The Genetic landscape of diabetes

Preface

1. Introduction to Diabetes

2. Genetic Factors in Type 1 Diabetes

3. Genetic Factors in Type 2 Diabetes

4. Other Types of Diabetes

5. Gestational Diabetes


1. Introduction to Diabetes

Classification
History of Diabetes
Epidemiology
Physiology and Biochemistry of Sugar Regulation
The Story of Insulin

2. Genetic Factors in Type 1 Diabetes

IDDM1 Contains the HLA Genes
IDDM2 Contains the Insulin Gene (INS)
Other Type 1 Diabetes Susceptibility Loci: IDDM3IDDM18
An Inhibitor of the Immune Response (CTLA4)

3. Genetic Factors in Type 2 Diabetes

The Sulfonylurea Receptor (ABCC8)
The Calpain 10 Enzyme (CAPN10)
The Glucagon Receptor (GCGR)
The Enzyme Glucokinase (GCK)
The Glucose Transporter GLUT2
The Transcription Factor HNF4A
The Insulin Hormone (INS)
The Insulin Receptor (INSR)
The Potassium Channel KCNJ11
The Enzyme Lipoprotein Lipase (LPL)
The Transcription Factor PPARG
The Regulatory Subunit of a Phosphorylating Enzyme (PIK3R1)

4. Other Types of Diabetes

Genetic Defects of Beta Cell Function (MODY and Others)
MODY1: Caused by a Mutation in Transcription Factor HNF4A
MODY2: Caused by a Mutation in the Enzyme Glucokinase (GCK)
MODY3: Caused by a Mutation in Transcription Factor TCF1
MODY4: Caused by a Mutation in Transcription Factor IPF1
MODY5: Caused by a Mutation in Transcription Factor TCF2
MODY6: Caused by a Mutation in Transcription Factor NEUROD1
Genetic Defects in Insulin Action
Diseases in the Exocrine Pancreas
Diseases of the Endocrine System
Drug- or Chemical-induced Diabetes
Infections
Uncommon Forms of Immune-mediated Diabetes
Other Genetic Syndromes Sometimes Associated with Diabetes

5. Gestational Diabetes

The Genetic Landscape of Diabetes

Authors

Laura Dean, M.D. and Johanna McEntyre, Ph.D.

Laura Dean graduated from Cambridge University, England, with a medical doctorate in 2000. After completing a rotation of endocrinology, surgery, and general practice, Dr. Dean joined the Bookshelf as a visiting research fellow.

Johanna McEntyre gained a Ph.D. in biotechnology at Manchester Metropolitan University, England, and went on to be staff editor of Trends in Biochemical Sciences before joining the NCBI in 1997.

Acknowledgments

We thank Catherine McKeon, Ph.D., from the National Institute for Diabetes and Digestive and Kidney Diseases, NIH, for her support and guidance.

We are grateful to the following individuals who kindly reviewed the content:

Beena Akolkar, Ph.D., National Institute for Diabetes and Digestive and Kidney Diseases, NIH

Elizabeth Barrett-Connor, M.D., Professor and Chair of the Department of Family and Preventive Medicine, and Chief, Division Of Epidemiology, University of California San Diego School of Medicine

Inês Barroso, Ph.D., Wellcome Trust Sanger Institute, UK

Nancy Cox, Ph.D., Associate Professor, Department of Human Genetics, University of Chicago

Stefan Fajans, M.D., Professor Emeritus, Department of Internal Medicine, University of Michigan

Steven Gabbe, M.D., Dean of the School of Medicine, Vanderbilt University

Kai Ge, Ph.D., National Institute for Diabetes and Digestive and Kidney Diseases, NIH

Anna Gloyn, Ph.D., Diabetes Research Laboratories, Nuffield Department of Clinical Medicine, University of Oxford


Mark Goodarzi, M.D., Cedars-Sinai Medical Center

Raghavan Raju, Ph.D., National Institute of Neurological Disorders and Stroke, NIH

Copy editor: Belinda Beck

Graphic design: Todd Groesbeck



Preface

"The Genetic Landscape of Diabetes" is a guide to the variations in our DNA that may influence our risk of developing diabetes.

It is well known that a lifestyle of inactivity and excessive food intake plays an important part in diabetes risk. But diabetes is a genetic disease as well as a disease of lifestyle. Rare forms of diabetes are caused by a single gene mutation, but in most cases of diabetes, many genes are thought to be involved, together forming a "genetic risk".

Who should read this book?

Readers with an interest in science, patients with diabetes, physicians, high school students, and research scientists.

For patients and students, summaries provide outlines of the roles of genes, and background information introduces scientific information in a gradual way.

Research scientists and geneticists may be interested to read the "Molecular Information" for each gene. Here the book showcases the power and utility of NCBI tools for biomedical research. These tools include a gene "catalog" (Entrez Gene), the gene location (Map Viewer), searching for similar genes in other species (BLAST), and the latest research findings (PubMed and OMIM).

Why should you read this book?

"The Genetic Landscape of Diabetes" introduces the reader to what diabetes isfrom its discovery thousands of years ago to our modern-day understanding of how this disease, characterized by high blood sugar, develops.

The first chapter provides calculators that help you calculate your ideal body weight and BMI. Animated maps of the United States show the rise in obesity and diabetes.

Other chapters guide the reader through the genetic variations that may play roles in type 1 diabetes, type 2 diabetes, and other types. The genes discussed encode proteins that have diverse functions in cellsfrom transcription factors that influence the expression of other genes, to ion channels that control the release of insulin, from transporters that pump glucose into cells, to enzymes that speed up the break down of glucose.

The book closes with "NIH lectures"videos of some of the most recent lectures given by researchers who have been invited to the NIH to discuss obesity and diabetes.

What makes this book unique?

The genetics of diabetes is complicatedbut this book is not and is written for a wide audience. Because what we know about the genetics of diabetes is continually changing, links to live searches of the latest published literature and data will keep this book up to date. All of the content (the online book and the PDFs) is free.

1. Introduction to Diabetes

Diabetes mellitus is characterized by abnormally high levels of sugar (glucose) in the blood.

When the amount of glucose in the blood increases, e.g., after a meal, it triggers the release of the hormone insulin from the pancreas. Insulin stimulates muscle and fat cells to remove glucose from the blood and stimulates the liver to metabolize glucose, causing the blood sugar level to decrease to normal levels.

In people with diabetes, blood sugar levels remain high. This may be because insulin is not being produced at all, is not made at sufficient levels, or is not as effective as it should be. The most common forms of diabetes are type 1 diabetes (5%), which is an autoimmune disorder, and type 2 diabetes (95%), which is associated with obesity. Gestational diabetes is a form of diabetes that occurs in pregnancy, and other forms of diabetes are very rare and are caused by a single gene mutation.

For many years, scientists have been searching for clues in our genetic makeup that may explain why some people are more likely to get diabetes than others are. "The Genetic Landscape of Diabetes" introduces some of the genes that have been suggested to play a role in the development of diabetes.

2. Genetic Factors in Type 1 Diabetes

Type 1 diabetes is an autoimmune disorder in which the body attacks its pancreatic beta cells. The onset of type 1 diabetes is attributed to both an inherited risk and external triggers, such as diet or an infection. The hunt for these genetic and enviromental risk factors is on-going.

About 18 regions of the genome have been linked with influencing type 1 diabetes risk. These regions, each of which may contain several genes, have been labeled IDDM1 to IDDM18.

The most well studied is IDDM1, which contains the HLA genes that encode immune response proteins. Variations in HLA genes are an important genetic risk factor, but they alone do not account for the disease and other genes are involved.

There are two other non-HLA genes which have been identified thus far. One of these non-HLA genes, IDDM2, is the insulin gene, and the other non-HLA gene maps close to CTLA4, which has a regulatory role in the immune response

3. Genetic Factors in Type 2 Diabetes

Type 2 diabetes has been loosely defined as "adult onset" diabetes, although as diabetes becomes more common throughout the world, cases of type 2 diabetes are being observed in younger people. It is increasingly common in children.

In determining the risk of developing diabetes, environmental factors such as food intake and exercise play an important role. The majority of individuals with type 2 diabetes are either overweight or obese. Inherited factors are also important, but the genes involved remain poorly defined.

In rare forms of diabetes, mutations of one gene can result in disease. However, in type 2 diabetes, many genes are thought to be involved. "Diabetes genes" may show only a subtle variation in the gene sequence, and these variations may be extremely common. The difficulty lies in linking such common gene variations, known as single nucleotide polymorphisms (SNPs), with an increased risk of developing diabetes.

One method of finding the diabetes susceptibility genes is by whole-genome linkage studies. The entire genome of affected family members is scanned, and the families are followed over several generations and/or large numbers of affected sibling-pairs are studied. Associations between parts of the genome and the risk of developing diabetes are looked for. To date only two genes, calpain 10 (CAPN10) and hepatocyte nuclear factor 4 alpha (HNF4A), have been identified by this method.

4. Other Types of Diabetes

The vast majority of diabetes cases fall into the categories of type 1, type 2, and diabetes that occurs during pregnancy (gestational diabetes). However, up to 5% of cases have other specific causes and include diabetes that results from the mutation of a single gene.

5. Gestational Diabetes

During pregnancy there are many changes that take place in the mother's metabolisma rise in insulin resistance is one of these changes.

The placenta supplies a growing fetus with nutrients and produces a variety of hormones to maintain the pregnancy. Some of these hormones, such as human placental lactogen, have a blocking effect on insulin that usually begins 20 to 24 weeks into the pregnancy. The contra-insulin effect of placental hormones leads to higher levels of maternal blood glucose after eating (post-prandial levels) that may aid fetal growth.

Normally, the mother's beta cells can produce additional insulin to overcome the insulin resistance of pregnancy. As the placenta grows, more hormones are produced, and insulin resistance becomes greater. When the mother's production of insulin is not enough to overcome the effect of the placental hormones, gestational diabetes mellitus (GDM) results. GDM is defined as "carbohydrate intolerance of varying degrees of severity with onset or first recognition during pregnancy" (1) GDM complicates 7% of all pregnancies in the United States (2) and is more common in populations with a higher rate of type 2 diabetes mellitus, such as African Americans, Asian Americans, Hispanic Americans, and Native Americans (3,4).

The main complications of GDM are increased fetal size, which may complicate delivery, and hypoglycemia in the baby immediately after delivery. Women with GDM generally have normal blood sugar levels during the critical first trimester (before the 13th week) of pregnancy. This is in contrast to patients with type 1 diabetes, where hyperglycemia in this period may cause congenital birth defects.

After a positive screening test, the diagnosis of GDM is made by a glucose tolerance test. In this test, a sugary drink is given, and a series of blood tests are taken at set time intervals (Table 1). If hyperglycemia is detected, treatment begins with a change in diet and an increase in exercise. If these lifestyle changes fail to control blood glucose levels, insulin therapy is started.

Women with pre-existing diabetes require higher doses of insulin during pregnancy because of the increase in insulin resistance. If their diabetes is usually controlled using oral hypoglycemic agents, they are usually transferred to insulin to enable better glucose control and because the safety of most hypoglycemic agents has not been studied in pregnancy.

GDM can disappear within hours of giving birth, depending on individual factors such as beta cell function and predisposing factors such as obesity. However, a significant portion of women go on to develop type 2 diabetes. Because GDM and type 2 diabetes both feature insulin resistance and share risk factors such as obesity, it is possible that these two conditions may also share diabetes susceptibility genes.

References

1. Metzger BE, Coustan DR, et al. Summary and recommendations of the Fourth International Workshop-Conference on gestational diabetes mellitus. Diabetes Care 1998; 21 (suppl2):B161-B167. (PubMed)

2. Gabbe SG, Graves CR, et al. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol 2003; 102:857-868. (PubMed)

3. Engelgau MM, Herman WH, Smith PJ, et al. The epidemiology of diabetes and pregnancy in the U.S., 1988. Diabetes Care 1995; 18:1029-1033. (PubMed)

4. Gestational diabetes mellitus. Diabetes Care 2003; 26 Suppl 1:S103-S105. (PubMed)