Whole-body insulin clearance in people with type 2 diabetes and normal kidney function: Relationship with glomerular filtration rate, renal plasma flow, and insulin sensitivity.

OBJECTIVE: Kidney insulin clearance, proposed to be the main route of extra-hepatic insulin clearance, occurs in tubular cells following glomerular filtration and peritubular uptake, a process that may be impaired in people with type 2 diabetes (T2D) and/or impaired kidney function. Human studies that investigated kidney insulin clearance are limited by the invasive nature of the measurement. Instead, we evaluated relationships between whole-body insulin clearance, and gold-standard measured kidney function and insulin sensitivity in adults with T2D and normal kidney function. RESEARCH DESIGN AND METHODS: We determined insulin, inulin/iohexol and para-aminohippuric acid (PAH) clearances during a hyperinsulinemic-euglycemic clamp to measure whole-body insulin clearance and kidney function. Insulin sensitivity was expressed by glucose infusion rate (M value). Associations between whole-body insulin clearance, kidney function and insulin sensitivity were examined using univariable and multivariable linear regressions models. RESULTS: We investigated 44 predominantly male (77%) T2D adults aged 63 ± 7, with fat mass 34.5 ± 9 kg, lean body mass 63.0 ± 11.8 kg, and HbA1c 7.4 ± 0.6%. Average whole-body insulin clearance was 1188 ± 358 mL/min. Mean GFR was 110 ± 22 mL/min, mean ERPF 565 ± 141 mL/min, and M value averaged 3.9 ± 2.3 mg/min. Whole-body insulin clearance was positively correlated with lean body mass, ERPF and insulin sensitivity, but not with GFR. ERPF explained 6% of the variance when entered in a nested multivariable linear regression model op top of lean body mass (25%) and insulin sensitivity (15%). CONCLUSIONS: In adults with T2D and normal kidney function, whole-body insulin clearance was predicted best by lean body mass and insulin sensitivity, and to a lesser extent by ERPF. GFR was not associated with whole-body insulin clearance. In contrast to prior understanding, this suggests that in this population kidney insulin clearance may not play such a dominant role in whole-body insulin clearance.

Peripheral Insulin Extraction in Non-Diabetic Subjects and Type 2 Diabetes Mellitus Patients.

BACKGROUND: Insulin has to be transported across the capillary endothelium to stimulate muscle glucose uptake. We investigated insulin uptake from the peripheral circulation in non-diabetic (ND) individuals and in type 2 diabetes (T2D) patients. METHODS: Single-center cross-sectional study involving 40 ND (age 65±11 years) and 30 T2D patients (age 67±8 years). Thirty-six participants were studied in the fasted state (22 ND subjects and 14 T2D patients termed NDF and T2DF) and 34 participants 1-h following a glucose challenge (18 ND subjects and 16 T2D patients indicated as NDG and T2DG). Main outcome measure was fractional extraction (FE) of insulin (FEins) and glucose using the forearm balance method. RESULTS: In NDF, FEins was 18 (10-26) % at lower insulin levels (63 51-80] pmol/l), while in NDG at higher insulin levels (776 [543-1176] pmol/l), FEins was 9 (4-16) % (p = 0.01 vs. NDF). In NDF only, a negative correlation was observed between FEins and arterial plasma insulin load (rho = - 0.575;p = 0.006) and fasting plasma glucose levels (rho = - 0.551;p = 0.01). In T2DF FEins was 6 (1-19) % and not different from FEins in T2DG (10 2-14) %), and was not associated to fasting glucose. FEins tended to be higher in NDF compared to T2DF (p = 0.07). DISCUSSION: We propose that in ND individuals, besides passive diffusion, an active high-affinity pathway with limited capacity around lower physiologic insulin levels exists for insulin transendothelial transport, contributing to glycemic control. In T2D patients, this mechanism of peripheral insulin uptake is diminished or even absent. Modulation of insulin extraction from the circulation may be a novel target to improve glucose metabolism in T2D.

Sarcoidosis-related hypercalcaemia due to production of parathyroid hormone-related peptide.

Hypercalcaemia is frequently observed in patients with sarcoidosis. This is classically attributed to ectopic production of 1,25 dihydroxy vitamin D by sarcoid granulomas. We present a case of sarcoidosis-related hypercalcaemia with normal vitamin D levels. In this patient, production of parathyroid hormone-related peptide (PTHrp) was the cause for sarcoidosis-induced hypercalcaemia. As such, plasma PTHrp levels were increased and bone marrow granulomas stained positively for PTHrp expression. Medium-dose prednisolone treatment improved symptoms of sarcoidosis and normalised serum calcium, and PTHrp concentrations. Thus, production of PTHrp may be the cause for hypercalcaemia in some patients with sarcoidosis.

Ongoing HIV replication in cerebrospinal fluid under successful monotherapy.

We report a case of an HIV-infected patient who was successfully treated with ritonavir/lopinavir (r/LPV) monotherapy for several years. He presented with neurological symptoms and high HIV RNA levels in cerebrospinal fluid (CSF). Sequencing of the HIV from the CSF revealed mutations in the protease gene reflecting resistance against most protease inhibitors, that is, lopinavir and ritonavir. His regimen was switched and after 2 months the HIV RNA viral load was again undetectable in both plasma as well as in CSF. Monotherapy with r/LPV may not be sufficient to fully suppress viral replication in the central nervous system in all individuals and may lead to compartimentalization and the selection of resistant mutations of HIV in the central nervous system.

Effects on incident reporting after educating residents in patient safety: a controlled study.

BACKGROUND: Medical residents are key figures in delivering health care and an important target group for patient safety education. Reporting incidents is an important patient safety domain, as awareness of vulnerabilities could be a starting point for improvements. This study examined effects of patient safety education for residents on knowledge, skills, attitudes, intentions and behavior concerning incident reporting. METHODS: A controlled study with follow-up measurements was conducted. In 2007 and 2008 two patient safety courses for residents were organized. Residents from a comparable hospital acted as external controls. Data were collected in three ways: 1] questionnaires distributed before, immediately after and three months after the course, 2] incident reporting cards filled out by course participants during the course, and 3] residents' reporting data gathered from hospital incident reporting systems. RESULTS: Forty-four residents attended the course and 32 were external controls. Positive changes in knowledge, skills and attitudes were found after the course. Residents' intentions to report incidents were positive at all measurements. Participants filled out 165 incident reporting cards, demonstrating the skills to notice incidents. Residents who had reported incidents before, reported more incidents after the course. However, the number of residents reporting incidents did not increase. An increase in reported incidents was registered by the reporting system of the intervention hospital. CONCLUSIONS: Patient safety education can have immediate and long-term positive effects on knowledge, skills and attitudes, and modestly influence the reporting behavior of residents.

Aerococcus urinae: severe and fatal bloodstream infections and endocarditis.

Aerococcus urinae is a pathogen that rarely causes severe or fatal infections. We describe four cases of severe A. urinae bloodstream infections. All patients had underlying urologic conditions. Urine cultures, however, were negative.

Abacavir/lamivudine/zidovudine maintenance after standard induction in antiretroviral therapy-naïve patients: FREE randomized trial interim results.

Maintenance with a triple nucleoside reverse transcriptase Inhibitor (NRTI) regimen after successful induction with a dual NRTI/protease inhibitor (PI) combination may be advantageous, because of low pill burden, favorable lipids, and less drug interactions. This strategy to become free of PI-related problems without losing viral efficacy has not been formally tested. We performed a randomized, open-label, multicenter, 96-week comparative study in antiretroviral therapy (ART)-naïve patients with CD4 50 copies per milliliter). Two hundred seven patients had similar baseline (BL) characteristics: median CD4 180 cells/mm(3), median VL 5.19 log(10) copies per milliliter. One hundred twenty subjects (58%) met randomization criteria. Baseline VL differed significantly between dropouts and randomized subjects (median 5.41 versus 5.06 log(10) copies per milliliter, p = 0.017), as did CD4 cells (median 160 and 200 cells/mm(3), p = 0.044). Sixty-one subjects received TZV and 59 subjects continued NRTIs/PI. At week 48, 2 patients in the TZV group and 5 in the PI group did not have a sustained virologic suppression (log rank test; p = 0.379). CD4 counts increased significantly in both arms. In ART-naïve patients, TZV maintenance had similar antiviral efficacy compared to continued standard ART at 48 weeks after baseline. Patients on successful standard ART can be safely switched to a NRTI-only regimen, at least for the tested time period.

No virological failure in semen during properly suppressive antiretroviral therapy despite subtherapeutic local drug concentrations.

PURPOSE: The aim of the study was to investigate whether drug resistance occurs earlier in seminal than in blood plasma with the use of such HAART regimens, of which only the two NRTIs achieve therapeutic concentrations in seminal plasma. METHOD: Seminal and blood plasma of 12 patients, for 48-96 weeks on suppressive first-line therapy with saquinavir/ritonavir/didanosine/lamivudine, nelfinavir/didanosine/stavudine, or efavirenz/lamivudine/zidovudine were prospectively evaluated for HIV-1-RNA resistance mutations and drug concentrations. RESULTS: Saquinavir, nelfinavir, and efavirenz blood plasma concentrations were in the therapeutic range. Nelfinavir and efavirenz seminal plasma concentrations were below the limit of quantification. In only 2 of 9 seminal plasma samples, from 1 of 6 patients, the saquinavir concentration was above the minimum therapeutic level. The seminal plasma HIV-1-RNA concentration remained undetectable in all patients up to 96 weeks, and therefore drug resistance could not be demonstrated. Thus, despite suboptimal local drug concentrations, no virological failure occurred in seminal plasma after prolonged first-line HAART. CONCLUSION: This finding supports the hypothesis that the source of HIV in semen is a spillover from the blood/extraluminal tissue and that therefore seminal plasma drug levels may not be critical for viral suppression within the lumen of the male genital tract.