Morphology of palpably abnormal injection sites and effects on absorption of isophane(NPH) insulin

The absorption of isophane(NPH) insulin (Human Insulatard) from palpably abnormal thigh insulin injection sites was determined in 10 C-peptide negative diabetic patients. Absorption was compared with a control day study when the insulin was injected into normal thigh. Standard meals were given 30 and 240 min after the injection. Within 2 weeks the tissue morphology and adipose tissue depths at both injection sites were assessed by ultrasound scanning. Absorption of isophane(NPH) insulin was markedly defective from the abnormal compared with the normal injection sites (area under the free insulin curve to 10 h 115 +/- 15 vs 188 +/- 21 mU l-1 h; p less than 0.01). The area under the blood glucose curve from 270 min to the end of the study at 600 min was significantly greater after injection into the palpably abnormal injection site compared with normal thigh (80.4 +/- 5.2 vs 61.2 +/- 7.0 mmol l-1 h; p less than 0.05) representing a 22% improvement in blood glucose control on the normal injection site afternoon. The depth of abnormal injection site tissue was significantly greater than the depth of adipose tissue at the control site (17 +/- 6 vs 5 +/- 4 mm; p less than 0.001) and considerable disruption of the normal anatomy observed. These results demonstrate defective absorption of isophane(NPH) insulin from palpably abnormal injection sites and describe the morphology of the abnormal tissue.     

Exercise augments the absorption of isophane (NPH) insulin

In order to determine the effect of exercise on the rate of absorption of an isophane (NPH) insulin, 7 normal men were studied on two separate occasions using the euglycaemic clamp technique. On one day subjects undertook 60 min of exercise on a treadmill (5 km h-1, 5 degrees slope) 180 min after injection of human isophane (NPH) insulin (0.25 U kg-1), while on the control day they remained at rest throughout the 420 min study. Serum insulin concentrations rose in parallel after injection achieving similar values at 180 min on exercise and control days (13.7 +/- 1.2 (+/- SE) vs 12.0 +/- 1.5 mU l-1; NS), respectively. After the onset of exercise, insulin concentrations rose markedly to a peak of 29.8 +/- 2.2 mU l-1 after 50 min of exercise (p less than 0.001), compared with a slight fall on the control day to 10.4 +/- 1.7 mU l-1 (NS). At the end of the exercise period, serum insulin concentrations returned rapidly to control day values. Glucose infusion requirements rose significantly during the exercise period from 2.8 +/- 0.5 mg kg-1 min-1 to a peak at 235 min of 11.1 +/- 1.2 mg kg-1 min-1 (p less than 0.001), compared with an increase on the control day from 2.0 +/- 0.6 to 2.5 +/- 0.6 mg kg-1 min-1 (NS) over the same period. These results demonstrate an enhanced rate of absorption of an isophane (NPH) insulin during exercise in normal subjects.     

Insulin antibodies do not influence the absorption rate of subcutaneously injected insulin

The influence of insulin antibodies on absorption rate and plasma free insulin concentrations after subcutaneous injection of insulin, was studied in two groups of insulin-treated diabetic patients, one without insulin antibodies (n = 9) and a second with high plasma concentrations of antibodies (n = 14). Except for antibody concentration there were no differences in clinical variables. During 8 h after the injection of 12 U of iodinated neutral human insulin, residual radioactivity at the injection site, plasma glucose, and free and total insulin were measured. Significant differences in absorption rate of insulin were not found between the groups. Plasma glucose (basal value 16.8 +/- 4.4 SD vs 16.1 +/- 4.2 mmol l-1) and free insulin (basal value 8.3 +/- 1.4 vs 11.4 +/- 2.3 mU l-1, maximum after 90 min 36.9 +/- 19.5 vs 30.5 +/- 18.7 mU l-1) were never significantly different between the groups, nor were areas under the curve for free insulin (191.4 +/- 69.2 vs 170.8 +/- 98.6 mU l-1 h). In the high antibody group a small increase in bound insulin was found.     

Absorption of NPH (isophane) insulin in resting diabetic patients: evidence for subcutaneous injection in the thigh as the preferred site.

The absorption kinetics of NPH (isophane) insulin injected subcutaneously into the abdominal wall and subcutaneously (SC) and intramuscularly (IM) into the thigh was studied in 11 Type 1 diabetic patients. The thickness of the subcutaneous adipose tissue layer was measured by ultrasound. NPH (isophane) insulin injected IM into the thigh was absorbed faster than NPH insulin injected SC into the thigh (T50%, IM 8.0 +/- 0.6 h and SC 10.3 +/- 0.7 h, p less than 0.05). No difference in T50% values was found for injection into the abdominal wall (9.7 +/- 1.2h) compared with the thigh. The mean absorption rate from 1.5 to 13.5 h after injection was higher after injection IM into the thigh (6.4 +/- 0.3% of initial dose injected absorbed per h) than after SC injection into the thigh (5.2 +/- 0.3% h-1) and SC into the abdominal wall (5.1 +/- 0.3% h-1) (p less than 0.01). The most constant absorption rate was obtained after SC injection into the thigh (within-study day CV of the mean absorption rate 19.9 +/- 3.2% vs 34.4 +/- 3.2% after IM injection into the thigh and 27.1 +/- 4.9% after SC injection into the abdominal wall (p less than 0.02]. The study provides further evidence that the subcutaneous tissue of the thigh is the preferred injection site for NPH insulin.     

Ethnic differences in insulin secretion in women at risk of future diabetes.

The plasma glucose and insulin responses to oral glucose were studied in 44 women who had previously had gestational diabetes, but had reverted to normal glucose tolerance. Twenty were White, 14 Black, and 10 Asian. A group of race-, age- and weight-matched controls was also studied. Fasting values of glucose and insulin did not differ significantly between the study group and controls. During the 2 h 75-g OGTT the White and Black previously gestational-diabetic women had similar plasma glucose values to their controls, while the Asian previously gestational-diabetic women had significantly higher glucose values at 30 min (9.2 +/- 0.6 (+/- SE) vs 7.1 +/- 0.3 mmol l-1, p less than 0.02) and at 60 min (8.6 +/- 0.8 vs 6.2 +/- 0.4 mmol l-1, p less than 0.02). Compared with their race-matched controls, the White previously gestational-diabetic women had significantly lower insulin values at 60 min (median 41 range 2-91) vs 56 (15-118) mU l-1, p less than 0.05), and the Black previously gestational-diabetic women had lower values at both 30 min (17 (4-116) vs 53 (22-197) mU l-1) and 60 min (36 (4-148) vs 99 (12-169) mU l-1, p less than 0.05). The insulin values were similar during the OGTT in the Asian previously gestational-diabetic women and their controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and acceptance of two intensified conventional insulin therapy regimens: a long-term cross-over comparison

The efficacy and acceptability of multiple daily insulin injections (three preprandial injections of short-acting insulin (NovoPen) plus once daily extended-acting insulin) were compared with those of twice daily injections of short- and intermediate-acting insulin. Sixteen Type 1 diabetic patients participated in a cross-over study (6-month treatment periods). Total areas under 24-h plasma free insulin curves, assessed at the end of each study period, were not significantly different, but a greater area under this curve was found for the pen-injector regimen from 1200 to 1600 h (150 +/- 15 (SE) vs 106 +/- 7 mU l-1 h, p less than 0.01). Home blood glucose profiles showed significantly lower values with pen-injector therapy after lunch (7.1 +/- 0.6 vs 8.4 +/- 0.4 mmol l-1, p = 0.05) and before and after dinner (6.4 +/- 0.6 vs 8.8 +/- 0.5 mmol l-1, p less than 0.005, and 7.5 +/- 0.7 vs 9.4 +/- 1.1 mmol l-1, p less than 0.05). Mean daily blood glucose concentration was also lower (7.1 +/- 0.4 vs 8.2 +/- 0.5 mmol l-1, p less than 0.05). HbA1, fructosamine, hypoglycaemic reactions, and body weight were not significantly different. Thirteen patients decided to continue with pen-injector therapy at the end of the study.     

Insulin-mediated glucose disposal in type 1 (insulin-dependent) diabetic subjects treated by continuous subcutaneous or intraperitoneal insulin fusion

In order to determine if intraperitoneal insulin infusion could improve the insulin resistance of type 1 diabetic patients we have used the englycaemic insulin clamp technique in order to study the effects of insulin on glucose disposal in four C peptide negative type 1 diabetic patients treated by continuous subcutaneous or intraperitoneal insulin infusion and in five control subjects. Compared to control subjects, the diabetic patients treated by subcutaneous insulin infusion had a decreased maximal capacity of glucose utilization (diabetics: 12.6 +/- 0.3 mg.kg-1.min-1; controls: 15.7 +/- 0.7 mg/kg-1.min-1, p less than 0.01) and a trend towards higher half-maximally effective insulin concentrations (diabetics: 70 +/- 11 mU/l-1, controls: 48 +/- 4 mU/l-1). Treatment of the diabetic patients by intraperitoneal insulin infusion for 2 months decreased their mean peripheral free insulin levels (during subcutaneous infusion: 23.5 +/- 2.2 mU/l-1; during intraperitoneal infusion: 18.4 +/- 1.4 mU/l-1, p less than 0.05). However, mean daily insulin requirements were not decreased (during subcutaneous infusion: 0.59 +/- 0.05 U/kg-1.day-1; during intraperitoneal infusion: 0.57 +/- 0.03 U/kg-1.min-1). Moreover, the diabetic patients had a consistently lower maximal capacity of glucose utilization (12.6 +/- 0.7 mg kg-1.min-1) than control subjects (p less than 0.01) without modification of the half-maximally effective insulin concentration (62 +/- 10 mU.l-1). In conclusion, the only benefit of intraperitoneal insulin infusion was a reduction of peripheral free insulin levels; this decrease of peripheral insulinaemia was not associated with an improvement in the insulin resistance of diabetic patients.     

Studies of the Entero-insular Axis Following Pancreas Transplantation in Man: Neural or Hormonal Control?

To study the role of hormonal and neural factors in the control of the entero-insular axis the insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) responses to oral and intravenous glucose were investigated in 5 patients who had received a combined kidney and paratopic pancreas transplant, with physiological portal venous drainage. The incremental areas under the insulin and C-peptide responses to oral glucose were significantly greater than the responses to intravenous glucose (insulin: patients 7983 +/- 1937 (+/- SE) vs 3513 +/- 2188 mU l-1 min, p less than 0.002, control subjects 5505 +/- 1035 vs 1066 +/- 484 mU l-1 min, p less than 0.004; C peptide: patients 440 +/- 80 vs 144 +/- 61 nmol l-1 min, p less than 0.01, control subjects 200 +/- 38 vs 63 +/- 16 nmol l-1 min, P less than 0.01). The incretin effects for insulin (patients 4.4 +/- 1.4, control subjects 7.7 +/- 1.8) and C-peptide (patients 4.4 +/- 0.9, control subjects 3.7 +/- 0.9) and the GIP responses to oral and intravenous glucose were not significantly different between transplant patients and control subjects. As the incretin effect was preserved, despite a denervated pancreas, hormonal rather than neural factors may be more important in mediating increased insulin secretion after oral carbohydrate. The normal GIP response is compatible with its proposed role as an insulinotropic hormone.     

Comparative effects of two different multiple injection regimens on blood glucose control and patient acceptance in type 1 diabetes

In a randomized cross-over study we compared blood glucose control and patient acceptance of a 12-week basal-prandial regimen with short-acting insulin before meals and isophane (NPH) insulin at bedtime (4 injections) with a scheme with a second injection of isophane (NPH) insulin before breakfast (5 injections). Forty-three Type 1 diabetic patients (age 37 +/- 11 (+/- SD) years, duration of diabetes 15 (range 2-48) years, 26 males and 17 females) completed the study. Mean daily blood glucose was 8.6 +/- 2.4 mmol l-1 at baseline, and 8.1 +/- 2.2 mmol l-1 after the four-injection period and 7.9 +/- 2.0 mmol l-1 with five-injections (NS). HbA1c after 12 weeks was not different with the two treatments (6.6 +/- 1.1 vs 6.5 +/- 0.9%), neither was fasting blood glucose (9.6 +/- 4.2 mmol l-1 with 4 injections, and 9.0 +/- 4.4 mmol l-1 with 5 injections). Daily insulin dose did not differ between regimens (55 vs 56 U day-1). No differences in number or severity of hypoglycaemic events were observed. After the study, 13 patients preferred to continue the 5-injection regimen, and 21 patients preferred 4 injections. Treatment satisfaction with either regimen was equally high. It is concluded that dividing the intermediate-acting insulin into a morning and an evening dose did not lead to an improvement in blood glucose control in these moderately-controlled Type 1 diabetic patients.     

The action profiles of human NPH insulin preparations

The complete time-action profiles of four subcutaneously injected human NPH insulin preparations (Protaphane HM/Novo; Insulatard Human/Nordisk; Huminsulin Basal/Eli Lilly; Basal H-Insulin/Hoechst) have been investigated by means of the euglycaemic clamp technique (blood glucose 5.0 mmol l-1). Six normal male subjects were connected to a Biostator on five occasions in randomized order including a control study without insulin injection. A stable basal insulin level of about 10 mU l-1 was established by means of a low dose insulin infusion (0.1 mU kg-1 min-1) which subsequently suppressed C-peptide by 35 +/- 19% (mean +/- SD) to levels of around 0.3 nmol l-1. Twelve units of NPH insulin were injected subcutaneously into the abdominal wall and glucose infusion rates were monitored for 19 h. In the control study, the mean glucose infusion rate was 1.11 +/- 0.60 (range 0.32-1.95) mg kg-1 min-1. Maximal glucose infusion rates, reached 5-7 h after injection, were comparable (4.3-4.9 mg kg-1 min-1) for the four different preparations used. Glucose infusion rates returned to basal rates within the 19 h study period. Mean plasma free insulin levels peaked at 17.5-18.6 mU l-1 3-4.5 h after injection and returned to basal levels within 16 h. The time ranges of greater than 90, greater than 75, greater than 50, and greater than 25% of maximal insulin action (as estimated from glucose infusion rates) revealed no significant differences between the four insulin preparations tested. No significant insulin action was observed beyond 17 h after insulin injection of any preparation.     

Insulin absorption is faster when keeping the infusion site in use for three days during continuous subcutaneous insulin infusion

To evaluate the possible influence of regular infusion site changes on insulin absorption, fifteen type 1 diabetic patients using continuous subcutaneous insulin infusion (CSII) were studied on four occasions: the first day after an infusion site was settled, again the first day after a new infusion site was utilized and the two fourth days after the two infusion sites had been used for three days. A bolus of insulin (1 U/10 kg of body weight) was infused by the pump in the lower para-umbilical region. Plasma free insulin and blood glucose levels were determined before and during 240 min of the study at 30-min intervals. It was found that the peak times extracted from the individual insulin curves were shorter in 17 out of 23 curves when the fourth day was compared with the first day and the mean value of peak time of the fourth day was significantly shorter than that of the first day (56 +/- 11 vs 110 +/- 15 min, P less than 0.01). The mean area under the insulin curves during the first hour of the study tended to increase on the fourth day compared to that of the first day (25 +/- 2.2 vs 21 +/- 2.1 mU.l-1.min, P = 0.12). The decremental area of blood glucose on the fourth day was larger than on the first day (405 +/- 111 vs 82 +/- 160 mmol.l-1.min, P less than 0.05). We conclude that during CSII, the absorption rate of the injected insulin bolus is faster when the infusion site has been in use continuously for three days.     

Effect of calcitonin on gastric emptying and on postprandial gastrin and insulin release in patients with type I gastric ulcer

In a double-blind placebo-controlled study, the effect of calcitonin on gastric emptying and on serum concentrations of gastrin, insulin, glucose, calcium and phosphorus after a mixed solid-liquid meal was examined in six patients with type I gastric ulcer. Synthetic salmon calcitonin 415 pmol i.v. was given as a bolus followed by a 90-min infusion to reach an overall dose of 62.25 pmol.kg-1. Gastric emptying of a radiolabelled meal was measured with a gamma camera. Calcitonin suppressed gastric emptying in all patients examined. The mean gastric transit time, MTT90, increased from 38.1 +/- 0.4 min after placebo to 43.1 +/- 0.6 min after calcitonin (P less than 0.001). Calcitonin significantly blunted the postprandial gastrin release: AUC0-90 10,398 +/- 2886 ng. l-1 min (placebo) and 8238 +/- 2573 ng. l-1 min (calcitonin), P less than 0.05, and abolished the postprandial insulin release--AUC0-90 2244 +/- 230 mU.l-1 min (placebo) vs. 638 +/- 198 mU.l-1 min (calcitonin), P less than 0.01. A steady increase in the serum glucose during calcitonin infusion, reaching up to 5.6 +/- 0.31 mmol.l-1 at the end of the infusion, was observed. Calcitonin did not significantly affect serum calcium or phosphorus concentrations. The authors conclude that a delayed gastric emptying is to be expected in patients undergoing calcitonin treatment.     

How Does Glibenclamide Lower Plasma Glucose Concentration in Patients with Type 2 Diabetes?

Twelve patients with Type 2 diabetes and uncontrolled hyperglycaemia, never before treated with anti-diabetic drugs, were studied before and after several months of glibenclamide therapy. Fasting plasma glucose fell significantly (p less than 0.01) from 12.5 +/- 1.1 (mean +/- SE) to 8.3 +/- 0.4 mmol l-1 with glibenclamide therapy, as did glycosylated haemoglobin (from 12.0 +/- 0.9 to 8.4 +/- 0.7%). The improvement in blood glucose control was accompanied by an increase in postprandial plasma insulin concentration measured hourly from 0800 to 1600 h (p less than 0.001). Over the same period, plasma NEFA and lactate levels were significantly (p less than 0.001) lower after treatment with glibenclamide. Mean (+/- SE) insulin-mediated glucose metabolic clearance rate was evaluated during glucose clamp studies, and was significantly higher (p less than 0.001) after glibenclamide therapy at steady-state insulin levels of approximately 10 mU l-1 (53 +/- 3 vs 38 +/- 2 ml-2 min-1) and approximately 70 mU l-1 (78 +/- 9 vs 55 +/- 6 ml m-2 min-1). Hepatic glucose production was also lower following glibenclamide treatment at both the lower (56 +/- 5 vs 68 +/- 5 mg m-2 min-1) and higher 22 +/- 4 vs 32 +/- 6 mg m-2 min-1) insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin supplement in type 2 diabetic patients with secondary failure to oral agents ameliorates hepatic and peripheral insulin sensitivity but not insulin secretion

In order to investigate the mechanism of amelioration of metabolic abnormalities with supplementary doses of insulin, islet B-cell function and insulin sensitivity were measured in 10 patients with Type 2 diabetes in secondary failure to oral agents. A small dose of ultralente insulin (0.26 +/- 0.07 U kg-ideal-body-weight-1) was added in the morning before breakfast. After 3 months insulin therapy and progressive improvement of metabolic control (HbA1 from 10.5 +/- 0.4 to 9.0 +/- 0.3% at the end of insulin treatment, p less than 0.001), basal C-peptide and incremental area during an oral glucose tolerance test were unchanged. In vivo peripheral insulin sensitivity (euglycaemic clamp with insulin infusion of 40, 160, and 600 mU m-2 min-1, respectively) was significantly improved (glucose requirement: to 4.7 +/- 1.0 from 3.0 +/- 0.6 mg kg-1 min-1, p less than 0.05 at first insulin level; to 10.8 +/- 0.5 from 9.3 +/- 0.7 mg kg-1 min-1, p less than 0.01 at second level; to 13.3 +/- 0.6 from 11.8 +/- 0.8 mg kg-1 min-1, p less than 0.025 at third level). Basal hepatic glucose production was also significantly reduced (from 4.3 +/- 0.4 to 3.3 +/- 0.3 mg kg-1 min-1, p less than 0.05), and residual glucose production further suppressed after insulin supplement (from 1.1 +/- 0.4 to 0.3 +/- 0.2 mg kg-1 min-1 after 120 min at 100 mU l-1 plasma insulin, p less than 0.05). Specific insulin binding to mononuclear leucocytes was unchanged (from 3.1 +/- 0.3 to 3.5 +/- 0.3%, NS).     

Effects of intensive dietary treatment on insulin-stimulated skeletal muscle glycogen synthase activation and insulin secretion in newly presenting type 2 diabetic patients

Ten newly presenting, untreated, Europid Type 2 diabetic patients were studied before and after 8 weeks treatment with intensive diet alone. Nine normal control subjects were also studied. The degree of activation of skeletal muscle glycogen synthase (GS) was used as an intracellular marker of insulin action, prior to and during a 240-min insulin infusion (100 mU kg-1 h-1). Fasting blood glucose decreased from 12.1 +/- 0.9 (+/- SE) to 9.2 +/- 0.8 mmol l-1 (p less than 0.01), but there was no change in fasting insulin concentrations, 9.9 +/- 2.3 vs 9.3 +/- 2.1 mU l-1. Fractional GS activity did not increase in the Type 2 diabetic patients during the insulin infusion either at presentation (change -1.5 +/- 1.9%) or after treatment (change +0.9 +/- 1.8%), and was markedly decreased compared with the control subjects (change +14.5 +/- 2.8%, both p less than 0.001). Glucose requirement during the clamp was decreased in the Type 2 diabetic patients at presentation (2.2 +/- 0.7 vs 7.3 +/- 0.6 mg kg-1 min-1, p less than 0.001), and despite improvement following dietary treatment to 3.3 +/- 0.6 mg kg-1 min-1 (p less than 0.01) remained lower than in the control subjects (p less than 0.001). Fasting plasma non-esterified fatty acid (NEFA) concentrations were elevated at presentation (p less than 0.05), and failed to suppress normally during the insulin infusion. After treatment fasting NEFA concentrations decreased (p less than 0.05) and suppressed normally (p less than 0.05). Insulin secretion was assessed following an intravenous bolus of glucose (0.5 g kg-1) at euglycaemia before and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improvement in morning hyperglycaemia with basal human ultratard and prandial human actrapid insulin--a comparison of multiple injection regimens

Three 'pen'-administered multiple injection regimens have been compared with twice daily insulin injection regimens by means of 24-h profiles of plasma glucose and free insulin concentrations. Ten Type 1 diabetic patients received their usual twice daily insulin regimen and were then randomized to receive the same total daily insulin dose in four divided doses using (1) 50:50 premixed soluble and isophane, (2) 30:70 premixed soluble and isophane, and (3) preprandial soluble and evening crystalline-zinc insulins. Profiles were performed after 1 week on each regimen. Plasma glucose concentrations were similar during the twice daily regimen and the two premixed regimens, rising during the early hours of the morning to a peak between 0900 and 0930 h of 13.8 +/- 2.8 (+/- SD) mmol l-1 on the twice daily regimen, 13.6 +/- 5.3 mmol l-1 on the premixed 50:50 regimen, and 13.5 +/- 4.2 mmol-1 on the premixed 30:70 regimen. With the basal and prandial regimen, overnight plasma glucose concentrations were higher than with the other regimens between 2400 and 0300 h (p less than 0.05). Concentrations then fell until breakfast, and rose after this meal to a peak of 9.5 +/- 4.3 mmol l-1 (p less than 0.01). Mean plasma glucose concentrations were significantly lower than on the other three regimens between 0830 and 1100 h (p less than 0.05). Less variability was observed in 24-h mean plasma glucose concentrations during the basal and prandial regimen than during the other three regimens.     

Suppression of insulin secretion by falling plasma glucose levels is impaired in type 2 diabetes

The ability of Type 2 diabetic patients to suppress islet B-cell secretion in response to falling plasma glucose levels has been studied with two different protocols. (1) Five diet-treated diabetic patients and 6 normal subjects were studied after the termination of a hyperglycaemic clamp at 15 mmol l-1 for 150 min, with the plasma glucose levels then being allowed to fall and the glucose clamp re-established at 10 mmol l-1. The plasma insulin levels fell in normal subjects from 178 +/- 141 (+/- SD) mU l-1 at the end of the 15 mmol l-1 clamp to 147 +/- 97 mU l-1 (p less than 0.02) 20 min later, whereas in diabetic patients there was no significant change from 61 +/- 41 to 56 +/- 35 mU l-1, respectively (NS). (2) The second study was performed to assess the turn-off of islet B-cell secretion with diabetic patients and normal subjects starting at comparable plasma insulin levels. Twelve diet-treated diabetic patients and 11 normal subjects were given a continuous low-dose glucose infusion for 60 min at a rate of 5 mg kg-1 ideal body weight min-1, after which the infusion was turned off and the plasma glucose level allowed to fall.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characteristics of insulin resistance in Turner syndrome

The characteristics of insulin resistance, in Turner syndrome are still unclear. For this purpose in 4 patients with Turner syndrome and in 8 control females we performed an euglycaemic hyperinsulinemic glucose clamp at the following insulin infusion rates (50 and 100 mU/Kg x h), each period lasting 120 min. A simultaneous infusion of D-3-H-glucose allowed us to determine in basal conditions and during the clamp hepatic glucose output and glucose disappearance rate (Rd). In basal conditions plasma glucose (4.8 +/- 0.1 vs 4.6 +/- 0.2 mmol/1 p = NS) and plasma glucagon (102 +/- 7.5 vs 112 +/- 11.3 ng/l p = NS) were similar in both groups despite higher plasma insulin (19 +/- 1.8 vs 7 +/- 2.2 mU/l p less than 0.05) and C-peptide (1.0 less than 0.1 vs 0.8 +/- 0.06 pmol/l p less than 0.05) levels in patients with Turner syndrome. In the last 60 min of the lower insulin infusion rate glucose infusion rate (4.1 +/- 0.3 vs 2.9 +/- 0.4 mg/Kg x min p less than 0.05) and glucose disappearance rate (3.89 +/- 0.12 vs 2.63 +/- 0.11 mg/Kg x min p less than 0.01) were significantly reduced in patients with Turner. On the contrary hepatic glucose output was similarly suppressed in both groups of subjects. Doubling the insulin infusion rate, we obtained similar results in patients and controls respectively. So we conclude that in Turner syndrome the insulin resistance state is mainly due to a muscular receptor defect.     

Pharmacokinetics and pharmacodynamics of subcutaneously administered U40 and U100 formulations of regular human insulin.

Action profiles of 12 U of regular human insulin (Actrapid HM) administered subcutaneously as a U40 or U100 formulation were studied. Euglycaemic glucose clamps were performed on two separate days in 8 healthy subjects (basal i.v. insulin infusion 0.1 mU/kg/min, plasma glucose 5.0 mmol/l, mean +/- SD age 25 +/- 2 years, BMI 22.7 +/- 1.4 kg/m2). Serum insulin concentrations increased after injection of U40 or U100 from similar baseline values to maximal individual concentrations of 305 +/- 79 vs. 285 +/- 62 pmol/l (NS) after 90 +/- 33 vs. 114 +/- 58 min (NS). Ten, 15, and 20 min post injection insulin concentrations were significantly higher by an average of 30 pmol/l after U40 insulin vs. U100 insulin (p less than 0.05). Glucose infusion rates increased from comparable baseline rates to maximal individual glucose infusion rates of 10.7 +/- 2.4 vs. 10.9 +/- 3.0 mg/kg/min (NS) after 172 +/- 51 vs. 169 +/- (39) min (NS). At the three time points when significantly different serum insulin concentrations occurred soon after insulin injection, glucose infusion rates were not significantly different between U40 and U100. Although small differences in insulin pharmacokinetics were detected early after s.c. insulin injection (U40 was absorbed faster than U100 insulin) the pharmacodynamics of the U40 and U100 formulation of regular human insulin appear to be comparable in healthy subjects.     

Exercise-induced hypoglycaemia and subcutaneous insulin infusion

To assess whether exercise-induced hypoglycaemia could be prevented by interruption of insulin infusion (3 h) we studied diabetic patients treated with continuous subcutaneous insulin infusion (CSII). The studies were performed in 7 insulin-dependent diabetics (aged 31.4 +/- 4.8 (mean +/- SD) years, duration of diabetes 16.9 +/- 5.4 years), after an overnight fast and in the afternoon, 4 h after the last pre-meal bolus injection (exercise and control period). Bicycle exercise (45 min at 60% of maximum oxygen consumption) was started 30 min after the insulin infusion was stopped. During exercise there was a more pronounced decline in blood glucose in the afternoon (2.2 +/- 0.3 mmol/l, mean +/- SEM) than in the morning (1.4 +/- 0.4 mmol/l) (p less than 0.01). This corresponded to higher mean levels of free insulin during exercise in the afternoon (20 +/- 4.5 mU/I vs 12.0 +/- 1.0 mU/l, in the morning). Interruption of insulin delivery for 3 h resulted in a moderate increase of blood glucose, a gradual decrease of free insulin, and a moderate increase in free fatty acids and beta-hydroxybutyrate. During exercise in the afternoon 3 diabetics suffered from symptomatic hypoglycaemia (BG less than 2.8 mmol/l). In contrast with most of the other patients they showed no decline of free insulin during exercise. Thus even after interruption of basal rate insulin infusion moderate postprandial exercise may lead to hypoglycaemia if there is relative hyperinsulinism.