Nutritional Signaling Pathway Activities in Obesity and Diabetes

Zhiyong Cheng

• Publisher: Royal Society of Chemistry
• Year: 2020
• eBook ISBN: 9781839160615
• Edition: 1
• Topic: Medicine
• Subtopic: Nutrition, Dietics & Bariatrics

Nutrients can act as signalling molecules to initiate or mediate signalling transduction that regulates cell function and homeostasis. As such, altered nutrient status has been linked to dysregulated transcripts and protein expression, which affects mitochondrial function, autophagy, inflammation, metabolism and even gut microbiota. This book disseminates the cutting-edge knowledge pertaining to nutritional signalling activities in metabolism and metabolic derangements (e.g., obesity and diabetes), which covers the regulatory mechanisms and dietary interventions for disease prevention.

This book represents current nutritional and metabolic research. From the basic (molecular science) perspective, it covers metabolomics, proteomics, nutrigenomics, nuclear receptors and transcription factors, inflammatory pathways, autophagy, mitochondrial health and gut microbiota. From the clinical (translational science) perspective, this book covers clinical trials, precision nutrition, maternal nutrition and transgenerational health, and allometric scaling of dietary bioactives in translational metabolic research. It brings to the reader in-depth understanding of the nutritional aspect, cellular and molecular biology, as well as pathophysiology of obesity and diabetes. In addition, each chapter in this book includes a component of future direction or intervention perspective, making the new knowledge transformative and translational. Aimed at researchers and professionals interested in nutrition, dietetics and metabolic disorders, this book will also appeal to health science researchers.

CHAPTER 1

Diabetes and Obesity: An Overview of Nutritional Effects

SONIA DE ALWIS AND MICHAEL A. VIA^*

Division of Endocrinology, Diabetes, and Bone Disease, Mount Sinai Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, New York NY 10003, USA

^*E-mail: [email protected]

1.1Introduction

Type 2 diabetes (T2D) has evolved into a leading public health concern both for its high prevalence and devastating complications. Current global estimates of 422 million individuals affected by T2D represent a fourfold increase since 1980, with a continued rapid rise.¹ The International Diabetes Federation (IDF) similarly quotes 451 million individuals affected aged 18–99 years in 2017 (8.4%), with a projected prevalence of 693 million or 9.9% by 2045.² Interestingly, the rise in incidence comes at a time when accumulated evidence clearly demonstrates that T2D is a preventable disease.³ Prior to the 1900s, T2D and obesity were exceedingly rare, affecting two individuals per 100 000 population and 1 in 30 persons, respectively.⁴ The modern-day lifestyle has largely contributed to the overwhelming disease burden, in part due to the increasing availability of processed foods and a sedentary lifestyle facilitated by technology. Obesity, itself, confers a fourfold increase in risk of T2D, and represents the single greatest modifiable risk factor for development of the disease.⁵ In contrast to T2D, Type 1 diabetes (T1D) results from the loss of pancreatic β-cell production of insulin most often through autoimmune mechanisms.⁴ Though patients with T1D also benefit from dietary modification,⁵ strategies for T1D are beyond the scope of this chapter and book, which focus on insulin resistance syndromes. Given the extensive disease morbidity, mortality, and global healthcare expenditure, an intensive lifestyle intervention that includes a nutrient-rich dietary pattern, among other modifications, is vital for prevention and management of these chronic metabolic conditions.^6,7

1.2Mechanisms of Insulin Resistance and Metabolic Syndrome

The presence of insulin resistance may be demonstrated in patients long before the development of T2D and is believed to serve as the main underlying driver of the disease process.⁸ Obesity predisposes to insulin resistance through a number of complex mechanisms, in part related to increased adipocyte size and quantity and to adipocyte dysfunction.⁹ Adipose tissue, traditionally viewed as simple fat storage, is now more aptly recognized as an active endocrine organ that secretes adipokines, including adiponectin, leptin and resistin, which regulate multiple metabolic pathways involved in glucose homeostasis.^10–12 The excess caloric intake associated with obesity overwhelms adipocyte mechanisms, resulting in dysregulated adipokine secretion, and ultimately a pro-inflammatory state.¹³ Enlarged adipocytes further encourage macrophage recruitment to the tissue, prompting chronic low-grade inflammation.¹⁴ Once established, insulin resistance behaves as a highly disruptive state to regulation of metabolism, exerting widespread effects that include raised glucagon activity during meals that results in inappropriate prandial hepatic glucose release, impaired glucagon-like peptide 1 (GLP-1) release, leptin resistance, reduced ghrelin and adiponectin activity, systemic endoplasmic reticulum stress, systemic inflammation, and pancreatic β-cell dysfunction which culminate clinically as T2D.¹⁵ Similar pathophysiologic mechanisms are observed in other conditions of insulin resistance, including the metabolic syndrome (MetS), hypertriglyceridemia, non-alcoholic hepatosteatosis, and polycystic ovarian syndrome (PCOS).

MetS represents a composite of clinical risk factors that predict insulin resistance, and cumulatively contribute to high risk for atherosclerotic cardiovascular disease (ASCVD).¹⁵ Though published classifications vary slightly, the National Cholesterol Education Program Adult Treatment Panel III defines MetS by the presence of three of the following five parameters: (1) increased abdominal girth (waist circumference >102 cm in men and >88 cm in women); (2) hypertension (systolic blood pressure >130 mmHg and diastolic blood pressure >85 mmHg); (3) elevated circulating triglycerides (>150 mg dL^–1); (4) reduced circulating high-density lipoprotein (HDL) levels (<40 mg dL^–1 in men and <50 mg dL^–1 in women); and (5) elevations in serum glucose concentrations (fasting serum glucose >100 mg dL^–1).¹⁶ Using these criteria, MetS was observed in 33% of adults in the US population in 2012, and demonstrates a rising prevalence worldwide.¹⁷ Due to overlapping pathophysiology, hepatosteatosis, seen in approximately 30% of US adults, and PCOS, observed in 7–10% of reproductive-age women, are also highly prevalent in modern populations.^18,19

Dietary strategies leading to significant and sustained weight loss can successfully hamper the underlying pathophysiologic mechanisms and mitigate both the development and progression of syndromes of insulin resistance, including T2D and MetS, as well as hepatosteatosis and PCOS by extension (Figure 1.1).

Figure 1.1Adipocyte function in health and disease.¹³ Reproduced with permission © Mount Sinai Health System.

1.3Prevention Trials

Several landmark trials support the hypothesis that lifestyle interventions leading to weight loss can substantially alter metabolic factors that predispose to T2D and MetS. The first, in 1997, the Da Qing Trial²⁰ in China, involved 577 individuals with impaired glucose tolerance randomly assigned to either conventional lifestyle or one of three treatment groups consisting of dietary intervention, physical activity (PA), or both. All three intervention groups were associated with a significant reduction in the incidence of T2D as compared to control, with an incidence of 67.7%, 43.8%, 41.1%, and 46% with conventional lifestyle, dietary intervention, PA intervention, and both diet and PA interventions, respectively, providing early evidence for lifestyle intervention as a low-cost and effective method of preventing these challenging diseases.

The Finnish Diabetes Prevention Study²¹ (DPS) was another early, randomized trial to demonstrate a causative association between lifestyle modification and T2D prevention in high-risk individuals. The Finnish DPS consisted of 522 overweight adults aged 40–64 with impaired glucose tolerance randomized to either an intensive lifestyle group or a control group receiving standard of care dietary recommendations. With target weight loss of at least 5% body weight, the study showed a 58% risk reduction of developing T2D at 3 years, 43% at 7 years, and 32% reduction at 13-year follow-up compared to the control group. Marked improvement was also noted with respect to glycemic control and cholesterol levels with lifestyle intervention.

In a larger randomized trial of 3234 participants in the United States, the Diabetes Prevention Program²² (DPP) confirmed the findings of the Finnish DPS by further demonstrating the impact of an intensive lifestyle intervention for the prevention of T2D in high-risk populations. Results from the DPP showed a 58% reduction in the incidence of T2D with an intensive ...

Table of contents

• Cover
• Half Title
• Series Information
• Title Page
• Copyright Page
• Preface
• Contents
• Chapter 1 Diabetes and Obesity: An Overview of Nutritional Effects
• Chapter 2 Maternal Nutrition and the Risk of Obesity and Diabetes in the Offspring
• Chapter 3 Lessons Learned from Recent Clinical Trials Targeting Diets to Treat and Prevent Obesity and Diabetes
• Chapter 4 Nutritional Regulation of Inflammation in Obesity and Diabetes
• Chapter 5 The Interaction of Nutrition with Nuclear Receptors in Obesity and Diabetes
• Chapter 6 Nutritional Regulation of Mitochondrial Health and Its Implication in Treating Obesity and Diabetes: Lessons Learned From the Resveratrol–Sirt1 Axis
• Chapter 7 The Role of Intestinal Microbiota and Microbial Metabolites in the Development of Host Metabolic Syndrome
• Chapter 8 Metabolomics in Nutritional Metabolism, Obesity, and Diabetes
• Chapter 9 Proteomics in Nutrition, Obesity and Diabetes Research
• Chapter 10 Personalized Nutrition to Treat and Prevent Obesity and Diabetes
• Chapter 11 Allometric Scaling of Dietary Bioactives in Metabolic Research: The Present and Future
• Subject Index