Gastrointestinal mediation of glucose homeostasis and postprandial cardiovascular risk A thesis submitted by Dr Sony Sebastian Thazhath MBBS, MD For the degree of Doctor of Philosophy Discipline of Medicine University of Adelaide February 2016 Table of Contents Table of Contents ..................................................................................................................... II THESIS SUMMARY .................................................................................................................. XII DECLARATION .....................................................................................................................XVIII ACKNOWLEDGEMENTS ........................................................................................................ XX PUBLICATIONS ARISING FROM THE THESIS ............................................................ XXIII STATEMENT OF AUTHORSHIP .......................................................................................... 25 CHAPTER 1. GLUCOSE ABSORPTION IN SMALL INTESTINAL DISEASES .............. 50 1.1 Abstract ........................................................................................................................................ 50 1.2 Introduction ............................................................................................................................... 50 1.3 Physiology of glucose absorption ....................................................................................... 51 1.3.1 Gastrointestinal motility ............................................................................................................... 51 1.3.2 Digestion of carbohydrates .......................................................................................................... 53 1.3.3 Effects of sweet ‘tasting’ by the intestine ............................................................................... 54 1.3.4 Glucose transport across the small intestinal mucosa ..................................................... 56 1.4 Quantification of glucose absorption ................................................................................ 59 1.5 Diseases affecting glucose availability in the small intestine .................................. 61 1.5.1 Disorders of gastric motility ........................................................................................................ 61 1.5.2 Bariatric surgery .............................................................................................................................. 62 1.5.3 Dumping Syndrome ........................................................................................................................ 63 1.6 Disorders of carbohydrate digestion ................................................................................ 64 1.7 Disorders of glucose transporters in the intestinal mucosa ..................................... 65 1.8 Glucose absorption in critical illness ................................................................................ 66 1.9 Glucose absorption in short gut syndrome ..................................................................... 68 1.10 Glucose absorption in type 2 diabetes ........................................................................... 70 1.10.1 Disordered gastric motility ....................................................................................................... 70 1.10.2 Disordered carbohydrate digestion ....................................................................................... 71 1.10.3 Disorders of intestinal ‘sweet tasting’ .................................................................................. 71 1.10.4 Disorders of glucose transporters .......................................................................................... 72 1.11 Expert Commentary .............................................................................................................. 73 1.12 Five year view .......................................................................................................................... 73 1.13 Key issues ................................................................................................................................. 74 Figure 1............................................................................................................................................................ 75 Figure 2............................................................................................................................................................ 76 CHAPTER 2. DIABETIC GASTROPARESIS – RECENT INSIGHTS INTO PATHOPHYSIOLOGY, AND IMPLICATIONS FOR MANAGEMENT. ........................... 78 2.1 Abstract ........................................................................................................................................ 78 2.2 Introduction ............................................................................................................................... 78 2.3 Epidemiology ............................................................................................................................. 79 2.4 Physiology of normal gastric motility ............................................................................... 80 2.5 Motor abnormalities in diabetic gastroparesis ............................................................. 82 2.6 Etiology and natural history of symptoms in diabetic gastroparesis .................... 83 2.7 Pathophysiology of diabetic gastroparesis ..................................................................... 83 2.7.1 Role of nitric oxide as an inhibitory neurotransmitter in diabetic gastroparesis . 84 2.7.2 Role of ICC loss or dysfunction in diabetic gastroparesis................................................ 85 2.8 Diagnosis ..................................................................................................................................... 88 2.8.1 Scintigraphy ....................................................................................................................................... 89 Figure 1............................................................................................................................................................ 90 13 2.8.2 CO2 Breath test .............................................................................................................................. 91 2.8.3 Wireless Motility Capsule (WMC or “Smart Pill”) ............................................................... 91 2.8.4 Ultrasonography ............................................................................................................................... 92 2.8.5 Magnetic Resonance Imaging (MRI) ........................................................................................ 93 2.8.6 Electrogastrography ....................................................................................................................... 93 2.9 Assessment of severity of gastroparesis .......................................................................... 94 2.10 Management ............................................................................................................................ 94 2.10.1 Glycemic control and gastroparesis....................................................................................... 95 2.10.2 Dietary modification in diabetic gastroparesis ................................................................. 98 2.10.3 Prokinetics ....................................................................................................................................... 99 2.10.4 Antiemetics ................................................................................................................................... 102 2.10.5 Pain management ....................................................................................................................... 102 2.10.6 Intrapyloric botulinum injection ......................................................................................... 103 2.10.7 Gastric electric stimulation (GES)........................................................................................ 103 2.10.8 Surgical treatment ...................................................................................................................... 105 2.10.9 Stem Cells ....................................................................................................................................... 105 2.10.10 Psychological disorders and gastroparesis ................................................................... 106 2.10.11 Alternative therapies.............................................................................................................. 106 2.11 Prognosis of diabetic gastroparesis .............................................................................. 107 Figure 2......................................................................................................................................................... 108 2.12 Expert commentary............................................................................................................. 109 2.13 Five-year view ....................................................................................................................... 109 CHAPTER 3. METHODOLOGY ........................................................................................... 111 3.1 Introduction