Effects of telmisartan and ramipril on adiponectin and blood pressure in patients with type 2 diabetes

<b>Background:</b> Adiponectin is secreted by adipose tissue and may play a role in cardiovascular disease. We examined adiponectin levels in patients with type 2 diabetes who participated in the Telmisartan vs. Ramipril in Renal Endothelial Dysfunction (TRENDY) study. <b>Methods</b> A total of 87 patients were assessed at baseline and following 9 weeks treatment with the angiotensin-receptor blocker telmisartan (final dose, 80 mg; n = 45) or the angiotensin-converting enzyme inhibitor ramipril (final dose, 10 mg; n = 42). Adiponectin levels were measured in plasma by radioimmunoassay. <b>Results:</b> Adiponectin levels were inversely correlated with systolic (SBP; r = -0.240, P < 0.05) and diastolic (DBP; r = -0.227, P < 0.05) blood pressure at baseline and following treatment with telmisartan or ramipril (SBP: r = -0.228, P < 0.05; DBP: r = -0.286, P < 0.05). Changes in adiponectin levels were related to changes in SBP (r = -0.357, P < 0.01) and DBP (r = -0.286, P < 0.01). There was a significant increase in adiponectin levels in the telmisartan (0.68 (95% confidence interval (CI), 0.27 to 1.10) <sup>µ</sup>g/ml, P < 0.01) but not in the ramipril group (0.17 (95% CI, -0.56 to 0.90) <sup>µ</sup>g/ml, P = 0.67). Blood pressure reduction in the telmisartan group (DeltaSBP: -13.5 (95% CI, -17.0 to -10.0) mm Hg; ΔDBP: -7.6 (95% CI, -9.8 to -5.3) mm Hg, each P < 0.001) was significantly (P less than or equal to 0.01 for SBP and P < 0.01 for DBP) greater than in the ramipril group (ΔSBP: -6.1 (95% CI, -6.2 to -2.0) mm Hg; ΔDBP: -2.7 (95% CI, -5.0 to -0.5) mm Hg; P < 0.01 and P < 0.05, respectively). <b>Conclusion:</b> Adiponectin is correlated with blood pressure in patients with type 2 diabetes. Whether increased adiponectin contributes to the blood pressure–lowering effect of telmisartan needs further study

Genetic and epidemiological studies on the role of adiponectin and PTP1B in the metabolic syndrome

Abstract The metabolic syndrome is a cluster of components predisposing to type 2 diabetes and cardiovascular disease. Abdominal obesity and insulin resistance seem to be central in the metabolic syndrome, although no unifying pathophysiological mechanism is available. The aim of this thesis was to determine out how the variation in PTP1B and adiponectin gene as well as variations in the plasma adiponectin concentration contribute to the risk of obesity related diseases. PTP1B is a negative regulator of insulin signalling and therefore considered a candidate gene for type 2 diabetes. In the first study, it was found that three PTP1B polymorphisms studied have not strong impact on type 2 diabetes. However, one SNP may be slightly protective against type 2 diabetes, since it was more frequent in the healthy group compared to group of patients with type 2 diabetes. Another SNP was associated with body mass index (BMI). The combination of certain alleles of PTP1B and LEPR (leptin receptor) genes was also associated to BMI. Adiponectin is an adipocytokine expressed in adipose tissue. It has insulin sensitizing effects in liver and muscle and it has also beneficial effects on cardiovascular health. In the second study, the contribution of adiponectin genotypes with obesity-related phenotypes was studied. In Caucasians, the carriers of rare allele of Tyr111His polymorphism were more insulin resistant and at a higher risk of developing type 2 diabetes. In African-Americans, other polymorphisms were associated with BMI and lipids. Thus, the effects of polymorphisms on obesity related phenotypes seemed to be different between ethnic groups. Plasma adiponectin levels were measured from different study groups. In the third study, it was found out that low plasma adiponectin levels associated with different components of the metabolic syndrome and there was a trend towards reductions in adiponectin with an increasing number of components. Fourth study indicated that baseline low adiponectin level associated with a more than 2-fold risk for developing impaired glucose tolerance or type 2 diabetes in the follow-up study of normoglycemic middle-aged Finnish subjects. In the fifth study, plasma adiponectin levels were measured from postmenopausal women receiving estrogen replacement therapy. We observed a reduction in adiponectin levels in women having peroral estradiol which could be part of the "early harm" profile on cardiovascular risk factors of the peroral estrogen replacement therapy detected in clinical trials. These studies further strengthen the role of plasma adiponectin in the obesity related diseases and bring new information of polymorphisms in the adiponectin and PTP1B genes in different populations.Tiivistelmä Metabolinen oireyhtymä on kertymä tekijöitä, jotka altistavat tyypin 2 diabetekselle ja sydän- ja verisuonitaudeille. Keskivartalolihavuus ja insuliiniresistenssi, eli insuliinin heikentynyt teho, vaikuttavat olevan keskeisiä metabolisessa oireyhtymässä. Kuitenkaan taustalla olevaa syntymekanismia ei täysin tunneta. Väitöskirjatyön tavoitteena oli tutkia PTP1B- ja adiponektiinigeenin muuntelun sekä plasman adiponektiinitason yhteyttä metaboliseen oireyhtymään, sen osatekijöihin ja seurauksiin. PTP1B on insuliinin toimintaa soluissa estävä molekyyli. Ensimmäisessä tutkimuksessa havaittiin että kolme tutkittua PTP1B-geenin nukleotidimuutosta eivät ole vahvasti yhteydessä tyypin 2 diabetekseen. Eräs nukleotidimuutos saattaisi olla lievästi suojaava tyypin 2 diabetesta vastaan, sillä se oli yleisempi terveillä kuin tyypin 2 diabetesta sairastavilla. PTP1B:n ja leptiinireseptorigeenin eräiden alleelien yhdistelmä oli yhteydessä painoindeksiin. Adiponektiini on rasvakudoksen erittämä hormoni, jolla on suotuisia, insuliinin vaikutusta edesauttavia vaikutuksia elimistössä sekä edullisia vaikutuksia verenkiertoelimistössä. Toisessa työssä havaittiin että Amerikan valkoihoisilla, joilla oli eräs harvinainen adiponektiinigeenin alleeli (Tyr111His), oli heikompi insuliinin teho kuin henkilöillä joilla ei ollut kyseistä muutosta. Tämä alleeli oli yleisempi suomalaisilla tyypin 2 diabetesta sairastavilla kuin terveillä, mikä saattaa tarkoittaa että se liittyy suurentuneeseen riskiin tyypin 2 diabetekselle. Afroamerikkalaisilla taas toiset nukleotidimuutokset olivat yhteydessä lihavuuteen ja plasman rasva-arvoihin. Adiponektiinin pitoisuutta plasmassa mitattiin erilaisissa aineistoissa. Kolmannessa tutkimuksessa havaittiin, että matala pitoisuus oli yhteydessä metabolisen oireyhtymän eri osatekijöihin ja pitoisuus oli sitä matalampi, mitä enemmän osatekijöitä henkilöllä on. Neljännessä tutkimuksessa havaittiin että matala plasman adiponektiinipitoisuus oli yhteydessä suurentuneeseen riskiin saada huonontunut glukoosin sietokyky tai tyypin 2 diabetes tulevaisuudessa. Viidennessä tutkimuksessa adiponektiinitaso määritettiin naisilta jotka olivat ohittaneet vaihdevuodet ja saivat estrogeenikorvaushoitoa. Havaittiin että plasman adiponektiinitaso laski niillä naisilla, jotka saivat korvaushoitoa suun kautta. Tämä saattaisi osittain selittää suun kautta annettavan estrogeenikorvaushoidon epäedullista vaikutusta sydän ja -verisuonitautien riskitekijöihin. Tutkimus vahvistaa edelleen adiponektiinin merkitystä lihavuuteen liittyvissä sairauksissa ja tuo uutta tietoa adiponektiini- ja PTP1B-geenien muuntelun merkityksestä eri väestöissä

Inflammation and neutrophil oxidative burst in a family with NFKB1 p.R157X LOF and sterile necrotizing fasciitis

Abstract Loss-of-function (LOF) mutations in NFKB1, coding for p105, may cause common variable immunodeficiency due to dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κΒ) pathway. Monoallelic LOF variants of NFKB1 can predispose to uncontrolled inflammation including sterile necrotizing fasciitis or pyoderma gangrenosum. In this study, we explored the impact of a heterozygous NFKB1 c.C936T/p.R157X LOF variant on immunity in sterile fasciitis patients and their family members. The p50 or p105 protein levels were reduced in all variant carriers. Interleukin-1β (IL-1β) and interleukin-8 (IL-8) levels were elevated in vitro, potentially contributing to the very high neutrophil counts observed during fasciitis episodes. Phosphorylation of p65/RelA was reduced in p.R157X neutrophils suggesting defective activation of canonical NF-κB. Oxidative burst after NF-κB-independent phorbol 12-myristate 13-acetate (PMA) stimulation was similar in both p.R157X and control neutrophils. Comparable amounts of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex subunits were found in p.R157X and control neutrophils. However, a compromised oxidative burst was observed in p.R157X neutrophils following activation of NF-κB-dependent mechanisms following stimulation of toll-like receptor 2 (TLR2) and Dectin-1. Neutrophil extracellular trap formation was not affected by p.R157X. In summary, the NFKB1 c.C936T/p.R157X LOF variant has an impact on inflammation and neutrophil function and may play a role in the pathogenesis of sterile necrotizing fasciitis