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Biomedical subjects

J Proietto

Publications and source records attributed to J Proietto.

88 records · Page 5Linked to original sources
PubMed1985

Gliclazide therapy is associated with potentiation of postbinding insulin action in obese, non-insulin-dependent diabetic subjects.

Six obese, non-insulin-dependent diabetic subjects were studied before and 3 mo after treatment with the sulfonylurea gliclazide, 40-80 mg b.i.d. Fasting plasma glucose fell significantly from 13.4 +/- 1.6 (SEM) to 8.6 +/- 1.2 mmol/L, accompanied by a significant reduction from 40.6 +/- 3.7 to 29.8 +/- 2.8 mM X h of the plasma glucose response to 75 g oral glucose. Fasting plasma insulin showed a nonsignificant increase from 24.8 +/- 2.0 to 31.3 +/- 2.3 mU/L. The percent specific binding of tracer 125I-insulin to erythrocytes and monocytes did not change significantly (from 9.8 +/- 1.7 to 8.5 +/- 0.7 for erythrocytes and 1.7 +/- 0.3 to 1.6 +/- 0.4 for monocytes). Glucose utilization was measured at three levels of insulin infusion (40, 100, and 300 mU/kg/h) by the euglycemic clamp technique. Overall there was a significant (P less than 0.05) increase in the disappearance rate (Rd) and metabolic clearance rate (MCRg) for glucose at the two higher insulin infusion rates (MCRg: 3.3 +/- 0.7 to 5.1 +/- 0.7 and 5.9 +/- 0.9 to 7.9 +/- 0.9 ml/kg/min), but not at the lowest infusion rate (MCRg: 3.6 +/- 0.8 to 3.3 +/- 0.6). Thus, the chronic hypoglycemic effect of gliclazide in obese diabetic subjects was associated with an improvement in insulin-mediated glucose utilization at high plasma insulin concentrations. This enhanced effect of insulin after gliclazide treatment was not accompanied by increased monocyte or erythrocyte insulin binding, which suggests that it was due to potentiation of postbinding insulin-sensitive pathways.

Aged↗
PubMed1984

Impaired insulin action in newly diagnosed type 1 (insulin-dependent) diabetes mellitus.

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)

3-Hydroxybutyric Acid↗
PubMed1984

Hyperinsulinaemia and insulin resistance of cirrhosis: the importance of insulin hypersecretion.

The mechanism for the hyperinsulinaemia in cirrhosis was investigated using two different approaches. In the first study, the metabolic clearance rate of insulin was measured at steady state in 13 cirrhotic and 13 weight-matched control subjects. With comparable insulin infusion rates (1.00 +/- 0.19 versus 1.07 +/- 0.15 mU/kg/min), steady-state plasma insulin concentrations (104 +/- 25 versus 87 +/- 12 microU/ml; P greater than 0.5) and MCRIRI (13.6 +/- 1.6 versus 15.4 +/- 2.0 ml/kg/min; P greater than 0.5) were similar. In the second study, fasting and oral glucose stimulated C-peptide/insulin ratios were compared in 16 cirrhotic and 18 weight matched control subjects. Although fasting glucose levels were significantly higher in the cirrhotic groups, all values were in the normal range (5.5 +/- 0.3 versus 4.8 +/- 0.1 mmol/l, P less than 0.02). However, fasting insulin (0.171 +/- 0.02 versus 0.068 +/- 0.004 nmol/l) and C-peptide (1.02 +/- 0.13 versus 0.42 +/- 0.02 nmol/l) were strikingly higher (P less than 0.001) in cirrhotic subjects. On the other hand, fasting C-peptide/insulin ratios were not statistically different in the two groups (6.18 +/- 0.52 versus 6.77 +/- 0.46; P greater than 0.3). This suggests that beta cell hypersecretion was the principal cause of the fasting hyperinsulinaemia, rather than decreased insulin hepatic extraction. Following the glucose load in 13 of the control and seven of the cirrhotic group, the C-peptide/insulin ratio fell in both groups but was significantly lower in the cirrhotic compared to control subjects at 30, 60 and 120 min, consistent with possible impairment of hepatic insulin extraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Insulin resistance in cirrhosis: evidence for a post-receptor defect.

Receptor and post-receptor abnormalities of insulin action and their possible role in the insulin resistance of cirrhosis were examined in eight biopsy-proven cirrhotic subjects and eight age-weight matched healthy volunteers. To this end, oral glucose tolerance tests (OGTT), insulin dose response curves and insulin binding to circulating monocytes were determined for each subject. The dose-response curves for the cirrhotic subjects were significantly shifted to the right compared to the control subjects, indicating the presence of insulin insensitivity (ED50 223 +/- 30 versus 64 +/- 8 mU/l respectively; P less than 0.001). The magnitude of the right shift of the insulin-dose response curves correlated significantly (P less than 0.001) with the OGTT 2 h insulin levels (r = 0.74) and the insulin areas under the OGTT curves (r = 0.86). In contrast, insulin responsiveness was marginally elevated in the cirrhotic group (maximal glucose disposal 680 +/- 47 versus 574 +/- 21 ml/m2/min; P less than 0.05). Insulin binding to circulating monocytes was normal in the cirrhotic subjects. It is concluded that the insulin resistance of cirrhosis is due to a post-receptor defect in insulin action which reduces insulin sensitivity but not insulin responsiveness.

Blood Glucose↗
PubMed1983

Glucose utilization in Type 1 (insulin-dependent) diabetes: Evidence for a defect not reversible by acute elevations of insulin.

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)

Adult↗
PubMed1983

Insulin resistance in alloxan-diabetic dogs: evidence for reversal following insulin therapy.

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.

Animals↗
PubMed1983

The physiologic action of insulin on glucose uptake and its relevance to the interpretation of the metabolic clearance rate of glucose.

Glucose uptake (Ru) is dependent upon the concentrations of both glucose and insulin. The metabolic clearance rate of glucose (MCRG), has been used as an in vivo measure of insulin action, because it was said to be independent of the prevailing glucose concentration. The validity of this assumption has recently been challenged. In this study, the effect of insulin concentration on the rate of glucose uptake (Ru) and on the MCRG was studied during euglycemia (5.1 +/- 0.3 mmol/L) and moderate hyperglycemia (10.4 +/- 0.5 mmol/L) in 17 experiments on nine normal ambulant volunteers. Stable plasma insulin levels were maintained with fixed infusion rates of insulin (0-300 mU/kg/h) and somatostatin (7.5 micrograms/min). At low insulin concentrations (less than 5 microU/mL) the increase in glucose uptake in response to hyperglycemia was small (5.3 +/- 2.3 mumol/kg/min). In contrast, with insulin levels more than 25 microU/mL, there was a steep rise in glucose uptake with hyperglycemia (55 +/- 3 mumol/kg/min; range: 44-74 mumol/kg/min). The metabolic clearance rate of glucose fell by an average of 32% with hyperglycemia in the studies at the lowest insulin levels (2.2 +/- 0.6 v 1.5 +/- 0.1 mL/kg/min; 0.15 greater than P greater than 0.1). There was no change in the MCRG in the subjects studied at higher insulin levels. It is concluded that (1) low concentrations of insulin are essential for the increase in glucose disposal during hyperglycemia; and (2) provided insulin levels are more than 25 microU/mL and plasma glucose less than 11 mmol/L, MCRG is independent of the plasma glucose concentration and is therefore a valid measure of insulin-mediated glucose uptake.

Adult↗
PubMed1982

Differential effects of insulin therapy on hepatic and peripheral insulin sensitivity in Type 2 (non-insulin-dependent) diabetes.

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.

3-Hydroxybutyric Acid↗
PubMed1982

Insulin action and cirrhosis: insulin binding and lipogenesis in isolated adipocytes.

Insulin receptors and insulin stimulation of lipogenesis were studied in adipocytes from normal and cirrhotic subjects undergoing abdominal surgery. Despite the presence of hyperinsulinemia in the cirrhotic subjects, binding to receptors was not diminished compared to controls, whether expressed per cell number or cell size. Lipogenesis per cell surface area was higher basally (17.4 +/- 5.1 versus 3.8 +/- 1.6, p less than 0.05) and during maximal insulin stimulation (31.8 +/- 6.5 versus 10.4 +/0 3.9, p less than 0.01) in the cirrhotic subjects. However, cirrhotic and control adipocytes showed a similar increase above basal rates of lipogenesis with maximal insulin stimulation. The rate of lipogenesis was not correlated with fasting insulin level but was negatively correlated, basally (r = -0.61, p less than 0.05) and during maximal insulin stimulation (r = -0.52, p less than 0.05) with cell surface area. In contrast, insulin insensitivity, as quantified by ED50 for stimulation of lipogenesis, was positively correlated with fasting insulin level (r = 0.77, p less than 0.05) but was not related to cell size. It is concluded that the in vivo insulin resistance seen in cirrhosis is not due to any diminution in insulin binding or lipogenesis in adipocytes.

Adipose Tissue↗
PubMed1982

Validation of a practical in vivo insulin dose-response curve in man.

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.

Adult↗
PubMed1981

The metabolic effects of chronic hyperglucagonaemia.

A subject with a benign glucagonoma was studied before and after complete resection of his pancreatic tumour. Studies were undertaken pre- and post-operatively to determine the effects of chronic hyperglucagonaemia on glucose tolerance and glucose kinetics both in the fasting state and during physiological insulin infusions, employing the [3H]-3-glucose technique. In addition the plasma cyclic AMP response to an acute infusion of glucagon was studied pre- and post-operatively. The basal immunoreactive glucagon levels pre- and post-operatively were 10492 +/- 1296 and 149 +/- 15 pg/ml respectively. Pre- and post-operative oral glucose tolerance tests did not differ but were abnormal. Pre-operatively basal hepatic glucose production was normal and it was suppressed rapidly by the low dose insulin infusion, despite continuing hyperglucagonaemia. The metabolic clearance rate of glucose was slightly reduced. There was no plasma cyclic AMP response to a glucagon infusion, suggesting down-regulation of the glucagon receptor by the chronic hyperglucagonaemia. Post-operatively the hepatic glucose production and clearance rate of glucose fell, whereas the plasma cyclic AMP responses to the glucagon infusion reverted to a normal pattern. It is concluded that chronic hyperglucagonaemia is not a major factor in the development of the glucose intolerance, but it may lead to down-regulation of the biological action of glucagon.

Adenoma, Islet Cell↗
PubMed1980

The mechanism of the carbohydrate intolerance of cirrhosis.

Cirrhosis of the liver is frequently associated with carbohydrate intolerance but it is unknown whether this intolerance is due to increased hepatic glucose production (HGP), decreased glucose utilization, or both. HGP and the MCR of glucose [(MCR)G] were measured at steady state, basally and during an infusion of insulin (25 mU/kg x h) and glucose (11 mumol/kg x min), in 11 cirrhotics and 8 controls using the technique of a primed constant infusion of [3H]3-glucose. HGP was also estimated at nonsteady state during an infusion of glucagon (8 ng/kg x min). Basal HGP was significantly lower in cirrhotics compared to controls (10.2 +/- 0.6 vs. 13.2 +/- 0.6 mumol/kg x min; P < 0.0025). During the insulin/glucose infusion, HGP was suppressed to the same degree in both groups [in controls by 83% (13.2 +/- 0.6 to 2.2 +/- 0.8 mumol/kg x min) and in cirrhotics by 87% (10.2 +/- 0.6 to 1.3 +/- 0.4 mumol/kg x min)]. After the glucagon infusion, HGP rose by a similar degree in cirrhotics and controls. In contrast, basal (MCR)G was significantly lower in the nondiabetic cirrhotics (2.1 +/- .02 ml/kg x min; P < 0.005) and diabetic cirrhotics (1.2 +/- 0.2 ml/kg x min; P < 0.0005) compared to that in the control subjects (2.8 +/- 0.2 ml/kg x min). Moreover, there was a highly significant (P < 0.001) negative correlation between basal (MCR)G and the fasting glucose level (r = 0.82), and the degree of glucose intolerance as expressed by the 2-h glucose level determined by the oral glucose tolerance test (r = 0.87). It is concluded that the glucose intolerance of cirrhosis is due to a defect in peripheral glucose utilization.

Adult↗
PubMedDate not supplied

Influenza immunization in adults with diabetes mellitus.

The antibody responses to influenza vaccination of a group of adult diabetic patients were compared with responses in a healthy group of regular volunteer vaccinees. The initial and final geometric mean hemagglutination-inhibiting antibody titers were lower in the patient group, but the relative increase in titers was greater for each of the vaccine components. The percentage of fourfold rises in individual titers was greater in the diabetic group than in the control group. It was concluded that patients with diabetes mellitus responded normally to influenza vaccination. This was confirmed in an additional study. There was no significant difference in the antibody responses of patients treated with insulin or oral antidiabetic agents. There was no impairment of diabetic control as a result of influenza vaccination when this was evaluated by measuring the concentration of glycosylated hemoglobin, or by random blood glucose estimations. There was no significant change in the serum insulin level after immunization in patients on oral diabetic agents. It was concluded that influenza vaccination was safe and effective in adult diabetic patients.

Adult↗
PubMedDate not supplied

The role of low birthweight in the aetiology of type 2 diabetes.

The aetiology of type 2 diabetes is still poorly understood. Although it is clear that obesity is a risk factor for the disease, obesity leads to diabetes only in susceptible individuals. Both genetic and environmental factors determine this susceptibility. This review describes the emerging evidence that low birthweight caused by malnutrition or a genetic predisposition increases the risk of type 2 diabetes.

Birth Weight↗