Molecular Nutrition and Diabetes: A Volume in the Molecular Nutrition Series

Molecular Nutrition and Diabetes: A Volume in the Molecular Nutrition Series focuses on diabetes as a nutritional problem and its important metabolic consequences. Fuel metabolism and dietary supply all influence the outcome of diabetes, but understanding the pathogenesis of the diabetic process is a prelude to better nutritional control.

Part One of the book provides general coverage of nutrition and diabetes in terms of dietary patterns, insulin resistance, and the glucose-insulin axis, while Part Two presents the molecular biology of diabetes and focuses on areas such as oxidative stress, mitochondrial function, insulin resistance, high-fat diets, nutriceuticals, and lipid accumulation. Final sections explore the genetic machinery behind diabetes and diabetic metabolism, including signaling pathways, gene expression, genome-wide association studies, and specific gene expression. While the main focus of each chapter is the basic and clinical research on diabetes as a nutritional problem, all chapters also end with a translational section on the implications for the nutritional control of diabetes.

• Offers updated information and a perspective on important future developments to different professionals involved in the basic and clinical research on all major nutritional aspects of diabetes mellitus
• Explores how nutritional factors are involved in the pathogenesis of both type1 and type2 diabetes and their complications
• Investigates the molecular and genetic bases of diabetes and diabetic metabolism through the lens of a rapidly evolving field of molecular nutrition

• Language: English
• Publisher: Academic Press
• Release date: Dec 8, 2015
• ISBN: 9780128017616

Book preview

Molecular Nutrition and Diabetes

A Volume in the Molecular Nutrition Series

Editor

Didac Mauricio

Department of Endocrinology and Nutrition, CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), University Hospital & Health Sciences Research Institute Germans Trias i Pujol, Badalona, Spain

Table of Contents

Cover image

Title page

Series Preface

Copyright

Dedication

Contributors

Preface

Acknowledgments

Section 1. General and Introductory Aspects

Chapter 1. Nutrition and Diabetes: General Aspects

1. Introduction

2. Historical Perspective

3. Guidelines

4. Evidence from Clinical Trials

5. Further Research

6. Conclusions

Chapter 2. Dietary Patterns and Insulin Resistance

1. Introduction

2. Carbohydrates

3. Lipids

4. Proteins

5. Concluding Remarks

Chapter 3. β-Cell Metabolism, Insulin Production and Secretion: Metabolic Failure Resulting in Diabetes

1. Introduction to Pancreatic β-Cell Metabolism and Metabolic Links to Insulin Secretion

2. The Role of Glucose Metabolism, Fatty Acid Metabolism, and Amino Acid Metabolism in the Generation of Metabolic Stimulus–Secretion Coupling Factors

3. Nutrient Regulation of β-Cell Gene Expression

4. Metabolic Failure in β-Cell Dysfunction and Onset of Diabetes

5. The Cross-Talk of Apoptosis with ROS and ER Stress in β-Cell Dysfunction

6. Concluding Remarks

Chapter 4. Diet–Gene Interactions in the Development of Diabetes

1. Early History of the Disease and the Seesaw of the Dietary Therapies

2. Nutritional Management of Diabetes in the Twenty-First Century

3. Diabetes, a Complex Disease with a Significant Genetic Component

4. The Role of Gene–Diet Interactions in Diabetes Risk

5. Concluding Remarks

Chapter 5. Pathogenesis of Type 1 Diabetes: Role of Dietary Factors

1. Dietary Factors Involved in Type 1 Diabetes Development

2. T1D, Celiac Disease, and Gluten Intake

3. Dietary Gluten

4. Gluten Peptides Are Resistant to Intestinal Degradation

5. Dietary Gluten Influences the Development of T1D

6. The Immune Response to Gluten in T1D Patients

7. The Effect of Gluten on T1D Depends on Dose, Context, and Timing

8. Gluten Intake, T1D, and the Intestinal Microflora

9. Intestinal Alterations in Animal Models of T1D and Human Patients

10. The Number of Pancreas-Infiltrating Autoreactive T Cells Is Increased in the Intestinal Tissue

11. Intake of Gluten Changes Specific Immune System Parameters

12. Gluten Is Found in Blood and Could Affect the Pancreatic β Cells

13. Conclusion

Section 2. Molecular Biology of the Cell

Chapter 6. Oxidative Stress in Diabetes: Molecular Basis for Diet Supplementation

1. Introduction

2. Oxidative Stress and Oxidation Damage in Diabetes

3. Oxidative Stress and Oxidation Damage in Diabetic Complications

4. Antioxidants in Diabetes: Implications for Use of Bioactive Food Components

5. Conclusions

Chapter 7. Impact of Type 2 Diabetes on Skeletal Muscle Mass and Quality

1. Introduction

2. Regulation of Protein Degradation in Skeletal Muscle

3. Skeletal Muscle Mass in Insulin Resistance and T2D

4. TP53INP2 and its Role in Autophagy

5. TP53INP2 in Skeletal Muscle and T2D

6. Skeletal Muscle Quality in Insulin Resistance and T2D

7. Mitochondrial Dynamics, Mitophagy, and Insulin Resistance

8. Concluding Remarks

Chapter 8. Mechanisms Whereby Whole Grain Cereals Modulate the Prevention of Type 2 Diabetes

1. Introduction

2. Whole Grains versus Refined Flour

3. Meta-Analyses and Epidemiological Studies

4. Intervention Studies

5. Mechanisms of Action

6. Conclusions

Chapter 9. Peroxisome Proliferator-Activated Receptors (PPARs) in Glucose Control

1. PPAR: An Overview

2. Molecular Mechanisms of PPAR Activation

3. The Role of PPARs in the Control of Glucose Metabolism

4. Dietary-Derived PPAR Ligands as Supplementary Strategies in Glucose Control

5. Conclusions

Chapter 10. High-Fat Diets and β-Cell Dysfunction: Molecular Aspects

1. Introduction

2. Biology of the β Cell

3. Compensatory Response of the β Cell to High-Fat Diet-Induced Insulin Resistance

4. High-Fat Diet and β-cell Failure and Death

5. Concluding Remarks

Chapter 11. Native Fruits, Anthocyanins in Nutraceuticals, and the Insulin Receptor/Insulin Receptor Substrate-1/Akt/Forkhead Box Protein Pathway

1. Anthocyanins: General Characteristics

2. Anthocyanin Sources in Foods of Plant Origin

3. Health Effects of Anthocyanins

4. Insulin Signaling Pathway

5. Molecular Mechanisms of Insulin Resistance

6. Insulin Sensitizing and Antidiabetic Properties of Anthocyanins

7. Concluding Remarks

Chapter 12. Influence of Dietary Factors on Gut Microbiota: The Role on Insulin Resistance and Diabetes Mellitus

1. Introduction

2. Influence of Dietary Factors on Gut Microbiota

3. Impact of Prebiotics, Probiotics, and Exercise on Gut Microbiota

4. Gut Microbiota Interactions with Insulin Resistance and Diabetes

5. Gut Microbiota and Type 1 Diabetes

6. Future Perspectives

Chapter 13. Molecular Aspects of Glucose Regulation of Pancreatic β Cells

1. Introduction

2. Intracellular Glucose Signaling

3. Glucose as a Mitogenic Signal for β Cells

4. Glucose Signaling and β-Cell Transcription

5. Glucotoxicity

6. Concluding Remarks

Chapter 14. Metals in Diabetes: Zinc Homeostasis in the Metabolic Syndrome and Diabetes

1. Introduction

2. Zn and Insulin

3. A Potential Risk of Zn Deficiency for the Metabolic Syndrome and Diabetes

4. Effect of Diabetes on Zn Homeostasis

5. Prevention and/or Improvement of Metabolic Syndrome and Diabetes by Zn Supplementation as well as Possible Mechanisms

6. Conclusions

7. Potential Clinical Implication for the Management of Diabetic Patients

Chapter 15. Cocoa Flavonoids and Insulin Signaling

1. Introduction

2. Physiology of Insulin Action

3. Pathophysiology of Insulin Action

4. Dietary Flavonoids

5. Cocoa Flavonoids

6. Cocoa Flavonoids and Insulin Action

7. Conclusions

List of Abbreviations

Chapter 16. Dietary Proanthocyanidin Modulation of Pancreatic β Cells: Molecular Aspects

1. Proanthocyanidins: A Brief Description

2. Proanthocyanidins and Type 1 Diabetes

3. Type 2 Diabetes

4. Proanthocyanidin Effects in Glucose Homeostasis on Insulin Resistance and on T2D

5. Proanthocyanidin Effects on Insulin Sensing Tissues

6. Proanthocyanidin Effects on β-Cell Functionality: Control of Insulin Production

7. Proanthocyanidin Effects on the Incretin System

8. Human Studies

9. Conclusions

Chapter 17. Dietary Whey Protein and Type 2 Diabetes: Molecular Aspects

1. Introduction

2. Constituents of the WP

3. Studies in Support of the Antihyperglycemic Effect of Whey

4. What Do Exercise and Dietary Protein Have to Do with Hyperglycemia?

5. Type, Amount, and Form of Taking the Protein

6. Whey Proteins and the Incretins

7. Whey Peptides, Stress, and the Heat-Shock Proteins

8. Possible Strategies for a More Rational Use of Whey Peptides

9. Conclusions

Chapter 18. Dietary Fatty Acids and C-Reactive Protein

1. Introduction

2. CRP and Diabetes

3. Diet and CRP

4. Dietary Fatty Acids and CRP

5. Conclusions

Chapter 19. Alcoholic Beverage and Insulin Resistance–Mediated Degenerative Diseases of Liver and Brain: Cellular and Molecular Effects

1. Overview

2. Alcohol-Related Liver Disease

3. Alcohol-Related Neurodegeneration

4. Concluding Remarks

Section 3. Genetic Machinery and its Function

Chapter 20. Genetic Variants and Risk of Diabetes

1. Introduction

2. Genetic Variants for T2D

3. Genetic Variants for Insulin Secretion and Action

4. Growth Factor Receptor-Bound Protein 10

5. Rare and Low-Frequency Variants

6. Genetic Prediction of T2D

7. Future Directions

Chapter 21. MicroRNA and Diabetes Mellitus

1. Introduction

2. miRNA Biogenesis

3. miRNAs Acting in β-Cell Development

4. miRNAs Acting on Glucose-Stimulated Insulin Secretion

5. Regulation of Insulin Transcription by miRNAs

6. β-Cell Mass in Obesity and Pregnancy

7. β-Cell Failure in T2D

8. miRNAs in Skeletal Muscle, Adipose Tissue, and Liver

9. miRNAs Regulated by Nutritional State and Specific Ingredients

10. miRNAs as Circulating Biomarkers

11. Conclusions and Perspectives

List of Abbreviations

Chapter 22. Diabetes Mellitus and Intestinal Niemann-Pick C1–Like 1 Gene Expression

1. Cholesterol Homeostasis

2. Intestinal Cholesterol Absorption

3. Intestinal NPC1L1 Cholesterol Transporter

4. Transcriptional Regulation of NPC1L1

5. NPC1L1 and Diseases

6. NPC1L1 and Diabetes

7. Conclusion

Chapter 23. Dietary Long Chain Omega-3 Polyunsaturated Fatty Acids and Inflammatory Gene Expression in Type 2 Diabetes

1. Introduction

2. Inflammation in T2D

3. Inflammatory Gene Expression in T2D

4. Long Chain Omega-3 Polyunsaturated Fatty Acids on Inflammation and T2D

5. n-3 Polyunsaturated Fatty Acids on Neuroinflammation in Diabetes

6. Conclusion

Chapter 24. Polymorphism, Carbohydrates, Fat, and Type 2 Diabetes

1. Introduction

2. Effect of Dietary Carbohydrates and Fat on T2D

3. Polymorphisms and T2D

4. Interaction between Carbohydrates, Fat, and Gene Polymorphisms

5. Future Perspectives

Chapter 25. Genetic Basis Linking Variants for Diabetes and Obesity with Breast Cancer

1. Obesity and Breast Cancer

2. Insulin Resistance and Breast Cancer

3. Adiponectin and Adiponectin Receptor 1 Genes

4. Leptin and Leptin Receptor Genes

5. Fat Mass and Obesity Associated Gene

6. Obesity, Breast Cancer, and Methylation

7. Nutrigenomics Perspective to Reduce Obesity-Mediated Breast Cancer Risk

8. Conclusions

Chapter 26. Vitamin D Status, Genetics, and Diabetes Risk

1. Vitamin D Metabolism and Epidemiology

2. Vitamin D Deficiency and Diabetes Risk

3. Genetic Basis of Vitamin D Deficiency

4. Conclusions and Future Directions

Chapter 27. NRF2-Mediated Gene Regulation and Glucose Homeostasis

1. Introduction

2. Detoxification Processes in Cells

3. Antioxidative Stress Response Systems in Cells

4. Anti-inflammatory Function of NRF2

5. Molecular Basis of the KEAP1-NRF2 System Function

6. Pancreatic β Cells and Oxidative and Nitrosative Stresses

7. Roles of NRF2 on Antioxidative Response in Pancreatic β Cells

8. NRF2 Regulation of Inflammation and Other Cellular Responses in Pancreatic β Cells

9. Glucose Homeostasis in Insulin-Sensitive Tissues

10. Nutrition and NRF2 Inducing Phytochemicals

11. Conclusion

Chapter 28. Hepatic Mitochondrial Fatty Acid Oxidation and Type 2 Diabetes

1. Introduction

2. Lipogenesis as a Target to Reduce Liver Triacylglycerol Content

3. Stimulation of the Peroxisome Proliferator-activated Receptor-α

4. Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 as Target to Stimulate Hepatic Long-Chain Fatty Acid Oxidation

5. Targeting Liver Mitochondrial Fatty Acid Oxidation to Improve Hepatic Insulin Sensitivity

6. General Conclusion

Chapter 29. Current Knowledge on the Role of Wnt Signaling Pathway in Glucose Homeostasis

1. Introduction of the Wnt Signaling Pathway

2. Recognition of Wnt Signaling Pathway Components as Diabetes Risk Genes

3. TCF7L2 as a Diabetic Risk Gene and Its Role in Glucose Homeostasis

4. Summary and Perspectives

Index

Series Preface

In this series on Molecular Nutrition, the editors of each book aim to disseminate important material pertaining to molecular nutrition in its broadest sense. The coverage ranges from molecular aspects to whole organs, and the impact of nutrition or malnutrition on individuals and whole communities. It includes concepts, policy, preclinical studies, and clinical investigations relating to molecular nutrition. The subject areas include molecular mechanisms, polymorphisms, SNPs, genomic wide analysis, genotypes, gene expression, genetic modifications, and many other aspects. Information given in the Molecular Nutrition series relates to national, international, and global issues.

A major feature of the series that sets it apart from other texts is the initiative to bridge the transintellectual divide so that it is suitable for novices and experts alike. It embraces traditional and nontraditional formats of nutritional sciences in different ways. Each book in the series has both overviews and detailed and focused chapters.

Molecular Nutrition is designed for nutritionists, dieticians, educationalists, health experts, epidemiologists, and health-related professionals such as chemists. It is also suitable for students, graduates, postgraduates, researchers, lecturers, teachers, and professors. Contributors are national or international experts, many of whom are from world-renowned institutions or universities. It is intended to be an authoritative text covering nutrition at the molecular level.

V.R. Preedy

Series Editor

Copyright

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Dedication

To Aurora and Carla for taking care of me so lovingly when disease suddenly came into my life.

Contributors

Waddah A. Alrefai

Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

The Jesse Brown VA Medical Center, Chicago, IL, USA

Jaime Amaya-Farfan,     Food and Nutrition Department, Protein Resources Laboratory, Faculty of Food Engineering, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

Giovanni Annuzzi,     Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

Julie C. Antvorskov,     The Bartholin Institute, Rigshospitalet, Copenhagen, Denmark

Anna Ardévol,     MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain

Knud Erik Bach Knudsen,     Department of Animal Science, Aarhus University, Tjele, Denmark

Silvia Berciano,     Nutritional Genomics of Cardiovascular Disease and Obesity, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain

Piers R. Blackett,     Department of Pediatrics, Section of Endocrinology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Mayte Blay,     MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain

Lutgarda Bozzetto,     Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

Karsten Buschard,     The Bartholin Institute, Rigshospitalet, Copenhagen, Denmark

Lu Cai

Department of Pediatrics, University of Louisville, Louisville, KY, USA

Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA

Younan Chen,     School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Perth, WA, Australia

Fausto Chiazza,     Department of Drug Science and Technology, University of Turin, Turin, Italy

Carla Beatriz Collares-Buzato,     Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil

Massimo Collino,     Department of Drug Science and Technology, University of Turin, Turin, Italy

Giuseppina Costabile,     Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

Vinicius F. Cruzat,     School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Perth, WA, Australia

Leticia Cuéllar(Literature search in Chapter 1),     Servicio de Evaluación del Servicio Canario de la Salud (SESCS), Santa Cruz de Tenerife, Spain

Lidia Daimiel-Ruiz,     Nutritional Genomics of Cardiovascular Disease and Obesity, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain

Louise T. Dalgaard,     Department of Science, Systems and Models, Roskilde University, Roskilde, Denmark

Suzanne M. de la Monte

Department of Medicine, Rhode Island Hospital, Providence, RI, USA

Department of Pathology, Rhode Island Hospital, Providence, RI, USA

Department of Neurology, Rhode Island Hospital, Providence, RI, USA

Department of Neurosurgery, Rhode Island Hospital, Providence, RI, USA

The Liver Research Center, Rhode Island Hospital, Providence, RI, USA

Rhode Island Hospital, Providence, RI, USA

The Warren Alpert Medical School of Brown University, Providence, RI, USA

Nathalia Romanelli Vicente Dragano,     Laboratory of Cell Signaling, Obesity and Comorbidities Research Center (OCRC), Faculty of Medical Sciences (FCM-Unicamp), University of Campinas, Campinas, SP, Brazil

Pradeep K. Dudeja

Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

The Jesse Brown VA Medical Center, Chicago, IL, USA

Eduardo Esteve

Unit of Diabetes, Endocrinology and Nutrition, Biomedical Research Institute (IDIBGi), Hospital ‘Dr. Josep Trueta’ of Girona, Girona, Spain

CIBERobn Fisiopatología de la Obesidad y Nutrición, Girona, Spain

José Manuel Fernández-Real

Unit of Diabetes, Endocrinology and Nutrition, Biomedical Research Institute (IDIBGi), Hospital ‘Dr. Josep Trueta’ of Girona, Girona, Spain

CIBERobn Fisiopatología de la Obesidad y Nutrición, Girona, Spain

Lidia García

Servicio de Evaluación del Servicio Canario de la Salud (SESCS), Santa Cruz de Tenerife, Spain

Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Madrid, Spain

Manohar L. Garg,     Nutraceuticals Research Group, School of Biomedical & Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia

Rosa Gasa

Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomediques August Pi i Sunyer, Barcelona, Spain

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain

Julian Geiger,     Department of Science, Systems and Models, Roskilde University, Roskilde, Denmark

Ravinder K. Gill,     Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

Jean Girard

INSERM, Institut Cochin, Paris, France

CNRS, Paris, France

Université Paris Descartes, Paris, France

Ramon Gomis

Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomediques August Pi i Sunyer, Barcelona, Spain

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain

University of Barcelona, Hospital Clínic, Barcelona, Spain

Noemí González-Abuín,     MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain

Luis Goya,     Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN-CSIC), Madrid, Spain

Ettore Griffo,     Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

Merete Lindberg Hartvigsen,     Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

Mette Skou Hedemann,     Department of Animal Science, Aarhus University, Tjele, Denmark

Kjeld Hermansen,     Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

Susan Huse

Department of Pathology, Rhode Island Hospital, Providence, RI, USA

The Warren Alpert Medical School of Brown University, Providence, RI, USA

Tianru Jin,     Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, Canada

Knud Josefsen,     The Bartholin Institute, Rigshospitalet, Copenhagen, Denmark

Miran Kim

Department of Medicine, Rhode Island Hospital, Providence, RI, USA

The Liver Research Center, Rhode Island Hospital, Providence, RI, USA

Rhode Island Hospital, Providence, RI, USA

The Warren Alpert Medical School of Brown University, Providence, RI, USA

Vijay Kumar Kutala,     Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, India

Wolfgang Langhans,     Physiology and Behavior Laboratory, Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland

Gilbert C. Liu,     Department of Pediatrics, University of Louisville, Louisville, KY, USA

Pablo C.B. Lollo

Food and Nutrition Department, Protein Resources Laboratory, Faculty of Food Engineering, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

Faculty of Health Sciences, Federal University of Grande Dourados (UFGD), Dourados, Mato Grosso do Sul, Brazil

Jose Lopez-Miranda,     Lipids and Atherosclerosis Unit, IMIBIC/Reina Sofıa University Hospital, University of Cordoba and CIBER Fisiopatologia Obesidad y Nutricion (CIBERobn), Instituto de Salud Carlos III, Cordoba, Spain

Laura López Ríos(Figure in Chapter 1)

Endocrinology and Nutrition Department, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain

Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

Valeriya Lyssenko

Steno Diabetes Center A/S, Gentofte, Denmark

Department of Clinical Sciences, Diabetes and Endocrinology Unit, Lund University Diabetes Center, Lund University, Sweden

Pooja Malhotra,     Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

Abdelhak Mansouri,     Physiology and Behavior Laboratory, Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland

Carmen Marin,     Lipids and Atherosclerosis Unit, IMIBIC/Reina Sofıa University Hospital, University of Cordoba and CIBER Fisiopatologia Obesidad y Nutricion (CIBERobn), Instituto de Salud Carlos III, Cordoba, Spain

Anne y Castro Marques,     Universidade Federal do Pampa-Campus Itaqui, Itaqui, RS, Brazil

Maria Ángeles Martin,     Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN-CSIC), Madrid, Spain

Xiao Miao,     Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China

Victor Mico,     Nutritional Genomics of Cardiovascular Disease and Obesity, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain

Marciane Milanski,     Laboratory of Metabolic Disorders, Faculty of Applied Sciences, University of Campinas – UNICAMP, Limeira, São Paulo, Brazil

Priscila N. Morato

Food and Nutrition Department, Protein Resources Laboratory, Faculty of Food Engineering, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

Faculty of Health Sciences, Federal University of Grande Dourados (UFGD), Dourados, Mato Grosso do Sul, Brazil

Carolina S. Moura,     Food and Nutrition Department, Protein Resources Laboratory, Faculty of Food Engineering, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

Shaik Mohammad Naushad,     School of Chemical and Biotechnology, SASTRA University, Thanjavur, India

Philip Newsholme,     School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Perth, WA, Australia

Anna Novials

Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomediques August Pi i Sunyer, Barcelona, Spain

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain

Jose M. Ordovas

Nutrition and Genomics Laboratory, JM-USDA-Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA

Nutritional Genomics of Cardiovascular Disease and Obesity, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain

Montserrat Pinent,     MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain

Carina Prip-Buus

INSERM, Institut Cochin, Paris, France

CNRS, Paris, France

Université Paris Descartes, Paris, France

M. Janaki Ramaiah,     School of Chemical and Biotechnology, SASTRA University, Thanjavur, India

Sonia Ramos,     Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN-CSIC), Madrid, Spain

Wifredo Ricart

Unit of Diabetes, Endocrinology and Nutrition, Biomedical Research Institute (IDIBGi), Hospital ‘Dr. Josep Trueta’ of Girona, Girona, Spain

CIBERobn Fisiopatología de la Obesidad y Nutrición, Girona, Spain

David Sala,     Development, Aging and Regeneration Program (DARe), Sanford-Burnham Medical Research Institute, La Jolla, CA, USA

Sofia Salö

Department of Science, Systems and Models, Roskilde University, Roskilde, Denmark

Danish Diabetes Academy, Odense, Denmark

Rosa M. Sánchez Hernández

Endocrinology and Nutrition Department, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain

Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

Dharambir K. Sanghera

Department of Pediatrics, Section of Genetics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Joan-Marc Servitja

Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomediques August Pi i Sunyer, Barcelona, Spain

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain

Anja E. Sørensen

Department of Science, Systems and Models, Roskilde University, Roskilde, Denmark

Danish Diabetes Academy, Odense, Denmark

Jian Sun,     Cardiovascular Center, The First Hospital of Jilin University, Changchun, China

Jency Thomas,     Department of Human Biosciences, LaTrobe University, Victoria, Australia

Adriana Souza Torsoni,     Laboratory of Metabolic Disorders, Faculty of Applied Sciences, University of Campinas – UNICAMP, Limeira, São Paulo, Brazil

Marcio Alberto Torsoni,     Laboratory of Metabolic Disorders, Faculty of Applied Sciences, University of Campinas – UNICAMP, Limeira, São Paulo, Brazil

Akira Uruno,     Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

Ana M. Wägner

Endocrinology and Nutrition Department, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain

Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

Shudong Wang

Cardiovascular Center, The First Hospital of Jilin University, Changchun, China

Department of Pediatrics, University of Louisville, Louisville, KY, USA

Yonggang Wang,     Cardiovascular Center, The First Hospital of Jilin University, Changchun, China

Julia C. Wiebe

Endocrinology and Nutrition Department, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain

Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

Kupper A. Wintergerst

Department of Pediatrics, University of Louisville, Louisville, KY, USA

Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA

Gemma Xifra

Unit of Diabetes, Endocrinology and Nutrition, Biomedical Research Institute (IDIBGi), Hospital ‘Dr. Josep Trueta’ of Girona, Girona, Spain

CIBERobn Fisiopatología de la Obesidad y Nutrición, Girona, Spain

Yoko Yagishita,     Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

Masayuki Yamamoto,     Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

Antonio Zorzano

Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain

Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain

CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain

Preface

The life of mankind has changed dramatically, from the industrial society of the twentieth century to the age of technology invading our daily lives during the past few years. This major change has occurred only in a few decades' time. Although malnutrition is still a major nutritional challenge in some countries, the epidemic of obesity and type 2 diabetes mellitus has emerged as a major global issue related to dietary intake changes. Furthermore, although not affecting as many people, type 1 diabetes also creates a major burden because of its impact on younger patients and its increasing incidence in different regions around the world. Nutritional factors are clearly involved from the beginning in different sequences of the pathogenetic process that leads to diabetes mellitus. Therefore, we are in great need of gaining much more insight into the molecular pathways and the molecular mediators involved in the pathogenesis of diabetes and associated conditions. On the other hand, medical nutrition therapy is one of the mainstays of the treatment of diabetes mellitus. This has important implications in terms of introducing the best evidence-based approaches to the treatment of diabetes that should be based on high-quality research findings. But, again, although the body of evidence on which the nutritional management of the disease is based has increased significantly especially in recent years, there is still a long way to go.

The content of the book is organized into three sections. The introductory section includes chapters that aim to address the general concepts of nutrition related to diabetes. The initial introductory chapter addresses general aspects of the clinical nutritional approach to the management of diabetes. The remaining chapters in this section focus on the molecular mechanisms related to nutrition involved in the pathogenesis of hyperglycemia (i.e., insulin secretion and insulin action) including diet–gene interactions. The second section deals with the molecular biology of diabetes and focuses on areas such as oxidative stress, mitochondrial function, insulin resistance, high-fat diets, nutraceuticals, and lipid accumulation. The final section explores the genetic machinery behind diabetes and its metabolic-associated disturbances, including signaling pathways, gene expression, genome-wide association studies, and specific gene expression. It is not possible to include in one book all the potential areas of interest to those professionals working in the field of nutrition and diabetes. Nevertheless, in this first edition, the aim is to keep the focus of this series on molecular nutrition and cover important areas of interest in the field.

In conclusion, I truly hope that the content of the book will attract the interest of readers that need to gain insight on the different issues and challenges of their daily work. The book represents a timely and useful contribution to the rapidly expanding field of molecular nutrition in diabetes. I hope that its content not only helps the reader to answer questions, but also helps induce the passion to generate and solve important research questions that should ultimately contribute to the prevention and treatment of the large population of people with diabetes mellitus. I also hope that the content attracts the interest of a wide array of professional profiles. It has been a privilege to serve as the editor of this book that features contributions of researchers from all around the globe providing state-of-the-art reviews.

Didac Mauricio, MD, PhD

Editor

Acknowledgments

I thank Professor Victor R. Preedy for trusting me as the lead editor of this book. I am also grateful to all authors for accepting to participate in this endeavor and for contributing their expertise. I also wish to express my gratitude to the editorial team at Elsevier, Inc. in San Diego for their support, especially Jeff Rossetti for being always on the other side of my mailbox and for his excellent work as Editorial Project Manager.

Section 1

General and Introductory Aspects

Outline

Chapter 1. Nutrition and Diabetes: General Aspects

Chapter 2. Dietary Patterns and Insulin Resistance

Chapter 3. β-Cell Metabolism, Insulin Production and Secretion: Metabolic Failure Resulting in Diabetes

Chapter 4. Diete–Gene Interactions in the Development of Diabetes

Chapter 5. Pathogenesis of Type 1 Diabetes: Role of Dietary Factors

Chapter 1

Nutrition and Diabetes

General Aspects

Julia C. Wiebe¹,², Rosa M. Sánchez Hernández¹,², Lidia García³,⁴, Ana M. Wägner¹,²,  Figure by Laura López Ríos¹,²,  Literature search by  and Leticia Cuéllar³     ¹Endocrinology and Nutrition Department, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain     ²Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain     ³Servicio de Evaluación del Servicio Canario de la Salud (SESCS), Santa Cruz de Tenerife, Spain     ⁴Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Madrid, Spain

Abstract

Nutrition is a key component in the treatment of diabetes, and an extensive body of research is proof of the interest it elicits. Recommendations to patients have changed dramatically in the past century: before the discovery of insulin, patients were advised to fast or to base their intake on protein and fat. Carbohydrate allowance was progressively increased after insulin became available and current guidelines no longer recommend a certain percentage of total caloric intake in the form of any macronutrient. Present recommendations aim at promoting cardiovascular health and adjusting treatment to carbohydrate intake, the latter especially in people with type 1 diabetes. The aim of this chapter is to review available, clinically relevant evidence on dietary interventions in the management of type 1 and type 2 diabetes and their complications.

Keywords

Clinical nutrition; Diabetes management; Guidelines; HbA1c; History; Lipids; Macronutrient; Randomized controlled trials; Systematic review

1. Introduction

Overweight and obesity are currently associated with more deaths worldwide than underweight, according to a report by the World Health Organization in 2014.¹ Obesity, a problem previously prevalent only in rich regions, is now a public health challenge also in low- and middle-income countries. Worldwide, 44% of diabetes can be attributed to overweight and obesity.¹ Indeed, diabetes incidence has also increased in a parallel manner to obesity, reaching epidemic proportions. In 2014, the estimated global prevalence of diabetes was 9% among people aged 18  years and older.²

Nutrition is a key component of diabetes management, where it fulfills general (adequate growth and development, weight maintenance) and specific (cardiovascular (CV) protection, glycemic control) purposes. At the same time, eating has strong cultural implications and changes, and limitations to food intake have a great impact on quality of life.³,⁴ Thus, when giving dietary advice, it is crucial to focus on those recommendations whose benefits are based on strong, clinical evidence.

When the terms nutrition and diabetes are used to start a search in PubMed, they result in 18,920 hits (February 9, 2015). If nutrition OR diet are combined with diabetes, the number increases to 55,575 hits. Nevertheless, when the search is limited to randomized controlled trials, only 1049 and 3686 hits are found, respectively. Thus, although the interest and research on nutrition and diabetes are extensive, the highest level of clinical evidence represents only a minor fraction of the published studies.

The aim of this chapter is to review the relevant, clinical evidence available about the effects of nutritional interventions on the control of type 1 diabetes (T1D) and type 2 diabetes (T2D) and their complications. For this purpose, the most recently published international guidelines on the subject have been considered (Section 3) and a systematic review of randomized controlled trials has been performed (Section 4). In addition, to put present evidence into context, a historical description of nutritional recommendations and their changes in the past century is provided (Section 2).

2. Historical Perspective

Nutritional recommendations for diabetes have changed dramatically in the past century. Before the discovery of insulin, patients with T1D were advised to fast in order to obtain sugar-free urine. Once this was achieved, dietary carbohydrate content was increased by 10  g/day until persistent glycosuria appeared.⁵ This was done using green, bulky vegetables and, depending on the patient's tolerance, also some garden vegetables and sometimes even potatoes and cereal. Fruit generally remained a minor fraction of carbohydrate intake in these patients, preferably used as dessert. The carbohydrate tolerance of each patient was used to design his or her maintenance diet, where the maximum carbohydrate allowance was the highest amount at which the urine remained sugar-free. Protein intake was calculated to consist of 1.0–1.5  g/kg; the rest of the calories were accounted for by fat. The diet was adapted to the severity of diabetes and to the presence/absence of acidosis.⁵ The progression from a vegetable day, containing only 5  g of carbohydrate, is described by Hill as follows: ...carbohydrate 15  g, protein 25  g, fat 150  g. From this, the diet is slowly raised, increasing first the fat, then the protein and lastly the carbohydrate. The fat is never raised above 200  g and the calories seldom above 2200. On this, the patients hold their weight, feel well, and usually remain sugar-free.⁶ After the discovery of insulin, the carbohydrate allowance increased progressively, as did the recommended total caloric intake⁷ (Table 1). In 1933, Elliott Joslin recommended the following: At present the diet I give my patients is approximately carbohydrate 140  g, protein 70  g, fat 90  g. Children need much more protein and if they require more calories I am inclined to give these calories equally divided between carbohydrate and fat. Indeed, advocates for a normal diet for the affected children started their campaigns, based on better nutritional results, fewer acute complications, and last, but not least, better acceptance.⁸ The 1940s and 1950s witnessed a debate on whether patients with diabetes should be on a controlled or a free diet.⁹,¹⁰ Several studies showed similar results on weight and hypoglycemia, although larger glucose fluctuations were observed with the free diet.¹¹ In the discussion, Forsyth et al. stated From our experience of a group of 50 diabetics given liberal diets and insulin over a period of five years we are satisfied that, if adolescents and obese diabetics are excluded, clinical control, as defined earlier in this paper, can be attained in most patients. However, the degree of hyperglycemia and glycosuria and the daily fluctuation of blood-sugar levels are undoubtedly greater in such patients than in those on controlled diets. Nevertheless, soon, evidence appeared to support that hyperglycemia was associated with a higher risk of retinopathy and vessel calcification.¹²,¹³ Thus, emphasis was put on the degree of glycemic control, while still supporting a relatively free diet. According to Forsyth herself: By the term ‘free diet’ we imply liberty rather than license. Simple instructions are given to ensure the quality of the diet, and regular timing of meals is considered essential. Concentrated carbohydrates, such as table sugar, jam, chocolate, and sweets, are restricted. The American Diabetes Association (ADA) released its first exchange lists to facilitate constant dietary composition.¹⁴ The link between dietary fat and atherosclerosis was recognized and, thus, fat intake was progressively reduced, especially at the expense of saturated fat.¹⁵,¹⁶

The first oral agents (sulfonylureas and phenformin) were available for the treatment of diabetes from the late 1950s,¹⁷ adding tools to the treatment of mild, adult-onset diabetes (Figure 1). Home monitoring of glucose in the urine in the 1960s led to home blood glucose monitoring in the 1970s and, thus, gave patients better chances of improving their glycemic control.¹⁸ The discovery in 1976 and later implementation of glycated hemoglobin (HbA1c) as a marker of glycemic control and predictor of chronic diabetes complications was another important breakthrough that paved the way for what was to be achieved less than two decades later.¹⁹ The importance of diabetes education was acknowledged by the constitution of the Diabetes Education Study Group within the European Association of the Study of Diabetes in 1979, under the leadership of Jean-Philippe Assal.

Table 1

Historical Changes in Macronutrient Intake (% of Total Daily Caloric Intake) Recommendations for People with Diabetes

ADA, American Diabetes Association; CH, carbohydrate (% of total daily caloric intake); F, fat; P, protein; NS, not specified.

a Chance GW. Outpatient management of diabetic children. BMJ 1969;2:493–5.

Figure 1  Selected historical milestones conditioning the (nutritional) treatment of diabetes.

Evidence published in the 1980s²⁰ questioned the need to refrain from simple sugars such as sucrose,²¹,²² a recommendation that had settled like a dogma and is sometimes still heard today.

In the 1990s, calorie restriction for overweight patients was emphasized, fat was limited to 30–35% of total caloric intake, and saturated fat to 10%, especially in people with T2D.²³ Children with diabetes are advised to eat a normal diet, taking carbohydrate content into consideration and distributing food regularly throughout the day to avoid hyper- and hypoglycemia. Special diabetes foods were not considered necessary.²⁴ Indeed, Ingrid Mühlhauser and Michael Berger's group in Germany proved that, with adequate training, a free diet was possible, without deterioration of glycemic control.²⁵ The publication of the results of the Diabetes Control and Complications Trial in 1993 set the standards of treatment for T1D that are valid still today.²⁶

At the turn of the twenty-first century, dietary recommendations for diabetes focus on fat restriction (<30% of total caloric intake), especially at the expense of saturated fat (<7–10%), and on achieving a healthy weight. Patients on intensive insulin treatment are advised to quantify carbohydrate content in their meals and adjust their premeal insulin dose thereafter.²⁷,²⁸

3. Guidelines

To assess present recommendations, available diabetes guidelines published between 2009 and 2014 have been reviewed. Table 2 summarizes their main features and Table 3 displays the recommendations based on review of the evidence and the level of evidence attributed to each statement, according to the cited document. Most diabetes management guidelines include some sort of nutritional recommendation, which ranges from very general to more specific advice. The ADA updated its recommendations recently,²⁹ and its 2013 position statement is probably the most extensive and detailed guideline currently available. A few months after its publication, the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines were released after thorough, systematic review of the available evidence. The AHA/ACC recommendations are not specifically aimed at people with diabetes, but it is reasonable to use them as a complement to diabetes guidelines where specific studies in diabetes do not provide enough evidence.

Table 2

Main Features of the Diabetes Guidelines (2009–2014) Examined

T1D, type 1 diabetes; T2D, type 2 diabetes.

a Those based on review of the evidence and providing diabetes-specific recommendations, as well as level of evidence, are described in more detail in Table 3.

Most current guidelines emphasize the importance of a healthy diet, similar to that recommended for the nondiabetic population, aimed at improving CV protection. Indeed, several guidelines refer to general nutritional recommendations as part of diabetes management.³⁰,³¹ For example, the Australian guidelines for the management of T2D, read: The diet recommended for a person with diabetes [...] is qualitatively little different from the Mediterranean (MED) diet, or that recommended for all people (irrespective of whether they have diabetes, hypertension or dyslipidemia).³⁰ Nevertheless, specific recommendations for diabetes are also available from several guidelines (Table 3).

3.1. Caloric Intake

Present guidelines agree that one of the aims of nutrition therapy is to adapt energy intake to patients' needs,²⁹,³² which will mainly depend on age, baseline body weight, and physical activity. The ADA recommends: For overweight or obese adults with type 2 diabetes, reducing energy intake while maintaining a healthful eating pattern is recommended to promote weight loss.²⁹

3.2. Carbohydrate

Unlike older recommendations, most present guidelines do not define an optimal amount of carbohydrate intake. Furthermore, food quality, rather than type of carbohydrate is emphasized: fresh, fiber-rich foods are advised to replace processed foods, containing high amounts of added sugar and fat (and, thus, calories). Glycemic index (GI) and glycemic load are more controversial concepts, which is reflected by the lack of agreement in the different guidelines.

Table 3

Recommendations and Evidence Rating (When Available and Understandable) According to Different Guidelines

AACE, American Association of Clinical Endocrinologists; GI, glycemic index; MUFA, monounsaturated fatty acids; NE, no evidence; T1D, type 1 diabetes; T2D, type 2 diabetes; TCI, total caloric intake. A, B and C show decreasing levels of evidence, as self-defined by the individual guidelines. See Table 1 of Diabetes Care 2008;31(Suppl. 1):S1–S2.

a The AACE uses a four-category, numerical quality of evidence rating.

Carbohydrate counting for insulin adjustment is central in the management of T1D, and this recommendation is present in most documents counseling about this disease.²⁹,³³–³⁵ The ADA guidelines give specific advice regarding carbohydrate quantification and distribution according to glucose-lowering treatment to prevent hypoglycemia, as well as to treat the latter.²⁹

3.3. Fat

Modifications in fat intake are aimed at improving CV health. Thus, advice in diabetes guidelines is comparable to that found for the general population³⁶ and is based more on the type than the total quantity of fat consumed. Patients are advised to reduce saturated and trans fat intake and to consume sources rich in polyunsaturated (PUFA), omega-3 fatty acids, and monounsaturated fatty acids (MUFAs).²⁹,³⁵

3.4. Protein

Recommendations on protein intake have remained rather stable over the years (Table 1) and across guidelines (Table 3). The only exception is the management of diabetic nephropathy, in which protein restriction was the rule until recently. Presently, there is disparity in this recommendation.

3.5. Sweeteners

Sugar-sweetened beverages are discouraged because of their high caloric content and their association with obesity. Noncaloric sweeteners (e.g., aspartame, cyclamate) are described as an option to reduce calorie and carbohydrate intake.²⁹,³²,³⁴

3.6. Supplements

Only three of the reviewed guidelines specifically mention micronutrient and/or herbal supplements and none of them recommends them.²⁹,³⁵,³⁷

3.7. Sodium Intake

Salt intake recommendations do not differ from those made to the general population. Unspecific³²,³⁵ or specific (to less than 2.3  g/day) sodium intake reduction²⁹ is recommended, which is consistent with the 2013 AHA/ACC guideline to reduce CV risk.³⁶

3.8. Translation into Food Intake

Most previous recommendations could be summarized as the following advice to patients: control portion size if weight is an issue; base your daily diet on vegetables, fruit, whole grains, legumes, and low-fat dairy products; and eat fish (preferably oily) at least twice per week. Choose fresh products whenever possible to prepare you own meals and avoid processed foods, especially meats, sweets, and sugar-containing beverages.

4. Evidence from Clinical Trials

In this section, we summarize evidence published in systematic reviews and meta-analyses of clinical studies, updated with more recent randomized controlled trials (RCTs), on the effect of different types of diets or nutritional supplements on glycemic control and other CV risk factors. Our main sources of information have been: (1) A systematic review and meta-analysis³⁸ including 16 RCTs (3037 participants) of at least 6  months' duration assessing the effect of various diets on glycemic control, lipids, and weight loss, following Cochrane guidelines. (2) A systematic review³⁹ also including nonrandomized and smaller randomized controlled trials as well as observational studies and case–control studies, published between 2001 and 2010, with at least 10 participants per study group. (3) These two systematic reviews were updated by a literature search (MEDLINE, MEDLINE in process, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects), in October 2014, by two of the authors (J.C.W., R.M.S.), focused on RCTs (at least 6  months' duration and 50 participants per group), which resulted, after screening 2801 references, in five additional studies of interest not mentioned in the systematic reviews on macronutrients: one RCT assessing GI,⁴⁰ two on low-carbohydrate diets,⁴¹,⁴² and two on high-protein diets.⁴³,⁴⁴ To analyze supplements, micronutrients, and specific diets, our systematic literature search was complemented by other studies, identified by a hand search. For the review of the different eating patterns and carbohydrate counting in T1D, a systematic review³⁸ and the literature search were complemented by studies identified by a hand search.

The interventions were classified into five groups, in which four included almost exclusively studies in T2D and the last one reported on nutritional education in patients with T1D.

4.1. Macronutrient Composition

According to the ADA's Recommendations for the Management of Adults With Diabetes position statement, there is little evidence for an ideal caloric combination of carbohydrate, protein, and fat.²⁹ Thus, the ADA advises that distribution of calories among macronutrients should be based on individual eating patterns, preferences, and metabolic goals.²⁹

However, numerous studies have attempted to identify the optimal mix of macronutrients for the meal plans of people with diabetes.

4.1.1. Protein Content

Diets in which 20–30% or more of the total caloric intake come from proteins are considered high protein. The two studies analyzed in a recent meta-analysis³⁸ compared a high-protein (26.5–30%) diet with a control diet (15–19% of calories from proteins).⁴⁵,⁴⁶ Even though no significant differences were found in glycemic control, weight, or lipids in the single studies, combined analysis of pooled data showed significantly lower HbA1c concentrations (−0.28%; P  <  0.00001) in the high-protein diet group and no change in urinary albumin excretion.⁴⁵ A systematic review³⁹ including three smaller, short (4–16  weeks) RCTs⁴⁷–⁴⁹ showed contradictory results on glycemic control and CV risk factors. Finally, an additional, much larger RCT (418 participants randomized),⁴⁴ comparing two diets with 15% versus 30% protein, with the difference accounted for by carbohydrate, showed no differences between groups for weight, HbA1c, lipids, blood pressure, or renal function at one year.

4.1.1.1. Protein Intake in Diabetic Kidney Disease

Moderate protein restriction is recommended for patients with diabetic nephropathy in several recent guidelines,²⁷,³⁴ although the last position statement by the ADA²⁹ does not give this advice. The reason for this is the publication of new evidence on this issue.

In patients with early renal disease (urinary albumin/creatinine ratio 3–30  mg/mmol), no differences were found in renal function, albuminuria, or blood pressure 1  year after following a high-protein (30%, 1.2  g/kg) diet, when compared with a standard-protein (20%, 0.9  g/kg) diet.⁴³ Three earlier systematic reviews and a meta-analysis studied the effect of modified or low-protein diets on glycemic control, CV risk factors, and renal function in people with T1D or T2D.³⁹,⁵⁰,⁵¹ Four long (1–4  years), albeit relatively small, RCTs included patients (23–47 per group) with microalbuminuria,⁵² macroalbuminuria,⁵³,⁵⁴ or both.⁵⁵,³⁹ In two of the studies, daily protein intake was reduced compared with the control group (0.86–0.89  g vs 1.02–1.24  g),⁵³,⁵⁴ whereas in the other two, protein intake turned out to be higher in the planned lower-protein group than in the control groups.⁵²,⁵⁵ No significant differences for glycemic control, CV risk factors, or renal function (glomerular filtration rate, proteinuria, serum albumin) were found between the groups. The studies analyzed in the mentioned systematic review³⁹ were also included in another systematic review and in a meta-analysis, which reached similar conclusions.⁵⁰,⁵¹

4.1.2. Carbohydrate Content and Quality

Macronutrient distribution of a standard diet ranges from 55 to 65% carbohydrate, <30% fat, and 10–20% protein,³² but no official definition of low- (or high-) carbohydrate diets exists. For the purpose of this review, a low-carbohydrate diet was defined as 20–40% of total caloric intake and a high-carbohydrate diet as >65%.³⁸

A recent systematic review³⁹ of seven RCTs and two meta-analyses examined the effects of moderate- or high-carbohydrate diets on glycemic control in patients with T2D⁴⁵,⁴⁷,⁴⁹,⁵⁶–⁶⁰ or T1D.⁶¹ Comparison of the studies was difficult, given the differences in fat and protein contents of the control diets, duration of follow-up (5–74  weeks), and the number of participants.¹⁰–⁹⁹ Four studies found no significant differences in glycemic control,⁴⁵,⁴⁹,⁵⁶,⁵⁷ one RCT found significantly lower HbA1c in the lower-carbohydrate diet, whereas another study found improved LDL cholesterol with a high-carbohydrate diet and two studies found improved triglyceride with a low-carbohydrate diet.³⁹ A systematic review,³⁸ which assessed the outcome of two additional RCTs comparing a high-carbohydrate diet with a diet high in MUFAs and a high-fiber diet to a low-fat diet, found no significant differences in weight, glycemic control, or lipids.⁶²,⁶³

A systematic review³⁹ on low carbohydrate diets included 11 studies, seven of which with a very low-carbohydrate content⁶⁴–⁷⁰ and four with a moderately low content.⁷¹–⁷⁴ The analyzed clinical trials³ and RCTs⁸ included adults with T2D with varying duration of follow-up (14 days–1 year) and sample sizes (10–55 participants). HbA1c decreased in four of the very low and two of the moderate carbohydrate groups, but studies were small, of short duration, not all of them were RCTs, and dropout rates were high. High-density lipoprotein (HDL) cholesterol seemed to improve with reduction of total carbohydrate intake, but an impact from differences in caloric intake and weight loss on the results is possible.³⁹ A meta-analysis including several of the mentioned RCTs⁶⁵,⁶⁷,⁶⁸,⁷⁴–⁷⁸ showed that, overall, low-carbohydrate diets had no significant effects on weight, reduced HbA1c modestly (0.12% points), and increased HDL cholesterol by 0.11  mmol/L (4.2  mg/dL).³⁸

Results of two independent studies comparing very low-carbohydrate to low-fat diets showed no differences between groups in HbA1c or associated CV risk factors.⁴¹,⁴²

Table 4

Description of Dietary Interventions Mentioned in the Text and Their Effect on Glycemic Control and CV Risk Factors

CV, cardiovascular; GI, glycemic index; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PUFA, polyunsaturated fatty acids; T1D, type 1 diabetes.

4.1.2.1. Low GI

GI is defined by the postprandial glucose excursion occurring after the ingestion of a carbohydrate-containing food compared with white bread or glucose. Many fresh, unprocessed, and fiber-rich foods have a low GI (see Table 4). A meta-analysis included three RCTs comparing low GI (defined as GI between 39 and 77) with other diets.⁷⁴,⁷⁹,⁸⁰ A modest (0.14% points) but significant decrease in HbA1c was seen, as was an increase in HDL in the low-GI diet, but no significant reductions in LDL cholesterol, triglyceride, or weight.³⁸ However, when compared with a low-carbohydrate diet, a low-GI diet seems to be inferior in reducing HbA1c.⁶⁸ Smaller, shorter studies do not add significant knowledge to the mentioned meta-analysis.³⁹

4.1.3. Fat Content

Low-fat (<30% of total calories) diets are often assigned to the comparison group in studies assessing low-carbohydrate diets.³⁸ A systematic review assessed seven RCTs on low-fat eating patterns in people with diabetes,³⁹ with only one of them in T1D.⁶¹ HbA1c was reduced in one study,⁸¹ whereas no significant effects were seen on lipids.⁴⁹,⁵⁶,⁵⁷,⁶¹,⁸¹–⁸³ Vegan and vegetarian diets are also relatively low in fat and are described later (see Section 4.2.2).

Although there is limited research on this issue in diabetes, reductions in saturated fat below 7% have proved beneficial for the reduction of CV risk in earlier studies, especially at the expense of the reduction in low-density lipoprotein (LDL) cholesterol.³⁶ Mediterranean-style eating patterns, which are rich in MUFA, are discussed later (see Section 4.4.1).

4.1.4. Summary

A meta-analysis of RCTs showed small but significant effects of low-carbohydrate and low-GI diets on HbA1c. Assessment of high-protein diets was based on two studies only, which limits the conclusions that can be drawn. Currently, there is no evidence to restrict protein intake below what is recommended for the general population in patients with diabetic nephropathy.

4.2. Supplements

Even though a well-balanced diet is essential for the treatment of T2D, there are data showing insufficient intake of some micronutrients,⁸⁴,⁸⁵ as well as supplementation with others in more than half of the patients.⁸⁴ The most frequently consumed supplements in a Polish study were magnesium, herbs, antioxidant vitamins, B-group vitamins, and omega-3 fatty acids.⁸⁴ In this section, we try to shed light on the effects of supplements of specific interest in diabetic nutrition.

4.2.1. Herbal Products

There is currently no solid evidence that herbal products improve glycemic control. A systematic review included 27 studies assessing individual herbs, of which 15 were RCTs, mostly short term and small, with limited quality. The authors concluded that evidence was insufficient to draw conclusions.⁸⁶ A high-quality, very well-performed RCT showed promising effects of cinnamon, with 0.5% point reductions in HbA1c and 5/3  mmHg in systolic/diastolic blood pressure,⁸⁷ but a more recent, systematic review including 10 RCTs did not confirm their effects.⁸⁸

4.2.2. Whole Grains

Results from two large prospective cohort studies including almost 120,000 patients indicated that higher whole grain consumption (defined as foods containing the entire grain seed) was associated with lower total and CV mortality, independent of other dietary and lifestyle factors.⁸⁹ To assess the effect of whole grain consumption on glycemic control and CV risk markers in patients with diabetes, two small (15–20 participants), short (5–12  weeks) RCTs comparing whole grains with fiber in people with T2D, were performed.⁹⁰,⁹¹ Consumption of whole grains was not associated with any changes in HbA1c and neither study found any significant differences in CV risk markers.³⁹

4.2.3. Omega-3 Fatty Acids

High triglyceride concentrations are considered a CV risk factor, and n-3 PUFA consumption reduces them. However, results on safety of n-3 PUFAs are contradictory. Although some older studies using high doses (≥10  g/day fish oil) have reported unfavorable effects on glucose metabolism, recent trials using lower doses (2–4  g/day) have shown that n-3 PUFA supplementation improves triglyceride levels without impairing glucose metabolism in hypertriglyceridemic patients with T2D.⁹²

In a systematic review assessing the effects of n-3 PUFA,³⁹ one of six RCTs⁹³ found a significant decrease in HbA1c and three⁹⁴–⁹⁶ showed increases in HDL cholesterol, when compared with corn or olive oil.

4.2.4. Nuts

Most tree nuts and peanuts are rich in PUFA, whereas walnuts and pine nuts are rich in MUFA. However, effects of nut-enriched diets in people with diabetes are contradictory.⁹⁷–¹⁰⁴ They do not seem to alter glycemia and results regarding lipid changes are mixed.³⁹

4.3. Micronutrients

Evidence of the effect of micronutrients on glycemic control and CV risk factors is limited by variation in micronutrient dosing, baseline and achieved micronutrient levels and heterogeneity in study quality and methodology. A systematic review of RCTs found limited evidence for chromium supplementation on glucose metabolism and lipids.¹⁰⁵ Results of clinical studies evaluating the effect of magnesium on glycemic control are contradictory. Although one RCT restored serum magnesium levels and improved metabolic control in T2D patients with decreased serum magnesium concentrations,¹⁰⁶ another one performed in patients with normal concentrations did not have an effect on glycemic control or plasma lipid concentrations.¹⁰⁷ Studies assessing the effect of vitamin D on glycemic control also showed conflicting results,¹⁰⁸–¹¹² and an RCT assessing the influence of dairy calcium intake did not affect HbA1c or CV risk factors.¹¹³

4.4. Eating Patterns

Eating patterns or dietary patterns are food groups consumed in characteristic combinations.¹¹⁴ Several factors influence these eating patterns, such as the availability of different kinds of foods, cultural patterns, traditions, health beliefs, and economy.¹¹⁵ The most relevant eating patterns in the context of diabetes and CV health, reviewed in this section, are the MED style, vegetarian, and Dietary Approaches to Stop Hypertension (DASH) dietary patterns.²⁹

4.4.1. Mediterranean (MED) Style

The MED dietary pattern is characterized by a high proportion of MUFA, mainly from olive oil; abundant amounts of plant foods such as fruit, vegetables, breads, cereals, and nuts; moderate consumption of fish and poultry; and low intake of dairy products (mostly cheese and yogurt), red and processed meats, and sweets. MED typically has a low content of saturated fat (7–8% of energy) and a total fat intake varying between <25% and >35% of total daily intake, depending on the region. It has mainly been studied in Mediterranean countries.¹¹⁶

The CV benefits of MED have been identified in observational cohort studies,¹¹⁷,¹¹⁸ in secondary prevention in a 4-year trial after a first myocardial infarction,¹¹⁹ and,

Reviews for Molecular Nutrition and Diabetes

[RalfLott · Rating: 3 out of 5 stars]

Interesting in parts, but it completely lacks any examination of ketogenic/very low carbohydrate diets. (A diet of 20-40% carbohydrates is merely lower carb than others.. .) Disappointing.