Johan Iversen

Evidence for a Feedback Inhibition of Insulin on Insulin Secretion in the Isolated, Perfused Canine Pancreas

An isolated in vitro canine pancreas per fusion preparation is described which is suitable for prolonged (five hours) study of insulin secretion. The preparation remains in good condition throughout the experimental period judged by various parameters. Feedback inhibition of insulin on insulin secretion was studied in the preparation. Experiments were performed at different concentrations of glucose in the influx medium. At 150 mg. per cent of glucose a considerable reduction of the insulin secretion was obtained when exogenous porcine insulin was added to the influx medium in concentrations from 180 μU./ml. to 420 μU./ml. In eight experiments where the exogenous insulin concentration in the influx medium was equal to or exceeded pre-inhibition efflux values the obtained insulin inhibition amounted to 25-78 per cent of the pre-inhibition values. In one of the eight experiments the exogenous insulin concentration was less than the pre-inhibition value; however, the same effect was obtained. A feedback mechanism of insulin on insulin secretion from the beta cell has thus been demonstrated at levels of perfusate insulin which occur in vivo.

Effect of Acetyl Choline on the Secretion of Glucagon and Insulin from the Isolated, Perfused Canine Pancreas

During perfusions with glucose concentrations of 25 and 150 mg./100 ml., the effect of infusions of acetyl choline on glucagon and insulin release was investigated in five perfusion experiments. Acetyl choline at concentrations of 10 to 100 μM. stimulated release of glucagon both at the low glucose strength as well as at the high concentration, which in itself inhibits basal glucagon release. Glucagon was released in a monophasic pattern, resembling the release pattern found after catecholamines and contrasting with the biphasic pattern obtained after stimulation with gastrointestinal hormones and amino acids, as previously reported from our laboratory. Acetyl choline always stimulated release of insulin in a biphasic pattern, at the high glucose concentration, while no consistent effect was obtained at the low glucose concentration. At the termination of the acetyl choline infusions, a rebound increase in insulin was observed during perfusion with both low and high glucose concentrations. Infusion of atropine at a concentration of 25 μM. completely abolished the stimulatory effect of acetyl choline on both glucagon and insulin release. The results suggest that the parasympathetic nervous system may play a direct role in the control mechanism of the release of the pancreatic hormones during food ingestion.

Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in β-cell function

The pathophysiology of insulin resistance in human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) is not fully clarified. We investigated 18 men with HALS and 18 HIV-positive males without lipodystrophy (control subjects). Duration and modality of antiretroviral therapy were similar between study groups. A hyperinsulinemic euglycemic clamp showed an impaired glucose disposal rate (GDR) in HALS patients (5.6 v 8.3 mg glucose/min. kg(FFM), P =.0006). As demonstrated by indirect calorimetry, HALS patients showed an impaired nonoxidative glucose metabolism (NOGM, 2.2 v 4.2, P =.006), whereas levels of basal and insulin-stimulated oxidative glucose metabolism (OGM) (2.4 v 2.3, P =.55, and 3.3 v 4.0, P =.064, respectively) were not significantly different between groups. Despite comparable total fat masses, dual energy x-ray absorptiometry (DEXA) scans showed that the percentage of limb fat (ie, peripheral-fat-mass/[peripheral-fat-mass + trunk-fat-mass]. 100%) was reduced in HALS patients (36% v 46%, P =.0002). Multiple linear regression analysis indicated that percentage of limb fat explained 53% of the variability of GDR and 45% of the variability of NOGM in HALS patients. In HALS patients, leg fat mass correlated positively with NOGM (r =.51, P <.05), whereas abdominal fat mass and NOGM did not correlate (P =.91). Analyzing the relationship between first phase insulin secretion and insulin sensitivity, 6 HALS patients compared with none of the control subjects exhibited impaired insulin secretion (P <.05). Our data suggest that fat redistribution independently of antiretroviral therapy is highly related to insulin resistance in HALS patients. Furthermore, in HALS patients, impaired glucose metabolism most likely relates to decreased NOGM and to defects in beta-cell function.

Impact of switching antiretroviral therapy on lipodystrophy and other metabolic complications: a review

Following the introduction of highly active antiretroviral therapy (HAART), metabolic and morphological complications known as HIV associated lipodystrophy syndrome (HALS) have been increasingly common. The approaches to target these complications span from resistance exercise, diet and use of the antidiabetics metformin or glitazones to high dose recombinant human growth hormone therapy or switching antiretroviral regimen. When looking at the effect of switching therapy, focus has been addressed to protease inhibitor (PI) based regimens, as PI was the first component of HAART recognized to be correlated with the disfiguring body-alterations known as HALS. More recently, however, regimens containing nucleoside reverse-transcriptase inhibitors (NRTI) have attracted attention. Reviewing switch studies regarding metabolic parameters and body shape changes, certain trends emerge. Switching from PI, the metabolic complications such as dyslipidaemia and insulin resistance seem to be partly reversible, whereas the morphologic alterations appear to be unchanged. In studies in which NRTIs are switched, dyslipidaemia appears unaffected, but a modest improvement in peripheral lipoatrophy has been reported. However the results are often inconsistent and difficult to interpret, mostly because of limitations in study design, patient number and duration of follow-up. The need for larger, controlled, randomized, long-term studies is evident.

β-Cell dysfunction and low insulin clearance in insulin-resistant human immunodeficiency virus (HIV)-infected patients with lipodystrophy

Objective  To obtain a better understanding of the physiological aspects of glucose homeostasis in human immunodeficiency virus (HIV)‐infected patients with lipodystrophy, we evaluated separately β‐cell function and insulin sensitivity after an oral glucose load.

Different growth hormone sensitivity of target tissues and growth hormone response to glucose in HIV-infected patients with and without lipodystrophy

Growth hormone (GH)-secretion in HIV-lipodystrophy is impaired; however, GH-sensitivity of GH-target tissues remains to be evaluated. We measured overnight fasting concentrations of GH-sensitive insulin-like growth-factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) including GH binding protein (GHBP), a marker of GH-receptor sensitivity, in antiretroviral treated HIV-infected patients with (LIPO) and without lipodystrophy (NONLIPO) and antiretroviral naïve HIV-infected patients (NAÏVE). Three h GH-suppression tests using oral glucose were undertaken to determine dynamics of GH-secretion. IGF-I and IGFBP-3 were increased in LIPO compared with NONLIPO (p<0.05), but did not differ significantly between NONLIPO and NAÏVE. Area under the curve of GH (AUC-GH) during the GH-suppression test was decreased in LIPO compared with NONLIPO (p<0.05). Ratio of limb to trunk fat, which was decreased in LIPO compared to NONLIPO and NAÏVE (p<0.001), correlated positively with AUC-GH and rebound-GH (p<0.05). All groups displayed suppression of GH during the suppression test (p<0.05) and all groups, except LIPO, displayed a rebound of GH (p<0.05), which probably is explained by persistently increased plasma glucose in LIPO compared with NONLIPO and NAÏVE (p<0.01). GHBP was inversely correlated with AUC-GH (p<0.01). Our data suggest that GH-target tissues in LIPO are at least as GH-sensitive as in HIV-infected patients without lipodystrophy.

Preanalytical handling of samples for measurement of plasma lactate in HIV patients

Lactic acidosis is a feared side effect of nucleoside analog treatment, one of the cornerstones in the management of HIV infection. Precise and reliable lactate measurements are prerequisites for the diagnosis of hyperlactatemia. The effects of venous stasis, time to measurement and storage temperature on p‐lactate levels, p‐glucose levels, anion gap and pH were investigated. Ten HIV patients (n=8 on highly active antiretroviral therapy) and 4 healthy control subjects were studied. Blood was drawn without stasis at time 0 and with stasis for 2 and 8 min into heparin‐preserved test tubes. The tubes were placed at a room temperature (25°C) and on crushed ice and consecutively monitored for up to 360 min. The mean increases in p‐lactate in blood kept in test tubes at 25°C, measured from 0 to 60 min and from 240 to 360 min, were increased in HIV patients compared with controls (0.78 mmol/Lh±0.02 vs. 0.63 mmol/Lh±0.05, (p=0.009) and 0.65 mmol/Lh±0.03 vs. 0.53 mmol/Lh±0.05, (p=0.042)). It was found that placing the tubes on crushed ice rather than keeping them at 25°C controlled glycolysis and lactate production measured over a 6‐h period (0.033 mmol/Lh±0.006 vs. 0.32 mmol/Lh±0.01, (p<0.0001) and 0.064 mmol/Lh±0.008 vs. 0.64 mmol/Lh±0.02, (p<0.0001)). The total increases in lactate levels in the test tubes placed on crushed ice for 4 h and in those kept at 25°C for 15 min were comparable (0.28±0.03 mmol/L vs. 0.20±0.03). Compared with storage at 25°C, keeping the test tubes on crushed ice also preserved pH and anion gap over a 6‐h measurement period (pH: 0.026±0.004 vs. 0.12±0.01 and anion gap: −0.8±0.4 mmol/L vs. 4.1±0.4). Two minutes of venous stasis had no influence on p‐lactate levels (0.02±0.04 mmol/L, p=0.70), whereas 8 min of stasis increased p‐lactate levels by 0.11±0.04 mmol/L, p=0.009. It is concluded that major errors in measurements of p‐lactate, anion gap and pH can be prevented by placing test tubes on crushed ice for up to 4 h until measurement.

suPAR associates to glucose metabolic aberration during glucose stimulation in HIV-infected patients on HAART

OBJECTIVE We have recently shown that the level of soluble urokinase plasminogen activator receptor (suPAR), which is associated with the immune status of HIV-infected patients undergoing highly active antiretroviral therapy (HAART), correlates with the insulin action of such patients. Here we extend these findings by investigating the association of suPAR to glucose metabolic insufficiency during an oral glucose challenge (OGTT). METHODS In 16 HIV-infected patients with lipodystrophy and 15 HIV-infected patients without lipodystrophy, glucose tolerance, insulin sensitivity (ISI(composite)), prehepatic insulin secretion, proinsulin level and suppression of free fatty acids (FFA) were determined during an OGTT. Stability of suPAR was tested in 6 HIV-infected patients during a 3h OGTT. RESULTS Lipodystrophy was associated with a 70% increase in plasma suPAR (P<0.05). During the OGTT, plasma suPAR correlated inversely with ISI(composite) and positively with 2h plasma glucose, fasting insulin secretion, fasting intact proinsulin and FFA level during the OGTT (all P<0.05). In multiple regression analyses, in which anthropometric measures (BMI, limbadiposity and fat mass), immune markers (CD4, HIV-RNA, duration of HIV infection), and dyslipidemia (plasma total cholesterol, triglyceride and free fatty acid level during the OGTT) were included, suPAR remained a significant marker of glucose tolerance and insulin sensitivity. Plasma suPAR exhibited a small CV (11%) during the 3h OGTT. CONCLUSIONS suPAR associated to important glucose metabolic aberrations in HIV-infected patients on HAART. Moreover, suPAR was stable after a glucose challenge. Future research is required to confirm these findings and explore the potential of suPAR as marker of dysmetabolism in HIV-infected patients.

Treatment of threatened premature labor with 6α-methyl-17α-acetoxyprogesterone

Abstract The effect of 6α-methyl-17α-acetoxyprogesterone in the treatment of threatened premature labor was studied in 63 cases. The drug, Perlutex, was administered in the form of tablets, 60 Mg. 3 times daily for 3 days and then 20 Mg. 3 times daily for 4 days. Fuchs and Stakemanns series, from 1956 through 1957 in the same obstetric department, was used as a control. Agreement was found in respect to age, previous obstetric history, symptoms, and signs. Delivery was successfully postponed in an equal number of cases in all groups.

Long-term high-physiological-dose growth hormone reduces intra-abdominal fat in HIV-infected patients with a neutral effect on glucose metabolism.

The aim of the study was to investigate the effect of long‐term high‐physiological‐dose recombinant human growth hormone (rhGH) therapy on fat distribution and glucose metabolism in HIV‐infected patients.