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Understanding Diabetes

By Jacob G. Ghazarian, Ph.D.
Wolfson College, University of Oxford

We will better understand diabetes if we first become familiar with some of the fundamental terminology used to describe the metabolic derangements associated with the biochemistry of this genetically inherited disease.

First, the terms used to describe the types of this disease include: the type I and type II of Diabetes Mellitus (T1 for insulin-dependent diabetes or juvenile-onset diabetes and T2 for insulin-independent diabetes or maturity-onset (adult-onset) diabetes) and Diabetes Insipidus. Two other terms that do not involve the elevated blood glucose level which characterizes diabetes are Kidney Diabetes (renal glucosuria - sugar in urine) and Bronze Diabetes. They are misnomers. The former is a result of kidney damage and the latter is an abnormality in iron metabolism.

The clinical conditions that are indicative of diabetes are Hyperglycemia (hyper-glyc-emia, high-sugar-blood) or Hypoglycemia (hypo- low), Glucosuria (glucose in urine), Glycosuria (sugar in urine which includes pentosuria, lactosuria, galactosuria and ftuctosuria). Other conditions are Polyuria (high urine output), Polydipsia (excessive thirst), Polyphagia (high food intake) and Ketongenesis (ketone synthesis) hence the characteristic so-called Acetone Breath.

The cellular biochemical processes controlled by the hormones Insulin and Glucagon are Lipolysis (lipo-lysis, lipid-break (use), Glycogenesis (glycogen-synthesis), Gluconeogenesis (glucose synthesis from non-carbohydrate sources, i.e. from fats and proteins). And finally, Cell Desensitization and Receptor Down-Regulation are terms that attempt to describe the reasons for the absence of insulin effects in type II diabetes. Diabetes is a disease characterized by changes in glucose metabolism that result in grossly abnormal pattern of glucose usage as the body’s main energy fuel. The changes are expressed as glucose overproduction by the liver and its underutilization by other tissues and organs. It is the most common life-threatening metabolic disease in the world. Individuals who are type I diabetic appear to have specific genes that make them more susceptible to the disease than others.

Digestible plant carbohydrates, as starch and dextrin, are mostly linear polymers of glucose which are referred to as poly-saccharides. Dextrins are often referred to as “complex carbohydrates.” These along with free glucose and certain other mono-saccharides such fructose, ribose and xylulose, and di-saccharides such as sucrose, lactose and maltose are the principal carbohydrates in foods. The starches and dextrins constitute about 55% of consumed dietary carbohydrates. They are found in cereal grains, legumes, potatoes and other tubers. Sucrose is found in syrups, honey and some fruits while lactose is the main milk sugar. About 35% of consumed dietary carbohydrates is as sucrose and 5% each as lactose and maltose. The indigestible poly-saccharides are the plant celluloses, lignins, pectins and gums and form the fiber in foods. Glycogen is the animal equivalent of starch but is a non-linear polymer and is highly branched. It is the principal storage carbohydrate in the liver and muscle tissue.

Fundamentally, diabetes is a disease that ultimately leads to hyperglycemia because of the inability of tissue cells to internalize glucose from the blood. As blood glucose levels continue to increase to a concentration above normal kidney’s ability to reabsorb the glucose from the blood as it is filtered by the kidney, glucosuria (and glycosuria) begins to be manifested as a clinical symptom. This is said to have exceeded kidney’s threshold to filter glucose. The rise in blood glucose levels can either be due to ingested dietary sugars or from the excessive synthesis of glucose by the liver, as will be explained below. Glucose starvation of tissue cells and reduction in their energy levels underline polyphagia. Also, kidney’s inability to reabsorb water, especially in diabetes insipidus, leads to dehydration thus polyuria and polydipsia.

Type I diabetes commonly develops in people younger than age 20 thus it is also known as juvenile-onset diabetes. It often occurs abruptly and is caused by an absolute deficiency of insulin due to a large decline in the number of _ cells of the pancreas that produce this hormone. Thus, type I diabetes is said to be “insulin-dependent.” It can be treated by periodic administration of insulin. The control of the type I disease by exogenous insulin administration is indicative of the presence of functional insulin receptors in the membranes of target cells. Receptors are membrane structures that recognize specific ligands associated with transport and internalization of substances across cell membranes. There is some evidence that suggests type I diabetes is an autoimmune disease.

Type II diabetes on the other hand, occurs despite sufficient circulating insulin, which is indicative of defects in the mechanisms associated with insulin-mediated uptake and internalization of glucose by target cells. All cells and in particular liver and skeletal cells become refractive to insulin action either because their membranes have fewer insulin receptors or that their receptors are structurally defective, hence the term insulin-independent diabetes. The disease usually occurs in middle-aged obese people and as in type I it is characterized by hyperglycemia but such individuals also suffer from hypertriglyeridemia (high blood levels of protein-lipid-cholesterol conjugates). However unlike type I there is no observed ketosis. Since the disease occurs later in life it is also referred to as maturity-onset diabetes. The clinical symptoms of type II diabetes are mild and the associated hyperglycemia and hypertriglyceridemia can usually be controlled by restrictive diets, exercise and anti-diabetic drugs.

Type II patients characteristically demonstrate hyperinsulinemia and there is an inverse relationship between insulin levels and the number of insulin receptors. The higher the basal insulin levels the fewer are the receptors on cell membranes. Furthermore prolonged exposure of receptors to their specific ligand -insulin in the case of diabetes- often cause loss of responsiveness to the ligand. This process of adaptation or desensitization is reversible but nonetheless this reversibility potential is quite rare in type II diabetes. Often slight structural alterations in either the ligand or in its receptor may cause the absence of the expected cellular response upon their interaction. For example, defective insulin may still bind to its cell receptor yet not be able to conduct its signaling function that internalizes glucose. The diagram below is a summary of the biochemical events that describe diabetes mellitus. Constant loss of glucose in the urine, either due to deficiency or ineffectiveness of circulating insulin, depletes body’s reserves of carbohydrates (glycogen) thus accelerating breakdown of body’s fat reserves (lipolysis) to fatty acids which are then converted by the liver to small organic acids. These acids cause a form of acidosis called ketosis by lowering the pH of the blood which can result in death. Similarly, gluconeogenesis by the liver accelerates the breakdown of body’s reserves of proteins caught up in a vicious cycle of glucose production and excretion. In a non-diabetic the hormone glucagon, which is produced by the _ cells of the pancreas to counters the effects of insulin, is secreted in conditions of hypoglycemia to mobilize glucose from glycogen in the liver as a balancing process to restore blood glucose. Since diabetics are hyperglycemic, this balancing effect of glucagon is essentially absent.

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