Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo

Metformin (Met) is a biguanide oral hypoglycemic agent used in the treatment of noninsulin-dependent diabetes mellitus (NIDDM). To define whether the glucose-lowering effects are mediated via alterations of insulin receptors, the effects of Met in vitro in rat adipocytes and in vivo in patients with poorly controlled NIDDM were studied. In vitro exposure of rat adipose tissue to metformin for 20 h resulted in a significant increase in insulin binding (mean +/- SEM percent specific [125I]insulin bound per 10(5) adipocytes: control, 1.35 +/- 0.13; Met, 1.69 +/- 0.18; P less than 0.02). No change occurred after 2 h of exposure or less. In contrast, after only 1 h of preincubation. Met alone stimulated [U-14C]glucose oxidation by 58 +/- 15.5% (P less than 0.01). Met did not stimulate glucose oxidation in the presence of a high insulin concentration. For the in vivo studies, oral glucose tolerance tests and monocyte [125I]insulin binding assays were performed before and after 7 days of Met treatment (2 g/day) in 18 patients with poorly controlled NIDDM. All patients responded to Met with a decrease in fasting and postglucose plasma glucose concentrations, but no change in insulin concentrations [pre-Met vs. post-Met: fasting plasma glucose, 210 +/- 10 vs. 157 +/- 11 mg/dl (P less than 0.001); fasting plasma insulin, 20.3 +/- 3.1 vs. 18.4 +/- 2.0 microU/ml]. When insulin binding was examined, 8 patients with decreased binding each responded to Met with a 50% or greater increase (group 1), while 10 patients with normal binding had no increase after treatment (group 2). However, both groups had similar lowering of glucose concentrations [fasting plasma glucose: group 1, 205 +/- 19 vs. 153 +/- 20 (P less than 0.001); group 2, 214 +/- 11 vs. 160 +/- 13 (P less than 0.001)]. We conclude that 1) Met has an acute insulin-like effect in vitro independent of its ability to increase insulin binding; 2) Met acts in vivo predominantly at a postreceptor site to lower plasma glucose; 3) the glucose-lowering effect is independent of pretreatment insulin binding status; and 4) the increase in insulin binding after Met treatment in patients with NIDDM and low insulin binding occurs without changes in insulin concentrations.     

Socio-demographic factors and self-reported funtional status: the significance of social support

Background  

The aim of the present work was to investigate the relative importance of socio-demographic and physical health status factors for subjective functioning, as well as to examine the role of social support.     

In vitro and in vivo activity of murine lymphokine-activated killer cells after cryopreservation

The in vitro and in vivo effects of cryopreservation on the cytotoxic activity of murine lymphokine-activated killer (LAK) cells were studied. LAK cells were generated by incubation of spleen lymphocytes of BALB/c mice for 3 days with recombinant interleukin-2 (rIL-2) and subsequent cryopreservation. Cytotoxicity was determined in a 51Cr release assay. After thawing, cytotoxic activity was reduced (40.4% 51Cr release at an effector:target cell ratio of 40:1 as compared to 68.5% 51Cr release before freezing) and could be restored to precryopreserved levels by reincubation with rIL-2 for 2 days after thawing (78.8% 51Cr release). These cells were then tested in BALB/c mice injected with RAW 112 cells, a pre-B-cell lymphoma line. The results demonstrate that the survival rate of mice injected with cryopreserved and restimulated LAK cells (50% survival greater than 180 days after injection) did not differ significantly from that of mice injected with fresh unfrozen LAK cells (60% survival greater than 120 days, 50% survival greater than 180 days). Cryopreserved LAK cells have potential use in adoptive immunotherapy.