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Biomedical subjects

M Bryer-Ash

Publications and source records attributed to M Bryer-Ash.

33 records · Page 2Linked to original sources
PubMed1994

Vanadyl sulfate prevents fructose-induced hyperinsulinemia and hypertension in rats.

To determine whether insulin resistance and hyperinsulinemia are causally related to fructose-induced hypertension, we used vanadyl sulfate, a drug that improves insulin sensitivity in rats. Chronic oral vanadyl treatment was initiated in 6-week-old male Sprague-Dawley rats. One week after vanadyl was started, rats were fed either normal rat chow or a fructose-enriched diet. Plasma glucose and insulin levels and systolic blood pressure were measured weekly for 4 weeks. Fructose feeding induced hyperinsulinemia (fructose-fed, 366.6 +/- 8.4 versus control, 276 +/- 10.8 pmol/L, P < .001) and increased blood pressure (fructose-fed, 160 +/- 3.0 versus control, 124 +/- 3.0 mm Hg, P < .001). Vanadyl (0.4 to 0.6 mmol/kg per day) prevented the rise in plasma insulin (treated, 211.2 +/- 6.0 pmol/L, P < .001) and blood pressure (treated, 127 +/- 3.0 mm Hg, P < .001) in the fructose-fed rats without a change in plasma glucose. No change in blood pressure was seen in the control group. After 4 weeks, euglycemic clamps were performed on 20-hour fasted, conscious, mobile rats. Low-dose porcine insulin infusion (14 pmol/kg per minute) with concomitant somatostatin infusion resulted in similar steady-state plasma glucose and insulin levels in the various groups. Hepatic glucose production was suppressed and similar among various groups under clamp conditions. Insulin sensitivity index (micromoles of glucose per kilogram per hour per picomole per liter of insulin) was reduced in the fructose-fed rats compared with controls (fructose-fed, 0.9 +/- 0.4 versus control, 5.4 +/- 1.2, P < .002).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Bis(maltolato)oxovanadium(IV) attenuates hyperinsulinemia and hypertension in spontaneously hypertensive rats.

We previously reported that bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium complex, decreased plasma insulin concentrations in nondiabetic rats without affecting plasma glucose levels (McNeill JH, Yuen VG, Hoveyda HR, Orvig C: Bis(maltolato)oxovanadium(IV) is a potent insulin mimic. J Med Chem 35:1489-1491, 1992). In this study, chronic oral BMOV treatment was started in 6-week-old spontaneously hypertensive (SH) rats and their Wistar-Kyoto (WKY) controls, and the effects of the drug on insulin sensitivity, plasma insulin, and blood pressure (BP) were studied. BMOV (0.35-0.45 mmol.kg-1.day-1) caused a sustained reduction in plasma insulin (198 +/- 6 vs. untreated 366 +/- 13.2 pM, P < 0.0001) and systolic BP (149 +/- 3 vs. untreated 184 +/- 3 mmHg, P < 0.0001) in SH rats. No changes were seen in WKY rats (plasma insulin: treated 228 +/- 4.8 vs. untreated 222.6 +/- 3.6 pM, P > 0.05; BP: treated 134 +/- 3 vs. untreated 134 +/- 5 mmHg, P > 0.05). At 13 weeks of age, euglycemic clamps were performed in fasted, conscious, mobile rats. During low-dose insulin infusions (14 pmol.kg-1.min-1) with concomitant somatostatin administration, neither hepatic glucose output nor total body glucose uptake differed between the untreated SH and WKY rats. Insulin sensitivity, expressed as steady-state glucose clearance per unit of plasma insulin, was higher in the untreated SH compared with the untreated WKY rats (2.1 +/- 0.2 vs. 1.2 +/- 0.1 ml.kg-1.h-1.pM-1, P < 0.002). BMOV further enhanced insulin sensitivity in SH rats (3.6 +/- 0.4, P < 0.002 vs. untreated SH rats).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Characterization of insulin-stimulated seryl/threonyl protein kinases in rat skeletal muscle.

Post-insulin receptor signal transduction is mediated by a cascade of seryl/threonyl protein kinases which includes a family of mitogen-activated protein (MAP) kinases, ribosomal protein S6 kinases, and casein kinase-2. Previous studies have characterized these kinases primarily in cultured or isolated cells. We have demonstrated that intravenous injection of insulin into fasted rats significantly stimulated the activities of MAP kinases and S6 kinases in skeletal muscle, independently of the blood glucose levels in these animals. Anion exchange chromatography on Mono Q afforded the resolution of at least five peaks of insulin-stimulated myelin basic protein kinase activity. By immunological criteria, these myelin basic protein kinases included the p42mapk and p44erk1 as well as other potentially novel 44-kDa MAP kinases. Insulin-activated ribosomal S6 kinases were resolved into two major peaks by Mono Q chromatography, the latter of which contained a 100-kDa isoform of p90rsk as revealed by immunoblotting with an anti-rsk-peptide antibody. A 32-kDa S6 kinase in the earlier peak may represent a novel protein kinase in this tissue. Skeletal muscle casein kinase-2 was not significantly stimulated following insulin injection into rats under our experimental conditions. These results indicate that the intact rat can serve as a useful model system to investigate the mechanisms of insulin signal transduction.

Amino Acid Sequence↗
PubMed1993

Altered distribution of insulin between intravascular and interstitial compartments in STZ-induced diabetic rats.

These studies were undertaken to determine the distribution of insulin between the intravascular and interstitial compartments in 19 nondiabetic and 16 high-dose (60 mg/kg) STZ-induced diabetic rats. Anesthetized male rats underwent cannulation of the thoracic lymph duct with continuous collection of lymph by passive drainage; 90-min hyperinsulinemic (0, 14, 28, or 42 pmol.kg-1 x min-1) glucose clamps were performed with serum glucose held at the preinfusion level. Integrated lymph samples were collected, with serum collection at the midpoint. Before insulin infusion, insulin levels in lymph as a percentage of levels in serum were higher in the diabetic rats (lymph = 103 +/- 8% of 52 matched serum values, mean +/- SE) compared with nondiabetic rats (lymph = 83 +/- 3% of serum; n = 84, P < 0.008). Under steady-state conditions during insulin infusion (66-90 min), lymph insulin as a percentage of serum insulin decreased significantly in nondiabetic animals (range 53-62% in all insulin-infused groups, vs. 94% in the absence of insulin infusion, P < 0.0001). However, in the diabetic animals, the proportion was similar in the presence or absence of infused insulin (range 57-63% in insulin-infused groups vs. 70% in the absence of infused insulin, P = NS). Lymph flow rate was significantly higher in diabetic than nondiabetic rats (37.7 +/- 7.2 vs. 17.9 +/- 1.5 microliters/min [mean +/- SE], P < 0.02). Distribution of [14C]inulin was uniform between the two compartments in all animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1993

The effect of glyburide on beta-cell sensitivity to glucose-dependent insulinotropic polypeptide.

OBJECTIVE: To assess whether treatment with glyburide alters beta-cell sensitivity to GIP in NIDDM patients. RESEARCH DESIGN AND METHODS: We studied 5 untreated NIDDM patients in a meal study (Ensure, 240 ml/M2) and a 2-h hyperglycemic glucose clamp study (glucose 5.4 mM above fasting). From 60 to 120 min of the clamp, GIP was infused in a primed continuous manner at a rate of 2 pmol.kg-1 x min-1. Subjects then were treated with glyburide. After they had been on a stable dose of medication for 1 mo, the meal study and glucose clamp studies were repeated. RESULTS: In response to treatment, a decrease in fasting glucose and an increase in weight was observed (12.8 +/- 1.8 vs. 8.5 +/- 0.8 mM and 74.3 +/- 6.3 vs. 76.1 +/- 6.3 kg, respectively, P < 0.05). In response to the meal study, the AUC for glucose was less, for insulin was increased, and for GIP was unchanged after treatment (16.9 +/- 2.1 vs. 12.6 +/- 6.9 mM, P < 0.05; 161 +/- 47 vs. 242 +/- 60 pM, P < 0.05; and 199 +/- 22 vs. 219 +/- 18 pM, respectively). During the hyperglycemic clamp, steady-state glucose and 90- to 120-min GIP values were equivalent before and after treatment (18.0 +/- 1.3 vs. 18.3 +/- 1.3 mM and 302 +/- 59 vs. 298 +/- 37 pM, respectively). The 90-120 min insulin responses to the hyperglycemic clamp were greater after therapy (123 +/- 37 vs. 283 +/- 80 pM, P < 0.05) reflecting increased beta-cell responses to GIP. CONCLUSIONS: We conclude that glyburide enhances beta-cell sensitivity to GIP.

Adult↗
PubMed1991

Regulation of rat insulin-receptor kinase by glucose in vivo.

The effects of acute and chronic hyperglycemia on the kinase activity of insulin receptors in vivo were studied in the rat. Skeletal muscle-derived insulin receptors were isolated, with preservation of the in vivo phosphorylation state, from nondiabetic rats subjected to hyperinsulinemic clamps at either euglycemia (mean 5.2 mM) or hyperglycemia (14.4 mM) or from streptozocin-induced diabetic rats at euglycemia (5.1 mM) or hyperglycemia (14.2 mM). Kinase activity toward histone of insulin receptors from nondiabetic animals rendered hyperglycemic for 80-90 min was 50% higher than that of receptors from rats clamped at euglycemia (mean +/- SE 4.5 +/- 0.4 vs. 3.0 +/- 0.3 fmol of phosphate into histone, respectively, P less than 0.02), although kinase activity of receptors isolated from animals rendered diabetic for 10-14 days before hyperglycemic or euglycemic clamps showed no such effect. These results suggest that acute hyperglycemia may increase insulin-receptor kinase activity in vivo, possibly augmenting glucose disposal thereby, whereas the chronic hyperglycemia of diabetes mellitus results in metabolic derangements that nullify this effect.

Adenosine Triphosphate↗
PubMed1989

Rat insulin-receptor kinase activity correlates with in vivo insulin action.

Tyrosine kinase activity of skeletal muscle-derived insulin receptors isolated from rats that had undergone euglycemic clamps at various insulin infusion rates was examined. Receptors were isolated under conditions designed to preserve their in vivo phosphorylation state, and their kinase activity toward histone was measured in the absence of in vitro exposure to insulin. Results showed that significant activation of the insulin-receptor kinase occurred after exposure in vivo to mean serum insulin concentrations as low as 34 +/- 3.5 microU/ml and that maximal activation was achieved by insulin levels less than or equal to 2000 microU/ml. There was a highly significant correlation between receptor kinase activity and serum insulin concentration in the physiologic range (r = .92, P less than .0001) and between kinase activity and glucose utilization rate (r = .74, P less than .0001). These findings further support a role for the insulin-receptor kinase in insulin action in vivo, and this model provides a novel method for the study of the effect of factors known to influence insulin action on the insulin-receptor kinase under physiologic conditions.

Adenosine Triphosphate↗
PubMed1988

Plasma renin and prorenin (inactive renin) in diabetes mellitus: effects of intravenous furosemide.

PRA, active renin, and prorenin were measured in 32 normotensive diabetic patients and 14 normal subjects of similar ages before and after iv injection of 40 mg furosemide. The majority of the diabetic patients had normal PRA and active renin levels before and after furosemide, but in 4 normal subjects and 5 diabetic patients PRA did not rise after furosemide treatment to at least 0.25 ng angiotensin I/(L.s) as previously found in 90% of normal subjects. Two thirds of the diabetic patients had higher plasma prorenin levels than the normal subjects. Four of the 5 diabetic patients whose PRA failed to rise to the usual level after furosemide treatment attained a plasma prorenin level higher than any normal subject, suggesting that furosemide stimulated synthesis and secretion of prorenin, but that conversion of prorenin to active renin was impaired. These 5 diabetic patients also had higher plasma creatinine and potassium levels as well as an increased frequency of albuminuria compared with the other diabetic patients. In contrast, the 4 normal subjects whose PRA failed to reach the usual level after furosemide treatment had low unresponsive prorenin levels, indicating that furosemide did not evoke the expected increase in prorenin or renin synthesis. We conclude that the inability of some diabetic patients to increase PRA after furosemide treatment is not dependent on failure of renin synthesis, but reflects an impairment of the normal processing of prorenin, leading to high levels of prorenin in plasma.

Adult↗
PubMed1985

Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications.

Plasma renin exists in an active form or as an inactive zymogen that resembles a prorenin present in homogenates of human kidneys. We examined the relation of diabetes and its microvascular complications with the level of plasma inactive renin activated by dialysis to pH 3.3. Plasma inactive renin was measured in 235 diabetic patients and 90 nondiabetic controls. In the controls, the level of plasma inactive renin increased slightly with age but was never above 50 ng per milliliter per hour. In young diabetic patients studied within three years of the onset of diabetes the concentration of inactive renin was normal, and in some older diabetics without complications it remained within the age-adjusted normal range for many years. However, in patients with retinopathy or albuminuria, plasma inactive renin was above the normal range with few exceptions, reaching levels 50 to 200 per cent above the upper limits of normal in patients with nephropathy. The frequency of neuropathy was also significantly higher among patients with levels above the normal range. In 37 per cent of the diabetics followed during one to three years of conventional treatment, plasma inactive renin increased significantly, but in another group of diabetics under intensive treatment, the level rose in only 7 per cent and fell in 43 per cent. We conclude that there is a close association between a high level of plasma inactive renin and the presence of microvascular complications, and that the level of inactive renin can be modified by intensive treatment of diabetes.

Adolescent↗
PubMed1984

Hypertension caused by an aldosterone-secreting adenoma. Occurrence in a 7-year-old child.

A 7-year-old girl had hyperaldosteronism due to an adrenal cortical adenoma, a rare, surgically remediable cause of hypertension. Although the plasma potassium concentration was only slightly below normal, and the plasma aldosterone concentration was in a high normal range, the consistently suppressed plasma renin activity suggested primary aldosteronism. This diagnosis was confirmed by the failure of saline infusion to lower the plasma aldosterone concentration. Glucocorticoid-remediable hyperaldosteronism was excluded when dexamethasone did not reduce the high plasma aldosterone concentration. An enlarged left adrenal gland was observed in the computed tomographic scan, and blood from the left adrenal vein contained much more aldosterone than blood from the right adrenal vein. Surgical excision of the left adrenal gland, containing an adenoma, was followed by a return of BP and biochemical measurements to their normal ranges. This case demonstrated the importance of a rational systematic approach in the evaluation of children with sustained unexplained hypertension and the need to obtain plasma renin activity values when either hypokalemia is present or initial investigations fall to provide a diagnosis.

Adenoma↗
PubMed1983

Increased inactive renin in diabetes mellitus without evidence of nephropathy.

PRA, active renin, and inactive renin (IR; activated by dialysis to pH 3.3 and 7.4) were measured in the plasma of 53 patients with diabetes mellitus and 32 normal volunteers (group 1). Proteinuria was present in 21 diabetics (group 3; nephropathy) and absent in 32 diabetics (group 2). The mean PRA was lower in group 3 than in groups 1 and 2. PRA less than 0.2 ng/ml . h occurred more frequently and at a younger age in uncomplicated diabetics than in normal controls. Despite very low PRA, plasma aldosterone was normal in most of the diabetics. IR was significantly higher than normal in the uncomplicated diabetics and was greatly increased in diabetics with nephropathy. Since the kidneys are a principal source of IR, and since patients with diabetic nephropathy have consistently elevated plasma IR, it is possible that increased plasma IR in patients without proteinuria or reduced renal function might be an early sign of renal involvement. However, as other explanations of increased plasma IR exist, the hypothesis must be tested by longitudinal studies of diabetic patients.

Adult↗
PubMedDate not supplied

Human pancreatic islets transfected to produce an inhibitor of TNF are protected against destruction by human leukocytes.

The objective of this study was to determine whether transfection of human islets with an adenovirus construct encoding an inhibitor of tumor necrosis factor (TNFi) was effective at limiting damage to beta cells induced by human peripheral blood leukocytes (huPBL). Human islets transfected with TNFi or control islets were transplanted under the kidney capsule of NOD-scid mice. After a 15-day engraftment period, half of the mice received injections of activated huPBL and half received buffer injections. Islet graft function was assessed by two different methods, both of which use a species-specific radioimmunoassay to determine human insulin. In some mice, insulin production following intraperitoneal glucose injection was determined in serum. In other mice, total graft insulin content was determined by acid ethanol extraction. Histochemical stains were performed on some kidneys at the termination of the experiment to evaluate graft presence, transgene expression, and huPBL infiltration. In huPBL injected mice, graft performance was maintained in mice whose grafts were transfected with TNFi but declined substantially in control groups with sham transfected or beta-galactosidase transfected islet grafts. Similar results were obtained using either glucose-stimulated insulin release or graft insulin content as a measure of graft survival. There was no significant difference in graft function between control groups receiving buffer injections, regardless of whether the islets had been transfected. Human leukocytes were found in all huPBL groups regardless of islet transfection status. We conclude that transfection of human islets with an adenovirus encoding TNFi protects beta cells from destruction induced by human leukocytes. The local production of TNFi does not prevent graft infiltration by leukocytes, only the destruction of grafts by the infiltrating leukocytes. These results raise the possibility that local expression of an inhibitor of the proinflammatory cytokine TNF-alpha may also prevent graft failure in clinical islet transplantation.

Animals↗