|
Year: 2004 | Volumen: 41 # 3
Insulin Resistance Pharmacology: Cur rent Situation and Perspectives.
Authors: González, C.D.; Santoro, S.G.; Sinay, I.
Insulin-resistance is the pathophysiological expression of the metabolic syndrome. Therefore, it is intimately
related to obesity, hypertension, diabetes and hyperlipidemia. The aim of this article is to review the pharmacological
strategies specifically assigned to lower insulin-resistance, and to describe a number of projects in this
area which might achieve certain success in the future. According to Laborde and Manchem 3 the following
pharmacological aims can be considered: hepatic glucose production inhibitors, insulin-sensitizers, lipid metabolism
modifiers, and insulin receptor activators, among others. In the first group biguanides, glucagon receptor acantagonists,
and inhibitors of glycogen synthase-kinase, hepatic glycogen-phosphorilase, pyruvate-dehydrogenase-
kinase, fructose 1,6-biphosphatase and glucose–6-phosphate are included. Metformin, a biguanide, lowers
with a intermediate efficacy the hepatic output of glucose. As regards its mechanism of action, it inhibits the
complex I of the respiratory chain, consequently stimulating pyruvate kinase and inhibiting pyruvate-carboxilase,
therefore glyconeogenesis from lactate is reduced 4-5. It also stimulates AMPK which enhances non sterified
fatty acid oxidation, and lowers hepatic glucose and cholesterol production 7. In addition, it has effects on
certain factors associated to macrovascular disease (lowers PAI-1, factor VII, fibrinogen and platelet adhesion)
and an anti-inflammatory activity 7. There are two non peptidic molecules, BAY-27-9955 12 and NNC-25-250413,
capable of antagonize the effects of glucagon in the hepatic production of glucose. With reference to the inhibition
of glycogen synthase kinase 3, there are six families of agents in early development 14, as well as the
other groups of inhibitors of the hepatic production of glucose. Among the insulin-sensitizers, thiazolidinediones,
PPARg agonists, are well known for lowering insulin-resistance by raising the expression of GLUT 4, enhancing
lipogenesis, reducing non sterified fatty acids and the use of glucose by the muscle, lowering hepatic
glyconeogenesis and stimulating hepatic glucose intake. Furthermore they produce a down regulation of TNFa,
interleukine 6 and resistin (apparently linked to the development of insulin-resistance) 16. An anti-inflammatory,
anti-atherogenic as well as an anti-hypertensive effect have been reported 17-18. In addition, table 1 shows diverse
PPAR agonists in development. Moreover, there are some agents capable of activating the RxR receptor,
which is a protein that after linking PPARg stimulates the transcription of certain molecules related to glucose
metabolism 21. Another target related to insulin-sensibilization is the stimulation of b3 adrenergic receptor. However,
there are two main problems related to their use in humans: lack of enough specificity and biodisponibility.
Table 2 shows the state of these projects 20. Another possibility is the inhibition of PTB-B1, an enzyme
that ends insulin intracellular signal. Table 3 shows the projects in this area 20. The third group, lipid modifiers,
is referred mainly to inhibitors of 11b-HSD 1, an enzyme that catalyzes the conversion of cortisone to cortisol.
Among them, thiazolidinediones, BVT-2733 and carbenexolone analogs can be considered 25-26. Finally, insulin
receptor activators can be subdivided in those independent of insulin (L-783281, which do not need insulin for
their activity) and dependent of insulin (TLK-16998) 3. Concluding: as insulin-resistance precedes type 2 diabetes
mellitus, and is probably an independent risk factor for cardiovascular disease 28, the development of specific
drugs for its treatment acquires major importance for the prevention and management of those entities 27.
Copyright © 2004 por la Sociedad Argentina de Endocrinología y Metabolismo
Key words: Insulin resistance, Biguanids, Cardiovascular Risk
|
