Besides secreting exocrine digestive enzymes into the duodenum, the pancreas has endocrine functions centered in the islands of Langerhans. These structures are found primarily in the tail and body of the pancreas, the hormones involved are glucagon and insulin, and secretion is directly into the bloodstream. Diabetes mellitus results from abnormality in the production or the use of insulin. Production abnormality involves the islet beta cells and can be of two types: deficient beta-cell insulin production, or relatively normal synthesis but abnormal release. Besides production abnormality, diabetes may result from extrapancreatic factors such as peripheral tissue cell receptor dysfunction producing resistance to the cellular action of insulin, or abnormalities of nonpancreatic hormones that affect insulin secretion or blood glucose metabolism.

Categories of diabetics

The two types of idiopathic islet cell insulin abnormalities are associated with two of the most important clinical categories of diabetics. The first is the type I, or insulin-dependent, category of the National Diabetes Data Group (NDDG). Type I diabetes usually (but not always) begins relatively early in life and is more severe. Patients require insulin for management and show severe insulin deficiency on blood insulin assay. The second type of diabetes mellitus is the NDDG type II, or noninsulin-dependent diabetes, affecting about 80% of diabetics. Type II diabetes usually (but not always) begins in middle age or afterward, is frequently associated with overweight body status, is associated with less severe blood glucose abnormality, and can be treated by diet alone, oral medication, or small doses of insulin. Some type II persons show significantly elevated or normal insulin production on insulin blood level assay but a decrease in liver and peripheral tissue insulin use (insulin resistance). Others have varying degrees of decreased insulin production, although usually not as severe as the insulin deficiency of textbook type I diabetics.

There is a small subgroup of teen-aged diabetics who have disease resembling type II adult diabetes. A recent report links this to mutation in the gene for glucokinase. There are also a few adult diabetics with type II disease who are not overweight, and a small subgroup of adult diabetics who have disease resembling type I.

The NDDG has two other categories of diabetics. The first group is associated with various nonidiopathic conditions and syndromes (“secondary diabetes”) that either destroy pancreatic tissue (pancreatitis, pancreatic carcinoma, hemochromatosis) or produce abnormal glucose tolerance due to various extrapancreatic influences such as hormones, drugs, and insulin receptor abnormalities. The second category is gestational diabetes, diabetes that begins in pregnancy.

Laboratory tests for diabetes

Most laboratory tests for diabetes attempt to demonstrate pancreatic islet cell malfunction, either deficient insulin production or abnormal insulin release, using either direct or indirect blood insulin measurement. For many years direct blood insulin measurement was technically too difficult for any but a few research laboratories. Therefore, emphasis in clinical medicine was placed on indirect methods, whose end point usually demonstrated the action of insulin on a relatively accessible and easily measurable substance, blood glucose. Immunoassay methods for insulin measurement are now commercially available. However, in most cases direct insulin assay has not proved more helpful than blood glucose measurement in the diagnosis of diabetes, since in general the quantitative result and the pattern of blood glucose values permit one to separate diabetics into the two basic type I and type II groups with a reasonable degree of accuracy. In addition, blood glucose measurement is far less expensive, more readily available, and less technically demanding than current immunoassay methods.

For reasons already noted, blood glucose measurement is still the mainstay for diagnosis of diabetes. Unfortunately, certain flaws are inherent in all systems using blood glucose for this purpose. These problems derive from any technique that attempts to assay one substance by monitoring its action on another. Ideally, one should measure a substrate that is specific for the reaction or enzyme in question under test conditions that eliminate the effects on use by any other factors. The blood glucose level does not meet any of these criteria.

Blood glucose regulation

The blood glucose level depends primarily on the liver, which exerts its effect on blood glucose homeostasis via its reversible conversion of glucose to glycogen, as well as via gluconeogenesis from fat and protein. Next most important is tissue utilization of glucose, which is mediated by pancreatic insulin but is affected by many factors in addition to insulin.

The actual mechanisms involved in the regulation of blood glucose levels are complex and in many cases only partially understood. Insulin is thought to increase glucose transport into cells of most tissues (except red blood cells [RBCs] and possibly brain and intestinal mucosa) and to stimulate glucose oxidation and synthesis of fat, glycogen, and protein. In addition, insulin has a direct effect on the liver by suppressing glucose formation from glycogen (glycogenolysis).

The liver is affected by at least three important hormones: epinephrine, glucagon, and hydrocortisone (cortisol). Epinephrine from the adrenal medulla stimulates breakdown of glycogen to glucose by converting inactive hepatic cell phosphorylase to active phosphorylase, which mediates the conversion of glycogen to glucose-1-phosphate. In addition, there is evidence that gluconeogenesis from lactate is enhanced by the action of the enzyme adenosine 3,5-monophosphate. Glucagon is a hormone produced by the pancreatic alpha cells and released by the stimulus of hypoglycemia. It is thought to act on the liver in a manner similar to that of epinephrine. Cortisol, cortisone, and similar 11-oxygenated adrenocorticosteroids also influence the liver but in a different manner. One fairly well-documented pathway is enhancement of glycogen synthesis from amino acids. This increases the carbohydrate reserve available to augment blood glucose levels; thus, steroids like cortisol essentially stimulate gluconeogenesis. In addition, cortisol deficiency leads to anorexia and also causes impairment of carbohydrate absorption from the small intestine.