Drugs online research references
Diabetologia. 1998 Jan;41(1):2-8.
Potentiating effect of metformin on insulin-induced glucose uptake and glycogen metabolism with Xenopus oocytes.
Detaille D, Wiernsperger N, Devos P.
Laboratory of Comparative Biochemistry and Physiology, Facultes Universitaires Notre-Dame de la Paix, Namur, Belgium.
Xenopus laevis oocytes were chosen as the in vitro model for this study with the aim of reconsidering metformin action on the main insulin-responsive glucose pathway. Metformin alone, when present at a therapeutic dose (20 micromol/l) in the incubation medium, did not alter the basal rate of glucose uptake or of glycogen synthesis as measured by [U-14C] D-glucose incorporation. The drug had no effect on the main rate-limiting enzyme implicated in this pathway, i.e. glycogen synthase. In contrast, when combined with 2 micromol/l insulin, metformin led to a specific rise of both free and stored glucose, by 42.4 and 102.3% respectively. Moreover, a short-term preincubation of mature oocytes with metformin, but in the absence of glucose, enhanced significantly the amount of synthase a when stimulated by 50 nmol/l insulin (basal 17.4 +/- 5.7%, metformin 21.3 +/- 4.1%, insulin 31.2 +/- 4.6%, metformin together with insulin 62.7 +/- 4.2%, p < 0.005, n = 5). Interestingly, the microinjection of this biguanide, at a final concentration of 20 nmol/l, allowed a similar biochemical response. These data clearly suggest that metformin could act primarily at postreceptor steps which are thought to be key sites in controlling the cellular glucose homeostasis.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9498621&dopt=Abstract
Eur J Pharmacol. 1999 Jan 8;364(2-3):205-9.
The biguanide compound metformin prevents desensitization of human pancreatic islets induced by high glucose.
Lupi R, Del Guerra S, Tellini C, Giannarelli R, Coppelli A, Lorenzetti M, Carmellini M, Mosca F, Navalesi R, Marchetti P.
Department of Endocrinology and Metabolism, Ospedale Cisanello, University of Pisa, Italy.
Pancreatic islet desensitization by high glucose concentrations is a temporary and reversible state of beta-cell refractoriness to glucose (and possibly other secretagogues), due to repeated or prolonged pre-exposure to increased glucose concentrations. We evaluated whether the oral antidiabetic agent metformin affects this phenomenon in isolated, human pancreatic islets, and whether the possible effects of the biguanide are influenced by the presence of a sulphonylurea, glyburide. Islets prepared from five human pancreases were incubated for 24 h in M199 culture medium containing either 5.5 or 22.2 mmol/l glucose, with or without a therapeutic concentration (2.4 microg/ml) of metformin. Then, the islets were challenged with either 3.3 mmol/l glucose, 16.7 mmol/l glucose, or 3.3 mmol/l glucose + 10 mmol/l arginine, and insulin release was measured. After incubation in the absence of metformin, the human islets exposed to 22.2 mmol/l glucose showed no significant increase in insulin release when challenged with 16.7 mmol/l glucose (confirming that hyperglycemia desensitizes pancreatic beta-cells). In the presence of metformin, the islets fully maintained the ability to significantly increase their insulin release in response to glucose, even when previously exposed to 22.2 mmol/l glucose. No major effect on arginine-induced insulin release was observed, whatever the culture conditions. The protective action of metformin was observed also when glyburide was present in the incubation medium, whereas the sulphonylurea alone did not affect insulin release from the islets previously exposed to high glucose concentrations. These in vitro results suggest that metformin can prevent the desensitization of human pancreatic islets induced by prolonged exposure to increased glucose concentrations.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9932725&dopt=Abstract
J Pharm Pharmacol. 2000 Aug;52(8):1011-6.
Uptake and dispersion of metformin in the isolated perfused rat liver.
Chou CH.
Institute of Clinical Pharmacy, Medical College, National Cheng Kung University, Tainan, Taiwan.
Although metformin is a widely used oral antihyperglycaemic, the exact mechanisms of its cellular uptake and action remain obscure. In this study the hepatic extraction and disposition kinetics of metformin were investigated by use of an isolated in-situ rat liver preparation. The liver was perfused in single-pass mode with protein-free Krebs bicarbonate medium at a flow rate of 20 mL min(-1). During constant infusion with 1 mg L(-1) metformin hydrochloride the hepatic uptake of metformin approached equilibrium within 10 min. The steady-state availability, F, determined from the ratio of outflow concentration to input concentration, was 0.99+/-0.02 (mean +/- s.d., n = 4). The outflow profile of metformin resulting from a bolus injection of 25 microg into the portal vein, had a sharp peak then a slower declining terminal phase. The mean transit time (MTT; 49.5+/-14.5, n = 6) and normalized variance (CV2; 4.13+/-0.05) of the hepatic transit times of metformin were estimated by numerical integration from the statistical moments of the outflow data. The volume of distribution of metformin in the liver (1.58+/-0.28 mL (g liver)(-1)) was estimated from its MTT. The volume of distribution is greater than the water space of liver, indicating that metformin enters the hepatic aqueous space and becomes distributed among cellular components. The magnitude of CV2 for metformin is greater than for the vascular marker sucrose, suggesting that distribution of metformin into hepatic tissue is not instantaneous. In conclusion, hepatic uptake of metformin is rate-limited by a permeability barrier. Although metformin is accumulated in the liver, the organ does not extract it.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11007073&dopt=Abstract
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