Simulated postaggression metabolism in healthy subjects: metabolic changes and insulin resistance.

Postaggression metabolism (PAM) is difficult to study in critically ill patients. The objective of this study was to simulate PAM in healthy subjects to quantify insulin sensitivity under these conditions. Six healthy men (age, 24 +/- 1 years; body mass index, 22.0 +/- 0.7 kg/m2 [mean +/- SE]) received an intravenous (i.v.) infusion of insulin-counteracting hormones (epinephrine 100 ng/kg/min, glucagon 16 ng/kg/min, hydrocortisone 5 microg/kg/min, and growth hormone [GH]-releasing hormone 50 microg/h) for 4 hours in addition to glucose (270 mg/kg/h). Control experiments used glucose only. In additional experiments, insulin sensitivity was measured by a two-step hyperinsulinemic glucose clamp with and without concomitant hormone infusion (insulin infusion rate, 2.5 and 5.0 mU/kg/min for hormone infusion or 1.0 and 2.5 mU/kg/min for control experiments). Plasma stress hormones reached levels comparable to severe PAM (epinephrine, 1,085 +/- 89 pg/mL; glucagon, 1,100 +/- 114 pg/mL; cortisone, 1,004 +/- 32 ng/mL; and GH, 20.6 +/- 6.1 pg/mL) in the hormone infusion experiment. This resulted in hyperglycemia and hyperinsulinemia (steady-state blood glucose, 19.7 +/- 0.4 mmol/L; serum insulin, 352 +/-8 pmol/L) in comparison to the control experiments with glucose infusion only (maximal blood glucose 7.2 +/- 0.8 mmol/L; serum insulin, 110 +/- 16 pmol/L). The insulin sensitivity index (S(I)) was 88% +/- 6% lower during hormone infusion (0.6 +/- 0.4 mL/min/m2/microU/min) compared with the control experiments (4.5 +/- 1.3 mL/min/m2/microU/min). Infusion of insulin-counteracting hormones at high doses allows simulation of the changes in carbohydrate metabolism observed in PAM in healthy subjects. The observed profound decrease in insulin sensitivity explains the hyperglycemia observed in nondiabetic critically ill patients. With this experimental setup, standardized investigations of therapeutic interventions in PAM should be possible.

Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients: using the rapid acting insulin analogue [Lys(B28), Pro(B29)] human insulin.

The time-action profile of the insulin analogue insulin lispro ([Lys(B28), Pro(B29)] human insulin) with its rapid onset and short duration of action might be more suitable to limit hyperglycaemic excursions after a meal rich in rapidly absorbable carbohydrates in comparison to regular human insulin. A randomized, double-blind study was performed in 10 Type I diabetic patients with good metabolic control (HbA1c 7.0 +/- 0.5%). After a baseline period of 3 h (blood glucose clamped at 6.7 mmol l-1, i.v. insulin infusion of 0.2 mU kg-1 min-1 throughout the study), the patients ate a pizza, drank a cola and had a carbohydrate-rich dessert (total carbohydrate content 140 g). Immediately before the meal 15.4 +/- 3.5 U of either insulin preparation were injected subcutaneously. Blood glucose concentrations were monitored continuously thereafter. Following the injection of insulin lispro the area under the blood glucose curve after the meal was 78% of that of regular insulin (1.76 +/- 0.34 vs 2.26 +/- 0.68 mol l-1 *240 min-1; p < 0.01). Maximal blood glucose excursions were higher and were reached later after regular insulin as compared to insulin lispro (11.9 +/- 2.8 vs 9.9 +/- 1.4 mmol l-1; p < 0.05; 66 +/- 37 vs 41 +/- 7 min; p < 0.05). Maximal individual differences in the blood glucose excursions (regular human insulin minus insulin lispro) were 4.8 +/- 2.2 mmol l-1 (p < 0.0001 against zero) after 110 +/- 37 min. In Type 1 diabetic patients prandial blood glucose excursions after a carbohydrate rich meal were reduced after preprandial injection of insulin lispro in comparison to human regular insulin.

Prospective study on the detection of insulinomas by endoscopic ultrasonography.

BACKGROUND AND STUDY AIMS: The correct localization of insulinomas using endoscopic ultrasonography (EUS) has been reported to be as high as 80% in multicenter patient cohorts. PATIENTS AND METHODS: Over 24 months, we prospectively investigated 14 patients (11 women, three men) with a definite biochemical diagnosis of endogenous hyperinsulinism prior to surgical exploration and removal of an insulinoma. The endoscopic investigator was not aware of any other imaging results if they had been performed in referring hospitals. RESULTS: The overall sensitivity of EUS in the detection of pancreatic insulinomas was 57% (eight of 14 tumors); the sensitivity for insulinomas in the head of the pancreas was 83% (five of six); and 37% (three of eight) for tumors in the tail of the pancreas. The actual median diameter of undetected tumors was 11 x 9.5 mm, the median volume 0.66 ml (range 0.13 - 2.6 ml). The median diameter of correctly detected tumors was 16 x 11 mm, the median volume 1.37 ml (range 0.7 - 6.3 ml), the differences not being significantly different. In two patients, false-positive results were caused by peripancreatic lymph nodes. CONCLUSIONS: The sensitivity of EUS in the detection of pancreatic insulinomas depends on the location of the tumor, and possibly on the size of the tumors. Tumors not detected by EUS were likely to be smaller than detected tumors, and were likely to be located in the tail of the pancreas.

Time-action profiles of the intermediate-acting insulin analogue des(64,65)-human proinsulin.

Des(64,65)-proinsulin (DPRO) is one of several endogenous intermediates arising during the conversion of proinsulin to insulin. In pharmaceutic preparations it is a clear solution containing no other proteins. Animal experiments and preliminary human studies indicated that DPRO should have a protracted time-action profile similar to that of NPH-insulin. Accordingly, we compared the time-action profiles of these two preparations, using the euglycaemic glucose clamp-technique in 9 healthy male volunteers. Different doses of DPRO (0.1, 0.15, 0.2 U/kg) or equipotent doses of NPH ( 0.2, 0.3, 0.4 U/kg) were injected subcutaneously into the abdominal wall. The maximal metabolic effect (GIRmax) of DPRO was greater than that of NPH-insulin (p < 0.05). With increasing doses, GIRmax differed significantly for DPRO but not for NPH-insulin. The time to maximal metabolic effect (tmax) was similar for the three doses of either preparation. However, tmax was reached 30 min earlier with DPRO than with NPH-insulin (p < 0.01). the decline to half-maximal after maximal activity was significantly faster with DPRO than with NPH-insulin (p < 0.0001). Subcutaneous injection of DPRO thus produced a time-action profile between that of regular insulin and NPH-insulin.

Four week administration of an ACE inhibitor and a cardioselective beta-blocker in healthy volunteers: no influence on insulin sensitivity.

In most, but not all, studies antihypertensive treatment with angiotensin converting enzyme inhibitors (ACE inhibitors) improves insulin sensitivity, whereas beta-blockers decrease insulin sensitivity. However, there was a significant increase in body weight with beta-blockers and changes in the body potassium homeostasis with ACE inhibitors. In order to compare the drug specific metabolic effects of an ACE inhibitor and a cardioselective beta-blocker controlling these factors, we measured insulin sensitivity in a randomized, double-blind cross-over study in 22 healthy volunteers (age 27 +/- 3 years; BMI 22.0 +/- 1.5 kg m-2 (mean +/- SD)) during euglycaemic glucose clamps before and after 4 weeks' administration of 5 mg Lisinopril or 5 mg Bisoprolol. Both drug phases were separated by 4 weeks of no drug administration. During the insulin sensitivity measurements potassium concentrations were clamped at basal levels by means of a variable i.v. potassium infusion. Body weight was monitored at weekly intervals and kept constant within +/- 1 kg of the subjects' baseline weight throughout the entire study period. Insulin sensitivity did not change significantly during either drug administration period. The insulin sensitivity index of the 22 volunteers after administration of the ACE inhibitor was 7.9 +/- 2.4 mL min-1 m2 microU-1 mL-1 (basal index 8.3 +/- 1.9 mL min-1 m2 microU-1 mL-1, and 7.5 +/- 2.1 mL min-1 m2 microU-1 mL-1 after administration of the beta-blocker (basal index 8.2 +/- 1.9 mL min-1 m2 microU-1 mL-1; NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative dose-related time-action profiles of glibenclamide and a new non-sulphonylurea drug, AG-EE 623 ZW, during euglycaemic clamp in healthy subjects.

Insulin and glucose responses to glibenclamide were studied in comparison to a novel non-sulphonylurea drug (AG) by means of the euglycaemic clamp technique. Nine fasting male subjects were connected to a Biostator and 1.75, 3.5 or 7.0 mg glibenclamide or 1.0, 2.0 or 4.0 mg AG were given and blood glucose concentrations were clamped at 10% below basal values. Glucose infusion rates were registered over 10 h after administration of the tablet. Maximal glucose infusion rates after glibenclamide were 40% higher compared to AG (1.75 vs 1.0 mg, 3.5 vs 2.0 mg, 7.0 vs 4.0 mg, respectively) and were reached after 3-3.5 h for all doses. After glibenclamide, area under the glucose infusion curves and maximal incremental serum insulin responses were higher by 25-40% and by 30% compared to AG when low, medium and high doses of each drug were tested. However, a linear dose relationship was obtained for both drugs when the glucose infusion rate was plotted against the area under the insulin curve. In fact, both drugs were equipotent on a molecular weight basis. The hypoglycaemic index of both drugs (integrated glucose infusion rate divided by integrated insulin release) expressed per mumol of drug revealed a dose-dependent and parallel inverse curvilinear relation to increasing doses. This methodological approach allowed us to quantify and compare the metabolic effects of oral hypoglycaemic agents under standardised experimental conditions.

The influence of diet and physical activity on insulin sensitivity.

This article reviews the effects of diet and exercise on insulin sensitivity in patients with type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Dietary caloric restriction operative through weight loss decrease the insulin resistance characteristic of the disease by increased glucose transport. The precise localization of this effect is unknown, as is the defect in the insulin signalling pathway in type II diabetes. Inherent problems are the inability to clearly separate obesity and type II diabetes and methodological difficulties in the distinction of dietary effects from exercise-induced effects. The mechanism of exercise-induced insulin sensitivity has gained considerable understanding through the detection of the glucose transporter molecule GLUT-4 in muscle. It is now clear that the presence of insulin is not mandatory and mere electrical stimulation of the muscle produces similar effects through distinct signalling pathways. Exercise-induced increased blood flow and decreased vascular resistance may also play an important role. In contrast to these newer experimental data, clinical studies and feasibility studies aimed to implement exercise as a valuable therapeutic measure in type II diabetes have failed to delineate promising long-lasting effects and can therefore not be generally recommended. Encouraging epidemiological data have recently been found with respect to the prevention of type II diabetes by increased physical activity in patients at risk.

Action profile of the rapid acting insulin analogue: human insulin B28Asp.

The time-action profile of the human insulin analogue B28Asp, which displays faster absorption rates from subcutaneous tissue compared to soluble human insulin, was studied under euglycaemic glucose clamp conditions (blood glucose 5.0 mmol l-1) in 14 healthy male volunteers. Subcutaneous injection of 0.15 U kg-1 body weight (range 9.5-14.3 U) of the insulin analogue or soluble human insulin resulted in half-maximal glucose infusion rates (after subtraction of mean baseline glucose infusion rates) that were reached significantly earlier after injection of B28Asp (45 +/- 11 (SD) min) as compared to human insulin (58 +/- 25 min, p < 0.05). Forty-five and 60 min after injection of human insulin, glucose infusion rates had increased by 3.4 +/- 1.8 and 4.8 +/- 2.3 mg min-1 kg-1 above baseline glucose infusion rates, reflecting 30 +/- 15 and 42 +/- 17% of maximal action of 10.6 +/- 2.7 mg min-1 kg-1. Following the injection of B28Asp, glucose infusion rates increased by 6.3 +/- 2.7 after 45 min and by 7.9 +/- 2.8 mg min-1 kg-1 after 60 min above baseline glucose infusion rates, reflecting 64 +/- 28% and 81 +/- 26% of maximal action of human soluble insulin (p < 0.001). Peak glucose infusion rates after injection of B28Asp were significantly higher and were reached earlier than after subcutaneous injection of soluble human insulin (p < 0.05 and p < 0.001). The human insulin analogue B28Asp showed a significantly faster onset of action as compared to soluble human insulin.

A case of lipoatrophy with human insulin-therapy.

A case of progressive insulin-induced lipoatrophy is reported in an insulin-dependent diabetic patient having been treated exclusively with human insulin. The lipoatrophy was stopped after insulin therapy was changed from subcutaneous injections to continuous subcutaneous infusion with human insulin.

Are CAT-scans necessary for preoperative localization of insulinomas?

OBJECTIVES: Do CAT-scans provide useful information in terms of preoperative localization of insulinomas after a biochemical diagnosis is established or may CAT-scan imaging be safely abandoned? PATIENTS AND METHODS: CAT-scan results from 30 consecutive patients between 1980-1990 with established insulinomas were retrospectively evaluated with regard to actual tumour size (volume) and identification and localization as verified during surgery. RESULTS: In all patients, the tumours were easily detected by manual palpation during surgery, although the size of 67% of the tumours (n = 20) was less than 2.5 cm3. In only 7 patients (23%) the tumour had been correctly localized by computer tomography. Detected tumours were significantly larger than undetected tumours (median size 5.3 vs 1.3 cm3; p < 0.005). CONCLUSION: Despite the low sensitivity of computer tomography as documented in this study, all patients with an insulinoma were definitely cured after surgical intervention. Thus, CAT-scans are neither necessary nor helpful for preoperative localization of insulinomas.

Timing between the subcutaneous administration of insulin and consumption of a carbohydrate rich meal.

There is considerable uncertainty as to the appropriate timing of preprandial injections of short acting insulin before consumption of a meal. 8 healthy male volunteers were subjected to a glucose clamp (glucose 4.2 mmol/l) by means of a continuous insulin infusion on two occasions. On each occasion the subjects ingested a standardized meal. Twelve units of short acting insulin were injected subcutaneously either immediately before (A) or 30 min prior to the meal (B). In a control study (C) only the meal was consumed. The maximal increment of insulin concentrations after sc injection was 53.1 (6.9) mU/l in A and 58.6 (5.1) mU/l in B and thus comparable to C (52.8 (4.7) mU/l), however it was reached 30 to 60 min later as compared to endogenous stimulation. Injection 30 min prior to meal resulted in higher insulin concentrations early after the meal, but the glucose infusion rate doubled to 5.3 (0.3) mg/kg/min before the meal in order to prevent hypoglycaemia. Omission of this time interval is less hazardous, but bears the risk of late postprandial hyperinsulinaemia.

Determination of insulin sensitivity: methodological considerations.

During the past decade, it became obvious that in contrast to defective insulin secretion in type I diabetes, defective insulin action (insulin resistance) is the most pertinent feature of type II diabetes. In addition, it has been known for a long time that obesity and insulin resistance are closely linked. Recently, hypertension also has been shown to often coincide with insulin resistance, although any causal relationships are still hypothetical. Last, several widely used pharmacological drugs such as diuretics, adrenergic blockers, and angiotensin-converting enzyme inhibitors may influence insulin sensitivity. Therefore, growing interest has emerged to most accurately measure insulin sensitivity. Although considerable knowledge has accumulated as to the actual mechanisms of insulin-dependent glucose transport, the signal transduction pathway of insulin remains poorly understood. When insulin sensitivity is measured, it is the overall glucose uptake that is quantified under controlled conditions. Other actions of insulin, such as the transport of ions, (e.g., sodium and potassium), synthesis of insulin-like growth factor-binding proteins, translocation of transporter proteins, and regulation of enzyme activities, are much more difficult to quantify. Of the many approaches used to quantify insulin action, the euglycemic hyperinsulinemic clamp technique has emerged as the most reliable tool, fulfilling clinical and scientific demands equally. In combination with tracer methodology and calorimetry, a detailed view into the quantitative aspects of insulin action at different target cells is possible. Whether insulin resistance extends to other known actions of insulin in addition to those on glucose metabolism remains open to debate.

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.

Action profiles of fast onset insulin analogues.

Recombinant DNA technology allows the production of insulin analogues with faster absorption rates from subcutaneous tissue as compared to conventional human regular insulin. We report the time-action profiles of 12 U subcutaneously injected insulin analogues (B9Asp + B27Glu or B10Asp) as evaluated against human regular insulin by means of the euglycaemic clamp technique (blood glucose 5.0 mmol/l) in healthy men. After injection of 12 U of either insulin preparation identical values were found for maximal insulin action (maximal glucose infusion rate, time to peak action), total amount of glucose infused as well as area under the curve of glucose infusion rate. Half-maximal glucose infusion rate was reached significantly earlier after injection of modified insulins (mean +/- SD 38 +/- 7 and 43 +/- 5 min) as compared to regular insulin (56 +/- 14 min, p less than 0.01). Forty-five min after injection of both insulin analogues glucose infusion rate had increased by 7.4 +/- 1.8 or 6.1 +/- 1.8 mg.kg-1.min-1, reflecting 83 +/- 27 or 67 +/- 15% of maximal regular insulin action. In conclusion, the two tested insulin analogues showed similar action profiles, but a significantly faster onset of action as compared to regular insulin.

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.

[Action profile of human ultralente insulin compared with human NPH-insulin]. / Wirkungsprofil von humanem Ultralente-Insulin im Vergleich mit humanem NPH-Insulin.

The effect of human NPH insulin (Protaphan HM) and of human ultralente insulin (Ultratard HM) on the profile of blood-glucose concentration was compared, using the glucose clamp technique, in normal subjects after subcutaneous injection of 12 U each. After Protaphan, insulin concentration rose by 11.0 +/- 1.6 microU/ml; maximal glucose infusion rate (GIR) after five hours was 4.7 +/- 0.5 mg/kg.min. But after the same dosage of Ultratard, insulin concentration rose by only 4.7 +/- 1.0 microU/ml (P less than 0.02) on a maximal GIR after ten hours of 3.2 +/- 0.5 mg/kg.min (no significant difference). Ultratard had up to 70% of the maximal Protaphan effect, the infused amount of glucose, up to maximal effect at 9.5 h (72 +/- 9 g), being significantly lower (P less than 0.02) than after Protaphan (130 +/- 18 g). After, respectively, 16 (Protaphan) and 20 (Ultratard) hours, basal insulin levels were again reached. GIR 19 h after Protaphan injection was 1.3 +/- 0.4 mg/kg.min, while 24 h after Ultratard it was 1.5 +/- 0.2 mg/kg.min, which was not significantly different from the basal rate. The difference between Protaphan and Ultratard lies in the marked initial effect of NPH insulin, up to 10 h after injection. In the later phase of the effect profile both insulins were similar at the chosen dose of 12 U.