Development of adult diabetes

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(B). Compared with a normal subject, the obese subject requires a continually elevated output of insulin (orange curves) to avoid an excessive rise of blood glucose levels (green curves) during a glucose load. When the secretory capacity of the pancreas decreases, this is first noted as a rise in blood glucose during glucose loading (latent diabetes). Subsequently, not even the fasting blood level can be maintained (manifest, overt diabetes). A diabetic condition has developed, although insulin release is not lower than that in a healthy person (relative insulin deficiency).

Treatment. Caloric restriction to restore body weight to normal is associated with an increase in insulin receptor number or cellular responsiveness. The releasable amount of insulin is again adequate to maintain a normal metabolic rate.

Lullmann, Color Atlas of Pharmacology © 2000 Thieme

Therapy of first choice is weight reduction, not administration of drugs! Should the diabetic condition fail to resolve, consideration should first be given to insulin replacement (p. 260). Oral antidiabetics of the sulfonylurea type increase the sensitivity of B-cells towards glucose, enabling them to increase release of insulin. These drugs probably promote depolarization of the ß-cell membrane by closing off ATP-gat-ed K+ channels. Normally, these channels are closed when intracellular levels of glucose, hence of ATP, increase. This drug class includes tolbutamide (5002000 mg/d) and glyburide (glibencla-mide) (1.75-10.5 mg/d). In some patients, it is not possible to stimulate insulin secretion from the outset; in others, therapy fails later on. Matching dosage of the oral antidiabetic and caloric intake follows the same principles as apply to insulin. Hypoglycemia is the most important unwanted effect. Enhancement of the hypoglycemic effect can result from drug interactions: displacement of antidiabetic drug from plasma protein-binding sites by sulfon-amides or acetylsalicylic acid.

Metformin, a biguanide derivative, can lower excessive blood glucose levels, provided that insulin is present. Metformin does not stimulate insulin release. Glucose release from the liver is decreased, while peripheral uptake is enhanced. The danger of hypoglycemia apparently is not increased. Frequent adverse effects include: anorexia, nausea, and diarrhea. Overproduction of lactic acid (lactate acidosis, lethality 50%) is a rare, potentially fatal reaction. Metformin is used in combination with sulfonylureas or by itself. It is contraindicated in renal insufficiency and should therefore be avoided in elderly patients.

Thiazolidinediones (Glitazones: ro-siglitazone, pioglitazone) are insulin-sensitizing agents that augment tissue responsiveness by promoting the synthesis or the availability of plasmalem-mal glucose transporters via activation of a transcription factor (peroxisome proliferator-activated receptor-y).

Insulin receptor binding needed for euglycemia

Insulin binding

Normal receptor number

Insulin binding

Normal receptor number

Insulin concentration

A. Insulin concentration and binding in normal and overweight subjects

A. Insulin concentration and binding in normal and overweight subjects

Marcus Gunn Jaw Winking Syndrome

Therapy of 1st choice

Diagnosis: latent overt Diabetes mellitus

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