Increased insulin sensitivity and cellular insulin binding in obese diabetics following treatment with glibenclamide.

The aim of the present study was to examine the effect of glibenclamide on the insulin receptors, the insulin sensitivity and the insulin secretion in obese non-ketotic diabetics. Two groups of 9 obese diabetics were studied before and after 10 days' treatment with a 1200 kcal's diet and a 1200 kcal's diet + 10 mg/day of glibenclamide, respectively. In the group treated with diet alone we found no significant alteration of the insulin secretion pattern (P greater than 0.1). However, the insulin sensitivity increased 37% (P less than 0.01). Furthermore, the insulin binding to monocytes increased (P less than 0.01) due to a 36% rise of the binding affinity. In the group treated with glibenclamide and diet the insulin secretory pattern was unchanged, too (p greater than 0.1). The insulin sensitivity, however, increased 83% (P less than 0.01). Moreover, the insulin binding was raised (P less than 0.01) as a result of a 80% rise of the number of insulin receptors. In 4 patients who were treated with diet (1200 kcal/day) plus glibenclamide and in 5 patients who were treated with diet alone (1200 kcal/day) the insulin binding to monocytes was studied during treatment for 1 year. After 1 year we found a significantly (P less than 0.005) higher cellular insulin binding in the glibenclamide treated patients compared to the patients who got diet alone. We conclude that 1) the augmentation of the insulin sensitivity is of great importance for the normalization of the diabetic state in obese, 2) the increase in insulin binding may be of importance for the increase in insulin sensitivity, 3) glibenclamide appears to enhance the insulin sensitivity through an increase in the number of insulin receptors.     

The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency

OBJECTIVE: Optimization of physiological replacement of glucocorticoid in patients with adrenal insufficiency is controversial. The present study was undertaken to compare the relative impact of three different regimes of glucocorticoid replacement in patients with adrenal insufficiency on parameters of bone turnover and insulin sensitivity. PATIENTS: Six female and three male patients with adrenal insufficiency and 17 female and 14 male control subjects participated. DESIGN: This was an open study conducted in a university teaching hospital. Schedule 1 (S1) consisted of hydrocortisone 10 mg with breakfast and 5 mg with lunch. S2 was similar to S1 with the addition of 5 mg hydrocortisone with the evening meal. S3 utilized dexamethasone 0.1 mg/15 kg body weight given per day with breakfast only. Each schedule was given for at least 4 weeks in random sequence to nine patients with adrenal insufficiency. METHODS: Blood was obtained at 0900 h (fasting) and at 1300 h for measurement of the ionized calcium (Cai), PTH, 25-hydroxyvitamin D and the bone formation markers intact osteocalcin and amino-terminal propeptide of type 1 procollagen (PINP). Timed urine collections were made under standardized conditions, that is while fasting between 0700 and 0900 h (basal) and between 0900 and 1300 h for measurement of the bone resorption markers, free deoxypyridinoline (FDPD) and cross-linked N-telopeptide of type 1 collagen (NTX). Blood was drawn for measurement of fasting plasma glucose and serum insulin levels. Insulin (0.075 IU/kg) was administered i.v. while the patient was fasting prior to the first glucocorticoid replacement dose on each study day. Plasma glucose was measured before and 3, 6, 9, 12 and 15 min after insulin administration to calculate the glucose disappearance rate (Kitt). Insulin resistance (IR) and beta-cell function were estimated using the homeostasis model assessment (HOMA). Glucocorticoid dosage was given according to the various schedules at approximately 0930 h. RESULTS: During all three treatment schedules the serum Cai level was significantly lower than that seen in control subjects. PTH levels in patients taking the three replacement schedules and in normal subjects were similar. Serum 25-hydroxyvitamin D levels were not suppressed in the patients during any of the three treatment schedules. The bone resorption marker urinary FDPD under basal conditions was significantly lower during S3 (dexamethasone) than during either hydrocortisone schedules, S1 or S2. Urinary NTX values were not significantly different in the three study groups. The bone formation markers intact osteocalcin and PINP were similar in the three replacement schedules. The indices of IR and beta-cell function tended to be higher during treatment with dexamethasone than with S1 or S2 but did not achieve statistical significance. CONCLUSIONS: These data indicate that all three replacement schedules were associated with low serum ionized calcium levels without evidence of a compensatory increase in PTH levels. These findings are consistent with direct or indirect suppression of the bone remodelling cycle and suppression of PTH levels. Bone turnover in patients with adrenal insufficiency treated with schedule 3, dexamethasone, was associated with lower bone turnover than patients treated with hydrocortisone schedules 1 or 2. While indices of insulin sensitivity measured during schedules 1, 2 and 3 did not achieve statistical significance, there was an obvious trend for greater insulin resistance to occur with schedules 3 using dexamethasone.     

Increased insulin sensitivity and basal insulin effectiveness in postprandial reactive hypoglycaemia

Glucose clamp experiments have shown that patients with reactive postprandial hypoglycaemia (PRH) frequently have an increased glucose disposal, but the relative involvement of insulin sensitivity (SI) and glucose effectiveness (Sg) in this process remains unknown. The minimal model approach was used to compare 13 patients in whom moderate reactive hypoglycaemia (<3.3 mmol) had been previously diagnosed and 13 matched controls. The intravenous glucose tolerance test (IVGTT, 0.5 g/kg glucose IV) with 0.02 U/kg insulin given at the 19th min and frequent sampling over 180 min shows that PRH patients exhibit a higher glucose tolerance coefficient Kg (2.99±0.26 vs 2.19±0.12;P<0.02), higher SI [22.9±6.4 vs 7.18±0.14 min^–1/(U/ml) · 10^–4;P<0.01] and higher Sg (3.84±0.35 vs 2.92±0.79 min^–1 · 10^–2;P<0.05). The increase in Sg is explained by an increase in its component basal insulin effectiveness (BIE: 1.2±0.27 min^–1 · 10^–2 in PRH subjects vs 0.58±0.07;P<0.05) rather than an increase in Sg at zero insulin. The increase in BIE results from the high values of SI. In 4 PRH subjects SI and Sg were within the normal range, and the increase in Kg evidenced in the 9 others was explained by an increase in SI alone in 3 cases, in Sg alone in 1 case, and both SI and Sg in 5 cases. Thus, in sedentary subjects, the previously reported rise in tissue glucose assimilation is mainly explained by an increased insulin-mediated glucose disposal rather than non-insulin-mediated glucose disposal.     

Insulin secretion, adipocyte insulin binding and insulin sensitivity in thyrotoxicosis

The pattern of insulin secretion following an oral glucose load and the insulin receptor status and insulin sensitivity of adipocytes have been studied in patients with thyrotoxicosis and in matched controls. Thyrotoxic subjects showed normal basal and peak levels of serum immunoreactive insulin (peak, 69.0 +/- 6.8 vs 54.3 +/- 8.8 mU/l) and serum C-peptide (peak, 1.95 +/- 0.13 vs 1.71 +/- 0.12 nmol/l for thyrotoxic and control subjects, respectively). Peak serum proinsulin was higher in the thyrotoxic group (64.8 +/- 7.3 vs 39.0 +/- 3.7 pmol/l; P less than 0.01). Maximum specific insulin binding to adipocytes was decreased in the thyrotoxic group (1.80 +/- 0.18 vs 2.62 +/- 0.27%; P less than 0.025) and half-maximum displacement of tracer insulin was similar in the two groups, suggesting that reduced receptor number rather than reduced affinity accounted for the difference. However, adipocyte insulin sensitivity was normal as judged by half-maximal stimulation values of 13.9 +/- 3.6 vs 11.4 +/- 2.1 pmol/l, respectively for lipogenesis and 24.3 +/- 2.2 vs 24.6 +/- 3.6 pmol/l, respectively for glucose transport. Hence, thyroid hormone excess appears to affect adipocyte insulin receptor number directly, but change in receptor number is not associated with change in adipocyte insulin sensitivity in hyperthyroidism. The normal insulin secretion together with the failure to demonstrate abnormal insulin sensitivity of one of the major peripheral tissues suggests that disturbed hepatic rather than peripheral insulin responsiveness may be responsible for the glucose intolerance of hyperthyroidism.     

Decreased insulin binding to adipocytes precedes both hyperinsulinemia and decreased insulin binding to erythrocytes in cafeteria-fed rats

The relationship between food intake, obesity, insulin binding to adipocytes and erythrocytes, plasma insulin and plasma glucose was studied in an animal model of nutritional obesity--'the cafeteria-fed rats'--after 3 days, 10 days, and 3 weeks of cafeteria feeding. The antilipolytic effect of insulin was also studied. The cafeteria-fed rats ate more carbohydrates after 3 days of diet, while from the 10th day, as previously found, they ate about the same amount of carbohydrates but more lipids and increased in weight. Insulin binding to adipocytes started to decrease (P less than 0.05) 10 days after beginning the cafeteria diet despite the absence of hyperinsulinemia. This decrease in insulin binding to adipocytes was accompanied by a decrease in the responsiveness of adipocytes to the antilipolytic effect of insulin. Hyperinsulinemia (P less than 0.01) appeared only after 3 weeks. At the same time, insulin binding to erythrocytes started also to decrease (P less than 0.05). Plasma glucose levels in the cafeteria-fed rats were unchanged when compared to their controls at any time of the study. There was no correlation between body weight, plasma insulin and insulin binding, to adipocytes and to erythrocytes, at any time of the study. Thus it is possible that factors other than hyperinsulinemia could be involved in the decrease in insulin binding to both adipocytes and erythrocytes.     

Increased adrenal sensitivity to angiotensin II in idiopathic hyperaldosteronism.

Plasma aldosterone increases briskly during upright posture in patients with idiopathic hyperaldosteronism, despite only small increases in PRA and presumably small increases in angiotensin II. To examine the postulate that small increments in angiotensin II mediate these brisk increases in aldosterone, we infused graded doses of angiotensin II into normal subjects and patients with idiopathic hyperaldosteronism and compared the changes in levels of plasma aldosterone in the two groups. Supplemental sodium and dexamethasone were given before the infusion to minimize the influence of endogenous angiotensin II and ACTH. In response to the infusion of angiotensin II, increases in the levels of plasma aldosterone of patients with idiopathic hyperaldosteronism were significantly greater than those of normal subjects. In addition, levels of plasma aldosterone increased at a lower rate of infusion of angiotensin II in patients than in normal subjects. It is concluded that patients with idiopathic hyperaldosteronism have increased adrenal sensitivity to angiotensin II. This increased sensitivity may explain the brisk increases in aldosterone that occur during upright posture in these patients.     

Increased insulin sensitivity in patients with aldosterone producing adenoma

OBJECTIVE Primary aldosteronism is a recognized endocrine cause of glucose intolerance. A blunted insulin response to glucose in patients with primary aldosteronism is well known, but insulin sensitivity has not been thoroughly determined. We investigated insulin sensitivity and insulin secretion in patients with aldosterone producing adenoma. DESIGN Glucose tolerance and insulin responses to glucose were evaluated using a standard 75 g oral glucose tolerance test in patients with aldosterone producing adenoma before and after surgery, and in control subjects. Parameters for insulin resistance (HOMA-R) and pancreatic β-cell function (HOMA-βF) were derived from a homeostasis model assessment. PATIENTS Fifteen patients with aldosterone producing adenoma and 41 control subjects with normal glucose tolerance matched for age and body mass index, were studied. Eight patients were re-evaluated after surgical removal of the adenoma. In 5 patients ¹²⁵I-insulin binding to erythrocytes was also measured. MEASUREMENTS Plasma glucose was measured by a glucose oxidase method. Plasma insulin, aldosterone and renin activity were measured by radioimmunoassay. RESULTS Both fasting plasma glucose and insulin were lower in the patients than in the controls. Although the areas under the curve for plasma glucose during the oral glucose tolerance test did not differ, that for plasma insulin was less in the patients with hyperaldosteronism. Insulin sensitivity was increased in the patients, as evidenced by decreased HOMA-R compared with controls, while HOMA-βF was comparable between the groups. ¹²⁵I-insulin binding to erythrocytes was higher in 5 patients than in 19 normal controls. After surgical removal of adenoma, neither fasting plasma glucose nor the glucose area under the curve during the oral glucose tolerance test changed. However, fasting plasma insulin and the insulin area under the curve increased significantly. HOMA-R increased and HOMA-βF remained unaltered. CONCLUSION Insulin sensitivity was increased in untreated patients with aldosterone producing adenoma. Enhanced insulin receptor binding may contribute to this increased insulin sensitivity.     

Increased insulin sensitivity in patients with idiopathic reactive hypoglycemia

We performed a euglycemic hyperinsulinemic glucose clamp in 20 patients selected from a large number of subjects referred to our clinic with symptoms suggesting reactive hypoglycemia. Diagnosis was made on the basis of blood glucose measurements during symptoms in their daily life and confirmed by a 5-h oral glucose tolerance test. The patients were divided into the following groups: 8 patients with idiopathic reactive hypoglycemia (IRH), i.e. biochemical hypoglycemia associated with symptoms and plasma insulin concentrations in the normal range; 6 patients with nonhypoglycemia (NH), i.e. patients experiencing the symptoms evoking hypoglycemia at essentially normal plasma glucose levels; and 6 patients with alimentary hypoglycemia secondary to previous gastric surgery (GS). Eight normal volunteers formed the control group (N). Hypoglycemia in this study was considered to be present when plasma glucose concentrations were below 2.5 mmol/L. The peak cortisol levels after glycemic nadir were higher (2P less than 0.05) in IRH compared to GS and N. In the same group, a partially deficient glucagon response to hypoglycemia was noted. During the euglycemic clamp, the glucose uptake appeared to be significantly greater in the IRH group than in NH, GS, and N groups (8.13 +/- 0.49 vs. 7.02 +/- 0.35, 6.48 +/- 0.22, and 6.66 +/- 0.42 mg/kg.min, respectively; 2P less than 0.05). Therefore, our data suggest that increased insulin sensitivity represents a feature of idiopathic reactive hypoglycemia.     

Effects of dietary changes on cellular insulin binding and in vivo insulin sensitivity

The effect of a low-sucrose, low-fat diet on insulin sensitivity, insulin binding to monocytes, and insulin secretion in nonketotic diabetic patients was studied. Ten obese diabetics were studied for 1 yr before and during treatment with a 1200–1500-kcal diet, whereas six diabetics of normal weight were studied for 3 mo before and after treatment with a 2200–2400-kcal diet. In the obese group, no change was found in the insulin response to i.v. injection of glucose during treatment (p > 0.1), but the insulin sensitivity was normalized after 1 yr (p < 0.01). The clinical normalization and the improvement of insulin sensitivity were accompanied by a parallel normalization of the binding of insulin to monocytes (p < 0.01). In the group of normal-weight diabetics, both the insulin sensitivity (p < 0.05) and the insulin binding to monocytes (p < 0.05) were normalized after a 3-mo treatment period, but the insulin secretion increased (p < 0.05) without reaching normal values. We conclude that most nonketotic diabetic patients can be controlled by diet treatment alone. The mechanism of action of the low-fat, low-sucrose diet seems for the greatest part to be a normalization of the insulin sensitivity, which is partly caused by a normalization of the cellular insulin binding.     

Effect of gliquidone on insulin binding to rabbit erythrocytes

A study was made of the effects of acute or chronic treatment of rabbits with 10 mg gliquidone (Glurenorm)/kg body weight on erythrocyte insulin receptors. The binding of 125I-labelled insulin to the population of whole red blood cells was not affected by either treatment. Because of the heterogeneity of the erythrocytes, subpopulations were selected according to their specific gravity, which is directly related to cell age. The lowest-density fraction showed a 30% greater capacity of the insulin receptors without any change in affinity after chronic therapy with gliquidone, but no effects were observable after acute treatment. The highest-density fraction was not affected by either acute or chronic administration of gliquidone. Therefore, all other things being equal (blood sugar, plasma insulin levels), young erythrocytes are sensitive to sulphonylurea, whereas old ones are not. Irrespective of the compound tested, this observation suggests that receptor sensitivity might be tissue-specific or age-specific or both, and that the stage of maturation of a cell is a determining factor.     

Decreased insulin binding to erythrocytes in subjects with Klinefelter's syndrome

Insulin binding to specific erythrocyte receptors was investigated in group of 25 subjects with Klinefelter's syndrome (47 XXY genotype) and 14 healthy male volunteers. Insulin binding was significantly decreased in Klinefelter subjects (P less than 0.01 at insulin concentrations of 0.051 and 0.136 mmol/liter); however, their fasting glucose concentration was normal (87 +/- 17), and the glucose disappearance rate was slightly increased (2.3 +/- 0.9; P less than 0.2). These data indicated a compensatory, mechanism involved in the glucose metabolism in Klinefelter's syndrome.     

Increased insulin sensitivity is associated with reduced insulin and glucagon secretion and increased insulin clearance in man

Insulin secretion is increased in insulin resistance. In this study, we examined whether high insulin sensitivity results in low insulin secretion. Twelve male master athletes [age 25.6 +/- 4.1 (mean +/- SD) yr] and seven male sedentary students (age 25.0 +/- 2.0 yr) underwent a hyperinsulinemic, euglycemic clamp and a glucose-dependent arginine stimulation test. Athletes had high insulin sensitivity [230 +/- 18 vs. 92 +/- 12 (nmol glucose/kg.min)/(pmol insulin/liter), P < 0.001] and low insulin response to arginine (at fasting glucose 135 +/- 22 vs. 394 +/- 60 pmol/liter, P < 0.001), which resulted in unaltered disposition index (32.8 +/- 3.8 vs. 33.5 +/- 3.3 micro mol glucose/kg.min, NS). Also, the C-peptide response to arginine was reduced (at fasting glucose 0.71 +/- 0.09 vs. 0.89 +/- 0.09 nmol/liter, P = 0.034). However, the C-peptide reduction was not as large as the insulin reduction yielding increased disposition index in athletes when calculated from C-peptide data (184 +/- 9 vs. 76 +/- 11 micro mol glucose/kg.min, P < 0.001). This difference is explained by increased insulin clearance among the athletes during the first 5 min after arginine (81.1% +/- 1.8% vs. 53.6% +/- 4.7%, P < 0.001). Also, the glucagon response to arginine was reduced in the athletes (58.8 +/- 6.7 vs. 90.1 +/- 9.9 ng/liter at fasting glucose, P = 0.009). We conclude that high insulin sensitivity results in low islet hormone secretion and increased insulin clearance.     

Increased insulin sensitivity and decreased insulin secretion in offspring of insulin-sensitive type 2 diabetic patients

To investigate the early defects of glucose metabolism in insulin-sensitive type 2 diabetes, we performed oral and frequently sampled intravenous glucose tolerance tests (OGTT and FSIGT) with minimal model analysis in 15 offspring of Japanese type 2 diabetics with normal insulin sensitivity (insulin resistance index of homeostasis model assessment [HOMA-R] < 2.0) and in 20 healthy control subjects without a family history of type 2 diabetes. The frequency of impaired glucose tolerance (IGT) was 40% (6 of 15) in the offspring and 0% (0 of 20) in the controls. Fasting plasma glucose (4.8 +/- 0.1 v4.6 +/- 0.1 mmol/L, P = .18) and immunoreactive insulin ([IRI] 29.9 +/- 2.5 v 28.3 +/- 2.5 pmol/L, P = .64) were comparable between the offspring and the controls. The rate of glucose disappearance (KG) was significantly lower in the offspring versus the control group (2.00 +/- 0.22 v 2.60 +/- 0.17 min(-1), P= .03). The insulin sensitivity index (Si) was significantly greater in the offspring versus the controls (2.68 +/- 0.41 v 1.71 +/- 0.17 x 10(-4) min(-1) x pmol/L , P = .02). First-phase insulin secretion (FPI) to intravenous glucose was significantly lower in the offspring versus the control group (886 +/- 110 v 2,296 +/- 267 min x pmol/L, P< .01). Glucose effectiveness (SG) was comparable between the offspring and control groups. The disposition index (Si x FPI) was significantly lower in the offspring versus the controls (2,106 +/- 256 v 3,652 +/- 490 x 10(-4), P = .02). When the offspring were subdivided into 2 groups by glucose tolerance status, both normal glucose tolerance (NGT) offspring and IGT offspring showed a significant decrease in FPI and increase in Si. Thus, although the offspring of insulin-sensitive type 2 diabetics had increased insulin sensitivity, the impairment in insulin secretion was more dominant. Our results suggest that the early metabolic abnormality in insulin-sensitive type 2 diabetes is an insulin secretory dysfunction despite increased insulin sensitivity.     

Increased 125I-labelled concanavalin A binding to erythrocytes in diabetes mellitus

Summary Percentage binding of ¹²⁵I-labelled concanavalin A to erythrocytes in diabetic patients was significantly higher than that in normal subjects (12.2 ±2.8 versus 8.1±1.8%, mean ± SD, p< 0.001). Insulin-dependent diabetic patients showed significantly higher concanavalin A binding than non-insulin-dependent diabetic subjects (15.0±1.4 versus 11.4±2.5%, p<0.01). There was a highly significant correlation between percentage binding of ¹²⁵I-labelled concanavalin A and glycosylated haemoglobin.     

Increased insulin sensitivity in young, growth hormone deficient children

OBJECTIVE: Although growth hormone (GH) has well documented insulin antagonistic effects, GH deficient adults often demonstrate insulin resistance. In young GH deficient children, increased susceptibility to hypoglycaemia might indicate increased insulin sensitivity; however, this has not been documented. We therefore determined insulin sensitivity in GH deficient and GH sufficient children. DESIGN AND PATIENTS: Prospective study of children undergoing insulin tolerance tests for clinical investigation of GH or cortisol secretion at a regional Paediatric Endocrine/Growth Clinic between October 1986 and December 1997. Ninety-one tests were performed in children with GH deficiency and 142 tests in children with normal GH response to insulin (peak GH > or = 20 IU/l). MEASUREMENTS: The standard insulin tolerance test was modified to permit frequent measurements of glucose (0, 5, 10, 15, 20, 30, 45, 60 and 90 minutes). Rate of log glucose disappearance in the first 15 minutes was calculated as a direct measure of insulin sensitivity. RESULTS: GH deficient children were more insulin sensitive than GH sufficient children (P = 0.004) and had lower glucose nadirs post-insulin (P = 0.005). Subgroup analysis revealed that these differences were greater in younger (< 12 years old) or pre/early pubertal children. In 14 prepubertal children, exogenous sex steroid priming resulted in lower insulin sensitivity (P < 0.05) compared to nonprimed tests. CONCLUSIONS: Young GH deficient children were more insulin sensitive than children with normal GH secretion. This difference attenuated with age and puberty, possibly secondary to pubertal sex steroids; however, insulin resistance as reported in GH deficient adults, was not observed in adolescents.     

Insulin binding to monocytes and insulin sensitivity in anorexia nervosa

In six female patients with anorexia nervosa, we examined specific binding of ¹²⁵I-insuIin to monocytes and in vivo sensitivity to insulin before and after treatment. Insulin sensitivity was determined by the rate of glucose disappearance during an intravenous insulin tolerance test (K_ITT).In the untreated state, the patients with anorexia nervosa were 26 to 41 per cent below ideal weight and amenorrheic. Fasting plasma glucose and insulin levels were, respectively, 20 per cent and 55 per cent below those observed in healthy controls. Insulin binding to monocytes was 70 per cent greater than that in controls. Scatchard analysis of the insulin binding data revealed an increase in binding capacity with no change in binding affinity. During the insulin tolerance test, K_ITT (9.7 ± 0.7 per cent · min^?1) was 50 per cent greater in untreated patients than in healthy controls.Following treatment with behavior modification, there was a gain in body weight to within 2 to 11 per cent of ideal body weight, and menstrual function returned. Plasma glucose and insulin levels rose to values similar to those in healthy controls. Insulin binding declined by 40 per cent to values comparable to those in the controls. The decrease in insulin binding was due to a reduction in binding capacity. The plasma glucose response to the insulin tolerance test (K_ITT) fell 50 per cent below pretreatment values to levels comparable to those in healthy controls.Both before and after treatment, an inverse correlation was observed between plasma insulin concentration and insulin binding to monocytes whereas a direct correlation was demonstrable between insulin binding to monocytes and k_ITT.The data indicate that in anorexia nervosa insulin binding to monocytes and in vivo sensitivity to insulin are increased. The increase in insulin binding may be a consequence of a decrease in plasma insulin and may, in turn, be responsible for the increase in insulin sensitivity. The increases in insulin binding and insulin sensitivity return to normal following regain of body weight.     

The effect of continuous subcutaneous insulin infusion on insulin binding to erythrocytes in diabetes mellitus

The effect of continuous subcutaneous insulin infusion (CSII) on glycaemic control and insulin binding to erythrocytes was studied in six diabetic patients. A marked improvement in blood glucose control during CSII was observed in these patients previously on conventional therapy. Specific 125I-insulin binding to erythrocytes of the diabetics before the institution of CSII was significantly lower than that of age-, weight- and sex-matched nondiabetic subjects, 6.5 +/- 0.1% vs. 9.8 +/- 0.3% (P less than 0.05). After 4-6 months of CSII, insulin binding was restored to normal levels. This normalization in insulin binding to erythrocytes of patients on CSII was due to a 35% increase in active binding sites, together with a small change in binding affinity.     

Postnatal decrease in insulin binding to erythrocytes in infants of diabetic mothers

To clarify the role of insulin receptors in the macrosomia and the tendency to hypoglycemia in infants of mothers with insulin-treated diabetes mellitus (IDM) we studied insulin binding in erythrocytes from mixed umbilical blood and from peripheral venous blood collected when the infants were 3-14 days old. Normal infants were matched for gestational and postnatal age. The IDM infants were macrosomic, with significantly higher birth weights relative to gestational age than the control infants. Plasma free insulin concentrations in cord blood were 15-fold higher in the IDM than in the normal infants and more than 3-fold higher in the peripheral venous blood at the median age of 4 days. Hypoglycemia occurred in 12 of the 17 IDM and in none of the normal infants. In umbilical blood insulin binding to erythrocytes was similar in the IDM and normal infants. In both groups insulin binding decreased during the first postnatal weeks, but the decrease was significantly greater in the IDM than in the normal infants. The decrease in insulin binding to erythrocytes was a consequence of decreased receptor affinity as well as decreased receptor concentration in the IDM infants, but was mainly due to decreased receptor concentration in the normal infants. We conclude that insulin binding to its erythrocyte receptor in cord blood in IDM infants is similar to that in normal infants in spite of the simultaneous gross hyperinsulinemia in the IDM infants. The resulting increase in insulin action would then contribute to the tendency toward hypoglycemia and may be partly responsible for the macrosomia in IDM infants. The marked postnatal decrease in insulin binding in IDM infants is a possible explanation for their diminishing risk of hypoglycemia after the first few days of life in spite of persisting hyperinsulinemia.     

Increased insulin binding to pancreatic islets of aged rats

In rat pancreatic islets, the effect of old age (24-month-old) on [125I]insulin binding, glucose-induced insulin release and inhibition of insulin secretion by exogenous insulin were studied. The results were compared with corresponding data obtained from young (3-month-old) rats. Specifically bound [125I]insulin in islets of old rats was increased by 40% (P less than 0.02) compared to that in young rats. Scatchard plots of displacement studies indicated an increase in receptor number rather than receptor affinity. The insulin-releasing capacity of 16.7 mM glucose did not differ between islets of old and young rats when medium insulin was bound to added antiinsulin serum. In the presence of 16.7 mM glucose (without the addition of antiinsulin serum), insulin secretion was less in islets of old rats compared to that in young rats (283 +/- 38 vs. 528 +/- 29 microU/ml; P less than 0.001). Exogenous insulin inhibited glucose (16.7 mM)-induced insulin release more in islets of old rats than in those of young rats. In conclusion, the present in vitro results may be interpreted to reflect increased insulin binding to islets of aged rats and, consequently, increased inhibition of glucose-mediated insulin secretion due to increased feedback of insulin.