Waist circumference does not predict circulating adiponectin levels in sub-Saharan women-0

<p><b>Copyright information:</b></p><p>Taken from "Waist circumference does not predict circulating adiponectin levels in sub-Saharan women"</p><p>http://www.cardiab.com/content/6/1/31</p><p>Cardiovascular Diabetology 2007;6():31-31.</p><p>Published online 16 Oct 2007</p><p>PMCID:PMC2098752.</p><p></p>t circumference (mid panel) and insulin resistance (lower panel) in men (left) and women (right). Spearman correlation coefficient (r) and significance (p) indicated in the figures

Natural Killer Cell Function, an Important Target for Infection and Tumor Protection, Is Impaired in Type 2 Diabetes

<div><p></p><p>Patients with Type 2 diabetes (T2D) are highly susceptible to infection and have an increased incidence of some tumors, possibly due to immune system dysfunction. In the innate cellular immune system, Natural Killer (NK) lymphocytes are important effectors responsible for controlling infections and combating tumor development. We analyzed NK cell subsets in 51 patients with long-standing T2D. Compared with healthy blood donors, diabetic patients showed a profound decrease in both NKG2D-positive NK cells (44% <i>vs.</i> 55.5%, P<0.01) and NKp46-positive cells (26% <i>vs.</i> 50%, P<0.01). Decreased expression of these receptors was associated with functional defects, such as reduced NK degranulation capacity when challenged with the tumor target cell line K562 (10.3 <i>vs.</i> 15.8%, P<0.05). This defect could be restored <i>in vitro</i> by stimulating NK cells from T2D patients with IL-15 (P<0.05). NKG2D expression was found to be negatively correlated with HBA1c level (r = −0.50; P = 0.009), suggesting that sustained hyperglycemia could directly influence NK cell defects. We demonstrated that endoplasmic reticulum (ER) stress, an important mediator in diabetes-associated complications, was inducible <i>in vitro</i> in normal NK cells and that tunicamycin treatment resulted in a significant decrease in NKG2D expression (P<0.05). Furthermore, markers of the Unfolded Protein Response (UPR) BiP, PDI and sXBP1 mRNAs were significantly increased in NK cells from T2D patients (P<0.05, P<0.01, P<0.05, respectively), indicating that ER stress is activated in vivo through both PERK and IRE1 sensors. These results demonstate for the first time defects in NK cell-activating receptors NKG2D and NKp46 in T2D patients, and implicate the UPR pathway as a potential mechanism. These defects may contribute to susceptibility to infections and malignancies and could be targetted therapeutically.</p> </div

Decreased NKp46 mRNA expression in NK cells from type 2 diabetic patients.

<p>Quantitative RT-PCR was used to assess expression of NKp46 and NKG2D mRNAs in NK cells from healthy donors (n = 7) and diabetic patients (n = 7). Transcript levels are presented as mean±SEM. Only NKp46 mRNA is down-regulated. *:P<0.05.</p

Assessing ER stress and UPR activation in NK cells from diabetic patients.

<p>mRNA levels for <i>BiP</i>, <i>PDI</i> and s<i>XBP1</i> were quantified by quantitative RT-PCR in NK cells from healthy donors (n = 17) and type 2 diabetic patients (n = 18). Transcript levels are presented as mean±SEM. *:P<0.05; **: P<0.01.</p

Tunicamycin induces ER stress and UPR activation, and decreases NKG2D expression in normal PBMCs <b><i>in vitro</i></b><b>.</b>

<p>PBMCs from healthy donors were incubated in the absence (Ctrl) or in the presence (Tm) of 1.25 µg/mL tunicamycin for 6 hours. (A) ER stress markers <i>BiP</i>, <i>HERP</i>, <i>GRP94</i> and <i>PDI</i>, (B) IRE1α pathway marker <i>spliced XBP1</i> (s<i>XBP1</i>) and (C) PERK pathway markers <i>ATF4</i>, <i>GADD34</i> and <i>CHOP</i> mRNA amounts were determined by quantitative RT-PCR in normal PBMCs. Transcript levels are presented as mean±SEM (n = 6). *:P<0.05. (D) NKG2D, NKp46 and NKG2C expressions were quantified by flow cytometry (n = 12). *:P<0.05.</p

Demographic characteristics of the 51 diabetic patients.

<p>Demographic characteristics of the 51 diabetic patients.</p

The deletion of the GR in the pancreas increases serotonin synthesis is islets.

<p>(A) Tph1, (B) Tph2 mRNA levels and (C) serotonin contents in islets from control mice (GR^Lox/Lox, white bars), mice that carry the PdxCre transgene (GR^+/+—PdxCre, gray bars) and mice that are deleted for the GR in the pancreas (GR^Lox/Lox–PdxCre, black bars). Values are means ± SD. * p<0.05, ** p<0.01 when comparing GR^- to control mice using a non parametric Mann-Whitney test (n = 3–4 per group).</p

GCs inhibit Tph1 and Tph 2 expression and serotonin synthesis in beta cells.

<p>(A) Tph1 and (B) Tph 2 mRNA levels in isolated wild type mouse islets cultured in control conditions (white bars) or treated with 10⁻⁷M Dexamethasone for 24h (black bars). (C) Serotonin contents in mouse islets cultured in control conditions (white bars) or treated with 10⁻⁷M Dex for 24h (black bars). (D) Tph1 and (E) Tph 2 mRNA levels in MIN6 cells cultured in control conditions (white bars) or treated with 10⁻⁷M Dex for 24h (black bars). (F) Serotonin contents in MIN6 cells cultured in control conditions (white bars) or treated with 10⁻⁷M Dex for 24h (black bars). Results are expressed as means ± SD for n = 4 independent experiments. * p<0.05 and ** p<0.01 when comparing Dex-treated <i>vs</i> control islets or MIN6 cells, using a Mann-Whitney non parametric test.</p

Decreased functional properties of diabetic NK cells and effects of IL-15.

<p>(A) CD107a degranulation assay using PBMCs from diabetic (n = 18) or control subjects (n = 16) challenged with K562 cells. Representative flow cytometry experiments are shown. (B) Overnight incubation in the presence of IL-15 (10 ng/mL) significantly increases NKG2D expression on NK cells from T2D patients (n = 7), as assessed by flow cytometry. A representative flow cytometry experiment is shown. (C) Stimulation with IL-15 (10 ng/mL) restores CD107a degranulation for PBMCs from diabetic patients (n = 7) challenged with K562 target cells. A representative flow cytometry experiment is shown *: P<0.05.</p

GCs inhibit exendin-4 activation of Tph1 and Tph 2 in beta cells.

<p>(A) Tph1 and (B) Tph2 mRNA levels in MIN6 cells cultured in control conditions (white bars) or treated with 10⁻⁷M Dexamethasone (black bars), with 100 ng/ml exendin-4 (Ex) (dark grey bars) or with both for 24h (light grey bars). (C) Representative immunoblot for Tph1 and Actin on protein extracts from MIN6 cells under the same conditions (upper panel) and quantification of the signals (lower panel). (D) Tph activity in MIN6 cells in the same conditions. (E) Serotonin contents measured in the same conditions. Results are expressed as means ± SD for n = 6 independent experiments. * p<0.05 ** p<0.01 and *** p<0.001 when comparing the different groups using a ANOVA test.</p