Improved Nutrition in Early Life and Cardiometabolic Outcomes in Guatemala Open Access
He, Siran (Spring 2020)
Abstract
There is a global epidemic of cardiometabolic diseases. Metabolic flexibility, which can be assessed through meal challenges, is integral to cardiometabolic health. Previous research drew inconsistent linkages between early-life nutrition and cardiometabolic conditions in adulthood. The overarching goal of this dissertation is to investigate the pathways through which early nutrition affects long-term cardiometabolic health.
This research is nested within the Institute of Nutrition of Central America and Panama (INCAP) Longitudinal Study in Guatemala, a cluster randomized controlled trial conducted in 1969-77 with subsequent follow-up studies. In 2015-17, plasma samples were obtained both at the fasted state and two-hour after a meal challenge. We performed assays for lipids, glycemic markers, and inflammation markers.
First, through difference-in-difference modeling and mediation analysis, we examined the role of leptin. We observed that leptin partially mediates the pathway between early-life nutrition and glycemic status (only in women). The mediation was associated with improved pancreatic β-cell function, and not with reduced insulin resistance. Second, to describe the metabolic flexibility in this population, we assessed the postprandial biomarker responses, and compared the responses across strata of cardiometabolic phenotypes. We observed that the underlying pathways, particularly glycemic pathway, differed across cardiometabolic phenotypes. Subsequently, we compared metabolic flexibility between those who were exposed to improved nutrition in early life versus others. At the multi-marker level, overall postprandial biomarker responses did not differ by early-life nutritional exposure. However, response in the glycemic domain differed between exposure groups. At the single-marker level, glucose response was attenuated in the improved nutrition group. These findings strengthened our previous observation of reduced fasting glycemia among those exposed to improved nutrition. We postulated that nutrition improvements in early life contribute to euglycemia by enhancing metabolic flexibility.
By integrating assessments of metabolic flexibility into a long-term cohort study, we extended previous research in this population. We also provided context for this work through a systematic review and meta-analysis to summarize global evidence on the association of nutrition interventions in early life and cardiometabolic outcomes. Altogether, the findings support evidence-based maternal and child nutrition interventions to promote long-term cardiometabolic health and to avoid unintended consequences.
Table of Contents
CHAPTER 1: INTRODUCTION...1
1.1 BACKGROUND 1
1.2 SPECIFIC AIMS 6
1.3 OVERVIEW OF THE CHAPTERS 8
CHAPTER 2: LITERATURE REVIEW PART I...10
2.1 ABSTRACT 10
2.2 INTRODUCTION 12
2.3 METHODS 13
2.4 RESULTS 17
2.5 DISCUSSION 21
2.6 TABLES, FIGURES, AND SUPPLEMENTAL MATERIALS 28
2.7 REFERENCES 57
CHAPTER 3: LITERATURE REVIEW PART II ...69
3.1 INTRODUCTION 69
3.2 CARDIOMETABOLIC BIOMARKERS AT THE FASTED STATE 71
3.3 STRESS-INDUCED RESPONSES IN BIOMARKERS 81
3.4 BIOMARKER-CENTERED CONCEPTUAL FRAMEWORKS 89
CHAPTER 4: METHODOLOGY...96
4.1 OVERVIEW OF METHODOLOGY 96
4.2 STUDY POPULATION 97
4.3 SOURCES OF DATA 98
4.4 LABORATORY METHODS 102
4.5 SAFETY AND CONFIDENTIALITY 107
4.6 ASCERTAINMENT OF DATA QUALITY 108
4.7 STATISTICAL ANALYSIS 110
4.8 METHODOLOGIES IN THE CORE CHAPTERS 118
CHAPTER 5: MANUSCRIPT FOR SPECIFIC AIM 1...120
5.1 ABSTRACT 120
5.2 INTRODUCTION 122
5.3 SUBJECTS AND METHODS 123
5.4 RESULTS 130
5.5 DISCUSSION 132
5.6 TABLES AND FIGURES 137
5.6 REFERENCES 148
CHAPTER 6: MANUSCRIPT FOR SPECIFIC AIM 2...152
6.1 ABSTRACT 152
6.2 INTRODUCTION 154
6.3 MATERIAL AND METHODS 155
6.4 RESULTS 159
6.5 DISCUSSION 162
6.6 TABLES, FIGURES, AND SUPPLEMENTAL MATERIALS 170
6.7 REFERENCES 187
CHAPTER 7: MANUSCRIPT FOR SPECIFIC AIM 3...191
7.1 ABSTRACT 191
7.2 INTRODUCTION 193
7.3 METHODS 195
7.4 RESULTS 199
7.5 DISCUSSION 202
7.6 TABLES, FIGURES, AND SUPPLEMENTAL MATERIALS 208
7.7 REFERENCES 220
CHAPTER 8: SUMMARY AND CONCLUSIONS...226
8.1 SUMMARY OF MAIN FINDINGS 226
8.2 LIMITATIONS 230
8.3 STRENGTHS AND INNOVATIONS 234
8.4 PUBLIC HEALTH IMPLICATIONS 236
8.5 FUTURE DIRECTIONS 240
8.6 CONCLUSIONS 242
APPENDIX I: LAY SUMMARY OF THE DISSERTATION...243
APPENDIX II: SUPPLEMENTAL TABLE FOR CHAPTER 2...245
REFERENCES FOR CHAPTERS 1, 3, 4, 8...281
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