Biomedical subjects
Publications and source records attributed to R S Gray.
An infant with persistent hyperinsulinism had hypertrophic cardiomyopathy that progressed until near-total pancreatectomy was performed. After pancreatectomy the condition resolved. Hyperinsulinism may be a cause of treatable cardiomyopathy.
Serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) are endogenous components of the central nervous and endocrine systems of the chicken. To determine the effects of these monoamines on antibody-mediated immunity. New Hampshire chickens of Line UNH 105 were injected intravenously with 5-HT (100 micrograms/kg of body weight) and DA (1 mg/kg of body weight). One milliliter of a 5% SRBC suspension was injected intravenously 30 min later. Both IgM and IgG splenic plaque-forming cells were assayed 5 days after antigen injection. For in vitro studies, spleen lymphocytes from SRBC-primed chicks were incubated with DA and 5-HT followed by quantitation of IgM and IgG plaque-forming cells. The in vivo incubation of splenic lymphocytes with specific antagonists was used to ascertain the presence of monoamine receptors on lymphocytes. The 5-HT significantly enhanced IgM plaque-forming cells compared with controls following in vivo [550 +/- 85 (SE) cells/10(6) splenic lymphocytes versus 359 +/- 44] but not in vitro exposure. The IgG plaque-forming cells were not affected by 5-HT. The DA significantly suppressed IgM plaque-forming cells responses following in vivo (284 +/- 46 versus 499 +/- 66) and in vitro (254 +/- 57 versus 451 +/- 51) exposure. Significant suppression of IgG plaque-forming cells was found in vivo (287 +/- 40 versus 462 +/- 75) and in vitro (153 +/- 36 versus 371 +/- 81) following treatment. Specific DA antagonists, apomorphine and metoclopramide, did not alleviate the in vitro suppressive effect of DA.
Twelve non-obese non insulin dependent diabetics whose mean +/- SE fasting blood glucose was 12.9 +/- 0.9 mmol/l despite maximal doses of sulphonylureas, received 8 weeks of guar (5 g tid before meals) and 8 weeks of metformin (0.5 g tid) following a six week washout period, in a cross-over design. Guar significantly lowered fasting cholesterol and triglyceride concentrations but did not alter glucose concentrations. Conversely, metformin significantly reduced fasting and post-prandial glucose concentrations but had no influence on plasma lipids.
A case of steroid-responsive malignant lymphoma of the optic chiasm is reported in a 58-year-old woman presenting with subacute vision loss, headaches, and decreased hearing. The exquisite sensitivity of magnetic resonance imaging (MRI) of the parasellar area and the usefulness of MR-directed stereotactic biopsy in identifying a chiasmatic lesion are shown. Primary CNS lymphomas are briefly reviewed. Ophthalmologists will be asked to evaluate patients with malignant lymphoma of the optic chiasm with increased frequency in the future, as CNS lymphomas are expected to be the most common neurological neoplasm by 1991.
A single-blind comparison of the effectiveness of miglitol (BAY-m-1099) and placebo in controlling postprandial hyperglycaemia was performed in 13 insulin dependent diabetics. Each subject received placebo and miglitol for four weeks, with an intervening two week placebo (washout) period, and underwent a 9.5 hr glycaemic profile after each four week treatment period. The area under the glucose curve was significantly (p less than 0.01) reduced by miglitol although no reduction in fasting blood glucose, HbA1, plasma lipids, insulin dosage or weight was observed. Side effects were not appreciably more common when patients received miglitol than when receiving placebo.
The effect of acarbose, an alpha-glucosidase inhibitor, on glycaemic control, was compared with placebo in a double-blind, randomised, group comparison study during 16 weeks in 20 non-obese non-insulin dependent diabetic patients in whom sulphonylurea treatment had been withdrawn. There was significant deterioration in glycaemic control as assessed by HbA1 following withdrawal of the sulphonylurea. There was no significant improvement in HbA1 between weeks 0 and 16 in either the acarbose (11.3% and 12.4% respectively) or the placebo group (10.6% and 12.2% respectively). In both the acarbose and placebo treated groups fasting glucose and insulin concentrations were unaltered. This study also suggests that acarbose was not an effective substitute for sulphonylureas in non-obese Type 2 diabetes uncontrolled by diet alone.
The biological action and pharmacokinetics of insulin were assessed in nine type 1 (insulin-dependent) diabetic patients before and after 3 months conventional insulin treatment, and in seven age and weight-matched non-diabetic controls, by means of the euglycaemic insulin clamp technique. The mean (+/- S.E.) metabolic clearance rate of insulin, when infused at 1 mU/kg/min, was similar in untreated and treated diabetic patients and in controls (22.7 +/- 2.0, 19.3 +/- 3.8, and 22.9 +/- 3.3 ml/kg/min) but, when infused at 6 mU/kg/min, was greater (p less than 0.01 and less than 0.01) in untreated patients (18.0 +/- 2.5 ml/kg/min) than in treated patients (11.5 +/- 1.4 ml/kg/min) and controls (12.7 +/- 1.3 ml/kg/min). Insulin-mediated glucose disposal was reduced (p less than 0.01 and less than 0.01) at insulin infusion rates 1 and 6 mU/kg/min in untreated patients (18.5 +/- 1.9 and 33.8 +/- 4.5 mumol/kg/min) when compared with controls (35.8 +/- 3.4 and 62.0 +/- 4.7 mumol/kg/min) and was improved (p less than 0.01 and less than 0.01) following insulin treatment (36.1 +/- 4.6 and 64.8 +/- 4.2 mumol/kg/min). Daily insulin requirement fell by 33% following 3 months insulin treatment with improvement in mean HbA1 from 16.3 +/- 0.7 to 8.2 +/- 0.4%, but without significant increase in endogenous insulin secretion. The 'honeymoon phenomenon', which has traditionally been attributed exclusively to resurrection of endogenous insulin release, may also be related to normalization of insulin action following institution of insulin treatment.
Sixteen insulin dependent diabetics of long standing, with undetectable fasting plasma C peptide concentrations, and eight non-diabetic controls were each infused intravenously with biosynthetic human and highly purified beef insulin (1 mU/kg/min) while euglycaemia was maintained by a Biostator. No difference was observed between the two insulins in respect of insulin pharmacokinetics or biological action. The diabetics showed appreciable insulin resistance, manifested by a 40% reduction in the rate of insulin mediated glucose disposal, which was unrelated to the presence of insulin antibodies. Insulin binding antibodies, however, increased insulin's clearance rate and distribution space and prolonged its pharmacological and biological half lives. The rate at which insulin action was lost, after an intravenous infusion, was more rapid in diabetics without insulin antibody binding than in controls. In respect of their influence on insulin pharmacokinetics, moderate concentrations of insulin antibodies may be of positive advantage to all diabetics without endogenous insulin secretion and are not responsible for the insulin resistance of type 1 diabetes.
We studied the association between vitiligo and diabetes mellitus, and found that vitiligo is associated with insulin-dependent diabetes but not with non-insulin-dependent diabetes. This gives further weight to the theory that vitiligo is an autoimmune disease.
Insulin action and pharmacokinetics were compared, using the euglycaemic insulin clamp technique, in seven insulin-treated diabetics during the third trimester of pregnancy and one to three weeks post-partum. At an insulin infusion rate of 1 mU/kg/min, insulin mediated glucose disposal was significantly greater (p less than 0.02) following delivery (1.194 +/- 0.138 mmol/m2/min) than in pregnancy (0.761 +/- 0.072 mmol/m2/min) and the rate of decline in insulin mediated glucose disposal, at the end of the insulin infusion, was significantly greater (p less than 0.02) following delivery (24.78 +/- 4.22 mumol/m2/min2) than in pregnancy (15.17 +/- 2.00 mumol/m2/min2). The metabolic clearance rate, distribution space and pharmacological half-life of insulin were not significantly altered by pregnancy. These findings show that the third trimester of pregnancy is associated with steady state insulin resistance accompanied by a reduced rate of insulin deactivation, but normal insulin pharmacokinetics.
Plasma beta-thromboglobulin, platelet factor 4, fibrinogen, fibrinopeptide A, antithrombin III, factor VIII related antigen, alpha 2-macroglobulin, platelet count, and total glycosylated haemoglobin were measured in three well matched groups of subjects: non-diabetic controls, diabetics without retinopathy, and diabetics with proliferative retinopathy. beta-thromboglobulin and platelet factor 4 concentrations were significantly higher in the diabetics with retinopathy than in the controls and platelet factor 4 was also increased in the diabetics without retinopathy compared with controls. Fibrinogen concentration was raised in diabetics without retinopathy compared with controls, diabetics with retinopathy compared with controls, and diabetics with retinopathy compared with those without. Fibrinopeptide A concentration did not differ significantly between groups. Antithrombin III levels were increased in diabetics with retinopathy compared with controls, and in diabetics with retinopathy compared with those without. Factor VIII related antigen values were higher in both the diabetic groups when compared with the controls. Fibrinopeptide A concentration correlated with both beta-thromboglobulin and platelet factor 4 in each of the three groups. Haemostatic abnormalities in diabetes have been shown, although a hypercoagulable state has not been confirmed. These changes in platelet and coagulation function may be secondary to the development of microvascular disease and their role in the pathogenesis of retinopathy remains uncertain.
Type 1 diabetics receiving once (Group 1, n = 72) and twice (Group 2, n = 48) daily subcutaneous injections of conventional beef insulin were compared, on a cross-sectional basis, in respect of insulin antibody binding by serum and total glycosylated haemoglobin (HbA1). Patients in Group 1 had higher insulin antibody binding (25.2 +/- 15.8% vs 17.0 +/- 13.9%; p less than 0.01) and higher HbA1 levels (12.5 +/- 2.0% vs 11.0 +/- 1.8%; p less than 0.001) than patients in Group 2. An inverse correlation (tau = -0.28, p less than 0.01) was observed between HbA1 and insulin antibody binding in C-peptide non-secretors of Group 1 but not in Group 1 C-peptide secretors, nor in C-peptide secretors and/or non-secretors of Group 2. It is suggested that in Type 1 diabetics who receive a single daily insulin injection and who have no endogenous insulin secretion, insulin antibodies may aid glycaemic control by prolonging insulin action.
Although type I diabetic patients are clearly insulin deficient, it is unclear whether they have normal in vivo sensitivity to insulin. Recent studies which suggested that insulin resistance is a common feature of insulin-dependent diabetics have not taken into account their degree of metabolic control or the presence of circulating antibodies. In the present study, we performed multiple euglycemic glucose clamp studies to construct insulin dose-response curves in 5 well controlled and 5 poorly controlled type I diabetic patients and 21 age-matched normal subjects. Each study was performed on a separate day at insulin infusion rates of 15, 40, 120, 240, or 1200 mU/M2 X min. During the 40 and 120 mU/M2 X min infusions, steady state insulin levels of 96 +/- 8 (+/- SE) and 285 +/- 27 microU/ml respectively, were achieved within 25 min in normal subjects. In contrast, diabetic subjects did not achieve steady state insulin levels (62 +/- 8 and 212 +/- 16 microU/ml) until 90 min of infusion, and insulin antibodies were detectable in the serum of all these patients. The dose-response curve for insulin stimulation of glucose disposal in well controlled diabetic subjects was comparable to that in normal subjects, with half-maximally effective insulin levels of 84 microU/ml in the diabetic patients compared to 70 microU/ml in normal subjects and virtually identical maximal rates of glucose disposal (433 +/- 11 vs. 411 +/- 17 mg/M2 X min in controls). In contrast, the dose-response curve for poorly controlled diabetic subjects was significantly right-shifted (half-maximally effective insulin level, 112 microU/ml), with marked reduction in the maximal glucose disposal rate (324 +/- 25 vs. 411 +/- 17 mg/M2 X min in normal subjects). Basal hepatic glucose output was increased in both poorly controlled and well controlled type I diabetic patients (132 +/- 7 and 101 +/- 16 mg/M2 X min, respectively) compared to normal subjects (76 +/- 7 mg/M2 X min). However, during each insulin infusion, hepatic glucose output was virtually 100% suppressed in all 3 groups.(ABSTRACT TRUNCATED AT 400 WORDS)
Although sulfonylurea agents have been used in the clinical management of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM) for over two decades, the mechanisms responsible for their hypoglycemic action remain controversial. We have quantitated glycemic control, endogenous insulin secretion in response to mixed meals, adipocyte insulin binding, insulin-mediated peripheral glucose disposal, and basal hepatic glucose output in 17 type II diabetic subjects before and after 3 mo of therapy with the second-generation, sulfonylurea compound glyburide in an attempt to identify the factors responsible for the clinical response to the drug. In addition, 9 subjects were treated for an additional 15 mo to see if the response to the drug changed with time. The mean fasting serum glucose level fell from an initial value of 264 +/- 17 mg/dl to 178 +/- 16 mg/dl after 3 mo of drug therapy. Endogenous insulin secretion increased in all subjects, but the increase was most marked in those subjects who continued to exhibit fasting hyperglycemia (fasting serum glucose greater than 175 mg/dl) after 3 mo of therapy. Adipocyte insulin binding was unchanged after 3 mo of therapy, while the maximal rate of peripheral glucose disposal was increased by 23%, indicating enhancement of peripheral insulin action at a postreceptor site(s). Basal hepatic glucose output showed a significant correlation with the fasting serum glucose level both before and after therapy (r = 0.86, P less than 0.001) and fell from 141 +/- 12 mg/m2/min before therapy to 107 +/- 11 mg/m2/min after 3 mo of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
By means of the euglycaemic insulin clamp technique the rate of insulin-mediated peripheral glucose disposal (GDR) was compared in response to intravenous infusions of highly purified beef insulin (BI) and biosynthetic human insulin (BHI), infused at 1 and 6 mU/kg/min, in healthy volunteers. The metabolic clearance rates of BI and BHI were similar at the lower insulin infusion rate and were both greater than those observed at the higher insulin infusion rate, which were also similar, implying the process of insulin clearance to be saturable. The GDRs were similar in response to infusions of BI and BHI at each insulin infusion rate. The rates of insulin deactivation were similar, having discontinued BI and BHI infusions at 1 mU/kg/min.
Sera from patients with different types of protamine-insulin were assayed for IgG antibody to protamine. A high prevalence of circulating antibody was found in patients treated with either bovine isophane insulin (26 out of 28 patients; 26 of whom also had antibodies to insulin), or bovine protamine zinc insulin (27 out of 30 patients; all 30 had antibodies to insulin). In sera from 24 patients treated with highly purified porcine isophane insulin, protamine antibody was detected in nine; circulating insulin-antibody was detected in 12 patients, eight of whom had protamine-antibody; in the 12 patients with no detectable antibody to insulin, antibody to protamine was detected in only one (x2 = 8.7, p less than 0.01). This relationship between insulin and protamine antigenicity is of interest as it suggests that the protamine-insulin complex is itself immunogenic.
An attempt was made to compare the natural history of thyroid function in 80 diabetics having raised serum TSH concentrations (median 8.9 mU/l, range 5.8-46.3 mU/l) but serum T4 concentrations within the normal range (Group 1), and in 59 diabetics having normal serum TSH (median 1.9 mU/l, range 0.8-4.7 mU/l) and T4 concentrations (Group 2). Thyroid microsomal antibodies were present initially in 65% of patients in Group 1 and 15% of patients in Group 2. By 1981, 59 patients (74%) in Group 1 and 47 patients (80%) in Group 2 had been followed for a mean +/- SD duration of 4.2 +/- 1.8 and 4.2 +/- 1.5 years, respectively. Hypothyroidism developed in 9 patients in Group 1, but none from Group 2. Of patients in Group 1, hypothyroidism developed at a rate of 5% per annum in those with thyroid microsomal antibodies, but only 1% per annum in those without antibodies. Therefore, the risk of development of hypothyroidism is greatest in diabetics having both elevated serum TSH concentrations and thyroid microsomal antibodies and such patients should have regular review of thyroid function. Either risk factor alone appears to be a poor predictor of development of hypothyroidism.
The prevalences of thyroid disease, insulin-dependent and non-insulin-dependent diabetes were compared in first degree relatives of diabetics with and without coexisting autoimmune thyroid disease. Thyroid disease was more common in siblings of diabetics with thyroid disease than in those of diabetics without thyroid disease. Insulin-dependent diabetes was more common in siblings of diabetics with a personal or family history of thyroid disease than in those of diabetics without such a history. The prevalence of non-insulin-dependent diabetes was unrelated to that of thyroid disease but was greater in siblings of non-insulin-dependent diabetics than in those of insulin-dependent diabetics. These findings add further support to the aetiological distinction between insulin-dependent and non-insulin-dependent diabetes and suggest that further heterogeneity exists within the population of insulin-dependent diabetics based on the presence of a personal or family history of thyroid disease.