Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects.

AIMS/HYPOTHESIS: Metformin is widely used for treating type 2 diabetes mellitus, but its actions are poorly understood. In addition to diminishing hepatic glucose output, metformin, in muscle, activates 5'-AMP-activated protein kinase (AMPK), which alone increases glucose uptake and glycolysis, diminishes lipid synthesis, and increases oxidation of fatty acids. Moreover, such lipid effects may improve insulin sensitivity and insulin-stimulated glucose uptake. Nevertheless, the effects of metformin on insulin-sensitive signalling factors in human muscle have only been partly characterised to date. Interestingly, other substances that activate AMPK, e.g., aminoimidazole-4-carboxamide-1-beta-D: -riboside (AICAR), simultaneously activate atypical protein kinase C (aPKC), which appears to be required for the glucose transport effects of AICAR and insulin. METHODS: Since aPKC activation is defective in type 2 diabetes, we evaluated effects of metformin therapy on aPKC activity in muscles of diabetic subjects during hyperinsulinaemic-euglycaemic clamp studies. RESULTS: After metformin therapy for 1 month, basal aPKC activity increased in muscle, with little or no change in insulin-stimulated aPKC activity. Metformin therapy for 8 to 12 months improved insulin-stimulated, as well as basal aPKC activity in muscle. In contrast, IRS-1-dependent phosphatidylinositol (PI) 3-kinase activity and Ser473 phosphorylation of protein kinase B were not altered by metformin therapy, whereas the responsiveness of muscle aPKC to PI-3,4,5-(PO(4))(3), the lipid product of PI 3-kinase, was improved. CONCLUSIONS/INTERPRETATION: These findings suggest that the activation of AMPK by metformin is accompanied by increases in aPKC activity and responsiveness in skeletal muscle, which may contribute to the therapeutic effects of metformin.

[Immunomodulator structure-activity relationships: contribution of molecular modeling]. / Relations structures-activités des immunomodulateurs. Apport de la modélisation moléculaire.

Molecular modeling used to compare 64 immunostimulant compounds with pyrrolie quinolein or purine nuclei has pointed out that a common spatial structure is found in most of the active compounds. An additional study of immunostimulants (levamisole, muramyldipeptide) or immunosuppressive molecules (rapamycin) was performed. A common pharmacophore was found on every studied compound. It was composed of three neighboring electroattractive atoms and a further fourth atom. The favorable conformation of rapamycin for immunosuppressive action, which is not the more stable conformation, could explain the loss of its activity, or those of related macrolides, when some minor chemical modifications are tested. These findings validate the proposed concept and provide a view of the mechanism of action of most of the immunomodulator compounds for preparing novel compounds

[Percutaneous mitral valvuloplasty by Inoue's technique. Apropos of an experience of 71 cases]. / La valvuloplastie mitrale percutanée selon la technique d'Inoue. A propos d'une expérience de 71 cas.

Seventy-one consecutive, unselected patients underwent percutaneous mitral valvuloplasty by Inoue's technique between February and November 1990. The mean age was 53 years (range 32 to 75 years). Fifteen of the 71 patients had previously undergone surgical mitral commissurotomy. Three patients had Björk aortic valve prostheses. The mitral valve surface area increased from 1.1 +/- 0.2 cm2 to 1.95 +/- 0.5 cm2 (p less than 0.01) and the mean transmitral pressure gradient fell from 12 +/- 3 mmHg to 5 +/- 2 mmHg (p less than 0.05). Grade 3+ mitral regurgitation was observed in 4 patients. There were no cases of cardiac perforation or tamponade. The only complications were related to the catheterisation and not to the technique valvuloplasty (one case of prolonged fever which regressed with antibiotic therapy, one case of arteriovenous fistula at the site of femoral artery puncture). The QP/QS ratio was 1.1 +/- 0.2 at the end of the procedure. A QP/QS ratio greater than 1.5 was observed in one patient. A left-to-right shunt was observed in 53% of cases in the immediate post-valvuloplasty period with Doppler color flow imaging. In all, 78% of patients had a satisfactory result (mitral surface area greater than 1.5 cm2 and mitral regurgitation less than or equal to 2/4). These results are identical to those observed with the double balloon technique with a lower rate of complications. The duration of the procedure (104 +/- 13 min p less than 0.02) and of radioscopy (16 +/- 8 min, p less than 0.02) were shorter than with the double balloon technique.(ABSTRACT TRUNCATED AT 250 WORDS)

The double-balloon and Inoue techniques in percutaneous mitral valvuloplasty: comparative results in a series of 232 cases.

Immediate hemodynamic results of percutaneous mitral valvuloplasty were compared in two consecutive series of unselected patients from the same institution undergoing valvuloplasty with the double-balloon (161 patients) or the Inoue balloon (71 patients) technique. Before valvuloplasty, the patient series were comparable with regard to average age, gender repartition and most clinical, electrocardiographic, X-ray and hemodynamic variables. Poor anatomic forms of mitral stenosis were equally distributed in both series (41% vs. 45%, p = NS). The magnitude of mitral valve area increase and of mean mitral gradient decrease during percutaneous mitral valvuloplasty did not differ significantly in the Inoue balloon and double-balloon series (mean +/- SEM 1.1 +/- 0.2 to 1.95 +/- 0.5 and 1.0 +/- 0.2 to 1.97 +/- 0.5 cm2, respectively, for mitral valve area and 12 +/- 3 to 5 +/- 2 and 13 +/- 4 to 5 +/- 2 mm Hg, respectively, for mean mitral gradient). Four cases of 3+ mitral regurgitation occurred in the Inoue balloon series and 7 in the double-balloon series (p = NS). A good immediate result--defined as mitral valve area greater than or equal to 1.5 cm2 with greater than or equal to 25% in mitral valve area gain and mitral regurgitation less than 2+ at the end of the procedure--was observed in 78% of patients in both series. Three cases of tamponade due to chamber perforation and 14 cases of transient air embolism in the right coronary system due to balloon rupture were observed in the double-balloon series.(ABSTRACT TRUNCATED AT 250 WORDS)