Biomedical subjects
Publications and source records attributed to F Alford.
We report the case of a lady with multiple presentations and admissions with fever. The eventual diagnosis was made of adrenocorticosteroid deficiency.
Both insulin secretion and insulin sensitivity are important in the development of diabetes but current methods used for their measurements are complex and cannot be used for epidemiological surveys. This study describes a simplified approach for the estimation of first phase insulin release and insulin sensitivity from a standard 40-min intravenous glucose tolerance test (IVGTT), and compares these parameter estimations with the sophisticated minimal model analysis of a frequently sampled 3-h IVGTT and the euglycaemic clamp technique. For the simplified IVGTT, first phase insulin release was measured as the insulin area above basal post glucose load unit-1 incremental change (i.e. peak rise) in plasma glucose over 0-10 min, and insulin sensitivity as a rate of glucose disappearance (Kg) unit-1 insulin increase above basal from 0-40 min post-glucose load in 18 subjects who were studied twice, either basally or in a perturbed pathophysiological state (i.e. pre- and post-ultramarathon race, n = 5; pre- and post-20 h pulsatile hyperinsulinaemia, n = 8; pre- and post-thyrotoxic state, n = 5). A further 12 subjects were compared by IVGTT, and glucose clamp. In addition, seven dogs were studied three times by IVGTT during normal saline infusion and after short-term (1/2 hour) or long-term (72 hour) adrenaline infusions. First phase insulin release and insulin sensitivity estimated from the simplified IVGTT as calculated by the two methods correlated closely (rs = 0.89 and rs = 0.87, respectively), although less precisely in markedly insulin-resistant subjects and the slopes and y intercepts of the linear regression lines were similar in the basal and perturbed states.(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVE: To compare the magnitude and reproducibility of the FPIR measured during two different IVGTT protocols in nondiabetic subjects. RESEARCH DESIGN AND METHODS: Nine control subjects each had two pairs of IVGTTs with either a 4-min infusion of 0.5 g/kg glucose or a 1-min infusion of 0.3 g/kg glucose. Blood glucose and serum insulin were measured before and 1, 2, 3, 5, and 10 min after completion of the glucose infusion. The FPIR was measured with either 1 + 3-, 2 + 3 + 5-, or 1 + 3 + 5-min serum insulins, areas under the insulin curve (0-5 or 0-10 min), or the ratio of serum insulin to blood glucose area. RESULTS: The FPIR was higher in eight of nine subjects with the short-infusion test, but the within-subject variation of the two methods was identical. Reproducibility was not significantly improved with an integrated insulin area or insulin-to-glucose ratio measurement. CONCLUSIONS: Reproducibility of the FPIR measured during IVGTT is not significantly affected by the duration of the glucose infusion. However, the magnitude of the difference in FPIR observed between the two protocols highlights the need for standardization of the methodology if the IVGTT is to be used in studies of the preclinical stage of IDDM.
OBJECTIVE: We wished to assess the contributions of insulin secretion, insulin sensitivity and glucose-mediated glucose disposal to glucose tolerance in subjects exposed to chronic glucocorticoid excess. DESIGN: Patients with Cushing's disease were subjected to a frequently sampled intravenous glucose tolerance test before and at least 3 months after curative surgery and compared to a control group. PATIENTS: Seven patients with clinical and biochemically proven pituitary dependent Cushing's disease and 10 healthy control subjects were studied. MEASUREMENTS: Paired glucose and insulin plasma profiles were analysed by the Minimal Model method of Bergman, which provided simultaneous estimates of the glucose decay rate, insulin secretion, insulin sensitivity and glucose-mediated and non-insulin-mediated glucose disposal. Data were evaluated by non-parametric statistical analysis and reported as median and interquartile ranges. RESULTS: Basal glucose, insulin, C-peptide and glucagon levels were significantly raised preoperatively and fell towards normal post-operatively. Glucose tolerance assessed as glucose decay rate was reduced significantly preoperatively (pre: 1.3 (0.8-2.0) vs post: 1.6 (1.5-2.6) per min x 10(2), P less than 0.05). First phase insulin release was similar in the Cushing's disease and control subjects. In contrast, second phase insulin release was significantly greater preoperatively and remained high post-operatively compared to control subjects (pre: 18.8 (16.7-23.6) vs post: 16.7 (8.5-18.8) vs control 11.1 (4.5-15.4) mU/g/min2 x 10(-2), P less than 0.002). Median insulin sensitivity was reduced by 60% preoperatively in the Cushing's disease subjects compared to the post-operative Cushing's disease and control subjects (pre: 2.1 (1.3-4.2) vs post: 5.0 (3.2-7.3) vs control 5.1 (2.2-7.2) per min/mU/l x 10(4)). Median glucose-mediated glucose disposal was reduced by 40% in the pre and post-operative Cushing's disease subjects compared to the control group (pre: 1.1 (0.6-2.1) vs post: 1.1 (0.6-2.1) vs control 1.9 (1.4-2.6) per min x 10(2)), but this was not statistically significant. However, non-insulin-mediated glucose disposal was significantly reduced in the preoperative Cushing's disease subjects (pre: 0.55 (0.08-1.59) vs control 1.43 (0.94-2.27) per min x 10(2), P less than 0.05). In the Cushing's disease subjects, glucose tolerance correlated with both insulin sensitivity (rs = 0.84, P less than 0.01) and non-insulin-mediated glucose disposal (rs = 0.56, P less than 0.05). The fractional clearance rate of insulin was unaltered by Cushing's disease. CONCLUSIONS: Cushing's disease subjects are characterized by impaired glucose tolerance due to both reduced insulin sensitivity and non-insulin-mediated glucose disposal, in the presence of enhanced insulin secretion.
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This study examines the role of bilateral synchronous inferior petrosal sinus sampling (BSIPSS) in resolving two major issues in the pre-operative assessment of Cushing's disease, namely proof of pituitary dependent disease and accurate lateralisation of tumour within the pituitary. BSIPSS was technically successful in 16 of 20 patients. The central to peripheral ACTH gradients, supporting the diagnosis of pituitary dependent disease, was greater than 2.0 (2.0-27.2) in all patients with histologically proven ACTH-secreting pituitary tumours and in those who remained in remission following pituitary surgery. In addition, BSIPSS accurately localised the site of the tumour within the pituitary in 13 of the 16 technically satisfactory studies and thus contributed to the outcome of surgical treatment. In contrast CT scan demonstrated a definite tumour in only two patients.
In order to evaluate simultaneously in thyrotoxic subjects the relative contributions of insulin secretion, insulin-sensitivity (SI) and glucose-mediated (SG) glucose disposal to overall glucose tolerance, seven non-obese patients with thyrotoxicosis were studied by the minimal model analysis of the frequently sampled intravenous glucose tolerance test, before and greater than 1 month after being rendered euthyroid, and compared with eight healthy control subjects. Basal glucose, C-peptide and glucagon levels were similar in all groups but, in the toxic and euthyroid states, basal insulin levels were significantly elevated compared to the control group (11.2 +/- 2.0 and 7.9 +/- 1.1 vs 5.1 +/- 0.6 microU/ml, mean +/- SE, P less than 0.02). FFA levels were raised in the thyrotoxic subjects prior to treatment (0.95 +/- 0.11 vs 0.68 +/- 0.08 and 0.54 +/- 0.08 mmol/l, P less than 0.02). Glucose tolerance (Kg) was reduced in the thyrotoxic subjects compared to the euthyroid state (1.16 +/- 0.12 vs 1.44 +/- 0.13 per min, P less than 0.025) and control group (1.44 +/- 1.0 per min, 0.05 less than P less than 0.1). First phase (phi 1) and second phase (phi 2) insulin release were both significantly elevated in the thyrotoxic and euthyroid states compared to the control group (phi 1 7.10 +/- 1.88 and 5.29 +/- 1.03 vs 1.72 +/- 0.17 microU/mg/min X 10(-2), P less than 0.01; phi 2 18.64 +/- 3.14 and 16.74 +/- 4.48 vs 9.23 +/- 0.74 microU/mg/min X 10(-2) respectively, P less than 0.02). SG was similar in all groups but SI was significantly reduced in the thyrotoxic subjects compared to the control group (2.24 +/- 0.62 vs 5.92 +/- 1.50/min/microU/ml X 10(4), P less than 0.02) and rose post-treatment in the euthyroid subjects (4.23 +/- 1.75/min/microU/ml X 10(4)). In the thyrotoxic subjects before and after treatment, log SI correlated negatively with basal FFA levels (r = -0.57, P less than 0.05) and with phi 2 (r = -0.58, P less than 0.05). The fractional clearance rate of insulin was unaltered by the thyrotoxic state. It is concluded that in thyrotoxicosis the impairment of Kg is due to reduced insulin sensitivity in the presence of enhanced insulin secretion, but glucose-mediated glucose disposal is unaltered by the toxic state.
Hepatic glucose turnover, peripheral insulin sensitivity and insulin receptor binding were measured in four subjects with insulinoma before and 3 months after surgical resection of the insulinoma. Basal hepatic glucose production, quantitated employing a primed constant infusion of tritiated glucose, was low pre-operatively (5.2 +/- 1.7 mumol X kg-1 X min-1) but returned to normal post-operatively (14.9 +/- 2.8; normal subjects 13.9 +/- 0.8 mumol X kg-1 X min-1). Paired euglycaemic dose-response curves were developed for each subject. Insulin sensitivity, expressed as a right shift of the dose-response curve (ED50), was low pre- and post-operatively. However, insulin responsiveness (Vmax) remained normal (pre-operatively 13.9 +/- 2.2, post-operatively 13.8 +/- 0.8, normal subjects 16.7 +/- 0.8 ml X kg-1 X min-1). There was no consistent pattern in monocyte or erythrocyte receptor binding before or after surgery. These data suggest that the chronic hyperinsulinaemia causes suppression of hepatic glucose production, and a state of insulin insensitivity which appears to be due to a post-receptor defect.
Hepatic and peripheral insulin sensitivity were investigated in five newly diagnosed Type 1 (insulin-dependent) diabetic subjects before and after 1 week of twice daily insulin therapy. Eight weight-matched control subjects were also studied. Hepatic glucose production and glucose utilization were measured basally and during two sequential 2-h insulin (25 and 40 mU X kg-1 X h-1)/ glucose infusion periods. In the untreated hyperglycaemic diabetic patients hepatic glucose production was 16.3 +/- 2.6, 8.1 +/- 1.1 and 3.6 +/- 2.8 mumol X kg-1 X min-1 respectively for each of the three periods (mean +/- SEM), and fell with treatment to 12.5 +/- 1.4, 0.5 +/- 0.5 and 0.5 +/- 0.5 mumol X kg-1 X min-1. Hepatic glucose production for normal subjects was 13.4 +/- 0.7, 2.3 +/- 0.8 and less than 0.1 mumol X kg-1 X min-1. Glucose utilization was 12.7 +/- 1.4, 18.2 +/- 0.7 and 22.1 +/- 3.4 mumol X kg-1 X min-1 before treatment in the diabetic subjects, and 11.8 +/- 1.7, 20.9 +/- 3.3 and 30.1 +/- 3.6 after treatment. These values compare with those in the euglycaemic control subjects (13.4 +/- 0.7, 18.7 +/- 1.6 and 36.3 +/- 2.7 mumol X kg-1 X min-1). The pre-treatment metabolic clearance rate of glucose in all diabetic studies with insulin levels greater than 30 mU/l was 2.6 +/- 0.4 and rose to 3.9 +/- 0.5 ml X kg-1 X min-1 following insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
It has long been assumed that replacement of insulin in insulin-deficient diabetic patients will normalise glucose utilization. In this study, glucose utilization was measured in nine long-standing, poorly controlled diabetic patients and five control subjects, matched for age (33 +/- 3 versus 33 +/- 2 years) and ponderal index (22.9 +/- 1.3 versus 21.7 +/- 1.0). Glucose uptake was measured during steady state insulinaemia in the diabetic patients and control subjects, at euglycaemia (5.5 +/- 0.5 versus 5.4 +/- 0.3 mmol/l, respectively) and moderate hyperglycaemia (11.8 +/- 0.9 versus 10.2 +/- 0.7 mmol/l, respectively). At euglycaemia with similar free insulin levels (50 +/- 19 versus 43 +/- 9 mU/l; p greater than 0.6), the diabetic patients utilized less glucose than the control subjects (27.8 +/- 4.2 versus 56.4 +/- 5.7 mumol.kg-1.min-1;.p less than 0.005). During hyperglycaemia, the diabetic patients utilized almost as much glucose as the control subjects did at euglycaemia (49.9 +/- 6.4 versus 56.4 +/- 5.7 mumol.kg-1.min-1, respectively). In the control subjects, a 1-mmol/l rise in glucose concentration (with insulin remaining constant) resulted in a 12.3 +/- 1.3 mumol.kg-1.min-1 rise in glucose utilization. In contrast, in the diabetic patients, a 1-mmol/l rise in blood glucose resulted in a rise in glucose utilization of only 3.8 +/- 0.8 mumol.kg-1.min-1 (p less than 0.001), in the presence of similar concentrations of plasma insulin. This defect of glucose utilization in Type1 diabetic patients could not be reversed by acutely raising insulin to 247 +/- 23 mU/l.(ABSTRACT TRUNCATED AT 250 WORDS)
Hepatic glucose production and peripheral glucose utilization were measured basally and during infusion of insulin (25 and 40 m U X kg-1 X h-1) in normal dogs and in insulin-deficient diabetic dogs, before and after a 10-14 day period of insulin treatment. Basal hepatic glucose production was significantly raised in the diabetic dogs (21.4 +/- 2.5 mumol X kg-1. min-1; p less than 0.005) compared with normal dogs (11.9 +/- 2.5 mumol X kg-1 X min-1) and fell by 20% in diabetic dogs following insulin treatment (17.4 +/- 3.0 mumol X kg-1 X min-1). However, in all groups, hepatic glucose production suppressed equally well during the low dose insulin infusions, suggesting that the raised hepatic glucose production of diabetes is due to insulin deficiency and not hepatic insulin resistance. In addition, a marked defect of glucose utilization was found in the diabetic dogs (25 +/- 5 mumol X kg-1 X min-1; p less than 0.001) compared with normal dogs (99 +/- 15 mumol X kg-1 X min-1) during matched hyperinsulinaemia and hyperglycaemia. This defect of glucose utilization, as defined by euglycaemic insulin dose-response curves employing insulin infusion rates between 40-600 mU X kg-1 X h-1, demonstrated a marked reduction of glucose disposal in diabetic dogs. The severity of the insulin resistance closely paralleled the degree of hyperglycaemia. In contrast, following 10-14 days of insulin treatment, an improvement of glucose disposal was seen in all diabetic dogs. It is concluded that insulin deficiency leads to (a) increased hepatic glucose production, and (b) the development of marked peripheral insulin resistance, which is reversed by insulin treatment.
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Hepatic glucose production and metabolic clearance rate of glucose were measured using (3-3H) glucose at steady state, basally and during two sequential 2 h insulin (25 and 40 mU . kg -1 . h -1)/glucose (2 and 3 mg. kg -1 . min -1) infusion periods. Eight diabetic subjects were studied before and after 1 week of twice daily insulin therapy; six control subjects matched for age, weight and degree of obesity were also studied. In the diabetic patients, pre-treatment hepatic glucose production was 20.0 +/- 2.2, 9.9 +/- 2.9, and 1.4 +/- 0.8 mu mol . kg -1 . min -1 respectively (+/- SEM) for each of the three periods, and fell significantly with treatment to 12.8 +/- 1.7, 4.0 +/- 1.5 and 1.9 +/- 1.0 mu mol . kg -1 . min -1. Hepatic glucose production in normal subjects was 13.2 +/- 0.6, 2.2 +/- 0.8 and less than 1 mu mol . kg -1 . min -1. The pre-treatment metabolic clearance rate in all diabetic studies with insulin levels greater than or equal to 30 mU/l was 1.10 +/- 0.14 ml . kg -1 . min -1 and remained virtually unchanged following insulin therapy; this was significantly lower than in the control subjects (6.83 +/- 1.02, p less than 0.001). Basal non-esterified fatty acid levels were higher (p less than 0.02) in the pre-treated diabetic patients compared to post-treated diabetic patients and control subjects. Non-esterified fatty acids in each group fell to similar levels during the insulin infusions, but the rate of fall was slower in the pre-treated diabetic patients. Insulin receptor binding to erythrocytes was normal in the diabetic subjects and unchanged by treatment. Therefore, following insulin treatment of uncontrolled Type 2 (non-insulin-dependent) diabetes, the initially increased basal hepatic glucose production, and decreased hepatic sensitivity, return towards normal. However, the glucose clearance remains low, despite good diabetic control, and appears to be a major factor in the continuing glucose intolerance. As insulin receptor binding is normal, the defect of glucose clearance in Type 2 diabetes appears compatible with a post-receptor defect of glucose metabolism.
To adequately investigate the state of insulin resistance, an insulin dose-response curve should be constructed so that insulin sensitivity (right shift of dose-response curve) and insulin responsiveness (maximal response) can be determined. This paper describes and validates in man a practical in vivo insulin dose-response curve technique, using a modification of the euglycaemic clamp described by De Fronzo et al. Insulin action at steady state was expressed as metabolic clearance rate of glucose (MCRG) rather than overall rate of glucose disappearance (M or Rd). MCRG was chosen because at plasma insulin concentrations greater than 25 microunits/ml it was shown (n = 5) not to be altered by changes in blood glucose concentration (MCRG 379 +/- 23 and 408 +/- 19 ml/m2/min; at plasma glucose concentrations 5.4 +/- 0.3 and 10.2 +/- 0.7 respectively), whereas Rd was critically dependent on the prevailing blood glucose concentration (Rd 2007 +/- 128 and 4124 +/- 219 mumol m2/min respectively). MCRG was demonstrated to be stable over a 6 hr period (n = 8) and to be reproducible (n = 4). Insulin dose-response curves (MCRG Versus insulin concentration) were performed on two obese and seven normal weight individuals. The insulin dose-response curves were linearized, allowing accurate prediction of the maximal MCRG, as compared to the experimentally determined maximal response (r = 0.953 p less than 0.01). The use of this transformation obviates the need to employ very high insulin infusion rates to determine the maximal insulin response. In conclusion, the technique permits, in a single 6 hr study, a precise insulin dose-response curve to be constructed for accurately determining insulin sensitivity and responsiveness.
Two transplant procedures have been investigated in which one third of the pancreas was autotransplanted into the splenic pulp of dogs. The two procedures consist of simple mechanical dissociation of the pancreas or mechanical dissociation followed by collagenase digestion. The ability of the endocrine segment of the transplant to survive and function was assessed by stimulation with arginine and measurement of insulin and glucagon response. The results demonstrate that both transplant procedures result in functioning beta and alpha cells that rapidly secrete both insulin and glucagon in response to arginine stimulation. However, greater insulin responses were obtained when mechanically dissociated but nonenzyme digested pancreatic tissue was used for transplantation. The spleen appears to be an excellent transplant site for the reception of endocrine pancreatic tissue and allowed both beta and alpha cells to survive following transplantation.
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