotics and MKC have hypoglycemic effects that appear to be enhanced by gliclazide and all appear to interact at the level of ileal drug transporters. The combination of probiotic treatment, gliclazide and MKC exerted the greatest hypoglycemic effect in T1D rats. Accordingly, the application of this combination may have potential in improving the treatment of T1D.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Thesis (M.Sc. (Pharmacology))--Mahidol University, 1984.

Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Epidemiology, Department of Public Health Sciences. Title from pdf file main screen (viewed on October 11, 2009). Includes bibliographical references.