du jour

40 different V segments, about 25 different D segments, 6 different J segments, and so on.

Edward Jenner

The bapineuzumab trials seem to have been more of an unqualified failure. This antibody drug targets the amyloid-[besa] plaques, in hopes of awakening the immune system to clear them from the brain. But two trials in approximately 2,400 patients failed to show any benefit compared with a placebo,

The drug is meant to recognize and block amyloid-[besa] before it forms plaques. In patients with mild and moderate forms of disease, however, solanezumab failed to meet its main goals of slowing the decline in memory and other cognitive measures, or in the ability to perform tasks such as eating and maintaining personal care.

Whereas viral, bacterial, and autoimmune diseases of the CNS can resemble their extraneural counterparts morphologically, the concept of “neuroinflammation” has gradually expanded to also describe diseases that display none of Celsus’ cardinal signs, that do not attract conventional inflammatory cells, and that most neuropathologists would classify as degenerative rather than inflammatory.

In the absence of insulin, the entry of glucose into skeletal, cardiac, and smooth muscle and other tissues is decreased (Figure 24–8). Glucose uptake by the liver is also reduced, but the effect is indirect. Intestinal absorption of glucose is unaffected, as is its reabsorption from the urine by the cells of the proximal tubules of the kidneys. Glucose uptake by most of the brain and the red blood cells is also normal.

Disordered plasma glucose homeostasis in insulin deficiency. The heavy arrows indicate reactions that are accentuated. The rectangles across arrows indicate reactions that are blocked.

Diabetes is characterized by polyuria (passage of large volumes of urine), polydipsia (excessive drinking), weight loss in spite of polyphagia (increased appetite), hyperglycemia, glycosuria, ketosis, acidosis, and coma. Widespread biochemical abnormalities are present, but the fundamental defects to which most of the abnormalities can be traced are (1) reduced entry of glucose into various “peripheral” tissues and (2) increased liberation of glucose into the circulation from the liver. Therefore, there is an extracellular glucose excess and, in many cells, an intracellular glucose deficiency—a situation that has been called “starvation in the midst of plenty.” Also, the entry of amino acids into muscle is decreased and lipolysis is increased.

When insulin binds to its receptors, they aggregate in patches and are taken up into the cell by receptor-mediated endocytosis (see Chapter 2). Eventually, the insulin–receptor complexes enter lysosomes, where the receptors are broken down or recycled. The half-life of the insulin receptor is about 7 h.

Insulin receptors are found on many different cells in the body, including cells in which insulin does not increase glucose uptake.

Failure to grow is a symptom of diabetes in children, and insulin stimulates the growth of immature hypophysectomized rats to almost the same degree as growth hormone.

Insulin causes K+ to enter cells, with a resultant lowering of the extracellular K+ concentration. Infusions of insulin and glucose significantly lower the plasma K+ level in normal individuals and are very effective for the temporary relief of hyperkalemia in patients with renal failure.

In the tissues in which insulin increases the number of GLUTs in cell membranes, the rate of phosphorylation of the glucose, once it has entered the cells, is regulated by other hormones. Growth hormone and cortisol both inhibit phosphorylation in certain tissues. Transport is normally so rapid that it is not a rate-limiting step in glucose metabolism. However, it is rate-limiting in B cells.

The insulin then crosses the basal lamina of the B cell and a neighboring capillary and the fenestrated endothelium of the capillary to reach the bloodstream. The fenestrations are discussed in detail in Chapter 31.

Porcine insulin differs from human insulin by only one amino acid residue and has low antigenicity.

blood from the islets, like that from the gastrointestinal tract (but unlike that from any other endocrine organs) drains into the hepatic portal vein

 Increased ketone uptake

 Increased K+ uptake

Note that decreased outward recoil of the chest wall increases its compliance