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Biomedical subjects

M Buscema

Publications and source records attributed to M Buscema.

At least 37 records · Page 2Linked to original sources
PubMed1993

Glucose modulates glucose transporter affinity, glucokinase activity, and secretory response in rat pancreatic beta-cells.

Pancreatic islets were cultured for 24 h in medium containing either low (1.4), normal (5.5), or high (16.7 mM) glucose, and then insulin secretion was measured at the end of 1 h incubation at 37 degrees C. Insulin release in the absence of glucose was 64 +/- 20, 152 +/- 11, and 284 +/- 30 pg.islet-1.h-1 (mean +/- SE, n = 6, G1.4 and G16.7 vs. G.5.5, P < 0.05) and the response to 22 mM glucose stimulation was 640 +/- 136, 2460 +/- 276, and 1890 +/- 172 pg.islet-1.h-1, respectively (n = 6, G1.4 vs. G5.5, P < 0.01, G16.7 vs. G5.5, P = 0.065). The 50% maximal response of insulin secretion (increment over baseline) was reached at an average glucose concentration of 9.9 +/- 0.7 mM in islets preexposed to G5.5, and at glucose 13.3 +/- 0.9 and 4.8 +/- 0.4 mM (P < 0.05 in respect to G5.5) in islets preexposed to G1.4 and G16.7, respectively. To investigate the molecular mechanism responsible for this altered glucose sensitivity, we measured, in parallel experiments, the kinetic characteristics of glucose transport, glucokinase, and glucose utilization. Glucose transport was measured by evaluating 3-O-methylglucose uptake. The apparent Km of the low-affinity transporter (GLUT2) was 16.6 +/- 2.4 mM in isolated pancreatic cells cultured at 5.5 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

3-O-Methylglucose↗
PubMed1992

Nicotinamide partially reverses the interleukin-1 beta inhibition of glucose-induced insulin release in pancreatic islets.

Interleukin-1 beta (IL-1 beta) is known to inhibit glucose-induced insulin release by pancreatic islets. We studied the effect of nicotinamide, an inhibitor of poly[adenosine diphosphate (ADP)-ribose] synthetase and a free-radical scavenger, on this IL-1 beta-induced inhibition using rat pancreatic islets. In static experiments, groups of five islets were incubated for 24 hours in culture medium CMRL-1066, with or without 50 U/mL IL-1 beta, in the presence or absence of nicotinamide (dose range, 0 to 50 mmol/L), and then exposed for 1 hour to either 1.4 or 19.4 mmol/L glucose, 10 mmol/L arginine, or 10 mumols/L glyburide. Basal insulin secretion was 183 +/- 32 pg/islet/h (mean +/- SE, n = 7) and 176 +/- 39 (n = 7) in control islets and in islets exposed to 50 U/mL IL-1 beta, respectively. Glucose-stimulated insulin secretion was significantly reduced (185 +/- 41) in IL-1 beta-exposed islets in comparison to control islets (2,037 +/- 363). In parallel, arginine-stimulated insulin release was inhibited by IL-1 beta exposure (166 +/- 31 pg/islet/h, mean +/- SE, n = 3) in comparison to control islets (1,679 +/- 307). In contrast, IL-1 beta exposure did not significantly reduce glyburide-induced insulin secretion (1,516 +/- 231 and 1,236 +/- 214 in control and IL-1 beta-exposed islets, respectively; mean +/- SE, n = 3). When islets were simultaneously exposed to IL-1 beta and increasing concentrations of nicotinamide, a dose-dependent recovery of glucose-induced insulin secretion was observed, with the maximum effect at 25 mmol/L nicotinamide (1,007 +/- 123, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Glyburide and tolbutamide induce desensitization of insulin release in rat pancreatic islets by different mechanisms.

Insulin secretion was studied in rat pancreatic islets after 24-h exposure to various glyburide or tolbutamide concentrations. Glucose-induced insulin release was significantly (P < 0.05) reduced in islets cultured with 0.1 microM glyburide or 100 microM tolbutamide (2098 +/- 187, 832 +/- 93, and 989 +/- 88 pg/islet.h in control, glyburide-exposed, and tolbutamide-exposed islets, respectively). When glyburide-treated islets were stimulated with glyburide or tolbutamide, insulin release was also impaired compared to that in control islets (P < 0.05). In contrast, tolbutamide-exposed islets showed an impaired response to tolbutamide, but a normal response to glyburide. To investigate the mechanism of the sulfonylurea-induced impairment of insulin secretion, we measured insulin release and Rb+ efflux (a marker of the K+ channel activity) in a perifusion system and islet Ca2+ uptake under static conditions. Insulin release in response to 16.7 mM glucose increased in control islets from 9.4 +/- 1.1 to 131 +/- 19 pg/islet.min (first phase secretion peak). Simultaneously, the fractional 86Rb+ efflux declined from 0.015 +/- 0.002% to 0.006 +/- 0.001% (change in decrement, -63.5%). Glucose-induced insulin release in glyburide- and tolbutamide-treated islets was significantly reduced (first phase peak, 22.1 +/- 5 and 39.7 +/- 8 pg/islet.min, respectively; P < 0.05), and the fractional 86Rb+ efflux decrement was -21 +/- 6% for glyburide (P < 0.005 vs. control islets) and -65 +/- 4% (not different from control) for tolbutamide. When glyburide- or tolbutamide-exposed islets were stimulated with the corresponding sulfonylurea, insulin release was impaired compared to that in control islets (P < 0.05), but, again, 86Rb+ efflux was impaired (P < 0.05) only in glyburide-exposed islets. When 45Ca2+ uptake was studied, the increase in glucose concentration from 2.8 to 16.7 mM increased calcium uptake in control islets from 1.76 +/- 0.58 to 7.27 +/- 1.36 pmol/islet.2 min (n = 4). Preexposure to 0.1 microM glyburide did not change calcium uptake at a glucose concentration of 2.8 mM (1.44 +/- 0.45 pmol/islet.2 min) but significantly reduced calcium uptake stimulated by 16.7 mM glucose (3.21 +/- 0.35 pmol/islet.2 min; n = 4; P < 0.005 compared to control islets). In contrast, preexposure to 100 microM tolbutamide did not change either basal or glucose-stimulated calcium uptake (1.44 +/- 0.45 and 6.90 +/- 0.81 pmol/islet.2 min, respectively; n = 4). These data show that in vitro chronic exposure of pancreatic islets to the sulfonylureas glyburide and tolbutamide impairs their ability to respond to a subsequent glucose or sulfonylurea stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

In vitro effects of tumor necrosis factor-alpha on human thyroid follicular cells.

Tumor necrosis factor-alpha is assumed to be an important mediator in thyroid autoimmunity. In the present study we have shown that human thyrocytes possess a single specific binding site for recombinant tumor necrosis factor-alpha with an average of 9,300 receptors/cell (Kd = 1.9 x 10(-10) mol). The effects of the cytokine on thyroid cell proliferation were assessed by 3H-thymidine uptake as well as by the protein and DNA content of cell monolayers. Low dose tumor necrosis factor-alpha resulted in a moderate stimulation of cell proliferation with an increase of 3H-thymidine incorporation from 44,613 +/- 7,989 cpm under basal conditions to 63,326 +/- 6,822 cpm after 100 U/l tumor necrosis factor-alpha (p < 0.01). Higher doses of the cytokine were less effective. On average, bTSH stimulated cAMP production of human thyrocytes was significantly augmented after preincubation with recombinant tumor necrosis factor-alpha. The maximum effect was observed after 1,000 U/l tumor necrosis factor-alpha (281.5 +/- 107.0 vs 114.5 +/- 33.6 fmol cAMP/micrograms protein under basal conditions: p < 0.05), whereas higher doses of the cytokine were again less effective. This phenomenon could at least partly be explained by a cytokine-mediated downregulation of tumor necrosis factor-alpha binding. We conclude that in vitro tumor necrosis factor-alpha modulates in addition to its well known synergistic effect on interferon-gamma induced HLA class II expression the function and proliferation of human thyroid follicular cells as well. These effects are mediated via specific cell surface receptors.

Adult↗
PubMed1992

Comparison of combined therapies in treatment of secondary failure to glyburide.

OBJECTIVE: To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS: A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment. RESULTS: Both combined therapies significantly (P less than 0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P less than 0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P less than 0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients. CONCLUSIONS: The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight.

Blood Glucose↗
PubMed1991

Glucose regulates both glucose transport and the glucose transporter gene expression in a hamster-derived pancreatic beta-cell line (HIT).

We studied the effect of chronic exposure to high glucose on the glucose transport regulation in hamster pancreatic Beta cells in permanent culture (HIT). Cells were exposed to either 5.5 mmol/l or 16.7 mmol/l glucose for 48 h and then glucose transport was studied by measuring the (3H)-2-deoxyglucose uptake for 5 and 10 min at 37 degrees C. The 2-deoxyglucose uptake was lower in cells pre-exposed to glucose 16.7 mmol/l for 48 h compared to cells pre-exposed to 5.5 (12.0 +/- 1.6 vs 19.1 +/- 1.2 nmol/0.1 mg after 5 min, and 22.2 +/- 2.6 vs 39.0 +/- 2.9 after 10 min respectively, mean +/- SEM, n = 5, p less than 0.01). In order to investigate the mechanism(s) for glucose impairment of glucose transport, we studied the glucose carrier gene expression in the same cells by Northern and slot-blot analysis. When total RNA was extracted from HIT cells cultured at either 5.5 or 16.7 mmol/l glucose and then hybridized to 32P-labelled cDNA probes for the glucose transporter 1, the glucose transporter 2 and beta-actin, a significant reduction of both glucose transporter 1 (-63.9 +/- 4.1%, mean +/- SEM, n = 3) and glucose transporter 2 (-48.9 +/- 3.2%) mRNA was observed in HIT cells cultured with high glucose. In the same experiments no change of beta-actin mRNA was observed, suggesting that the effect of high glucose was specific on the glucose-transporter mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Chronic exposure to glibenclamide impairs insulin secretion in isolated rat pancreatic islets.

We investigated the effect of 24 h exposure to 100 nmol/l glibenclamide on insulin secretion in isolated rat pancreatic islets. The insulin content was similar in control islets and in islets preincubated with 100 nmol/l glibenclamide for 24 h. In islets preexposed to glibenclamide: 1) the subsequent response to a maximal glibenclamide stimulatory concentration (10 mumol/l, 1 h at 37 C) was greatly reduced in comparison to control islets (0.69 +/- 0.20% vs 2.16 +/- 0.41%; mean +/- SE; n = 14; p less than 0.001); 2) the response to 100 mumol/l tolbutamide stimulation was also reduced (0.55 +/- 0.15% vs 2.38 +/- 0.44%; n = 8; p less than 0.001); 3) the response to 16.7 mmo/l glucose, both in the presence or in the absence of 1 mmol/l IBMX, a phosphodiesterase inhibitor, was also diminished by about 50% (1.79 +/- 0.39% vs. 3.22 +/- 0.42%; n = 14, p less than 0.001). In glibenclamide pretreated islets, blunted responses to stimuli were confirmed also by dynamic studies using a perifusion system. The effect of glibenclamide preincubation was fully reversible: when islets cultured in the presence of glibenclamide were transferred to a glibenclamide-free medium for further 24 h, insulin release in response to glibenclamide stimulation returned to control values. We conclude that prolonged exposure of rat pancreatic islets to glibenclamide induces a reversible desensitization to a variety of metabolic stimuli. The inhibition by prolonged glibenclamide exposure of a common pathway in the mechanism of insulin release is one possible explanation for these results.

Animals↗
PubMed1991

Cytotoxic effect of IFN-gamma plus TNF-alpha on human islet cells.

We have previously reported that the combination of IFN-gamma plus TNF-alpha is able to induce the de novo expression of HLA class II on human beta cells. In the present study, we have investigated the effect of these cytokines, alone or in combination, on the function and viability of human islet cells in vitro. Three hour insulin release was markedly reduced in human islet monolayer cultures after 4 days' exposure to 1000 U/ml of the combination TNF-alpha plus IFN-gamma (36.7 +/- 7.7, % of the control +/- SEM) or to TNF-alpha alone (49.5 +/- 7% of the control) while IFN-gamma had little effect. On direct inspection cell damage was clearly detected only in the cultures treated with TNF-alpha plus IFN-gamma in which staining by indirect immunofluorescence (IFL) for insulin revealed that the number of beta cells was also significantly reduced, thus suggesting a real cytotoxic effect of this cytokine combination. This effect was not beta cell specific since glucagon release and the number of alpha cells were also reduced in the cultures exposed to IFN-gamma plus TNF-alpha. 51Cr release experiments supported the cytoxicity of these cytokines to normal islet cells. There was a time course relationship between class II induction (2 days) and the cytotoxic effect of IFN-gamma plus TNF-alpha (4 days) on the same islet cells. In conclusion, these results indicate that the combination of IFN-gamma and TNF-alpha exerts a cytotoxic effect on human islet cells in vitro.

Cell Survival↗
PubMed1991

Transfection with SV40 gene of human pancreatic endocrine cells.

At present, only islet cell lines of animal origin have been successfully generated (e.g. RIN, HIT). A fully differentiated human beta cell line would be advantageous for diabetes research. We now report the generation of a human endocrine pancreatic cell line obtained by transfection using a plasmid containing the early region of SV40 viral DNA. Viral integration and transcription was assessed by Southern and Northern blotting. This cell line has been growing continuously for more than 2 years and maintains several of the characteristics of the parental cells from which they were generated. The presence of Neuron Specific Enolase, Protein Gene Product 9.5, cytokeratin, microvilli, cytoplasmic electrodense granules and the secretion of insulin, glucagon and somatostatin supports the neuroendocrine origin of this cell line. However, hormone production progressively decreased and finally stopped at passage 8. Flow cytometric analysis showed that HLA expression in this cell line is readily induced by IFN-gamma and modulated by TNF-alpha. The establishment of this human endocrine cell line indicates the feasibility of immortalizing human islets by transfection with viral oncogenes. To obtain a fully differentiated cell line it may be necessary to use other DNA constructs which immortalize the cells without fully transforming their phenotype.

Antigens, Viral, Tumor↗
PubMed1991

De novo HLA class II and enhanced HLA class I molecule expression in SV40 transfected human thyroid epithelial cells.

Human thyroid follicular cells normally synthesize and express HLA Class I molecules but in glands affected by autoimmune or neoplastic diseases they express Class II molecules. We have investigated the effect of SV40 virus transformation on the expression of MHC molecules in human thyrocytes. Primary cultures of human thyroid from two different glands were transfected with the plasmid pX-8, containing the 'early' region of SV40 virus, and two continuous lines of thyrocytes were obtained. The cell lines maintained features of parental thyroid epithelial cells showing the characteristic cytokeratin filament network, microvillar protrusion and tight junctions. In addition, the SV40-transfected cells responded to graded doses of TSH with increased c-AMP production. Thyrocytes from both cell lines hyperexpressed Class I molecules and a significant proportion of them also acquired constitutive Class II expression, as determined by indirect immunofluorescence (IFL), flow cytometry and Northern blotting hybridization using a DR beta probe. These cells were found to be normally up-regulated by interferon (IFN)-gamma. Indirect IFL and flow cytometry analysis were used to detect and quantify the expression of HLA-DR, DP and DQ subregions. A co-ordinated expression (DR greater than DP much greater than DQ), reminiscent of the inappropriate HLA expression found in thyroid autoimmune disease in vivo and of the in vitro regulation in normal thyrocytes, was observed. Clones derived from these cell lines differed in their level of constitutive Class II expression and in their sensitivity to Class II induction by IFN-gamma. In conclusion, these thyroid cell lines could provide a useful tool for further investigation of HLA gene regulation in thyroid cells and for elucidating on the mechanism involved in the inappropriate HLA expression described in autoimmune and neoplastic diseases of the thyroid.

Autoantigens↗
PubMed1990

Chronic exposure to high glucose and impairment of K(+)-channel function in perifused rat pancreatic islets.

Prolonged exposure to high glucose levels impairs the ability of pancreatic islets to secrete insulin as a response to that stimulus. Because glucose, like other insulin secretagogues, elicits insulin secretion by inhibiting the ATP-sensitive K+ channels, in this study, we investigated the effect of prolonged (24-h) exposure of rat pancreatic islets to high (16.7 mM) glucose concentration on 86Rb efflux (used as a tracer for K+). The data obtained indicate that islets exposed to high glucose concentration have impaired function of the glucose-sensitive K+ channel, this phenomenon is temporarily related to a defective response of glucose-induced insulin release, and these alterations are reversible.

Adenosine Triphosphate↗
PubMed1989

[Recent aspects of the pathogenesis of endocrine autoimmune diseases in the human: what role does expression of class II HLA molecules in the endocrine target cell play?].

The inappropriate expression of HLA Class II molecules by the target cells of endocrine autoimmune diseases is a recent observation that has been intensively studied in thyroid autoimmunity and type I diabetes mellitus. In vitro studies have shown that interferon-gamma can induce Class II expression, either alone, as in thyrocytes, or in combination with other mediators like tumour necrosis factor or lymphotoxin, as in islet cells, pointing to possible mechanisms operating in vivo. Endocrine cells expressing Class II molecules are able to present their autoantigens to helper T cells, thus possibly inducing the autoimmune process. However, until now it is still unclear if the expression of Class II molecules by the target cells is the primary immune phenomenon, which might possibly be triggered by a latent viral infection of the endocrine cell. Alternatively, it might be a secondary response in an ongoing autoimmune process. Particularly data obtained in the diabetic pancreas favour the first possibility, but only progress in our understanding of the role of HLA antigens in immunoregulation will make it possible to interpret the phenomenon properly.

Autoimmune Diseases↗
PubMed1989

Retrovirus-like sequences in Graves' disease: implications for human autoimmunity.

On Southern blotting of DNA extracted from thyroid glands of five patients with Graves' disease, two probes (720 bp and 942 bp) for gag human immunodeficiency virus type 1 (HIV-1) gave a positive hybridisation signal in all samples tested. DNAs from peripheral blood mononuclear cells hybridised with the 720 bp gag HIV-1 probe in three of the five patients, none of whom had antibodies to HIV-1. Negative results were obtained with DNA from normal thyroid glands, thyroid neoplasms, various unrelated normal tissues, and virus-infected human cell lines. The intensity of the signal and the pattern of bands observed with the DNA of Graves' patients were heterogeneous and, in general, were not the same in the thyroid glands and peripheral blood mononuclear cells of individual patients. Similarly, no correlation was found between the positive hybridisation signals and other genetic and immunological indices or the duration of anti-thyroid drug treatment at the time the patients were investigated. The findings suggest the presence of a novel retrovirus, and the retrovirus-like sequences seem to be closely associated with thyroid autoimmunity.

Adolescent↗
PubMed1989

Inappropriate expression of HLA class II molecules in endocrine epithelial cells: the phenomenon, the new experimental data and comparison with animal models.

Physiologically, HLA Class II molecules are primarily expressed on immunoregulatory cells. In recent years, it has been shown that tissues affected by autoimmunity, including beta cells of 'diabetic' pancreases, 'inappropriately' express these glycoproteins. Cytokines are potent Class II inducers on a variety of cells but they exert a heterogenous effect when incubated with different human endocrine cells, i.e. thyroid cells are readily inducible, beta cells are much more resistant. The fine modulation of Class II expression by cytokines has been extensively studied and recent information on their action on endocrine cells is reported here. The possibility that distinct environmental factors from those postulated until now may be responsible for triggering the inappropriate expression of MHC molecules in epithelial cells in vivo is also emphasized. Despite several similarities between human Type I diabetes and spontaneous animal models of the disease, major differences still exist. Transgenic models have now been produced. However, even if they offer interesting new insights, they have not so far provided the decisive answer to explain the pathogenesis of human autoimmune diseases.

Animals↗
PubMed1989

Influence of tumor necrosis factor-alpha on the modulation by interferon-gamma of HLA class II molecules in human thyroid cells and its effect on interferon-gamma binding.

Cytokines are important modulators of immunological reactions, but it has been postulated that they might act on other unrelated epithelial cells. We studied the effects of recombinant interferon-gamma (rIFN gamma) and recombinant tumor necrosis factor-alpha (rTNF alpha) on normal human thyroid cells. We found that the combination of these two cytokines enhanced HLA class II molecule expression on these cells compared with the effect of rIFN gamma alone. This was proven by both immunofluorescence as well as a more sensitive and quantitative RIA. rTNF alpha alone had no effect on HLA class II molecule induction on the same thyrocytes, suggesting a synergistic rather than an additive action in combination with rIFN gamma. The addition of 600 U/ml rTNF alpha to low dose rIFN gamma (10 U/mL) enhanced class II expression by 50%, as quantified by RIA. We also demonstrated that normal thyrocytes possess distinct receptors for the two cytokines and that rTNF alpha probably augments IFN gamma binding, since it increased when the cells were first incubated with rTNF alpha. This increased binding provides an explanation for the synergistic action of rTNF alpha in enhancing class II molecule expression by rIFN gamma. We conclude that the presence of receptors for these cytokines on human thyroid cells gives a direct demonstration of their potential biological action on cells normally not involved in the immunological circuit. The phenomenon might also explain their direct or indirect involvement in vivo, such as in influencing inappropriate HLA class II molecule expression in epithelial cells affected by autoimmunity.

Binding Sites↗
PubMed1988

Metformin enhances certain insulin actions in cultured rat hepatoma cells.

The effect of the oral antidiabetic agent metformin on insulin regulation of glycogen metabolism, tyrosine-aminotransferase activity, and [1-14C]aminoisobutyric acid uptake was studied in H4IIE cultured rat hepatoma cells. Metformin enhanced both basal (from 0.213 +/- 0.016 to 0.262 +/- 0.024 nmol/mg protein, p less than 0.01) and insulin stimulated [3H] glucose incorporation into glycogen in a time-dependent and dose-dependent manner. A small effect of metformin was seen at 1 mumol/l, and its greatest effects were obtained at 10 mumol/l. At the same concentrations, metformin did not influence basal tyrosine-aminotransferase activity but it potentiated insulin stimulated tyrosine-aminotransferase activity (+29.2 +/- 1.4%, p less than 0.01) and prevented the loss of tyrosine-aminotransferase responsiveness to insulin in H4IIE cells desensitised by a previous exposure to insulin. In contrast, metformin had no effect on basal or insulin-stimulated [1-14C]aminoisobutyric acid uptake. Over the concentrations of metformin that enhanced insulin action in H4IIE cells, the drug had no significant effect on insulin binding to its receptor. These studies suggest, therefore, that metformin may influence cellular metabolism by potentiating certain insulin actions through mechanisms that may be beyond insulin receptor binding.

Aminoisobutyric Acids↗
PubMed1987

Direct effects of biguanides on glucose utilization in vitro.

The effect of the biguanides metformin and phenformin on glucose utilization in isolated cells was studied with IM-9 human lymphocytes. Both agents stimulated glucose consumption from the incubation media. Detectable effects of metformin were seen at 33 mumol/L and detectable effects of phenformin were seen at 1.7 mumol/L. Both agents, at similar concentrations, also stimulated [3H] 2-deoxy-D-glucose uptake. Studies with phenformin indicated that biguanides increase the Vmax of uptake without changing the Km. In contrast to the biguanides, IM-9 cells insulin did not influence either glucose consumption or [3H] 2-deoxy-D-glucose uptake. These data provide evidence, therefore, that biguanides may directly influence the cellular utilization of glucose.

Blood Glucose↗