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Biomedical subjects

M B Davidson

Publications and source records attributed to M B Davidson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Differential regulation of glucose transport and glucose transporter (GLUT-1) gene expression by vanadate, phorbol ester and okadaic acid in L6 skeletal muscle cells.

Vanadate, an inhibitor of protein tyrosine phosphatases (PTPases), elicited time-and-dose-dependent increases in glucose transport in rat muscle L6 cells in culture: the rate was increased by 150-175% over control in 24 h at 75-100 microM. In contrast, molybdate, another inhibitor of PTPases, failed to stimulate glucose transport. The effect of vanadate was not blocked by tyrosine kinase inhibitors, genistein or tyrphostin RG 50864, implying that tyrosine kinase activation may not mediate the action of vanadate. The ability of vanadate to stimulate glucose transport was preserved in cells whose protein kinase C (PKC) activity was down-regulated by prior exposure to phorbol esters (TPA), suggesting that the vanadate effect was unrelated to the TPA-sensitive PKC isoform(s). Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, was a potent activator of glucose transport increasing the rate 7-fold in 24 h at a concentration of 50 nM. The increases in GLUT-1 mRNA level in response to vanadate and TPA were paralleled bh much smaller increases in immunoreactive GLUT-1 protein level, whereas okadaic acid treatment markedly elevated GLUT-1 protein without a concomitant change in GLUT-1 mRNA levels.

Animals↗
PubMed1994

The hexosamine biosynthetic pathway and glucose-induced down regulation of glucose transport in L6 myotubes.

Based on experiments in cultured adipocytes, it has been proposed that glucose-induced down regulation of glucose transport is mediated by the conversion of fructose-6-phosphate to glucosamine-6-phosphate via the first and rate-determining enzyme of the hexosamine biosynthetic pathway, glutamine: fructose-6-phosphate amidotransferase (glutamine hexosephosphate aminotransferase). Evidence for this assertion was: (a) L-glutamine, the provider group for the aminotransferase was essential; (b) two inhibitors of glutamine hexosephosphate aminotransferase, 6-diazo-5-oxonorleucine (L form) and azaserine, blocked glucose-induced down regulation of glucose transport; (c) azaserine inhibited the activity of the aminotransferase, (d) glucosamine, which enters the hexosamine pathway distal to this enzyme was 40-times more potent than glucose; and (e) azaserine was unable to block the effect of glucosamine. Since muscle is quantitatively much more important than adipose tissue for whole body glucose utilization, we sought to determine if the hexosamine pathway was involved in glucose-induced down regulation of glucose transport in L6 myotubes. Glucose was effective, both in the presence and absence of glutamine in the incubation media. Glucosamine was also effective but was as equipotent as glucose. Small amounts of glutamine hexosephosphate aminotransferase were present in the L6 myotubes and although the leucine derivative (20 microM) inhibited the enzyme, it did not impair glucose-induced down regulation of glucose transport. Total GLUT-1 levels were similar when the cells were incubated in the absence or presence of 5 mM glucose or glucosamine although glucosamine was associated with a marked increase in a lower molecular weight band. These results do not suggest that the hexosamine biosynthetic pathway is involved in glucose-induced down regulation of glucose transport in L6 myotubes. Thus, this phenomenon is regulated differently in muscle and fat.

Animals↗
PubMed1994

Phenobarbital treatment enhances insulin-mediated glucose metabolism and improves lipid metabolism in the diabetic rat.

Previous studies with healthy volunteers and non-insulin-dependent diabetic (NIDDM) patients have shown a strong association between overall glucose metabolism and hepatic microsomal enzyme activity. In this study, the effects of 10-day oral administration of phenobarbital (PB), a potent inducer of the hepatic microsomal mixed-function oxidase system, on carbohydrate and lipid metabolism in the basal state and on glucose kinetics during submaximal hyperinsulinemic (5 mU.kg-1.min-1 insulin) clamps were investigated in nondiabetic rats and in rats made diabetic by the intravenous (IV) administration of either low-dose (40 mg/kg) or high-dose (55 mg/kg) streptozocin (STZ). In control rats receiving PB in drinking water (0.5 mg/mL), serum insulin and triglyceride levels were diminished without any change in glucose and cholesterol concentrations in the fed state. Administration of PB in drinking water (0.25 mg/mL) to both groups of diabetic rats decreased their water intake and serum triglyceride levels in the absence of an effect on glucose, insulin, and cholesterol concentrations in the fed state. However, fasting serum glucose levels and basal glucose turnover rates were lower in both groups of diabetic rats receiving PB. PB treatment increased the heparin-releasable lipoprotein lipase (LPL) activity of epididymal fat in both control and low-dose diabetic groups; this was not assessed in the high-dose diabetic group. Neither peripheral glucose utilization nor hepatic glucose production during submaximal insulin clamps was modified by PB treatment in nondiabetic rats. In contrast, PB administration enhanced insulin-mediated peripheral glucose utilization, as well as suppression of hepatic glucose production, in both low-dose and high-dose diabetic groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1994

Impaired glucose transport in skeletal muscle but normal GLUT-4 tissue distribution in glucose-infused rats.

This study was undertaken to determine if glucose toxicity in normal rats caused decreased whole body insulin-stimulated glucose disposal and in vivo impaired muscle glucose transport and, if so, whether it was mediated by changes in GLUT-4 content or tissue distribution. Rats were infused with 50% dextrose for 48 h after which they were clamped and injected with 2-deoxy-D-[3H]glucose. Hindlimb muscles were removed for measurement of uptake of radioactivity (glucose transport) and GLUT-4 levels in total, plasma and internal membrane fractions. Dextrose infusions caused significant hyperglycemia [15.5 +/- 1.4 vs. 6.7 +/- 0.3 (SE) mM], hyperinsulinemia [678 +/- 108 vs. 168 +/- 42 (SE) pM], and depressed insulin-mediated whole body glucose disposal [12.8 +/- 2.0 vs. 47.0 +/- 10.6 (SE) mg glucose.kg-1.min-1.pmol insulin-1.1(-1) x 10(3)]. Muscle glucose transport (ng.min-1.mg tissue-1) was significantly decreased in biceps (4.0 +/- 0.6 vs. 13.4 +/- 2.5), gastrocnemius (4.6 +/- 1.1 vs. 12.9 +/- 2.2), and plantaris (5.5 +/- 0.7 vs. 17.5 +/- 3.6) muscles compared with saline-infused rats. The difference in the soleus muscle (13.2 +/- 1.6 vs. 19.4 +/- 2.7) did not quite reach statistical significance. There were no differences in total, plasma, or internal membrane GLUT-4 content between the two groups. It is concluded that glucose toxicity causes impaired insulin-stimulated glucose transport, probably due to decreased activity of GLUT-4.

4-Nitrophenylphosphatase↗
PubMed1994

The influence of diabetes mellitus on the risk of abdominal aortic surgery.

Risk factors and postoperative complications of 153 diabetics (DM) who underwent an abdominal aortic operation for occlusive disease or an intact aneurysm from 1964 through June, 1988 were compared with 970 nondiabetics (nonDM) who underwent similar operations during the same time period. Heart disease, hypertension, cerebrovascular disease, and renal insufficiency were more prevalent in diabetics. Postoperatively, DM had a statistically significant increase in the incidence of myocardial infarction (DM 5.2%, nonDM 2.1%, P = .0434) and wound infection (DM 2.6%, nonDM 0.6%, P = .0359). The incidence of renal failure (DM 1.3%, nonDM 1.0%), stroke (DM 2.0%, nonDM 0.6%), and death (DM 3.9%, nonDM 2.9%) was higher in diabetics, but the differences were not statistically significant (P = NS). Operative mortality was greater for patients operated on for aneurysm (DM 5.3%, nonDM 3.2%) than for patients operated for occlusive disease (DM 3.3% versus nonDM 2.7%). Diabetics treated with insulin or oral agents had a higher complication rate than diabetics treated with diet alone or nondiabetics (insulin 13.0%, oral 13.4%, diet 4.2%, nonDM 8.6%). This study finds that diabetic patients can undergo an abdominal aortic operation with operative mortality comparable to that of nondiabetics. Diabetics have more postoperative complications than nondiabetics, but only myocardial infarction and wound infection are of statistical significance. Diabetics treated with insulin or oral agents have more complications than do diabetics treated by diet alone or nondiabetics.

Aged↗
PubMed1993

Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein.

Expression of globin genes in developing erythroid cells is controlled by upstream locus control regions. Activity of these regions in vivo requires an erythroid-specific nuclear factor (NF-E2) that binds AP-1-like recognition sites. Its tissue-specific component (p45 NF-E2) has been characterized by complementary DNA cloning as a new basic region-leucine zipper protein which dimerizes with a ubiquitous partner to form native NF-E2.

Amino Acid Sequence↗
PubMed1993

Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2.

The nuclear DNA-binding protein NF-E2 is thought to mediate the powerful erythroid enhancer activity of the alpha- and beta-globin locus control regions and participates in the control of genes encoding two enzymes of haem biosynthesis (porphobilinogen deaminase and ferrochelatase). The major component of NF-E2 is a 45K polypeptide (designated p45 NF-E2) that belongs to the basic region-leucine zipper family of transcription factors. This subunit of NF-E2 is specifically expressed in haematopoietic progenitor cells and differentiated cells of the erythroid, megakaryocyte and mast cell lineages. The gene encoding p45 NF-E2 (murine gene Nfe2) has been mapped to mouse chromosome 15 near the mutation microcytosis (mk). Homozygous mk mice have severe hypochromic microcytic anaemia as a result of decreased globin synthesis and defects in intestinal and erythroid iron absorption. Here we investigate whether the mk mutation lies within Nfe2 by characterizing the p45 NF-E2 gene and determining its DNA sequence in wild-type and mk alleles. The mk allele carries a missense mutation that causes substitution of valine by alanine at amino acid 173 of the p45 NF-E2 protein. Expression of p45 NF-E2 messenger RNA was detected in erythroid tissues of normal mice and in the duodenum of normal and severely anaemic beta-thalassaemic (Hbbd-th3/Hbbd-th3) mice. We propose that the mk mutation results in an impaired form of NF-E2 which fails to regulate both globin production and iron metabolism properly.

Amino Acid Sequence↗
PubMed1993

Protein and fat effects on glucose responses and insulin requirements in subjects with insulin-dependent diabetes mellitus.

The glucose responses (GR) and insulin requirements (IRs) were measured by a glucose-controlled insulin infusion system for 5 h after 12 patients with insulin-dependent diabetes mellitus consumed each of three meals: a 1890-kJ standard meal, the standard meal with 840 kJ added protein, and the standard meal with 840 kJ added fat. The GR to the protein-added meal was greater (P = 0.005) than to either the standard or fat-added meals, because of an increase in the late (last 150 min) GR. The late IR was greater for the protein-added meal (P < 0.005). The IR was not changed after the fat-added meal. Therefore, the addition of protein (but not fat) energy to a meal increases both the postprandial GR and late IR. This finding suggests that diabetic patients who inject premeal insulin may need to increase their insulin dose when protein is added to a meal.

Adult↗
PubMed1993

Effect of sodium butyrate on glucose transport and glucose-phosphorylating enzymes in RIN-m5F cells.

Sodium butyrate is widely used to differentiate insulinoma cell lines. However, sodium has been shown to decrease glucose phosphorylation in the liver and heart and decrease the expression of glucose transporter. Since these mechanisms are essential for glucose-induced insulin secretion, the ultimate function of the pancreatic beta-cell, we investigated the effect of sodium butyrate on both glucose-phosphorylating enzymes as well as glucose transport in the pancreatic cell line RIN-m5F. Treatment of RIN-m5F cells with 2.5 mM sodium butyrate for 72 h increased by twofold both hexokinase and glucokinase (GK) activities, as well as the gene expression of GK. Sodium butyrate treatment had no effect on GLUT-1 mRNA levels but increased the GLUT-2 mRNA 3.7-fold. Kinetic analysis of 2-deoxyglucose transport displayed a single curve with Km = 1.2 mM and Vmax = 10.9 pmol/micrograms protein/min in the untreated cells, values similar to the low Km glucose transport reported in the pancreatic beta-cells. This low Km transport component markedly decreased with sodium butyrate treatment, and interestingly a second component with a higher Km appeared, consistent with the increase in GLUT-2 mRNA. We conclude that the differentiating action of sodium butyrate involves increases in GK and GLUT-2 gene expression, which characterizes the differentiated state of the pancreatic beta-cell. However, the inhibitory effect of sodium butyrate on low Km glucose transport needs to be considered in the use of this compound to promote differentiation.

Animals↗
PubMed1993

Studies on mechanisms of hepatic insulin resistance in cafeteria-fed rats.

Whether hyperinsulinemia causes insulin resistance or vice versa is controversial. The development of hyperinsulinemia and insulin resistance was tracked in the cafeteria-fed rat to determine which occurred first. After 3 days of cafeteria feeding the rats were obese, manifested a small but significant decrease in fasting glucose levels, and showed no change in fasting insulin levels, basal hepatic glucose production (HGP), insulin binding to hepatic membranes, and glucose utilization during a euglycemic hyperinsulinemic clamp, but the rats did demonstrate an increased glucose disappearance rate associated with an enhanced insulin response to intra-arterial glucose and hepatic insulin resistance during the clamp. After 7 days of cafeteria feeding, the results were similar except that fasting hyperglycemia and hyperinsulinemia, an enhanced basal HGP, and decreased insulin binding developed. After 6 wk of cafeteria feeding, both hepatic and peripheral insulin resistances were present. After 7 days of cafeteria feeding in rats given streptozotocin or etomoxir, an inhibitor of free fatty acid (FFA) oxidation, hepatic insulin resistance persisted despite elimination of hyperinsulinemia and reduction of FFA oxidation. These data do not support a causal role for either hyperinsulinemia or enhanced lipolysis of hypertrophied fat stores and subsequent FFA oxidation in the liver in the development of hepatic insulin resistance in this animal model of obesity.

Animals↗
PubMed1993

Cost-effective screening for diabetic retinopathy using a nonmydriatic retinal camera in a prepaid health-care setting.

OBJECTIVE: To assess the efficacy of using a nonmydriatic Polaroid retinal camera as a method for screening diabetic patients for treatable diabetic retinopathy. RESEARCH DESIGN AND METHODS: All 522 diabetic patients followed in a health maintenance organization-affiliated diabetes program had retinal photos taken. Compliance with the routine referral to one of two retinal specialists (the examiners) was 74%. The results from the examiners were compared with the results of the reader of the retinal photos. RESULTS: Sensitivity was 100% and specificity was 82% for the diagnosis of serious diabetic retinopathy (preproliferative or proliferative retinopathy or macular edema) by the examiners compared with the diagnosis of any diabetic retinopathy by the reader. No patient had serious diabetic retinopathy inside or outside the photographic field that was missed because all patients with serious diabetic retinopathy showed some diabetic retinopathy within the photographic field. The reader tended to underrate the severity of the diabetic retinopathy, but when the reader diagnosed serious diabetic retinopathy, it was always present on exam. CONCLUSIONS: The nonmydriatic retinal camera is easy to use, inexpensive, and can be used as part of a general diabetes exam, independent of a physician, in patients who should, but may not, be referred to an ophthalmologist. Any patient with abnormal findings on photos should be referred to an ophthalmologist, and any patient with findings of serious diabetic retinopathy on the photos should be referred immediately for possible laser therapy.

California↗
PubMed1992

Rational use of sulfonylureas.

The clinical use of sulfonylureas described in this article is both rational and effective for diabetic patients. Sulfonylureas are not used (1) in patients with insulin-dependent (type I) diabetes, because they are completely ineffective or (2) in patients with non-insulin-dependent (type II) diabetes who respond satisfactorily to diet, because they are unnecessary. In a patient with type II diabetes who has few or no symptoms but does not respond satisfactorily to diet, a sulfonylurea is introduced at a low dose, with gradual increases until a satisfactory response occurs, thus avoiding hypoglycemia. When symptoms of type II diabetes are marked, initiation of therapy with maximum doses of a sulfonylurea quickly distinguishes patients who need insulin therapy from those who have a good chance of responding to an oral drug. Abuse of sulfonylureas occurs when patients who could benefit from diet alone are treated with the drugs unnecessarily or, more often, when patients with poorly controlled disease continue to take maximum doses of the drugs. The usual situation is one in which the patient refuses insulin therapy or the physician does not suggest starting it. In other cases, the poorly controlled patient may be allowed to continue with a combination of a sulfonylurea and an ineffective dose of insulin. In this circumstance, the oral drug should be discontinued and insulin doses increased until control is more satisfactory. Because evidence is so compelling that near euglycemia has a beneficial effect on diabetic retinopathy, nephropathy, and neuropathy, physicians really do patients a disservice by misusing sulfonylureas.

Aged↗
PubMed1992

Regulation of glucokinase and proinsulin gene expression and insulin secretion in RIN-m5F cells by dexamethasone, retinoic acid, and thyroid hormone.

In RIN-5mF cells, treatment with either dexamethasone or retinoic acid resulted in increased glucokinase activity. Treatment with dexamethasone (50 and 500 nM) increased glucokinase activity 140% and 260%, respectively, whereas treatment with retinoic acid (100 and 1000 nM) increased glucokinase activity by 50% and 80%, respectively. An additive effect was observed when 1000 nM retinoic acid was added to either 50 or 500 nM dexamethasone. Treatment with either of these factors resulted in increased glucokinase mRNA levels. In contrast, treatment with thyroid hormone (T3; 0.2 and 10 nM) had no effect on glucokinase activity, but decreased glucokinase mRNA levels. T3 did not affect the response of either activity or mRNA levels to retinoic acid. Binding experiments revealed the presence of a single class of T3 nuclear receptors, with a Kd of 0.46 x 10(-10) and a binding capacity of 3.84 pmol/mg protein in these cells. This suggests that the changes produced by T3 may be due to a physiological effect mediated via nuclear receptors. Proinsulin mRNA levels were increased by retinoic acid (10-100 nM) and dexamethasone (5-500 nM), but decreased by T3 (0.04-10 nM). Insulin secretion in the absence or presence of glucose and potassium was increased about 50% in cells previously treated with 1000 nM retinoic acid. T3 (0.2 nM) did not affect insulin secretion in the absence or presence of glucose or in the presence of secretagogues (potassium and glyceraldehyde). Dexamethasone (50 nM) did not significantly increase insulin secretion in the absence or presence of glucose or potassium. In contrast, dexamethasone decreased glyceraldehyde-induced insulin secretion by 60% (P less than 0.05). We conclude that the glucokinase and proinsulin genes respond in parallel to dexamethasone and retinoic acid (both increased) and to T3 (both decreased).

Animals↗