Peter Thye-Rønn

Insulin resistance in skeletal muscles in patients with NIDDM.

Skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM) are resistant to insulin; i.e., the effect of insulin on glucose disposal is reduced compared with the effect in control subjects. This defect has been found to be localized to the nonoxidative pathway of glucose disposal; hence, the deposition of glucose, as glycogen, is abnormally low. This defect may be inherited, because it is present in first-degree relatives to NIDDM patients two to three decades before they develop frank diabetes mellitus. The cellular defects responsible for the abnormal insulin action in NIDDM patients is reviewed in this article. The paper focuses mainly on convalent insulin signaling. Insulin is postulated to stimulate glucose storage by initiating a cascade of phosphorylation and dephosphorylation events, which results in dephosphorylation and hence activation of the enzyme glycogen synthase. Glycogen synthase is the key enzyme in regulation of glycogen synthesis in the skeletal muscles of humans. This enzyme is sensitive to insulin, but in NIDDM patients it has been shown to be completely resistant to insulin stimulation when measured at euglycemia. The enzyme seems to be locked in the glucose-6-phosphate (G-6-P)-dependent inactive D-form. This hypothesis is favored by the finding of reduced activity of the glycogen synthase phosphatase and increased activity of the respective kinase CAMP-dependent protein kinase. A reduced glycogen synthase activity has also been found in normoglycemic first-degree relatives of NIDDM patients, indicating that this abnormality precedes development of hyperglycemia in subjects prone to develop NIDDM. Therefore, this defect may be of primary genetic origin. However, it does not appear to be a defect in the enzyme itself, but rather a defect in the covalent activation of the enzyme system. Glycogen synthase is resistant to insulin but may be activated allosterically by G-6-P. This means that the defect in insulin activation can be compensated for by increased intracellular concentrations of G-6-P. In fact, we found that both hyperinsulinemia and hyperglycemia are able to increase the G-6-P level in skeletal muscles. Thus, insulin resistance in the nonoxidative pathway of glucose processing can be overcomed (compensated) by hyperinsulinemia and hyperglycemia. In conclusion, we hypothesize that insulin resistance in skeletal muscles may be a primary genetic defect preceding the diabetic state. The cellular abnormality responsible for that may be a reduced covalent insulin activation of the enzyme glycogen synthase. The compensation results in nearnormalization of glycogen synthesis, but the price diabetic subjects must pay to obtain this is hyperglycemia.

Effect of short-term hyperglycemia per se on nociceptive and non-nociceptive thresholds

&NA; Previous animal and human studies have indicated that nociceptive thresholds are decreased by acute hyperglycemia. The results of these studies may be challenged due to methodological problems. We therefore conducted a double‐blind, controlled, cross‐over study on the effect of acute hyperglycemia on nociceptive and non‐nociceptive thresholds in 10 type 1 (insulin‐dependent) diabetic patients (diabetes < 5 years) without symptoms or clinical signs of peripheral neuropathy. During an overnight fast, blood glucose concentration was normalized by refract insulin injections. Then, blood glucose was kept at 6 mmol/1 for 3 h by an intravenous infusion of glucose and insulin. On one study day, blood glucose was kept at 6 mmol/1 for a further 3 h and on another day, blood glucose was elevated to 12 mmol/1 during 0.5 h by additional glucose infusion and kept at that level for 2.5 h. Sensory testing was carried out twice during the initial 3 h with euglycemia and 3 times during the following period with either hyper‐ or euglycemia. The test procedure included determination of pain detection and pain tolerance thresholds to heat (wrists) and pressure (fingers) as well as detection thresholds to warmth/cooling (wrist), vibration (finger), and mechanical (wrist) stimulation. The changes in neither nociceptive nor non‐nociceptive thresholds showed any statistically significant differences between the 2 study days. The pressure pain detection and tolerance thresholds showed, however, minor decreases at each of the test days, probably due to cutaneous sensitization caused by the repeated measurements. Compared to baseline, the pressure pain thresholds decreased significantly on the day with hyperglycemia. None of the other thresholds showed such changes. It cannot be excluded that more pronounced or longer term hyperglycemia can cause changes in sensibility. We conclude that acute hyperglycemia (12 mmol/1) does not cause major changes in nociceptive or non‐nociceptive thresholds in the upper extremity, however, pressure pain thresholds was reduced significantly with hyper glycemia.

Glucose effectiveness and insulin sensitivity measurements derived from the non-insulin-assisted minimal model and the clamp techniques are concordant

We investigated the concordance between glucose effectiveness (SG) and insulin sensitivity (SI), derived from the unmodified dynamic non‐insulin‐assisted intravenous glucose tolerance test (IVGTT) implemented by SGMM and SIMM; simulation analysis and modelling/conversational interaction (SAAM/CONSAM) versus the eu/hyperglycaemic basal insulinaemic and the euglycaemic hyperinsulinaemic clamp (SGCLAMP and SICLAMP).

Leptospirosis-Associated Severe Pulmonary Hemorrhagic Syndrome with Lower Back Pain as an Initial Symptom.

Patient: Female, 45 Final Diagnosis: Leptospirosis Symptoms: Back pain • fever • headache • Hemopthysis • nausea • sepsis Medication: — Clinical Procedure: — Specialty: Infectious Diseases Objective: Rare disease Background: Leptospirosis is a zoonosis transmitted through urine of infected animals. Symptoms range from mild influenza-like symptoms to severe pulmonary hemorrhagic syndrome (SPHS); the latter are often fatal. The serogroup distribution in Denmark has changed from 1988 to 2012, with Icterohaemorrhagiae and Sejroe now being predominant. Case report: A 45-year-old Danish woman living in an area endemic for Hanta virus, without prior medical history, was admitted because of lower back pain radiating to the left hip, fever, headache, nausea, and malaise. Two weeks before admission she had been bitten by a mouse or a rat. Blood tests revealed raised white cells and CRP, electrolyte imbalances, raised creatinine, low thrombocytes, and a slightly decreased clotting factor (II, VII, and X). Treatment with broad-spectrum intravenous antibiotics and supporting therapy was initiated very quickly. Eight hours after admission she died from respiratory failure where severe hemoptysis was observed. Leptospiral DNA was later detected in a urine sample. Conclusions: This case represents leptospirosis with severe pulmonary hemorrhagic syndrome. In spite of immediate treatment with broad-spectrum antibiotics, the patient died a few hours after hospital admission.

Polymyalgia rheumatica and giant cell arteritis—three challenges—consequences of the vasculitis process, osteoporosis, and malignancy: A prospective cohort study protocol

Introduction: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are common inflammatory conditions. The diagnosis of PMR/GCA poses many challenges since there are no specific diagnostic tests. Recent literature emphasizes the ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to assess global disease activity in inflammatory diseases. 18F-FDG PET/CT may lead to the diagnosis at an earlier stage than conventional imaging and may also assess response to therapy. With respect to the management of PMR/GCA, there are 3 significant areas of concern as follows: vasculitis process/vascular stiffness, malignancy, and osteoporosis. Methods and analysis: All patients with suspected PMR/GCR referred to the Rheumatology section of Medicine Department at Svendborg Hospital, Denmark. The 4 separate studies in the current protocol focus on: the association of clinical picture of PMR/GCA with PET findings; the validity of 18F-FDG PET/CT scan for diagnosis of PMR/GCA compared with temporal artery biopsy; the prevalence of newly diagnosed malignancies in patients with PMR/GCA, or PMR-like syndrome, with the focus on diagnostic accuracy of 18F-FDG PET/CT scan compared with conventional workup (ie, chest X-ray/abdominal ultrasound); and the impact of disease process, and also steroid treatment on bone mineral density, body composition, and vasculitis/vascular stiffness in PMR/GCA patients. Ethics and dissemination: The study has been approved by the Regional Ethics Committee of the Region of Southern Denmark (identification number: S-20160098) and Danish Data Protection Agency (J.nr 16/40522). Results of the study will be disseminated via publications in peer-reviewed journals, and presentation at national and international conferences.

Lower back pain as an initial symptom of a fatal infection with leptospirosis.

3 OP04 HLA-B27 status is associated with TNF-α inhibitor treatment outcomes in ankylosing spondylitis and non radiographic axial spondyloarthritis. An observational cohort study from the nationwide DANBIO registry B Glintborg, IJ Sørensen, M Østergaard, NS Krogh, AA Mohamoud, LS Andersen, JL Raun, O Hendricks, MR Kowalski, L Danielsen, SR Christensen, N Al Chaer, R Pelck, H Nordin, JK Pedersen, DGA Kraus, IMJ Hansen, J Espesen, A Schlemmer, AG Loft, L Salomonsen, L Dreyer, ML Hetland