Determining the Effects of Fructose on Glycemic Control and Insulin Sensitivity in Individuals With and Without Diabetes using Meta- Analytical Tools

Transcription

1 Determining the Effects of Fructose on Glycemic Control and Insulin Sensitivity in Individuals With and Without Diabetes using Meta- Analytical Tools By Adrian I. Cozma A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Nutritional Sciences University of Toronto Copyright by Adrian Cozma (2014)

2 Determining the Effects of Fructose on Glycemic Control and Insulin Sensitivity in Humans using Meta- Analytical Tools Adrian I. Cozma Master of Science Department of Nutritional Sciences University of Toronto 2014 Abstract: The objective was to conduct two systematic reviews and meta- analysis of controlled feeding trials to investigate the effect of fructose on measures of glycemic control and insulin sensitivity, in humans. The glycemic control analysis of 58 trials (n=1021) showed a clinically significant reduction in HbA1c when fructose was isoenergetically substituted for other carbohydrates, without adverse effects on fasting glucose or insulin. When fructose supplemented the background diet, providing excess energy, fasting glucose was elevated. Similarly, the insulin sensitivity (IS) analysis (45 trials, n=791) found a tendency for improvement in whole- body IS with fructose substitution, with no change in hepatic IS or HOMA- IR. Fructose supplementation, however, impaired hepatic IS with a trend for impairment in whole body IS and HOMA- IR. Overall, the results suggest that replacement of moderate doses of carbohydrate with fructose may have a beneficial effect on glycaemia and IS, although this effect may be negated with excess calories. Abstract word count: 150 ii

3 TABLE OF CONTENTS TITLE PAGE NUMBER ABSTRACT... ii TABLE OF CONTENTS... iii LIST OF ABBREVIATIONS... v LIST OF FIGURES... viii LIST OF TABLES... xi CHAPTER I INTRODUCTION... 1 CHAPTER II LITERATURE REVIEW DIABETES MELLITUS PREVALENCE OF TYPE 2 DIABETES PATHOPHYSIOLOGY OF TYPE 2 DIABETES COMPLICATIONS AND MORTALITY OF TYPE 2 DIABETES RISK FACTORS OF TYPE 2 DIABETES DIAGNOSIS OF PREDIABETES AND TYPE 2 DIABETES MEASURES OF GLYCMEIC CONTROL MEASURES OF INSULIN SENSITIVITY FRUCTOSE AND TYPE 2 DIABETES SOURCES OF FRUCTOSE IN THE DIET POPULATION LEVELS OF SUGAR INTAKE IN THE US AND CANADA GUIDELINES FOR SUGAR AND FRUCTOSE CONSUMPTION ECOLOGICAL ANALYSES OF SUGARS AND CHRONIC DISEASE ANIMAL MODELS OF FRUCTOSE FEEDING PROSPECTIVE COHORT TRIALS TOTAL AND INDIVIDUAL SUGARS, METS, AND DM SUGAR- SWEETENED BEVERAGES, METS, AND DM EVIDENCE FROM CONTROLLED DIETARY TRIALS OF SUCROSE DIETARY SUCROSE TRIALS AND GLYCEMIC CONTROL DIETARY SUCROSE TRIALS AND INSULIN SENSITIVITY DIETARY SUCROSE TRIALS AND OTHER CARDIOMETABOLIC RISK FACTORS EVIDENCE FROM CONTROLLED DIETARY TRIALS OF FRUCTOSE iii

4 DIETARY FRUCTOSE TRIALS AND GLYCEMIC CONTROL DIETARY FRUCTOSE TRIALS AND INSULIN SENSITIVITY DIETARY SUCROSE TRIALS AND OTHER CARDIOMETABOLIC RISK FACTORS CHAPTER III OBJECTIVES AND RATIONALE OBJECTIVES RATIONALE CHAPTER IV DIFFERENTIAL EFFECTS OF FRUCTOSE ON GLYCEMIC CONTROL: A SYSTEMATIC REVIEW AND META- ANALYSIS OF CONTROLLED FEEDING TRIALS CHAPTER V EFFECT OF FRUCTOSE ON HEPATIC AND WHOLE- BODY INSULIN SENSITIVITY: A SYSTEMATIC REVIEW AND META- ANALYSIS OF CONTROLLED DIETARY FEEDING TRIALS CHAPTER VI OVERALL DISCUSSION AND LIMITATIONS OVERALL DISCUSSION LIMITATIONS MECHANISM OF ACTION CLINICAL IMPLICATIONS FUTURE DIRECTIONS CHAPTER VII CONCLUSIONS CHAPTER VIII REFERENCES iv

5 LIST OF ABBREVIATIONS ABBREVIATION DEFINITIONS 2H- GDT - Deuterated- glucose disposal test 2hPG - 2- hour plasma glucose A1c - Glycated haemoglobin ADA American Diabetes Association AHA - American Heart Association BMI Body mass index C Crossover CCS - Canadian Cardiovascular Society CDA Canadian Diabetes Association CHEP - Canadian Hypertension Education Program CI - Confidence interval CKD - Chronic kidney disease CVD Cardiovascular Disease DA - Dietary advice dbp - Diastolic blood pressure DBW - Desirable body weight DM Diabetes mellitus DM1 - Type 1 diabetes mellitus DM2 - Type 2 diabetes mellitus DNL De novo lipogenesis E Energy EASD European Association for the Studies of Diabetes EXP Experiment FBG - Fasting blood glucose FBI - Fasting blood insulin FDA Food and Drug Administration FPG - Fasting plasma glucose FSIVGTT Frequently sampled intravenous glucose tolerance test (with minimal model) GBP - Glycated blood proteins GI - Glycemic Index v

6 HbA1c Glycosylated Haemoglobin HC - High carbohydrate HDL High- density lipoprotein HC - High carbohydrate HEC - Hyperinsulinemic- euglycemic clamp HF - High fructose HFCS High- fructose corn syrup HGO - Hepatic glucose output HGP - Hepatic glucose production HI Hyperinsulinemic HOMA- IR - Homeostasis model assessment- estimated insulin resistance HR - Hazard ratio HTG Hypertriglyceridemic IBW - Ideal body weight IGT - Impaired glucose tolerance IOM - Institute of Medicine IP Inpatient IRR - Incidence rate ratio IS - Insulin sensitivity IVITT - Intravenous insulin tolerance test JNC7 - Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure LC - Low carbohydrate LDL Low- density lipoprotein LF - Low fructose M Metabolic MAP - Mean arterial blood pressure MetS The metabolic syndrome MRW - Mean relative weight NCEP- ATP III - Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults N Healthy NGT - Normal glucose tolerance OFFDM2 - Offspring of persons with type 2 diabetes mellitus vi

7 OGTT Oral glucose tolerance test OGTT- ISI - Oral glucose tolerance test derived insulin sensitivity index (Matsuda- DeFronzo) OP Outpatient OR - Odds ratio OW/OB - Overweight or obese P Parallel P1/P2 - Protocol 1/2 PM - Partial metabolic RBW - Relative body weight RR - Relative risk RW - Relative weight S Supplement sbp - Systolic blood pressure SLIVGTT - Stable- label intravenous glucose tolerance test (with minimal model) SMD - Standardized mean difference TC - Total cholesterol TG Triglycerides UK - United Kindom USA - United States of America USDA - United States Department of Agriculture WHO/FAO - Joint World Health Organization / Food and Agriculture Organization vii

8 LIST OF FIGURES CHAPTER II Figure 2.1. Percentage of dietary intake for total fructose by food source. Figure 2.2. Availability of added sugars (kg/capita/year) in Australia and the United Kingdom. Figure 2.3. Isocaloric and Hypercaloric Fructose Trials. CHAPTER IV Figure 4.1. Systematic search and selection strategy. Figure 4.2. Forest plots of controlled feeding trials of the effect of Isocaloric exchange of fructose for other sources of carbohydrate (A) or supplementation to provide the control diet with excess energy at high doses (B) on the pooled glycated blood proteins endpoint in diabetic and non- diabetic subjects. Figure 4.3. Forest plots of controlled feeding trials of the effect of Isocaloric exchange of fructose for other sources of carbohydrate (A) or supplementation to provide the control diet with excess energy at high doses (B) on the pooled fasting glucose endpoint in diabetic and non- diabetic subjects. Figure 4.4. Forest plots of controlled feeding trials of the effect of Isocaloric exchange of fructose for other sources of carbohydrate (A) or supplementation to provide the control diet with excess energy at high doses (B) on the pooled fasting insulin endpoint in diabetic and non- diabetic subjects. Appendix Figure 4.1A. Subgroup analyses of the effect of fructose in Isocaloric exchange for other sources of carbohydrate on glycated blood proteins (HbA1c and glycated albumin) in people with and without diabetes. Appendix Figure 4.1B. Subgroup analyses of fructose supplementation in Hypercaloric trials on glycated blood proteins (HbA1c and glycated albumin) in people with and without diabetes. Appendix Figure 4.2A. Subgroup analyses of the effect of fructose in Isocaloric exchange for other sources of carbohydrate on fasting glucose in people with and without diabetes. Appendix Figure 4.2B. Subgroup analyses of fructose supplementation in Hypercaloric trials on fasting glucose in people with and without diabetes. Appendix Figure 4.3A. Subgroup analyses of the effect of fructose in Isocaloric exchange for other sources of carbohydrate on fasting insulin in people with and without diabetes. viii

9 Appendix Figure 4.3B. Subgroup analyses of fructose supplementation in Hypercaloric trials on fasting insulin in people with and without diabetes. Appendix Figure 4.4A. Funnel plot for the effect of fructose on glycated blood proteins (glycated albumin and HbA1c) in the isocaloric feeding trials. Appendix Figure 4.4B. Funnel plot for the effect of fructose on glycated blood proteins (glycated albumin and HbA1c) in the hypercaloric feeding trials. Appendix Figure 4.5A. Funnel plot for the effect of fructose on fasting glucose in the isocaloric feeding trials. Appendix Figure 4.5B. Funnel plot for the effect of fructose on fasting glucose in the hypercaloric feeding trials. Appendix Figure 4.6A. Funnel plot for the effect of fructose on fasting insulin in the isocaloric feeding trials. Appendix Figure 4.6B. Funnel plot for the effect of fructose on fasting insulin in the hypercaloric feeding trials. CHAPTER V Figure 5.1. Summary of literature search and selection. Figure 5.2. Forest plots of controlled feeding trials investigating the effect of isocaloric exchange of fructose for other carbohydrate (A) or hypercaloric addition of fructose to background diet (B) on whole- body insulin sensitivity. Figure 5.3. Forest plots of controlled feeding trials investigating the effect of Isocaloric exchange of fructose for other carbohydrate (A) or hypercaloric addition of fructose to background diet (B) on hepatic insulin sensitivity. Figure 5.4. Forest plots of controlled feeding trials investigating the effect of isocaloric exchange of fructose for other carbohydrate (A) or hypercaloric addition of fructose to background diet (B) on HOMA- IR. Appendix Figure 5.1A. Subgroup analyses in the isocaloric feeding trials investigating the effect of isocaloric exchange of fructose for carbohydrate on whole- body insulin sensitivity in people with and without diabetes. Appendix Figure 5.1B. Subgroup analyses in the hypercaloric feeding trials investigating the effect of a control diet supplemented with 18% to 97% excess energy from fructose on whole- body insulin sensitivity in diabetic and non- diabetic participants. ix

10 Appendix Figure 5.2A. Subgroup analyses in the isocaloric feeding trials investigating the effect of isocaloric exchange of fructose for carbohydrate on hepatic insulin sensitivity in people with and without diabetes. Appendix Figure 5.2B. Subgroup analyses in the hypercaloric feeding trials investigating the effect of a control diet supplemented with 18% to 97% excess energy from fructose on hepatic insulin sensitivity in diabetic and non- diabetic participants. Appendix Figure 5.3A. Subgroup analyses in the isocaloric feeding trials investigating the effect of isocaloric exchange of fructose for carbohydrate on HOMA- IR in people with and without diabetes. Appendix Figure 5.3B. Subgroup analyses in the hypercaloric feeding trials investigating the effect of a control diet supplemented with 18% to 97% excess energy from fructose on HOMA- IR in diabetic and non- diabetic participants. Appendix Figure 5.4A. Funnel plot for the effect of fructose on whole- body insulin sensitivity in the isocaloric feeding trials. Appendix Figure 5.4B. Funnel plot for the effect of fructose on whole- body insulin sensitivity in the hypercaloric feeding trials. Appendix Figure 5.5A. Funnel plot for the effect of fructose on hepatic insulin sensitivity in the isocaloric feeding trials. Appendix Figure 5.5B. Funnel plot for the effect of fructose on hepatic insulin sensitivity in the hypercaloric feeding trials. Appendix Figure 5.6A. Funnel plot for the effect of fructose on HOMA- IR in the isocaloric feeding trials. Appendix Figure 5.6B. Funnel plot for the effect of fructose on HOMA- IR in the hypercaloric feeding trials. x

11 LIST OF TABLES CHAPTER II Table 2.1. Advantages and disadvantages of diagnostic tests for diabetes. Table 2.2. Advantages and disadvantages of different measures of hepatic and whole- body insulin sensitivity. Table 2.3. Summary of current dietary guidelines regarding the consumption of sugars and fructose and the prevention of chronic diseases. Table 2.4. Summary of studies investigating sugar and sugar- sweetened beverage intake in relation to MetS and DM2 incidence. CHAPTER IV Table 4.1. Characteristics of isocaloric and hypercaloric feeding trials Investigating the effect of fructose on glycemic control. CHAPTER V Table 5.1. Characteristics of isocaloric and hypercaloric feeding trials investigating the effect of fructose on hepatic and whole- body insulin sensitivity. xi

12 Introduction CHAPTER I - INTRODUCTION 1

13 Introduction 1. INTRODUCTION Type 2 diabetes mellitus (DM2) is rapidly emerging as the chief global public health concern of the 21 st century, with tremendous and widespread consequences for personal health, health care systems, and society as a whole. Current predictions suggest that the total number of people living with diabetes is projected to double by , leading to significant increases in heart disease, stroke, blindness, kidney disease, lower limb amputations, and central and peripheral nervous system impairment 2. Given the increasing incidence of obesity, these figures probably underestimate the future prevalence of diabetes. The risk of developing DM2 and premature cardiovascular disease is strongly linked to the metabolic syndrome, a condition characterized by excess central adiposity, elevated triglycerides, reduced high- density lipoprotein (HDL) cholesterol, hypertension and impaired glucose tolerance 3. Since these outcomes are complications of obesity, a number of dietary and environmental factors have been implicated in the development and progression of this cardiometabolic phenotype. Chief among them have been excessive consumption sugars containing fructose: high- fructose corn syrup (HFCS), sucrose, and fructose, owing to the increasing use of HFCS as a sweetener in the United States, and to fructose s unique ability to bypass a key regulatory enzyme in glycolysis 4. Ecological studies have linked the rise in fructose availability (from both sucrose and high fructose corn syrup) to the increasing prevalence of overweight and obesity in the United States, renewing interest and discussion about fructose research, and providing the ideological underpinnings for the emergence of a fructosecentric view of cardiometabolic disease 5. This view is supported by research on laboratory animals, particularly rodents, which have shown a clear and consistent adverse effect with the consumption of a high- fructose diet, and acute human trials overfeeding fructose at levels of exposure well beyond population levels of intake 6. Observational trials however, have failed to show a link between total, or individual sugar intake, and risk of DM2 7,8. Similarly, evidence from higher quality controlled trials of fructose feeding has been inconclusive, reporting neutral 9,10, adverse 11,12, and even beneficial effects 13,14 on key metabolic endpoints related to DM risk. An emerging body of evidence suggests that fructose consumption may be beneficial in select populations. A recent systematic review and meta- analysis investigating the effect of fructose on glycemic endpoints in controlled trials of individuals with diabetes, reported a glycemic benefit when fructose replaced isoenergetic amounts of other carbohydrate in the diet 15. This report is consistent with acute feeding trials done in the late 1970s 16 and early 1980s, 2

14 Introduction showing that fructose elicited a lower glycemic response than glucose (glycemic index of ), and with an early proof- of- concept randomized controlled trial reporting that fructose may be beneficial as an alternative sweetening agent in people with diabetes 18. There is also evidence that small catalytic doses of fructose at a level obtainable from fruit ( 10g per meal) decrease the glycemic response to high- GI meals in humans 19,20 and may also benefit glycemic control 21. It remains unclear however, whether the observed reductions realized from fructose intake extend to groups beyond people with diabetes, and whether the low GI properties of fructose may help to reduce postprandial glycemic responses to mixed meals sufficiently to improve insulin sensitivity. To fill the present knowledge gap, and to clarify the current evidence, we have updated our previous systematic review and meta- analysis of the effect of fructose on glycemic control in people with diabetes, extending it to include people without diabetes, and have conducted a second systematic review and meta- analysis to investigate the effect of fructose on insulin sensitivity. The following thesis work will report the results of the two systematic reviews and meta- analyses conducted to investigate the effects of dietary fructose consumption on measures of glycemic control (Chapter IV), and measures of insulin sensitivity (Chapter V), in individuals with and without diabetes. 3

15 Literature Review CHAPTER II LITERATURE REVIEW 4

16 Literature Review 2.1 DIABETES MELLITUS Diabetes mellitus (DM), more commonly referred to as diabetes, is a complex metabolic disorder characterized by hyperglycemia and insufficient pancreatic β- cell function 22. There are three major types of diabetes: Type 1 DM, where autoimmune destruction of pancreatic β- cells results in insulin deficiency, Type 2 DM, where pancreatic β- cells have become damaged or destroyed in response to the body s increasing demands to produce higher quantities of insulin with progressive insulin resistance, and gestational DM, where hyperglycemia develops during pregnancy. The second, DM2, is the most prevalent form of diabetes worldwide, accounting for approximately 85-95% of the total burden of diabetes among high- income countries, and even higher in low- and middle- income countries 1. The recent worldwide increase in obesity has resulted in an explosion in the prevalence of DM2, with very serious consequences for heart disease, stroke, blindness, kidney disease, lower limb amputations, and central and peripheral nervous system impairment 2. Future estimates predict a doubling of the number of people living with diabetes over the next twenty years, which is particularly concerning given that the development of DM2 can be delayed, or prevented, with balanced nutrition and sufficient exercise PREVALENCE OF TYPE 2 DIABETES The prevalence of DM2 is staggering. A 2013 update to the International Diabetes Federation s Diabetes Atlas reported that there were approximately 344 million people living with DM2 worldwide 1. Among these individuals, approximately 33 million reside in North America or the Caribbean. In Canada, most recent estimates suggest that approximately 3.33 million Canadians (or 10% of the population) are living with diagnosed DM2 23, PATHOPHYSIOLOGY OF TYPE 2 DIABETES Although the precise mechanisms underlying the development of insulin resistance and progression to DM2 are not entirely understood, there is wide agreement about its pathophysiology 25. As individuals gain weight, their tissue s sensitivity to insulin begins to decline. In response, pancreatic β- cells increase their production and secretion of insulin to maintain glucose homeostasis. If insulin resistance continues to decline, higher and higher quantities of insulin must be produced to facilitate glucose uptake into the tissues. Eventually, a point is reached where the pancreatic β- cells are no longer able to produce sufficient insulin, and glucose 5

17 Literature Review homeostasis begins to break down. As a result, without intervention, fasting glucose levels begin to rise leading to hyperglycemia COMPLICATIONS AND MORTALITY OF TYPE 2 DIABETES Consistent hyperglycemia, characteristic of prediabetes and DM2, increases the risk of developing serious diseases affecting the brain and blood vessels, eyes, mouth, heart, kidneys, and lower limbs 2. Diabetes is a leading cause of blindness, cardiovascular disease, kidney failure, and low- limb amputations 1. In addition, people with diabetes are also at increased risk of developing infections. Although it is difficult to precisely quantify the number of people that die from DM2 each year, diabetes and its complications are major causes of early death in most countries 1. Cardiovascular disease is especially concerning as it accounts for 50% or more of deaths due to diabetes, in some populations. Overall, people with diabetes live on average 5-10 years less, than those without the disease 27. Worldwide estimates predict that approximately 5.1 million people (8.4% of global all- cause mortality) aged years died from diabetes in In Canada, it is estimated that about one in every ten deaths (10.7%; approximately people) among adults aged 20 years or older, was attributable to DM RISK FACTORS OF TYPE 2 DIABETES A number of risk factors increase the risk of developing prediabetes and DM2. These include: obesity, poor diet, physical inactivity, advancing age, family history of diabetes, gestational diabetes and ethnicity 1. Central obesity is a key risk factor for DM2. Greater visceral fat mass, coupled with reduced lean muscle mass, is associated with insulin resistance and dyslipidemia 28. Similarly, excessive caloric intake and physical inactivity promote weight gain and the development of obesity. A person s risk of DM2 also increases with age, likely as a result of losing lean muscle mass and adoption of a more sedentary lifestyle. Most recently, interest in the role of genetics and epigenetics in the development of DM2, has revealed that a family history of diabetes can predispose a person to develop DM2. This observation may be explained by the thrifty genotype hypothesis, which postulates that prior selective selection of genes involved in more efficient energy and fat storage, during times of nutrient scarcity and famine, now predisposes us to 6

18 Literature Review obesity and cardiometabolic diseases, in times of excess. Differential possession of these thrifty genotypes may explain the differences in DM2 risk seen across ethnicities DIAGNOSIS OF PREDIABETES AND TYPE 2 DIABETES The Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada have set defined criteria for the diagnosis of prediabetes and DM2 29. A fasting plasma glucose value between mmol/l (referred to as impaired fasting glucose), a 2h postprandial glycaemia value between mmol/l from a 75g oral glucose tolerance test (referred to as impaired glucose tolerance), or a glycated hemoglobin (HbA1c) value between % is diagnosed as prediabetes. To be diagnosed with DM2, a patient must present with a fasting plasma glucose value 7.0 mmol/l, HbA1c value 6.5% (in adults), a 2h postprandial glycaemia value 11.1 mmol/l from a 75g oral glucose tolerance test, or a random plasma glucose value 11.1 mmol/l MEASURES OF GLYCEMIC CONTROL Glycemic control is most commonly assessed using one or a combination of the following measures: fasting plasma glucose, 2h postprandial glycemia (from a 75g- OGTT), glycated hemoglobin, or a random plasma glucose sample 29. Each measure has advantages and disadvantages, which are summarized in Table 1. Briefly, both fasting and random plasma glucose samples are fast and easy to obtain, but are limited in their measurement of glucose homeostasis at a single point in time. Administering a 75g- OGTT provides the benefit of a more dynamic assessment of glucose, but it is limited by high day- to- day variability in its results. HbA1c enables the assessment of long- term glucose control, but it cannot be used as a diagnostic in select patient populations. An additional limitation of glycated hemoglobin is that it can only be accurately used as a diagnostic in trials greater or equal to its half- life of approximately 36 days 30. For this reason, two trials in our glycemic control meta- analysis 13,18 used glycated albumin to measure long- term glycemic control, owing to its shorter half- life of approximately 20 days 31. 7

19 Literature Review Table 2.1. Advantages and disadvantages of diagnostic tests for diabetes. Adapted from 29. 2hPG = 2- hour plasma glucose; A1c = glycated hemoglobin; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test. Parameter Advantages Disadvantages FPG 2hPG in a 75- g OGTT A1C Well- established, single, standard measurement Easy and fast to conduct Well- established, standard measurement Measured any time of day (very convenient) Single, highly predictive measure of degree of hyperglycemia Low day- to- day variability Measures long- term glucose concentration High day- to- day variability Requires fasting (inconvenient) Static, single measure reflecting glucose homeostasis at just one point in time High day- to- day variability Inconvenient (requires continuous monitoring over 2-3 hours) Expensive to conduct Expensive to conduct Can be misleading if there are any underlying medical conditions that effect hemoglobin Values are altered by ethnicity and aging, and cannot be used in select populations Requires a standardized, validated assay MEASURES OF INSULIN SENSITIVITY A number of methods are available to assess hepatic and whole- body insulin sensitivity. As with glycemic control, each measure has advantages and disadvantages, which are summarized in Table 2. Briefly, insulin sensitivity measures using fasting values (fasting insulin, hepatic insulin sensitivity, and HOMA- IR) share the common advantage of being simple to obtain or compute, however, they also share a similar disadvantage of having high coefficients of variation. The remaining, more dynamic measures of insulin sensitivity, are better able to assess insulin sensitivity in specific tissues under conditions that are more physiologically relevant, but they are extremely time and cost intensive, and difficult to conduct. The hyperinsulinemic- eugylcemic clamp considered the gold standard for measuring insulin sensitivity fits into the later category. 8

20 Literature Review Table 2.2. Advantages and Disadvantages of Different Measures of Hepatic and Whole- Body Insulin Sensitivity. Advantages Disadvantages Hepatic Insulin Sensitivity Suppression of Endogenous Glucose Production Hepatic Insulin Sensitivity Index Homeostasis Model Assessment of Insulin Resistance (HOMA- IR) Similar to those reported below for the hyperinsulinemic- euglycemic clamp Tracers are safe and provide an excellent measure of true endogenous glucose production Provides a more useful estimate of hepatic insulin resistance than either fasting plasma insulin or hepatic glucose production would independently Easy to calculate Inexpensive Accurately predicts insulin resistance among normoglycemic individuals or those with mild diabetes; predictive power declines with increasing glycaemia Correlates well with hyperinsulinemic- euglycemic clamp (r=0.82) 34 Similar to those reported below for the hyperinsulinemic- euglycemic clamp Pulsatile nature of insulin secretion and diurnal fluctuations may limit the accuracy of the measure, particularly if only one measure of fasting insulin is used Assumptions underlying tracer methodology and the computation of the rate of hepatic glucose production may be incorrect Most studies only use one measure of fasting glucose and insulin, as opposed to three measures taken 5 minutes apart Assumes insulin sensitivity in the liver and peripheral tissues are equivalent Accuracy is limited by hyperglycemia High coefficient of variability, owing to the product of two highly variable measures Whole- Body Insulin Sensitivity Hyperinsulinemic- Euglycemic Clamp Provides a quantitative measure of insulin- mediated glucose disposal Provides a more physiological estimate of insulin sensitivity Enables dynamic assessments of insulin sensitivity at the exact site of interest (liver versus peripheral tissues) over time (5- min intervals) Can be individualized to the population studied and the research question asked Can be combined with other techniques to assess an enormous variety of information regarding physiologic aspects of glucose homeostasis Highly reproducible with a very low coefficient of variation Variables of interest (glucose, insulin etc.) can be manipulated independently Costly and invasive Complex method requiring trained personnel Sustained hyperinsulinemia is not representative of normal physiology Results may be difficult to compare between clamps, especially if they use different plasma glucose and/or insulin levels Cannot distinguish between insulin- dependent and insulin- independent glucose disposal 9

21 Literature Review Table 2.2. Continued Whole- Body Insulin Sensitivity Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGT) and Minimal Model Insulin Tolerance Test Matsuda- DeFronzo Insulin Sensitivity Index (derived from the 75g OGTT) Fasting Plasma Insulin Advantages Intravenous glucose administration avoids problems associated with glucose absorption or gastrointestinal hormone stimulation Minimal model adjusts for the effects of glucose on its own metabolism Conducted at near physiologic conditions Involves only one intravenous catheter Correlates well with hyperinsulinemic- euglycemic clamp (r=0.83 with glucose, r=0.89 with tolbutamide, and r=0.55 with insulin) Measures insulin- dependent glucose uptake and tissue sensitivity to glucose uptake independent of insulin Correlates well with hyperinsulinemic- euglycemic clamp (r=0.81) Can be calculated for persons with normal or impaired glucose tolerance or diabetes mellitus Correlates well with hyperinsulinemic- euglycemic clamp (r=0.73) Easy to obtain Inexpensive Accurately predicts insulin sensitivity among normoglycemic individuals Correlates well with hyperinsulinemic- euglycemic clamp Synthesized from 32,33. OGTT = oral glucose tolerance test. Disadvantages Correlation with hyperinsulinemic- euglycemic clamp declines in people who are markedly obese, impaired glucose tolerant, or diabetic Limited use in insulin deficient subjects Correlation with hyperinsulinemic- euglycemic clamp varies widely ( ) depending on the protocol used Does not allow the determination of the individual contributions of hepatic and peripheral tissues to overall insulin sensitivity Model is based on many assumptions about insulin and glucose kinetics, which may cause systematic errors Lengthy and invasive test Requires trained personnel Indirect estimate of overall insulin sensitivity Supraphysiologic does of insulin are used Does not differentiate peripheral versus hepatic insulin resistance Time- intensive Risk of hypoglycemia, particularly in normoglycemic or elderly diabetic subjects OGTT- derived measures of insulin sensitivity make it difficult to differentiate between peripheral, whole- body and hepatic insulin sensitivity separately Inaccurate in insulin- deficient states Results are poorly reproducible Time- intensive Non- specific (measures insulin sensitivity, secretion, distribution and degradation) Poor predictor of insulin sensitivity among individuals with prediabetes or DM2 Pulsatile nature of insulin secretion and diurnal fluctuations limits the measure s diagnostic utility 2.2. FRUCTOSE AND TYPE 2 DIABETES: Bray and colleagues (2004) 4 were the first to propose the idea that fructose may be implicated in the epidemic of obesity, showing a temporal relationship between the increasing 10

22 Literature Review availability of HFCS and the mirrored increase in the prevalence of overweight and obesity in the United States. Others drew further inferences postulating that excessive consumption of sugars, and particularly fructose, may represent a single etiology underlying the increased prevalence of both metabolic syndrome and type- 2 diabetes 35. In response to these claims, interest in the association between fructose and cardiometabolic disease risk has led to an incredible output of articles in the scientific literature, driven mainly by letters, editorials and commentaries, culminating in an invited commentary in the journal, Nature 5. Excessive fructose intake has now been implicated as the unique contributor to the increased global health burden of chronic cardiometabolic disease, with particularly focus on DM2, with calls to regulate it like tobacco or alcohol. These views represent a revival of those of John Yudkin, who argued that the consumption of sugar, not fat, was driving the epidemic of heart disease 36. Although this view fell out of favour by the early 1970s, as Ancel Keys swayed attention to the role of animal fat and cholesterol in heart disease, it has received a resurgence of support this past decade SOURCES OF FRUCTOSE IN THE DIET Sugars are typically found naturally in fruits and fruit products (predominantly as fructose), milk and milk products (lactose) or as additives in the form of sucrose (50% fructose) or high fructose corn syrup (42-55% fructose), utilized in the preparation and processing of refined foods 38. Among the sugars added to foods, fructose is most often cited as the major contributing factor to the rise in obesity and metabolic disorders in the United States 4. Since the mid 1970s, the introduction of corn sweeteners has led to a dramatic increase in the availability of high fructose corn syrup (HFCS), as it replaced sucrose in sugar- sweetened beverages in the US. The percent ratios of sucrose to HFCS to other sweeteners rose from 75:9:16 in 1978 to 44:42:14 in 2004, so the availability of sucrose (44%) and HFCS (42%) is approximately equal 39. There are several formulations of HFCS: HFCS- 42, HFCS- 55 and HFCS- 90, with distinct applications within the food production industry 38. HFCS- 42 is a mixture of 42% fructose and 53% glucose, and is used in beverages, processed foods, cereals, and baked goods. HFCS- 90 is composed of 90% fructose and 10% glucose and with the exception of a select few specialized applications; it is used predominantly to prepare HFCS- 55, a mixture of 55% fructose and 42% glucose, almost exclusively used to sweeten regular carbonated soft drinks. The most important sources of fructose in the US population are non- alcoholic beverages (46%) followed by grain products (17.3%) and fruit and fruit products (13.4%) (see Figure 2.1). 11

23 Literature Review HFCS- 55 and sucrose have similar composition, a near 1:1 glucose- to- fructose monosaccharide ratio, and the same relative sweetness 40. The main difference however, is that sucrose is a disaccharide with an alpha 1-4 glycoside bond joining fructose and glucose, whereas HFCS contains the two as monosaccharides free in solution. The covalent bond of sucrose is rapidly hydrolyzed in the lumen of the small intestine prior to absorption, releasing free glucose and fructose monosaccharides. There is therefore, broad scientific census that sucrose and HFCS are nutritionally and metabolically equivalent. Pure fructose, often confused with HFCS, is compositionally different from both sucrose and HFCS as it is composed of 100% fructose monosaccharides. Other% 3.2%% Milk%and%Milk% Products% 7.1%% Grain%Products% 17.3%% Nonalcoholic%Beverages% 46.0%% Fruit%and%Fruit%Products% 13.4%% Sugars%and%Sweets% 10.3%% Vegetables%and%Vegetable% Products% 2.7%% Figure 2.1. Percentage of Dietary Intake for Total Fructose by Food Source. Adapted from Marriott and colleagues POPULATION LEVELS OF SUGAR INTAKE IN THE US AND CANADA Although the availability of sugars has increased considerably since the mid 1970s 41, over the last decade, total added sugar intake has begun to decrease in the United States. A recent analysis of the National Health and Nutrition Examination Survey (NHANES) III from (n=42, 316) showed that the intake of added sugars in the U.S. has decreased from g/day (18.1% energy) to g/day (14.6% energy), with two- thirds of this reduction attributed to decreased intakes of sugar- sweetened beverages (SSBs) 42. Reductions in the contribution of 12

24 Literature Review fructose to the diet have also followed these trends. The mean intake of total fructose in the U.S. population has now reached 49- g/day (9.1% energy intake) with the top 5% of the population consuming 87- g/day (14.6% energy intake) 39. Of these intakes 41- g/day (84% total) and 78- g/day (90% total), respectively, are contributed by fructose from added sources. Another analysis of the NHANES III data reported similar results, concluding that if children and adults eliminated all sources of fructose except for fruits and vegetables, they would eliminate 82% and 75% of their entire fructose intake, respectively 43. Canadian data report a similar declining trend in population- levels of sugar consumption 44. Over the last three decades, despite the almost exclusive use of HFCS in sweetened beverages, added sugar intakes have been stable or modestly declining as a percentage of total energy. In 2010, Canadians were consuming between 11-13% of their total energy in the form of added sugars. This translates into roughly g/day (11%) to g/day (13%) GUIDELINES FOR SUGAR AND FRUCTOSE CONSUMPTION In an effort to prevent further weight gain in individuals at risk for, or living with DM2, international diabetes associations 29,45,46 have taken a harm- reduction approach to dietary sugar recommendations, setting upper thresholds for sucrose and fructose intake (see Table 2.3). The Canadian Diabetes Association s (CDA) updated 2013 Nutrition Therapy Guidelines state that added sugars (sucrose or fructose) can be substituted for other carbohydrates up to a maximum of 10% total daily energy intake, without risk for adverse effects, provided that blood glucose and lipids are well maintained 29. The American Diabetes Association (ADA) makes a similar statement in its most recent Nutrition Therapy Recommendations for the Management of Adults with Diabetes, suggesting an upper threshold of 12% energy from naturally occurring fructose, and that individuals avoid excess energy from sucrose 45. Both the CDA and ADA acknowledge that the consumption of naturally occurring fructose (such as in fruit) may benefit glycemic control, compared with isocaloric intake of sucrose or starch. Although the guidelines reach census in recommending that sucrose be avoided and that naturally occurring fructose be restricted, based on its putative potential to adversely effect blood lipids, differences in the thresholds for harm set by the different guidelines reflect some of the uncertainty in the evidence on which they are based. Other guidelines have taken a similar approach. Cardiovascular 47,48, hypertension 41,49,50, and dyslipidemia guidelines recommend liming added sugar consumption primarily to lower 13

25 Literature Review total calorie intake and maintain healthy body weight; to promote nutrient adequacy and the consumption of an overall healthy diet; and to prevent the onset of chronic diseases. The United States Department of Agriculture s recommendations are also based on the considerations mentioned above, however those of the joint World Health Organization and Food and Agriculture Organization of the United Nations (WHO/FAO) 56 and of the Institute of Medicine (IOM) 57 relate to reducing dental carries, and to ensuring adequate micronutrient consumption, respectively. 14

26 Literature Review Table 2.3. Summary of Current Dietary Guidelines Regarding the Consumption of Sugars and Fructose and the Prevention of Chronic Diseases. WHO/FAO = World Health Organization / Food and Agriculture Organization; USDA = United States Department of Agriculture; IOM = Institute of Medicine; ADA = American Diabetes Association; CDA = Canadian Diabetes Association; EASD = European Association for the Studies of Diabetes; AHA = American Heart Association; JNC7 = Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; CHEP = Canadian Hypertension Education Program; CCS = Canadian Cardiovascular Society; NCEP- ATP III = Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. GUIDELINE SUGARS FRUCTOSE General'Dietary'Advice WHO/FAO'2003'[56] '<10%'energy'free'sugars C USDA'2010'[55] 25%'energy'added'sugars C IOM'2002'[57] 25%'energy'added'sugars C Diabetes'Recommendations ADA'2013'[45] Avoid'excess'energy'from'sucrose 12%'energy'from'naturally'occuring'fructose CDA'2013'[29] 10%'energy'added'sucrose 10%'energy'added'fructose EASD'2004'[46] 10%'energy'total'free'sugars 30Cg/day'fructose Cardiovascular'Recommendations AHA'2006'[47] Minimize'added'sugars'from'beverages'and'foods C AHA'2009'[48] 100C150'calories/day''(~5%'total'energy)'added'sugars C Hypertension'Recommendations JNC7'[50] C C CHEP'[49] ' 5CTbsp/week'of'sugar Have'4C5'servings'of'fruit'daily Dyslipidemia'Recommendations CCS'2009'[52] A'diet'low'in'simple'sugars C CCS'2012'[51] C C NCEPC'ATP'III'[54] Reduce'sugar'containing'beverages C AHA'2011'[53]'(fasting'triglycerides) Borderline'(150C199'mg/dL) High'(200C499'mg/dL) Very'High'( 500'mg/dL) <10%'energy'added'sugar 5C10%'energy'added'sugar <5%'energy'added'sugar <100Cg/day'fructose 50C100Cg/day'fructose <50Cg/day'fructose 15

27 Literature Review ECOLOGICAL ANALYSES OF SUGARS AND CHRONIC DISEASE Although ecological studies are considered a weak level of evidence, they have been overwhelmingly cited in support of the fructosecentric view of cardiometabolic disease. Historically, the introduction of sugars into a population has preceded, and perhaps facilitated, an increase in the prevalence of obesity, and its associated comorbidities: DM2, premature cardiovascular disease, and cancer 35. Johnson and colleagues 35 (2009) have extensively reviewed the link between sugars and cardiometabolic disease among various indigenous populations, and within people who have immigrated to countries where sugar intake is high. They report a transition from healthy individuals absent of chronic disease to a population with excessive rates of obesity, diabetes and cardiovascular disease. Ecological studies provide a convincing case for the putative link between sugars and cardiometabolic disease; however, they are ultimately limited in their ability to establish an association, with certainty, due to the potential for residual confounding. Two recent ecological analyses have shown similar associations between the availability of HFCS 58 and total sugars 59 and an increased prevalence of type 2 diabetes. In an analysis of 43 countries, the prevalence of diabetes was 20% higher in countries that use HFCS compared to those that do not 58. Similarly, diabetes prevalence was found to increase by 1.1% for every 150 kcal per person per day increase in the total sugar availability in an analysis of 175 countries 59. Although adjustments for certain potential confounders were applied, residual confounding cannot be ruled out. Further, the estimates provided may be suspect due to the pooling of heterogeneous measurements of exposure (both for the availability of HFCS or sugars and the potential confounders for which adjustments were made) and disease incidence. It is important to note, however, that not all ecological data have shown a positive trend with sugar intake and diabetes rate. As the consumption of total nutritive sweeteners, including HFCS, increased in the United States during , their consumption declined substantially in Australia and the United Kingdom (Figure 2.2). In Australia, the prevalence of obesity among adults and children increased in line with other Western populations, despite a 10% decrease in the contributions of sugar from sugar- sweetened beverages. This Australian Paradox has called into question the value of focusing public health interventions on reducing the consumption of sugar and sugar- sweetened beverages, as a strategy to reverse societal trends in obesity 60. A similar paradox has also been seen in the United States over the last decade 42, where the prevalence of obesity and diabetes continues to rise, despite reductions in the intake of total added sugars

28 Literature Review Figure 2.2. Availability of Added Sugars (kg/capita/year) in Australia and the United Kingdom. Adapted from Barclay and Brand- Miller,

29 Literature Review ANIMAL MODELS OF FRUCTOSE FEEDING Animal studies have been frequently cited as providing considerable evidence of a biologically plausible mechanism for fructose s adverse metabolic effects. However, key metabolic and methodological differences between animal and clinical trials limit our ability to extrapolate these findings to humans. Fructose, unlike glucose, is uniquely able to bypass phosphofructokinase, allowing it to contribute significantly to the process of de novo lipogenesis (DNL), as an unregulated substrate, and to promote downstream metabolic complications (see Figure 2.3). It has been well established that excess fructose feeding in animals induces a metabolic syndrome phenotype with obesity, insulin resistance, hypertension, and dyslipidemia and the consistency of this effect has led to the development of a number of high fructose- fed animal models 66,67. In rodents, as many as 60-70% of total fatty acids are synthesized through this pathway, while in humans it is quantitatively insignificant, contributing <5% 6. Two recent reviews of isotopic tracer studies in humans have shown that DNL from fructose contributes less <1% to total triglyceride synthesis, whereas the conversion to glucose (~41%), lactate (~28%), glycogen (>15%) and its overall oxidation (~45%) is much higher 68,69. Furthermore, fructose is typically administered to animals at supraphysiologic doses ( 60% energy), an unrepresentative dose compared to the median population fructose intake of 10% of energy 39. These considerations greatly limit the utility of animal models beyond animal physiology and pharmacology. Fructose has also been shown to illicit adverse systemic effects in animal models through the elevation of uric acid (see Figure 2.3) 35, and the uncoupling of hormonal regulation of food intake 70. While select human studies have also provided support for uric acid mediated mechanisms 71 and impaired satiety signalling involving insulin, leptin and ghrelin 72,73, it is uncertain whether these mechanisms actually translate into downstream increases in obesity, diabetes, and cardiometabolic complications at population levels of exposure PROSPECTIVE COHORT TRIALS TOTAL AND INDIVIDUAL SUGARS, METS, AND DM2 Prospective cohort studies offer the highest quality evidence among observational study designs. Several prospective cohort studies have investigated the association between intake of total sugars, sucrose, or fructose and the risk of DM (see Table 2.4), reporting differential effects between sugar intakes measured as total or individual sugars (sucrose or fructose) or as 18

30 Literature Review sugar- sweetened beverages. Available prospective cohorts fail to report a consistent positive association between total fructose- containing sugars and incidence of DM2 74,75,77,78,80 (see Table 2.4). The results have been similarly inconclusive for data regarding individual sugars. Among the five trials reporting an association for fructose 74,78-81, two report positive associations RR (95%) 1.62 (1.01, 2.59) 80 and 1.27 (1.06, 1.54) 79, two report no association 78,81 and the final reports a negative association HR (95%) 0.88 (0.78, 0.99) 74 with DM2 risk. None of the trials measuring sucrose reported a significant positive association 74-83, in fact, a systematic review and meta- analysis of ten prospective cohort studies of sucrose reported a 15% lower risk of diabetes comparing extreme quintiles of intake 84. A similar lack of consistent association has been shown for total fructose- containing sugars and other related cardiometabolic diseases, including hypertension 85 and coronary heart disease (CHD) 86. Under conditions where positive associations were seen, comparisons were between the highest and lowest intakes of total fructose. There were no associations seen at levels of exposure equivalent to, or below, the 50 th percentile for fructose intake in the US 39. Gout is the one exception SUGAR- SWEETENED BEVERAGES, METS, AND DM2 Sugar sweetened beverage (SSB) consumption has been more consistently associated with an adverse effect on metabolic syndrome (MetS) and DM2. A systematic review and meta- analysis of the available prospective cohort studies (3 for MetS and 8 for DM2) 80,88-96 reported evidence of a significant association between sugar- sweetened beverages and risk of DM2 (RR = 1.26 (95% CI, 1.12, 1.41)) and MetS (RR = 1.20 (95% CI, 1.02, 1.42)), comparing the highest with the lowest levels of exposure 8. None of the studies included showed a significant association with adverse risk at levels of SSB consumption equivalent to or below the 50 th percentile for added sugars for fructose intake in the US 39,42. Other cardiometabolic outcomes have also been linked to the consumption of extreme doses of SSB. A recent World Health Organization (WHO) commissioned systematic review and meta- analysis showed that SSBs increase the risk for overweight and obesity (OR = 1.55 ((95% CI, 1.32, 1.82)), when comparing the highest and lowest intakes in children 97. Similar comparisons within individual cohort studies have shown increases in BMI 96 and a higher risk for hypertension 98, gout 87, CHD 99 and stroke 100. As was the case with MetS and DM2, these associations were not sustained at levels of intake equivalent to or below the 50 th percentile for added sugars or fructose 19