The present project investigated the effect of glucose, high dose insulin and normoglycemia (GIN) therapy in patients undergoing coronary revascularization surgery. A reduction in myocardial injury as measured by cardiac troponin I was the primary end point. Cardiac function based on hemodynamics and vasoactive drug requirements as well as clinical outcome were evaluated. Hormones and metabolites and cardiac metabolism were investigated concurrently as potential mechanisms of GIN therapy. The major findings of the present study are that GIN therapy reduced post-operative myocardial injury and myocardial dysfunction leading to a decrease in major complications following coronary artery bypass grafting surgery. The mechanism of the overall improvement in cardiac function and decreased morbidity following CABG with GIN therapy is likely to be multi-factorial, but from the present results, is influenced by improved myocardial metabolism. GIN therapy is thus an effective diet for the ischemic heart.

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Thesis (MSc)--Stellenbosch University, 2001. / ENGLISH ABSTRACT: Introduction: It is well documented that insulin offers cardioprotection under ischaemic stress. In the past it was believed that the protective effects of insulin, such as the (a) recruitment of glucose transporters to enhance glucose entry into the cell, (b) stimulation of glycolysis, (c) enhancement of glycogen synthesis, (d) improved protein synthesis, and (e) positive inotropic and chronotropic properties, were metabolic of origin, but lately the emphasis has shifted towards the diverse signal transduction pathways elicited by insulin. Although these beneficial effects of insulin on ischaemia/reperfusion induced injury have been studied for many years, the exact protective mechanism is still not resolved. Aim: To investigate the influence of insulin on the signaling pathways as a possible protective mechanism against ischaemia/reperfusion and therefore to investigate the possible roles and cross signaling of cyclic adenosine monophosphate (cAMP), protein kinase B (PKB) and p38 mitogen activated protein kinase (p38 MAPK) in the cardioprotection offered by insulin to the reperfused, ischaemic myocardium. Materials and methods: Isolated rat hearts were perfused retrogradely in accordance with the Langendorff technique (95%02, 5% C02). After 30 min of stabilization, hearts were subjected to 30 min global low flow ischaemia (0,2 ml/min), followed by 30 min of reperfusion. Hearts perfused with standard Krebs Henseleit solution containing 5 mM glucose were compared to hearts perfused with a perfusion solution containing 5 mM glucose and 0,3 IlIU/ml insulin. Wortmannin was added during either ischaemia or reperfusion. Left ventricular developed pressure (LVDP), rate pressure product (RPP), tissue cAMP and PKB and p38 MAPK activation were measured. Results: Insulin treated hearts showed improved functional recovery (P<0.05) during reperfusion after ischaemia vs. non-insulin treated hearts (85.5±4.6% vs. 44.8±4.9%). However, the addition of wortmannin (a Pl3-kinase inhibitor) to the perfusion solution during either ischaemia or reperfusion abolished the improved recovery. At the end of ischaemia, cAMP levels of the insulin treated hearts were elevated significantly, while the cAMP content in the non-insulin treated hearts returned to control levels. Addition of wortmannin during ischaemia abolished this rise in cAMP. Wortmannin added during reperfusion only did not alter the levels of cAMP at the end of reperfusion. Activation of p38 MAPK was transient during ischaemia for both insulin and non-insulin treated hearts. Addition of wortmannin during ischaemia did not alter p38 MAPK levels at the end of ischaemia. P38 MAPK was activated significantly (P<0.001) in the non-insulin treated hearts vs. insulin treated hearts during reperfusion. Wortmannin, added at the onset of reperfusion, could partially abolish the effects of insulin to suppress p38 MAPK activation after 30 min of reperfusion. Activation of PKB in insulin treated hearts was significantly higher than non-insulin treated hearts during stabilization and early ischaemia. This activity was depressed by 30 min of ischaemia in both presence and absence of insulin. Wortmannin, when added before induction of ischaemia did not further lower this. The presence of insulin resulted in occurrence of strong PKB activation during reperfusion, peaking at 15 minutes and diminishing at 30 minutes. Wortmannin, added at the onset of reperfusion, abolished PKB activity measured at the end of reperfusion. Conclusion: Insulin exerted a positive inotropic effect and delayed the onset to ischaemic contracture. Inhibition of Pl3-kinase by wortmannin abolished the protective effects of insulin, arguing for an insulin stimulated PKB involvement in cardiac protection. Insulin also increased cAMP production and attenuated activation of p38 MAPK, both associated with improved recovery. This evidence suggested possible cross signaling between different signaling pathways. / AFRIKAANSE OPSOMMING: Agtergrond: Insulin beskerm harte wat aan isgemiese stres blootgestel word. Alhoewel hierdie voordelige effekte van insulien reeds vir verskeie jare bestudeer is, is die presiese meganisme waarmee insulien die hart beskerm steeds nie duidelik nie. Navorsers het die beskermende effekte van insulien aan metaboliese gevolge soos: (a) verhoogde glukose transport d.m.v. inspanning van meer glukose transporters (b), stimulering van glikolise, (c) vebeterde glikogeensintese, (d) verhoogde proteiensintese, en (e) die positiewe inotropiese en chronotropiese eienskappe van insulien toegeskryf. Onlangs het die fokus verskuif na ander diverse seintransduksiepaaie. Doel: Die doel van hierdie studie was dus om die moontlike betrokkenheid van hierdie sientransduksiepaaie asook die interaksie tussen sikliese adenomonofosfaat (cAMP), proteïn kinase B (PKB) en p38 MAPK in die beskerming wat insulien aan die isgemiese, gereperfuseerde miokardium bied, te bestudeer. Materiale en Metodes: Geïsoleerde rotharte is geperfuseer in ooreenstemming met die Langendorff metode. Na 30 min van stabilisasie is harte blootgestel aan 30 min. globale lae vloei isgemie (0,2 ml/min), en daarna is harte vir 30 min. geherperfuseer. Harte wat geperfuseer is met 'n perfusaat wat 5mM glukose bevat is vergelyk met harte wat geperfuseer is met 'n perfusaat wat 5mM glukose en 0,3 ~IU/ml insulien bevat. Sommige harte is geperfuseer met 'n perfusie oplossing waar wortmannin bygevoeg is tydens óf isgemie óf tydens herperfusie. Linker ventrikulêre ontwikkelde druk (LVDP), tempo-druk produk (RPP), weefsel cAMP-vlakke asook PKB en p38 MAPK aktiwiteit is gemeet. Resultate: Insulien-behandelde harte het funksioneel beduidend beter herstel tydens herperfusie na isgemie as harte wat nie met insulien behandel is nie (85.5±4.6% vs. 44.8±4.9%). Byvoeging van wortmannin by die perfusie oplossing tydens óf isgemie óf reperfusie, het die toename in herstel wat gesien is in die insulien-behandelde harte, opgehef. Die cAMP vlakke in die insulienbehandelde harte het aan die einde van isgemie beduidend gestyg (P<0.001), terwyl vlakke in harte wat nie met insulien behandel is nie, na kontrole vlakke teruggekeer het. Die teenwoordigheid van wortmannin in die perfusie oplossing tydens isgemie, het die styging in cAMP voorkom , terwyl die byvoeging van wortmannin tydens herperfusie. nie die cAMP vlakke beïnvloed het nie. Die aktivering van p38 MAPK tydens isgemie was van verbygaande aard in beide die insulien-behandelde harte en harte wat nie met insulien behandel is nie. Die byvoeging van wortmannin tydens isgemie het nie die p38 MAPK aktivering beïnvloed nie. P38 MAPK is beduidend geaktiveer tydens herperfusie in harte wat nie met insulien behandel is nie vergeleke met die insulien-behandelde harte. Die byvoeging van wortmannin tydens reperfusie kon die effek van insulien om p38 MAPK aktivering te onderdruk, gedeeltelik ophef. PKB aktivering tydens die stabilisasie fase en vroeë isgemie was beduidend hoër in die insulien-behandelde harte vs. die harte wat nie met isulien behandel is nie. Die aktiwiteit is onderdruk deur 30 min isgemie ongeag die teenwoordigheid van insulien. Die byvoeging van wortmannin tydens isgemie het PKB aktivering nie verder verlaag nie. Die teenwoordigheid van insulien het 'n sterk aktivering van PKB tydens herperfusie veroorsaak met 'n piek na 15 min en 'n verlaging na 30 min. Wortmannin bygevoeg aan die begin van herperfusie, het PKB aktiwiteit opgehef aan die einde van reperfusie. Opsomming: Insulien het 'n positiewe inotropiese invloed gehad, en het die begin van isgemiese kontraksie vertraag. Die inhibisie van Pl3-kinase deur wortmannin het die beskermende effekte van insulin opgehef, wat 'n insulin gestimuleerde PKB betrokkenheid aandui. Insulien het ook verhoogte cAMP produksie en verlaagde p38 MAPK aktivering tot gevolg gehad, en beide is geassosieer met verbeterde herstel. Hierdie resultate dui dus op moontlike interaksie tussen die verskillende seintransduksiepaaie.

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This thesis is a step forward in evaluating insulin therapy and defining its role in cardiac surgery first described as Glucose-Insulin-Potassium (GIK) solution 40 years ago. / Chapter (I) includes a review of the literature on insulin therapy in cardiac surgery and illustrates the scientific bases and controversies in this therapy. / Chapter (II) entitled: "Myocardial Protection During Elective Coronary Artery Bypass Grafting Using High Dose Insulin Therapy" represents a manuscript that was presented in the following meetings: (A) Local meetings: (1) McGill cardiovascular research day, February 1/2007, Montreal, Canada. (2) Fraser Gurd annual research day, McGill surgery department, May 31/2007, Montreal, Canada. (B) National meetings: (1) 11th Annual Terrence Donnelly research day for Canadian cardiac surgery residents, May 26/2007, Toronto, Canada. (C) International meetings: (1) 43rd Annual meeting of the Society of thoracic surgeons (STS), January 30/2007, San Diego, United States. A full manuscript was submitted to "The Annals of Thoracic Surgery" for review. / Chapter (III) entitled: "High Dose Insulin Therapy Attenuates Systemic Inflammatory Response in Patients Undergoing Elective Coronary Artery Bypass Grafting" represents a manuscript that was presented in the following meetings: (A) Local meetings: (1) Fraser Guard McGill Surgery department annual research day, May 3/2006, Montreal, Canada. (B) National meetings: (1) 10th Annual Terrence Donnelly research day for Canadian cardiac surgery residents, May 26/2007, Toronto, Canada. (2) Young investigator forum, Canadian Society of Clinical Investigators (CSCI), September 28/2006, Ottawa, Canada. (3) 59 th annual meeting of Canadian Cardiovascular Society (CCS), October 21/2006, Vancouver, Canada. (C) International meetings: (1) American Heart Association (AHA), November 12/2006, Chicago, United states. / Abstracts from this work were published in the following journals: (1) Clinical and Investigative Medicine, Vol. 29, No. 4, August 2006. (2) The Canadian Journal of Cardiology, Vol. 22 supp D, October 2006 (3) Circulation, Vol. 114 supp, No. 18, October 2006. / A full manuscript was submitted to "the journal of thoracic and cardiovascular surgery" for review.

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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

While insulin omission has been found to be a common behavior in those with type I diabetes, it has been primarily studied within the context of disordered eating behavior. Previous research supports medical providers and patients lack of comfort in discussing insulin omission. This study was designed to answer two questions. Why do young adult college students with type I diabetes omit insulin? and what factors facilitate and act as barriers to open communication regarding insulin omission in the patient-provider interaction. A total 13 (10 females, 3 males) college students completed a qualitative interview focused on insulin omission and communication of this behavior to medical providers, and 11 of the 13 completed a modified EAT-26. Using consensual qualitative research methods CQR (Hill, Thompson, & Williams, 1997), domains that emerged were reasons for insulin, predominant reason for insulin omission, motivators to give insulin as prescribed (i.e., adhere), overall communication of insulin omission to medical providers, and factors facilitating and barriers inhibiting communication regarding insulin omission to medical providers. Typical reasons for insulin omission included forgetting or delaying and forgetting, worrying about hypoglycemia and its social implications, being in situations where limited access to food/medical supplies, planning to be physically active, or being unsure of carbohydrate count in food. Insulin omission as a weight loss behavior was not reported by any of the participants during the interviews and all denied using insulin as a way to control their weight or shape on the EAT-26. Clinical implications and future research directions are discussed. / Department of Counseling Psychology and Guidance Services

Type 2 diabetes mellitus (DM) is a progressive disease characterised by hyperglycaemia caused by defects in insulin secretion and insulin action. In early stages of type 2 DM, dietary and lifestyle changes are often sufficient to control blood glucose levels. However, over time, many patients experience β cell dysfunction and require insulin therapy, either alone or in combination with oral agents. There are guidelines available to structure the management of this disease state, including both the use of oral hypoglycaemic agents and or insulin. Besides health complications, there are economic burdens associated with the management of type 2 diabetes mellitus. The aim of this study was to determine the management of type 2 DM in a South African sample group of patients drawn from a large medical aid database. The objectives of the study were: to establish the prevalence of type 2 DM relative to age, examine the nature of chronic comorbid disease states, establish trends in the prescribing of insulin relative to other oral hypoglycaemic agents, investigate cost implications, and determine trends in the use of blood and urine monitoring materials by patients. The study was quantitative and retrospective and descriptive statistics were used in the analysis. DM was found to be most prevalent amongst patients between 50 and 59 years old. Results also demonstrated that 83% of DM patients also suffered from other chronic comorbid diseases, with cardiovascular diseases, especially hypertension and hypercholesterolaemia being the most prominent. This study also revealed that DM is predominantly managed with oral hypoglycaemic agents. Changes in drug prescribing, for chronic disease states such as DM may have medical, social and economic implications both for individual patients and for society and it is envisaged that the results of this study can be used to influence future management of DM. Keywords: Pharmacoepidemiology, management, type 2 diabetes mellitus