Understanding Diabetes and Endocrinology

Daryl Meeking

• Publisher: CRC Press
• Year: 2011
• eBook ISBN:
  9781482261578
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Diabetes is a common and debilitating condition encountered by all doctors worldwide, regardless of specialist interest. This book aims to give the reader an understanding of the background, diagnosis, investigation and management of diabetes and endocrine disease. This book is set out in three main sections. The first gives a background understand

CHAPTER 1 THE BASICS

DIABETES

THE IMPACT OF DIABETES

INSULIN ACTION

THE EPIDEMIOLOGY OF TYPE 1 DIABETES

THE PATHOPHYSIOLOGY OF TYPE 1 DIABETES

THE EPIDEMIOLOGY OF TYPE 2 DIABETES

THE PATHOPHYSIOLOGY OF TYPE 2 DIABETES AND INSULIN RESISTANCE

OTHER FORMS OF DIABETES

ENDOCRINOLOGY

THE THYROID GLAND – STRUCTURE AND FUNCTION

THE PARATHYROID GLANDS – STRUCTURE AND FUNCTION

THE ADRENAL GLANDS – STRUCTURE AND FUNCTION

THE PITUITARY GLAND – STRUCTURE AND FUNCTION

LIPID METABOLISM

THE REPRODUCTIVE ORGANS – STRUCTURE AND FUNCTION

DIABETES

THE IMPACT OF DIABETES

The condition diabetes mellitus may have been in existence for more than three thousand years. The two forms of diabetes were first described in the fifth century AD, one occurring in slim individuals who perished quickly (Type 1 diabetes) and the other in older overweight people who survived for longer (Type 2 diabetes).

By the end of the nineteenth century, Langerhans from Berlin had described small clusters of cells (islets of Langerhans) in the pancreas gland that were later found to be responsible for the production of a glucose-lowering hormone. The greatest break-through in the management of diabetes occurred in 1921 when insulin was discovered at the University of Toronto by the surgeon Frederick Banting and his student Charles Best. This led to insulin being manufactured and used for the treatment of diabetes.

Diabetes mellitus is a condition in which there is a persistent elevation of blood glucose concentration. It can be caused by reduced insulin action and/or insufficient amounts of insulin.

The two main types of diabetes are Type 1 diabetes (previously called insulin-dependent diabetes mellitus [IDDM] or juvenile onset diabetes) and Type 2 diabetes (previously called noninsulin dependent diabetes mellitus [NIDDM] or maturity-onset diabetes).

Type 1 diabetes can occur at any age but more commonly presents in children and young adults. It currently accounts for 5% of diabetes in developing countries and 15% of diabetes in Europe and North America. In most cases it is caused by an autoimmune destruction of the β-cells of the islets of Langerhans cells that are located in the pancreas gland. These cells produce the hormone insulin and their destruction leads to an absence of insulin production and secretion.

Type 2 diabetes has traditionally been considered a disease of the middle-aged or elderly but is now increasingly seen in younger adults and even children, due primarily to increasing rates of obesity. The majority of patients (80–85%) are obese. Obesity and a sedentary lifestyle are thought to be responsible for the dramatic increase in prevalence of this condition. Type 2 diabetes is caused by impaired insulin secretion and by resistance to the action of insulin in peripheral tissues. Features of Types 1 and 2 are presented in Table 1.

Diabetes is associated with serious tissue complications resulting from disease of larger (macrovascular) and smaller (microvascular) blood vessels. Micro-vascular complications occur due to disease of smaller blood vessels, principally affecting the eye (retinopathy), the kidney (nephropathy), and nerves (neuropathy). These strongly relate to the duration of diabetes and the severity of hyperglycaemia.

In the developed world diabetic retinopathy is the most common cause of blindness in those aged <65 years. Diabetic nephropathy is a common cause of renal failure. Peripheral and autonomic neuropathy can both contribute to the development of foot ulceration and increase the risk of amputation. It can also lead to impotence, diarrhoea and vomiting, postural hypotension, and collapse.

Table 1 Features of Type 1 and Type 2 diabetes

Macrovascular complications relate to disease of cardiac, cerebral, and peripheral arteries and is significantly more common in those with diabetes. An increased rate of atherosclerotic disease leads to an excess of ischaemic heart disease, strokes, and lower limb amputation.

The increased morbidity associated with diabetes accounts for more than 5% of total health care costs in Europe. The bulk of this cost relates to the long-term complications rather than the management of the condition itself. It is likely that 90% of the cost relates to disease in patients with Type 2 diabetes.

Life expectancy for a diabetes sufferer is reduced by about 25%. In developed countries, the age-specific mortality rates for those with Type 2 diabetes are approximately twice those of nondiabetic individuals. Most die from cardiovascular disease although nephropathy contributes largely to death rates in Type 1 diabetes.

Type 2 diabetes is increasingly affecting children. In Japan, 80% of childhood diabetes is now due to Type 2 diabetes. In the US this figure is approaching 40%.

INSULIN ACTION

Insulin is synthesized in and secreted from the islets of Langerhans in the endocrine tissue of the pancreas gland. The islets develop from endodermal outgrowths from fetal gut. The normal pancreas has about a million scattered islets of variable size. They comprise only 2% of pancreas volume. The islets contain four main cell types that produce different hormones:

β-cells produce insulin.

´-cells produce glucagons.

Δ-cells produce somatostatin.

PP cells produce pancreatic polypeptide.

β-cells are located mainly in the centre of the islet whereas the ´- and Δ-cells are located towards the periphery. These islet cells interact through direct contact and secretions. The pancreatic islets are innervated with autonomic nerves. Parasympathetic nerves stimulate insulin release while adrenergic sympathetic nerves inhibit insulin and stimulate glucagon. There are additional nerves that stimulate hormone release-producing neuropeptides such as vasointestinal peptide (VIP) and others that inhibit insulin secretion by producing neuropeptide Y (1a).

The main stimulator of insulin production is glucose. The stimulation occurs in a biphasic pattern. There is an acute first phase that lasts several minutes followed by a sustained second phase. The rate of insulin release is controlled by the activity of the enzyme glucokinase. Maximal insulin release occurs at glucose concentrations of 20 mmol/l. Glucose levels below 4 mmol/l, however, do not stimulate insulin release.

Glucose enters the β-cell by the GLUT-2 transporter before being phosphorylated by glucokinase and coupled to insulin release. Glycolysis produces adenosine triphosphate (ATP). This closes ATP sensitive potassium channels, depolarizes the β-cell membrane and leads to an influx of calcium. This leads to granule exocytosis and release of the insulin hormone (1b).

Figure 1 Diagram to illustrate pancreatic endocrine function.

Insulin is produced in the β-cells from a single chain precursor called proinsulin. This proinsulin is packaged into vesicles within the Golgi apparatus of the cell and is then mostly converted into insulin and connecting peptide (C-peptide). These two products are released from the cell in secretory granules through microtubules at the cell surface. Insulin consists of two polypeptide chains linked by disulphide bridges. Traditional manufactured insulin products are concentrated and self-associate to form hexamers. These hexamers need to dissociate into six monomers before they can be easily absorbed from subcutaneous tissue (2).

Insulin works by binding to cell surface receptors located in the membranes of virtually all mammal cells, ´ glycoprotein that consists of two extracellular ´ subunits and two ´ subunits spanning the cell membrane. When insulin binds to a ´ subunit this activates the tyrosine kinase enzyme, which in turn activates a complex mechanism of post-receptor signalling that ultimately regulates glucose transport and protein and glycogen synthesis. Glucose is carried into cells by a family of transporter proteins.

Liver cells (hepatocytes), fat cells (adipocytes), and skeletal muscle cells are particularly sensitive to insulin. Brain glucose uptake is not regulated by insulin.

Figure 2 Diagram of the insulin molecule.

In people without diabetes, blood glucose concentrations are maintained within a narrow range (typically 5–7 mmol/l). This is a balance between glucose release from the liver, glucose uptake into fat cells, skeletal muscle, an...

Table of contents

• Cover Page
• Understanding Diabetes & Endocrinology: a problem-orientated approach
• Dedication
• Acknowledgments
• Copyright Page
• Contents
• Introduction
• Abbreviations
• CHAPTER 1 THE BASICS
• CHAPTER 2 THE PROBLEMS: DIAGNOSIS, INVESTIGATION, AND COMPLICATIONS
• CHAPTER 3 THE SOLUTIONS: PREVENTION, MANAGEMENT, AND TREATMENT
• Section4: Answers to Cases
• Index