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Determining the Effect of Small Doses of Fructose and Its Epimers on Glycemic Control

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Determining the Effect of Small Doses of Fructose and Its Epimers on Glycemic Control Determining the Effect of Small Doses of Fructose and its Epimers on Glycemic Control by Jarvis Clyde Noronha A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Nutritional Sciences University of Toronto © Copyright by Jarvis Clyde Noronha 2017 ii Determining the Effect of Small Doses of Fructose and its Epimers on Glycemic Control Jarvis Clyde Noronha Master of Science Department of Nutritional Sciences University of Toronto 2017 Abstract Given that sugars have emerged as the dominant nutrient of concern in diabetes, there is a need for the development of alternative sweeteners. To assess the role of small doses (5g, 10g) of fructose and allulose on postprandial glucose metabolism, we conducted an acute randomized controlled trial in individuals with type 2 diabetes. We found that small doses of allulose, but not fructose, modestly reduced the postprandial glycemic response to a 75g oral glucose load. To assess whether low-dose (< 50-g/day) fructose and all its epimers (allulose, tagatose and sorbose) lead to sustainable improvements in long-term glycemic control, we conducted a systematic review and meta-analysis of controlled feeding trials. The available evidence suggested that fructose and tagatose led to significant reductions in HbA1c and fasting glucose. Our findings highlight the need for long-term randomized controlled trials to confirm the viability of fructose and its epimers as alternative sweeteners. iii Table of Contents Contents Abstract ............................................................................................................................ ii Table of Contents ............................................................................................................ iii List of Tables ................................................................................................................. vii List of Figures ................................................................................................................. ix Chapter 1 : Introduction ................................................................................................... 1 Chapter 2 : Literature Review .......................................................................................... 3 2.1 Diabetes ................................................................................................................ 4 2.1.1 Definition & Complications of Diabetes ....................................................... 4 2.1.2 Classification of Diabetes ........................................................................... 4 2.1.3 Prevalence and Economic Burden of Diabetes .......................................... 4 2.1.4 Diagnosis of Diabetes ................................................................................. 5 2.1.5 Postprandial Hyperglycemia & Type 2 Diabetes ........................................ 5 2.1.6 OGTT-Derived Indices of Insulin Secretion, Sensitivity & β-cell compensation ............................................................................................. 6 2.2 Fructose & its Epimers (Allulose, Tagatose, Sorbose) ........................................ 10 2.2.1 Background .............................................................................................. 10 2.2.2 Absorption, Metabolism & Excretion ......................................................... 11 2.2.3 Potential for Improving Postprandial Hepatic Glucose Metabolism .......... 18 2.3 Gaps in the Literature .......................................................................................... 29 Chapter 3 : Rationale, Objectives & Hypotheses ........................................................... 30 3.1 Rationale ............................................................................................................. 31 3.2 Objectives ........................................................................................................... 31 3.3 Hypotheses ......................................................................................................... 32 iv Chapter 4 : Effect of Small Doses of Fructose and Allulose on Postprandial Carbohydrate Metabolism in Type 2 Diabetes: A Randomized Crossover Trial ........ 33 4.1 Abstract ............................................................................................................... 34 4.2 Introduction ......................................................................................................... 35 4.3 Research Design and Methods ........................................................................... 36 4.3.1 Participants ............................................................................................... 36 4.3.2 Trial Design ............................................................................................... 36 4.3.3 Treatments ............................................................................................... 37 4.3.4 Protocol .................................................................................................... 37 4.3.5 Plasma Glucose and Insulin Analysis ....................................................... 38 4.3.6 Outcomes ................................................................................................. 38 4.3.7 Data Analysis ........................................................................................... 38 4.4 Results ................................................................................................................ 40 4.4.1 Flow of Study Participants ........................................................................ 40 4.4.2 Participant Characteristics ........................................................................ 42 4.4.3 Effect of Small Doses of Fructose and Allulose on Plasma Glucose and Insulin Responses .................................................................................... 43 4.4.4 Dose-Response Analysis ......................................................................... 45 4.4.5 Equivalence Test ...................................................................................... 46 4.4.6 Effect of Small Doses of Fructose and Allulose on Secondary Outcomes ................................................................................................. 47 4.4.7 Subgroup Analysis.................................................................................... 50 4.5 Discussion ........................................................................................................... 53 4.5.1 Summary of Findings ................................................................................ 53 4.5.2 Findings in Context of Previous Research ................................................ 53 4.5.3 Mechanism of Action ................................................................................ 54 4.5.4 Clinical Implications .................................................................................. 55 v 4.5.6 Strengths & Limitations ............................................................................. 55 4.6 Conclusions ......................................................................................................... 56 Chapter 5 : Effect of Small Doses of Fructose and its Epimers on Markers of Long- term Glycemic Control: A Systematic Review and Meta-Analysis of Controlled Feeding Trials ............................................................................................................ 57 5.1 Abstract ............................................................................................................... 58 5.2 Introduction ......................................................................................................... 60 5.3 Methods .............................................................................................................. 61 5.3.1 Data Sources and Searches ..................................................................... 61 5.3.2 Study Selection ........................................................................................ 64 5.3.3 Data Extraction ......................................................................................... 64 5.3.4 Data Synthesis and Analysis .................................................................... 64 5.3.5 Quality of Evidence Assessment .............................................................. 65 5.4 Results ................................................................................................................ 66 5.4.1 Search Results ......................................................................................... 66 5.4.2 Trial Characteristics .................................................................................. 67 5.4.3 Effect of Low-dose Fructose & its Epimers on HbA1c ............................... 70 5.4.4 Effect of Low-dose Fructose & its Epimers on Fasting Glucose ............... 70 5.4.5 Effect of Low-dose Fructose & its Epimers on Fasting Insulin .................. 71 5.4.6 Publication Bias ........................................................................................ 73 5.4.7 GRADE Assessment ................................................................................ 73 5.5 Discussion ........................................................................................................... 75 5.5.1 Summary of Findings ................................................................................ 75 5.5.2 Findings
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