The effects of acute hyperinsulinemia on bone metabolism.

Insulin signaling in bone-forming osteoblasts stimulates bone formation and promotes the release of osteocalcin (OC) in mice. Only a few studies have assessed the direct effect of insulin on bone metabolism in humans. Here, we studied markers of bone metabolism in response to acute hyperinsulinemia in men and women. Thirty-three subjects from three separate cohorts (n=8, n=12 and n=13) participated in a euglycaemic hyperinsulinemic clamp study. Blood samples were collected before and at the end of infusions to determine the markers of bone formation (PINP, total OC, uncarboxylated form of OC (ucOC)) and resorption (CTX, TRAcP5b). During 4 h insulin infusion (40 mU/m(2) per min, low insulin), CTX level decreased by 11% (P<0.05). High insulin infusion rate (72 mU/m(2) per min) for 4 h resulted in more pronounced decrease (-32%, P<0.01) whereas shorter insulin exposure (40 mU/m(2) per min for 2 h) had no effect (P=0.61). Markers of osteoblast activity remained unchanged during 4 h insulin, but the ratio of uncarboxylated-to-total OC decreased in response to insulin (P<0.05 and P<0.01 for low and high insulin for 4 h respectively). During 2 h low insulin infusion, both total OC and ucOC decreased significantly (P<0.01 for both). In conclusion, insulin decreases bone resorption and circulating levels of total OC and ucOC. Insulin has direct effects on bone metabolism in humans and changes in the circulating levels of bone markers can be seen within a few hours after administration of insulin.

[Systemic disease as cause of leg swelling]. / Systeemisairaus alaraajaturvotuksen syynä.

Symmetrical leg swelling formed in the course of the years is a common and in most cases benign phenomenon that is mostly encountered in the aged population, especially in women. Venous insufficiency of the lower limbs is the most common cause of symmetrical leg swelling among those over 50 years of age. Diseases of the essential organs such as the heart, the liver and the kidneys are excluded during the initial stage. Pitting edema occurs both in venous insufficiency and in right-sided heart failure. Basic tests and drug history are usually sufficient to exclude a host of general causes of the edema.

Central sympatholytic therapy has anti-inflammatory properties in hypertensive postmenopausal women.

OBJECTIVE: Postmenopausal phase expresses many unfavourable physiological changes that lead to increased risk for cardiovascular disease. We compared the effect of two sympatholytic antihypertensive drug treatments, the centrally acting imidazoline receptor-1 agonist moxonidine and peripherally acting beta-blocking agent atenolol on sensitive inflammatory markers in overweight postmenopausal women with diastolic hypertension. METHODS: This was a multicentre, multinational double-blinded, prospective study comparing moxonidine (0.3 mg twice daily) with atenolol (50 mg once daily) in 87 hypertensive postmenopausal overweight women who were not taking hormone therapy. Sensitive C-reactive protein, IL-6, TNFalpha, TNFalpha-RII and adiponectin were determined in the beginning of the study and after 8 weeks of medical treatment. RESULTS: TNFalpha increased in atenolol and decreased in moxonidine group (P = 0.0004 between the groups). Adiponectin concentration decreased dramatically in atenonol but did not change in moxonidine treatment group (P < 0.0001 between the groups). In logistic regression analysis only treatment group showed an independent effect on changes in adiponectin and TNFalpha concentrations. CONCLUSION: We believe that centrally acting sympatholytic agent moxonidine is beneficial in the treatment of postmenopausal women with hypertension by reducing inflammatory cytokine TNFalpha without changing protective adiponectin level.

13-cis-Retinoic acid therapy induces insulin resistance, regulates inflammatory parameters, and paradoxically increases serum adiponectin concentration.

13-cis-Retinoic acid treatment causes insulin resistance and disturbances in lipid and glucose metabolism. We studied how 13-cis-retinoic acid affects inflammatory factors and adiponectin. A total of 23 healthy patients (age, 24.9 +/- 0.9 years; body mass index, 22.6 +/- 0.7 kg/m(2)) who received 13-cis-retinoic acid treatment of acne participated in the study. The patients were studied before the treatment, after 3 months of therapy, and 1 month after the treatment. Inflammatory parameters were measured, and a 4-hour oral glucose tolerance test was performed at each visit. Treatment with 13-cis-retinoic acid resulted in a significantly elevated serum adiponectin concentration (from 24.9 +/- 2.5 to 29.4 +/- 3.6 mg/L, P < .05), hemoglobin A(1c) (from 5.27% +/- 0.05% to 5.42% +/- 0.06%, P < .01), C-peptide area under the curve (from 314.2 +/- 16.6 to 350.0 +/- 21.0 (nmol . min)/L, P < .05), and triglycerides (from 0.97 +/- 0.06 to 1.29 +/- 0.10 mmol/L, P < .05), whereas high-density lipoprotein cholesterol decreased (from 1.50 +/- 0.07 to 1.38 +/- 0.08 mmol/L, P < .05). The increase in adiponectin during 13-cis-retinoic acid therapy correlated with baseline triglycerides (r = 0.51, P < .02). Many inflammatory markers, which were nonsignificantly elevated during therapy, decreased significantly after cessation of treatment. These were C-reactive protein (median from 1.78 to 1.23 mg/L, P < .05), soluble intercellular adhesion molecule 1 (from 210 +/- 10 to 204 +/- 10 microg/L, P < .02), ceruloplasmin (256 +/- 17 to 231 +/- 17 microg/L, P < .02), and erythrocyte sedimentation rate (from 6.4 +/- 1.3 to 4.7 +/- 0.9 mm/h, P < .02). Interleukin 6 concentration was unaffected by the therapy, but decreased significantly after the treatment (from 2.18 +/- 0.46 to 1.65 +/- 0.43 ng/L, P < .05). In conclusion, although treatment with 13-cis-retinoic acid results in disturbances in glucose and lipid metabolism, paradoxically serum adiponectin concentration increases. 13-cis-Retinoic acid has profound effects on the regulation of inflammatory markers.

Soluble vascular cell adhesion molecule-1 and soluble E-selectin are associated with micro- and macrovascular complications in Type 1 diabetic patients.

OBJECTIVE: There are no large studies in Type 1 diabetic patients that have examined the relation between soluble adhesion molecules and micro- and macrovascular outcomes, although the risks of such complications are high. Therefore, the main objective is to examine the relationship between soluble (s) vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin and retinopathy, albuminuria, and cardiovascular disease (CVD) in Type 1 diabetic patients. METHODS: Cross-sectional data on 540 Type 1 diabetic patients, with a mean age of 40 years and diabetes duration of 22 years, from the EURODIAB Prospective Complications Study (PCS) were analysed. Retinopathy was assessed by centrally graded retinal photographs. Albumin excretion rate (AER) was used to define micro- and macroalbuminuria. CVD was defined as having physician diagnosed myocardial infarction (MI), stroke, coronary artery bypass graft (CABG) or angina, or Minnesota coded ischaemic electrocardiograms (ECGs). RESULTS: Unadjusted, there was a positive relationship between sVCAM-1 and sE-selectin with nonproliferative and proliferative retinopathy, micro- and macroalbuminuria, and CVD. After adjustment for age, sex, duration of diabetes, systolic blood pressure (BP), LDL-cholesterol, fasting triglycerides (TGs), smoking, body mass index (BMI), and glycated haemoglobin, as well as other complications, the strongest significant associations were shown between sVCAM-1 and macroalbuminuria, with an odds ratio of 1.83 (1.33-2.53) for every 100 ng/ml increase in sVCAM-1. CONCLUSIONS: In this large sample of Type 1 diabetic patients, it was shown that sVCAM-1 and sE-selectin have positive associations with retinopathy, albuminuria, and CVD. This suggests that adhesion molecules are important in the pathogenesis of vascular complications in Type 1 diabetes.

Leptin and adiponectin levels in acute pancreatitis.

OBJECTIVES: Obesity is a risk factor for a severe form of acute pancreatitis (AP). Because the underlying mechanisms are poorly known, we studied relationship between the severity of AP and plasma levels of leptin and adiponectin, 2 adipokines regulating the course of systemic inflammation. METHODS: The study comprises 12 patients with severe AP and 12 control patients with mild AP matched by age (+/-10 years), body mass index (+/-3 kg/m), sex, and etiology of AP. Quantikine Human Adiponectin and Quantikine Human Leptin Immunoassays (R&D Systems, Minneapolis, Minn) were used to measure the adipokine levels in the patients' plasma on admission and during the hospital stay. RESULTS: Median leptin concentrations on admission were 6.1 ng/mL (range, 1.6-72.9 ng/mL) in the severe AP group and 9.0 ng/mL (range, 2.5-36.3 ng/mL) in the mild AP group (P > 0.05). In severe AP, the value at days 2 to 4 (7.7 ng/mL; range, 1.6-13.9 ng/mL) did not differ from respective on-admission value (P > 0.05). In mild AP, the value at days 2 to 4 (3.8 ng/mL; range, 1.6-12.9 ng/mL) was lower than the respective on-admission value (P = 0.005). Adiponectin concentrations on admission were 5642 ng/mL (range, 1201-19,400 ng/mL) for severe AP and 6314 ng/mL (range, 1980-24,340 ng/mL) for mild AP (P > 0.05). Maximum variation of adiponectin level (the highest value minus the lowest value) was greater in severe AP than in mild AP (P = 0.001). CONCLUSIONS: In patients matched by age, sex, body mass index, and etiology, the on-admission plasma levels of adiponectin and leptin do not correlate with disease severity, suggesting that the adipokines do not affect the course of AP.

Vascular risk factors and markers of endothelial function as determinants of inflammatory markers in type 1 diabetes: the EURODIAB Prospective Complications Study.

OBJECTIVE: Inflammatory activity is increased in type 1 diabetes and may predispose to vascular disease. Its origin is not clear. We therefore investigated determinants of inflammation in type 1 diabetes. RESEARCH DESIGN AND METHODS: We performed a nested case-control study from the EURODIAB Prospective Complications Study of 543 European individuals having type 1 diabetes (278 men), diagnosed at <36 years of age. Case subjects (n = 348) were those with one or more complications of diabetes; control subjects (n = 195) were all those with no evidence of any complication. We determined levels of C-reactive protein, interleukin-6, and tumor necrosis factor-alpha, combined them in a "general score of inflammatory markers," and investigated their associations with vascular risk factors and markers of endothelial dysfunction by use of multiple linear regression analysis. RESULTS: Measures of inflammation were associated with sex, diabetes duration, glycemic control, the advanced glycation end product pentosidine, BMI, HDL cholesterol, triglycerides, and systolic blood pressure (standardized betas with the general score of inflammatory markers 0.15 [P = 0.002], 0.15 [P = 0.006], 0.18 [P < 0.0001], 0.12 [P = 0.005], 0.10 [P = 0.057], -0.15 [P = 0.001], 0.16 [P < 0.0001], and 0.09 [P = 0.042], respectively). In addition, measures of inflammation were strongly associated with markers of endothelial dysfunction, soluble vascular cell adhesion molecule-1, and soluble E-selectin (standardized betas with the general score of inflammatory markers 0.28 [P < 0.0001] and 0.19 [P < 0.0001]). CONCLUSIONS: We have shown that conventional risk factors for vascular disease and endothelial adhesion molecules are important determinants of inflammation in type 1 diabetic individuals, suggesting that strategies to decrease inflammatory activity in type 1 diabetes should focus not only on control of conventional risk factors, but also on improvement of endothelial function.