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Biomedical subjects

E A Ryan

Publications and source records attributed to E A Ryan.

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

One-year acarbose treatment raises fasting serum acetate in diabetic patients.

alpha-Glucosidase inhibitors such as acarbose improve blood glucose control in diabetes by delaying or reducing carbohydrate absorption. The fermentation of malabsorbed carbohydrate in the colon is associated with the production of gas, leading to flatulence, and short chain fatty acids such as acetate, which may have systemic effects. To see if acarbose raised fasting serum acetate in diabetic patients, we studied 85 subjects selected from the 267 who had completed a 1-year, double-blind, placebo-controlled, parallel design study of the effects of acarbose in the treatment of diabetes. At baseline, there was no significant difference between the 44 subjects subsequently randomized to placebo and the 41 randomized to acarbose, respectively, in fasting serum acetate (80 +/- 5 vs 71 +/- 4 mumoll-1) or glycosylated haemoglobin (HbA1C; 7.2 +/- 0.3 vs 7.4 +/- 0.3%). Compared to placebo, acarbose treatment significantly increased fasting serum acetate by 11 +/- 4 vs 2 +/- 3 mumoll-1 (p < 0.02) and reduced HbA1C by -0.59 +/- 0.16 vs -0.13 +/- 0.20% (p < 0.02). Acarbose treatment had no significant effect on serum cholesterol or non-esterified fatty acids, but was associated with a significant increase in flatulence. There was no relationship between changes in serum acetate and changes in HbA1C, serum cholesterol or symptoms. We conclude, in subjects with diabetes who tolerate therapy for a 1-year period, that acarbose treatment increases serum acetate. The magnitude of change in acetate was unrelated to side-effects or changes in blood glucose control or serum lipids.

Acarbose↗
PubMed1995

Long-term consequences in offspring of diabetes in pregnancy: studies with syngeneic islet-transplanted streptozotocin-diabetic rats.

To study the long-term effects of exposure to maternal hyperglycemia and insulin deficiency in utero, we used the syngeneic islet transplanted streptozotocin-diabetic rat model of diabetes in pregnancy and examined insulin secretion and action in 6-month-old offspring. Female rats were rendered diabetic with streptozotocin and then transplanted with 2500, 750, or 500 islets. Control animals were also studied, and one group whose islet transplants failed remained diabetic. During pregnancy, plasma glucose levels in the diabetic rats and the groups receiving 500 and 750 islets were 24.7 +/- 1.0, 15.3 +/- 1.4, and 7.9 +/- 0.5 mmol/liter, respectively, all significantly greater than the control value (5.6 +/- 0.3 mmol/liter; P < 0.05). The plasma glucose level in the 2500 islet group was 6.2 +/- 0.2 mmol/liter, which was not significantly higher than the control value. When the offspring were studied at 6 months, there was no significant difference between groups in either glucose or insulin levels after iv glucose, although acute insulin secretion tended to be higher in the offspring of the diabetic animals. A study of insulin action with the euglycemic clamp at two insulin levels showed that insulin sensitivity was reduced in the offspring of diabetic animals vs. controls (1.97 +/- 0.24 vs. 7.58 +/- 0.95 mumol/liter x 100/kg/min.pmol/liter; P < 0.05). Insulin sensitivity was also significantly reduced in the 2500, 750, and 500 islet group offspring (4.81 +/- 0.57, 4.82 +/- 0.64, and 4.01 +/- 0.63 mumol/liter x 100/kg/min.pmol/liter; P < 0.05) compared to that in the control. There were no differences in insulin sensitivity between male and female animals. In summary, animals displaying maternal insulin deficiency have offspring who are insulin resistant without any evidence of iv glucose intolerance or diminished insulin secretion.

Animals↗
PubMed1995

Defects in insulin secretion and action in women with a history of gestational diabetes.

Gestational diabetes mellitus (GDM) is associated with defects in insulin secretion and insulin action, and women with a history of GDM carry a high risk for the development of non-insulin-dependent diabetes mellitus (NIDDM). Assessment of subjects with a history of GDM who are currently normoglycemic should help elucidate some of the underlying defects in insulin secretion or action in the evolution of NIDDM. We have studied 14 women with normal oral glucose tolerance who had a history of GDM. They were compared with a group of control subjects who were matched for both body mass index (BMI) and waist-to-hip ratio (WHR). All subjects underwent tests for the determination of oral glucose tolerance, ultradian oscillations in insulin secretion during a 28-h glucose infusion, insulin secretion in response to intravenous glucose, glucose disappearance after intravenous glucose (Kg), and insulin sensitivity (SI) as measured by the Bergman minimal model method. The BMI in the post-GDM women was similar to that in the control subjects (24.9 +/- 1.2 vs. 25.4 +/- 1.4 kg/m2, respectively), as was the WHR ratio (0.80 +/- 0.01 vs. 0.76 +/- 0.01, respectively). The post-GDM women were slightly older (35.2 +/- 0.9 vs. 32.1 +/- 1.4 years, P = 0.04). The fasting plasma glucose levels were significantly higher in the post-GDM group than in the control group (4.9 +/- 0.1 vs. 4.4 +/- 0.1 mmol/l, respectively, P < 0.001) and remained higher at each of the subsequent determinations during the oral glucose tolerance test, although none had a result indicative of either diabetes or impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Activity Cycles↗
PubMed1995

Clinical experience with acarbose: results of a Canadian multicentre study.

Current therapeutic options for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) focus on regimens that primarily lower fasting blood glucose concentrations. In several short-term studies, the alpha-glucosidase inhibitor, acarbose, has been reported to significantly lower post-prandial plasma glucose levels as well as HbA1c. The primary objective of this present study was to assess the long-term efficacy of adjunctive acarbose therapy to improve metabolic control. Over a 1-y period, acarbose or placebo was administered to 4 groups of patients: those managed by diet only, diet and sulfonylurea, diet and biguanide, and diet and insulin. In all treatment groups, the addition of acarbose resulted in significant reductions in postprandial blood glucose levels. Additionally, HbA1C was significantly lower after 12 months of acarbose therapy, compared with placebo, in all groups except the diet and insulin group. The addition of acarbose consequently expands the armamentarium available to clinicians for the optimization of glycemic control in patients with NIDDM.

Acarbose↗
PubMed1994

The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. A multicenter controlled clinical trial.

OBJECTIVE: To evaluate the long-term efficacy of acarbose, an alpha-glucosidase inhibitor, in improving glycemic control in patients with non-insulin-dependent diabetes mellitus. DESIGN: A 1-year, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Seven university-affiliated, community-based, tertiary care diabetes clinics. PATIENTS: 354 patients with non-insulin-dependent diabetes mellitus were recruited; 77 were being treated with diet alone, 83 with diet and metformin, 103 with diet and sulfonylurea, and 91 with diet and insulin. Patients in each treatment group were randomly assigned to either acarbose or placebo for 1 year. Eighty-seven percent of patients receiving acarbose and 92% of those receiving placebo were included in the efficacy analysis (n = 316). MEASUREMENTS: At baseline and at 3-month intervals, levels of hemoglobin A1c (HbA1c), fasting and postprandial plasma glucose, fasting and postprandial serum C-peptide, and fasting serum lipids were measured. RESULTS: Compared with placebo, acarbose treatment caused a significant decrease in the mean postprandial plasma glucose peak (90 minutes) in all four groups (19.0 +/- 0.4 mmol/L to 15.5 +/- 0.4 mmol/L; P < 0.001). Analysis of the postprandial plasma glucose incremental area under the curve showed that the change from baseline to the end of the treatment period differed for placebo and acarbose recipients by 4.73 mmol.h/L in the diet alone group (P < 0.001), 2.06 mmol.h/L in the metformin group (P = 0.01), 2.65 mmol.h/L in the sulfonylurea group (P < 0.001), and 3.13 mmol.h/L in the insulin group (P = 0.001). Corresponding decreases in HbA1c levels occurred; these were 0.9% in the diet alone group (P = 0.005), 0.8% in the metformin group (P = 0.011), 0.9% in the sulfonylurea group (P = 0.002), and 0.4% in the insulin group (P = 0.077). Acarbose did not significantly affect mean serum C-peptide or mean serum lipid levels. CONCLUSIONS: Acarbose improved long-term glycemic control in patients with non-insulin-dependent diabetes mellitus regardless of concomitant antidiabetic medication.

Acarbose↗
PubMed1994

An evaluation of iodine-123 iodoazomycinarabinoside as a marker of localized tissue hypoxia in patients with diabetes mellitus.

Peripheral vascular disease is a serious and common complication in patients with diabetes mellitus (DM). Evaluation is, conventionally, by transcutaneous oxygen tension measurements (TcpO2), although this technique has some limitations in the evaluation of tissue viability. We have evaluated a new, radiolabelled, in vivo marker of tissue hypoxia, iodoazomycinarabinoside (IAZA), by comparing TcpO2 measurements with patterns of iodine-123 IAZA uptake in ten patients (19 lower limbs) with DM and peripheral vascular disease using conventional gamma camera imaging techniques. Normal uptake patterns were seen in limbs in which normal TcpO2 measurements were obtained. Diffusely increased uptake of [123I]IAZA was seen in limbs with reduced TcpO2. Focally increased uptake was seen in ulcers or in areas of atrophic skin change. A semi-quantitative measure showed an inverse correlation between [123I]IAZA and TcpO2 values. These data suggest that tissue hypoxia can be imaged in this population of patients and that severity of disease can be assessed. A longitudinal prospective trial is now being developed.

Adult↗
PubMed1994

Determinants of diet glycemic index calculated retrospectively from diet records of 342 individuals with non-insulin-dependent diabetes mellitus.

Controlled trials have shown that a diet with a low glycemic index improves blood glucose and lipid control in patients with diabetes. To study the distribution and determinants of diet glycemic index, we obtained two 3-d diet records from 342 free-living subjects with non-insulin-dependent diabetes. Mean +/- SD 24-h intakes were as follows: energy, 7170 +/- 1890 kJ; fat, 33.6 +/- 6.5% of energy; protein, 20.1 +/- 3.2% of energy; available carbohydrate, 45.3 +/- 7.2% of energy; and dietary fiber, 17.2 +/- 6.4 g. Diet glycemic index values (85.4 +/- 4.55, range, 70-97.8) were normally distributed. Diet glycemic index was inversely associated with intake of simple sugars, whether expressed in grams (r = -0.426), percent of energy (r = -0.446), or percent of carbohydrate (r = -0.453, P < 0.001). By step-wise-multiple-linear regression, grams carbohydrate and percent protein were also independently related to diet glycemic index. Differences in diet glycemic index between men and women, and between subjects on different types of diabetes therapy were explained by differences in intake of simple sugars.

Blood Glucose↗
PubMed1994

Gender differences in the metabolic response to graded numbers of transplanted islets of Langerhans.

Gender differences after treatment with streptozotocin (STZ) have been previously reported; however, differences in the glucose response to islet transplantation in STZ-induced diabetes in male and female rats after islet transplantation have not been examined. Male and female Wistar-Furth rats were made diabetic using STZ (55 mg/kg BW) and then given an intraportal islet transplant. Control animals received sham injections and sham transplant surgery; diabetic animals received STZ and sham surgery. In male animals, islet grafts contained 0 (diabetic), 250, 500, 1000, 1500, 2000, and 3000 islets; in female rats, grafts were made up of 0, 500 700, 750, 1000, or 2500 islets. STZ treatment had more dramatic effects on male than female rats. During the diabetic phase, body weights of male rats were significantly reduced compared to those of control male animals; this was not observed among females. Although all STZ-treated animals were hyperglycemic, plasma glucose levels in male diabetic rats were significantly higher than those in females during this phase (29.8 +/- 2.1 vs. 24.6 +/- 0.6 mM). After islet transplantation, body weight gain was positively associated with the number of islets transplanted in male rats (r2 = 0.59; P < 0.01), but not in females (r2 = 0.09; P > 0.8). In both male and female rats, animals that received 1000 islets or more were generally normoglycemic by 3 weeks posttransplant (males, 10.8 +/- 2.2 mM; females, 7.1 +/- 0.2 mM). Approximately 60% of male and female animals that received 500 islets achieved a reduction in plasma glucose levels. Mean plasma glucose levels were 17.2 +/- 2.3 in the females and 22.6 +/- 1.0 mM in males. However, a significantly larger proportion of female 500-islet animals (6 of 16) achieved a plasma glucose level of 9.5 mM or less compared with males receiving 500 islets (2 of 30). Multivariate regression analysis suggests that sex and islet number interact to affect glycemic normalization after islet transplantation. Gender differences appear to influence body weight and plasma glucose responses to islet transplantation. This finding may have particular relevance when a marginal number of functional islets are available.

Animals↗
PubMed1993

A new model for the study of mild diabetes during pregnancy. Syngeneic islet-transplanted STZ-induced diabetic rats.

Diabetes during pregnancy carries short- and long-term consequences for the offspring. Improved obstetrical and diabetic care has resulted in decreased morbidity and mortality in the neonate of the diabetic mother. Mild hyperglycemia is still found in both IDDM pregnant women and women with GDM. The long-term consequences of exposure to mild hyperglycemia in utero remain to be determined. In an effort to develop an appropriate animal model of mild diabetes during pregnancy, we mated female STZ-induced diabetic rats previously transplanted with specific numbers of islets of Langerhans (2500, 1000, 700, or 500 islets). Diabetic and nondiabetic sham-transplanted control groups also were studied. During pregnancy, the plasma glucose levels in the diabetic rats and the group receiving 500 islets (26.5 +/- 1.1 and 10.0 +/- 0.8 mM, respectively) were significantly greater than in control animals (5.4 +/- 0.5 mM, P < 0.0001). The mean glucose levels in rats receiving 700 or 1000 transplanted islets (6.8 +/- 0.2 and 6.5 +/- 0.2 mM) also were significantly greater than in control animals (P < 0.001). No difference was evident between control rats and the group receiving 2500 islets (5.8 +/- 0.2 mM). No gross congenital abnormalities were apparent in the offspring. The pup plasma glucose was significantly greater in the offspring of dams receiving either none (diabetic) or 500 islets (10.6 +/- 0.7 and 11.1 +/- 1.1 mM, respectively) compared with the offspring of nondiabetic control dams (4.4 +/- 0.3 mM, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Long-term follow-up after transplantation of insulin-producing pancreatic islets into patients with type 1 (insulin-dependent) diabetes mellitus.

Purified human islets and a kidney from the same donor were transplanted into four patients with Type 1 (insulin-dependent) diabetes mellitus. Two of the patients received additional islets that were isolated from multiple donors, cryopreserved, and stored in a tissue bank. The islets were embolized into the liver via the portal vein. Immunosuppression was induced with antilymphocyte globulin and maintained with azathioprine, prednisone and cyclosporine. In the first two patients, fasting serum C-peptide rose to levels of 0.5-2.0 ng/ml during the first 4-8 weeks and mixed meal feeding elicited increases to 2-3 ng/ml. C-peptide secretion persisted for 8 months, but at progressively lower levels and insulin therapy could not be withdrawn. In the next two patients who received cryopreserved islets in addition to fresh islets, serum C-peptide levels (fasting/post-meal) rose to 4-7 ng/ml and serum glucose was more stable, allowing withdrawal of insulin therapy after 69 days in one patient, and reduced insulin doses in the other. The insulin-independent patient has maintained normal fasting glucose, glycosylated haemoglobin, and oral glucose tolerance at 1 year following cessation of daily insulin therapy. Episodes of renal graft rejection occurred in three patients, including the insulin-independent patient. High-dose steroid therapy reversed the rejection in all instances, with apparent preservation of C-peptide secretion. These data show that transplantation of purified freshly-prepared and cryopreserved islets into Type 1 diabetic patients results in prolonged insulin secretion, and that sufficient function could be provided in one patient to sustain euglycaemia in the absence of insulin therapy at 1 year of follow-up.

Adult↗
PubMed1992

Kynurenic acid concentrations are reduced in Huntington's disease cerebral cortex.

Huntington's disease (HD) is characterized by gradually evolving selective neuronal death. Several lines of evidence suggest that an excitotoxic mechanism may play a role. Tryptophan metabolism leads to production of quinolinic acid, an N-methyl-D-aspartate (NMDA) receptor agonist, and to kynurenic acid, an antagonist at these same receptors. We recently found increased kynurenine to kynurenic acid ratios in HD postmortem putamen and decreased kynurenic acid concentrations in cerebrospinal fluid, consistent with decreased formation of kynurenic acid in HD brain. In the present study we used HPLC with 16 sensor coulometric electrochemical detection to measure kynurenic acid and 18 other electrochemically active compounds in 6 cortical regions, caudate and cerebellum from controls, HD, Alzheimer's disease (AD), and Parkinson's disease (PD) patients. Significant reductions in kynurenic acid concentrations were found in 5 of 6 cortical regions examined. Smaller reductions of kynurenic acid in the caudate, cerebellum and frontal pole were not significant. No significant reductions were found in the AD and PD patients. Both uric acid and glutathionine were significantly reduced in several regions of HD cerebral cortex, which could signify abnormal energy metabolism in HD. Since kynurenic acid is an antagonist of excitatory amino acid receptors, a deficiency could contribute to the pathogenesis of neuronal degeneration in HD.

Aged↗
PubMed1992

Insulin requirements in insulin-dependent and insulin-requiring GDM women during final month of pregnancy.

OBJECTIVE: To determine the significance of falling insulin requirements after the 36th wk of gestation in insulin-requiring pregnant women. RESEARCH DESIGN AND METHODS: Insulin requirements of women with IDDM and IRGDM were assessed from the 36th wk of pregnancy, with evaluation of maternal characteristics and fetal outcomes. RESULTS: In 32 pregnancies of women with IDDM, there was a 5 +/- 2% decrease in insulin requirements, and in 19 pregnancies of women with IRGDM, there was a 28 +/- 10% increase. Of the 62% of women whose insulin requirements declined, the decrement was 12 +/- 2% and was associated with longer duration of diabetes (12 +/- 2 vs. 6 +/- 1 yr, P less than 0.05) but not with age, prepregnancy BMI, weight gain, or maternal or fetal complications. Only 3 pregnancies in IRGDM women were associated with a decrease in insulin requirements. Although maternal parameters were no different from those with IDDM, infants born to women with IRGDM were smaller (3531 +/- 123 vs. 3874 +/- 94 g, P less than 0.005). CONCLUSIONS: Insulin requirements from the 36th wk of gestation commonly decreased in women with IDDM, associated with longer duration of diabetes but did not carry any adverse prognostic indication for the infants. Women with IRGDM experienced a continual increase in insulin requirements over the final weeks of pregnancy.

Adult↗
PubMed1991

Phenytoin-induced insulin insensitivity.

Phenytoin is known to induce hyperglycaemia. The mechanism has generally been considered primarily an inhibition of insulin release. We have recently treated a patient who became hyperglycaemic on phenytoin and whose markedly increased insulin requirements suggested an insulin resistant state. Reduction of the phenytoin dose resulted in amelioration of the hyperglycaemia. In vitro studies of phenytoin in a primary culture system of adipocytes that allowed assessment of both insulin receptor binding and post-binding function showed a 57% reduction in maximum [14C]3-0-methylglucose transport in the presence of phenytoin while having no effect on maximum insulin binding. These results suggest that phenytoin administration can result in insulin insensitivity by inducing a post-binding defect in insulin action.

Aged↗