Medical brain notes 47

  GLUCOSE HOMEOSTASIS   Carbohydrates, particularly glucose, are an important source of fuel for living organisms. Glucose is a major energy source for all cells, and some tissues (e.g., brain) need a continuous delivery of glucose. Maintenance of serum glucose concentrations within a normal physio-logical range, critical to the maintenance of normal fuel use, is primarily accomplished by two pancreatic hor-mones, insulin and glucagon. Derangements of gluca-gon or insulin regulation can result in hyperglycemia or hypoglycemia, respectively.   Glucose penetrates most tissues slowly unless in-sulin is present to facilitate its uptake; however, central nervous system (CNS) cells, capillary endothelial cells, gastrointestinal epithelial cells, pancreatic cells, and re-nal medullary cells are freely permeable to glucose.   The endocrine portion of the pancreas, called the  islets of Langerhans,  consists of cordlike groups of cells arranged along pancreatic capi...

  INSULIN   More than a century has passed since von Mering and Minkowski first demonstrated that pancreatectomized dogs exhibited signs and symptoms characteristic of dia-betes mellitus. Shortly thereafter, Banting and Best used pancreatic extracts to reverse these symptoms in diabetic patients, thus providing a basis for establishing a cause-and-effect relationship between insulin deficiency and diabetes. Insulin was subsequently isolated, crystal-lized, and eventually synthesized in the laboratory. Insulin replacement therapy has been widely used in the clinical management of diabetes mellitus for more than 70 years. In 1982, recombinant DNA (rDNA) derived  human insulin  was first produced and is now widely used   instead of insulin derived from beef or pork. More re-cently, insulin analogues have been produced that mod-ulate the activity and rate of insulin action.   Chemistry   Insulin is a relatively simple protein consisting of 51 amino acids a...

  DIABETES MELLITUS   Diabetes mellitus affects approximately 5 to 8% of the population. A large number of individuals are asympto-matic and do not know they have the disease. The re-cent rise in obesity in the United States accounts for much of the observed and anticipated rise in cases of di-abetes mellitus in this country. Although insulin treat-ment has greatly increased the life expectancy of the di-abetic patient, diabetes remains the third leading cause of death by disease, the second leading cause of blind-ness, and the second leading cause of renal failure.   Diabetes mellitus is a heterogeneous group of disor-ders characterized by abnormalities in carbohydrate, protein, and lipid metabolism. The central disturbance in diabetes mellitus is an abnormality in insulin produc-tion or action or both, although other factors can be in-volved. Hyperglycemia is a common end point for all types of diabetes mellitus and is the parameter that is measured to evaluate and mana...

  METABOLIC DISTURBANCES AND COMPLICATIONS OF THE DIABETIC STATE   There are only two major sources of blood glucose:  ex-ogenous,  or the ingestion of dietary carbohydrate, and  endogenous,  which is contributed by hepatic and renal   gluconeogenesis and hepatic glycogenolysis.  Diabetes   mellitus is a metabolic disorder in which carbohydrate metabolism is reduced while that of proteins and lipids is increased.  In diabetics, exogenous and endogenous glu-cose is not used effectively, and it accumulates in the blood ( hyperglycemia ). As blood glucose levels in-crease, the amount of glucose filtered by the glomeruli eventually exceeds the reabsorption capacity (T m , trans-port maximum) of the proximal tubule cells, and glu-cose appears in the urine ( glucosuria ). Protein catabo-lism and the rate of nitrogen excretion are increased when blood insulin falls to low levels; stimulation of he-patic gluconeogenesis converts amino acids to g...

  CLINICAL MANAGEMENT OF DIABETES   Diet is the cornerstone of the management of diabetes, regardless of the severity of the symptoms or the type of diabetes. Exercise is also an important component in managing diabetes, particularly in obese individuals with NIDDM who may have a component of insulin re-sistance as a consequence of obesity. Treatment regi-mens that have proved effective include a calorie-restricted diet in combination with exogenous insulin or oral hypoglycemic drugs. However, since diet, exercise, and oral hypoglycemic drugs (Table 67.2), often be-cause of noncompliance by the patient, will not always achieve the clinical objectives of controlling the symp-toms of diabetes, insulin remains universally important in therapeutic management. The administration of in-sulin is required for the treatment of type I (IDDM) and in cases of type II (NIDDM) that are refractory to management with oral hypoglycemic drugs.   Because the spectrum of patients with diabet...

  ORAL AGENTS FOR TREATING DIABETES MELLITUS   Although insulin has the disadvantage of having to be injected, it is without question the most uniformly ef-fective treatment of diabetes mellitus. Some milder forms of diabetes mellitus that do not respond to diet management or weight loss and exercise can be treated with oral hypoglycemic agents. The success of oral hy-poglycemic drug therapy is usually based on a restora-tion of normal blood glucose levels and the absence of glycosuria. Traditionally, the term  oral hypoglycemic  was used interchangeably with sulfonylureas, but more recently the development of several new drugs has broadened this designation to include all oral medica-tions for diabetes. Because these drugs do not have to be injected, oral agents enhance compliance in type II diabetics. These classes of drugs are not generally used in type I diabetes. The pharmacokinetic profile of oral agents for diabetes is depicted in Table 67.4.  

  Sulfonylureas   Sulfonylureas are the most widely prescribed drugs in the treatment of type II diabetes mellitus. The initial sulfonylureas were introduced nearly 50 years ago and were derivatives of the antibacterial sulfonamides. Although their structural similarities to the sulfon-amide antibacterial agents are readily apparent, the sul-fonylureas possess no antibacterial activity. Mechanism of Action   The primary mechanism of action of the sulfonylureas is  direct stimulation of insulin release from the pancreatic β-cells.  In the presence of viable pancreatic β-cells, sul-fonylureas enhance the release of endogenous insulin, thereby reducing blood glucose levels. At higher doses, these drugs also decrease hepatic glucose production, and the second-generation sulfonylureas may possess additional extrapancreatic effects that increase insulin sensitivity, though the clinical significance of these phar-macological effects is unclear. These mechanisms are sum...