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262 Hormones

Treatment of Maturity-Onset (Type II) Diabetes Mellitus

In overweight adults, a diabetic metabolic condition may develop (type II or non-insu- lin-dependent diabetes) when there is a relative insulin deficiency—enhanced demand cannot be met by a diminishing insulin secretion.

The cause of increased insulin requirement is an insulin resistance of target organs. The decrease in the effectiveness of insulin is due to a reduction in the density of insulin receptors in target tissues and a decreased ef ciencyof signal transduction of insulin-receptor complexes. Conceivably, obesity with increased storage of triglycerides causes a decrease in insulin sensitivity of target organs. The loss insensitivitycanbe compensated by enhancing insulin concentration. In panel (A), this situation is represented schematically by the decreased receptor density. In the obese patient, the maximum binding possible (plateau of curve) is displaced downward, indicative of the reduction in receptor numbers. At low insulin concentrations, correspondingly less binding of insulin occurs, compared with the control condition (normal weight). For a given metabolic effect (say, utilization of carbohydrates contained in a piece of cake), a certain number of receptors must be occupied. As shown by the binding curves (dashed lines), this can still be achieved with areduced receptor number; although onlyat a higher concentration of insulin.

Development of adult diabetes (B). A subject with normal body weight (left) ingests a specified amount of carbohydrate; to maintain blood glucose concentration within the physiological range, the necessary amount of insulin is released into the blood. Compared with a normal subject, the overweight patient with insulin resistance requires a continually elevated output of insulin (orange curves) to avoid an excessive rise of blood glucose levels (green curves) during an

equivalent carbohydrate load. When the insulin secretory capacity of the pancreas decreases, this is first noted as arise in blood glucose during glucose loading (latent diabetes mellitus). As insulin secretory capacity declines further, not even the fasting blood level can be maintained (manifest, overt diabetes).

Treatment. Caloric restriction to restore body weight to normal is associated with an increase in insulin responsiveness, even before a normal weight is reached. Moreover, physical activity is important because it enhances peripheral utilization of glucose. When changes in lifestyle are insuf cient in correcting the diabetic condition, therapy with oral antidiabetics is indicated (p.264).

Therapy of first choice is weight reduction, not administration of drugs!

A metabolic syndrome is said to be present when at least three of the following five riskfactors can be identified in apatient:

1.Elevated blood glucose levels

2.Elevated blood lipid levels

3.Obesity

4.Lowered HDL levels

5.Hypertension

Overweight and resistance to insulin appear to play pivotal roles in the pathophysiological process. The resulting hyperinsulinemia inducesarise in systemic arterial blood pressure and probably also a hyperglyceridemia associated with an unfavorable LDL/HDL quotient. This combination of risk factors lowers life expectancy and calls for therapeutic intervention. The metabolic syndrome has a high prevalence; in industrialized countries, up to 20% of adults are believed to suffer from it.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Treatment of Maturity-Onset Diabetes Mellitus

263

A. Insulin concentration and binding in normal and overweight subjects

 

Insulin binding

 

Normal receptor number

Insulin receptor

Normal

binding

diet

needed

 

for euglycemia

 

 

Decreased

 

receptor

 

number

 

Obesity

 

Insulin concentration

B. Development of maturity-onset diabetes

 

 

 

Oral

 

 

anti-

 

 

diabetic

Insulin release

 

 

Time

 

 

Glucose in blood

 

 

 

 

Diagnosis:

 

latent

overt

Weight reduction

Diabetes mellitus

 

 

Therapy of 1st choice

 

Therapy of 2nd choice

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

264 Hormones

Oral Antidiabetics

In principle, the blood concentration of glucose represents a balance between influx into the bloodstream (chiefly from liver and intestines) and egress from blood into consuming tissues and organs. In (A), drugs available for lowering an elevated level of glucose are grouped schematically in relation to these two processes.

Metformin is a biguanide derivative that can normalize an elevated blood glucose level, provided that insulin is present. The mechanism underlying this effect is not completely understood. Decreased glucose release from the liver appears to play an essential part. Metformin does not increase release of insulin and therefore does not promote hyperinsulinemia. The risk of hypoglycemia is relatively less common. Triglyceride concentrations can decrease. Metformin has proved itself as a monotherapeutic in obese type II diabetics. It can be combined with other oral antidiabetics as well as insulin. Frequent adverse effects include anorexia, nausea, and diarrhea. Overproduction of lactic acid (lactate acidosis) is a rare, potentially fatal reaction. It is contraindicated in renal insuf ciency and therefore should be avoided in elderly patients.

Oral antidiabetics of the sulfonylurea type increase the release of insulin from pancreatic B-cells. They inhibit ATP-gated K+ channels and thereby cause depolarization of the B-cell membrane. Normally, these channels are closed when intracellular levels of glucose, and hence of ATP, increase. This drug class includes tolbutamide (500– 2000 mg/day) and glyburide (glibenclamide) (1.75–10.5 mg/day). In some patients, it is not possible to stimulate insulin secretion from the outset; in others, therapy fails later. Matching of dosage of the oral antidiabetic and caloric intake is necessary. 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, for example, by sulfonamides or acetylsalicylic acid.

Repaglinide possesses the same mechanism of action as the sulfonylureas but differs in chemical structure. After oral administration, the effect develops rapidly and fades away quickly. Therefore, repaglinide can be taken immediately before a meal.

“Glitazone” is an appellation referring to thiazolidinedione derivatives such as rosiglitazone and pioglitazone. These substances augment the insulin sensitivity of target tissues. They are agonists at the peroxisome proliferator-activated receptor of the γ subtype (PPARγ), a transcription-regulating receptor. As a result, they (a) promote the maturation of preadipocytes into adipocytes,

(b) increase insulin sensitivity, and (c) enhance cellular glucose uptake. Besides fat tissue, skeletal muscle is also affected.

Rosiglitazone and pioglitazone are approved only for combination therapy when adequate glycemic control cannot be achieved with either metformin or a sulfonylurea alone. A combination with insulin is contraindicated. Adverse effects include weight gain and fluid retention (thus contraindication for any stage of congestive heart failure). Hepatic function requires close monitoring (withdrawal of troglitazone because of fatal liver failure).

Acarbose is an inhibitor of α-glucosidase (localized in the brush border of intestinal epithelium), which liberates glucose from disaccharides. It retards breakdown of carbohydrates, and hence absorption of glucose. Owing to increased fermentation of carbohydrates by gut bacteria, flatulence and diarrhea may develop. Miglitol has a similar effect but is absorbed from the intestine.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

 

 

 

Oral Antidiabetics

 

 

265

A. Oral antidiabetics

 

 

 

 

 

 

 

 

 

 

Metformin, a biguanide derivative

 

Glibenclamide, a sulfonylurea derivative

Cl

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

NH

SO2

 

CH2

CH2

NH

C

 

 

 

 

 

O

C

 

 

 

 

H3C

O

 

 

 

 

 

NH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H3C

N

CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

HN

C

 

B-cells

 

 

 

 

 

Glucose

 

 

of pancreas

 

 

 

 

 

 

 

 

NH

 

 

 

 

 

ATP-gated

 

 

 

 

 

 

 

 

 

 

 

 

C

NH

 

 

 

 

 

 

 

K+-channel

 

 

 

 

 

 

ATP

 

 

 

 

 

NH2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

K+

 

 

Blockade

 

 

K+

 

Inhibition of

 

 

 

 

 

 

 

 

 

 

 

hepatic glucose release

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Membrane

 

 

 

 

 

 

 

 

 

 

potential depolarized

 

 

Lactic acidosis

Hypoglycemia

Insulin secretion

 

 

 

 

 

 

 

 

 

 

 

 

Liver

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Insulin

 

 

 

 

 

 

 

Glucose

 

 

 

 

 

 

 

 

 

 

 

Influx

concentration

 

Egress

 

 

 

 

 

 

 

 

in blood

 

 

 

 

 

 

 

 

 

Intestines

 

 

 

 

 

 

 

 

 

 

 

 

Acarbose, a “false”

 

Rosiglitazone, a thiazolidinedione derivative

 

tetrasaccharide

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

S

 

 

 

 

 

N

CH2

CH2

O

 

C 2

 

 

Disaccharide

 

 

 

 

NH

 

 

 

H3C

 

 

 

 

H

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

α -Glucosidase

 

 

 

 

 

Pre-adipocytes

 

 

 

 

 

 

 

 

 

Adipocytes

 

Glucose

 

 

 

 

PPARγ

 

Insulin sensitivity

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

DNA

 

Glucose uptake

 

 

 

 

 

 

 

 

 

 

retards enteral

 

 

 

 

 

 

 

 

 

 

absorption of glucose

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fatty tissue

 

 

 

 

 

 

 

 

 

 

 

Weight gain

 

Contraindication in congestive

 

Intestinal complaints

 

 

 

 

heart failure, NYHA 1–4

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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