Sense of Coherence is associated with LDL-cholesterol in patients with type 1 diabetes – The PROLONG-Steno study

Aim It is a constant challenge for people with type 1 diabetes to maintain appropriate levels of HbA1c, blood pressure and blood lipids in order to prevent or delay deleterious effects of their illness. This study sought to investigate if Sense of Coherence (SOC) is associated with clinical risk factors in people with type 1 diabetes. Methods Questionnaire data, including measure of SOC, was collected from 125 patients with long duration of type 1 diabetes and linked to electronic patient records to obtain clinical measures on HbA1c, blood pressure, and blood lipids. Linear regressions and generalized additive models were applied to explore the associations between SOC and clinical biomarkers. Results Mean age of the participants was 60.7 years (standard deviation = 10.0), 44.0% were men. Medium and high SOC were associated with lower levels of LDL-cholesterol (p = 0.005). This association was non-linear with medium and high levels of SOC being advantageous whereas low SOC was associated with elevated levels of LDL-cholesterol. Moreover, we observed non-significant tendencies to associations between low SOC and low HDL-cholesterol, and elevated HbA1c. Conclusions Findings from this study suggest that high SOC may be protective against elevated LDL-cholesterol among people with type 1 diabetes. Interventions to improve self-management among people with low SOC may prove effective to prevent deterioration of metabolic risk factors

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

International audienceThe melanocortin receptors (MCRs) belong to the G-protein coupled receptors (family A). So far, 5 different subtypes have been described (MC1R- MC5R) and of these MC2R and MC5R have been proposed to act directly in adipocytes and regulate lipolysis in rodents. Using ACTH and a-melanocyte stimulating hormone (a-MSH) generated from proopiomelanocortin (POMC), as well as synthetic MSHanalogues to stimulate lipolysis in murine 3T3-L1 adipocytes it is shown that MC2R and MC5R are lipolytic mediators in differentiated 3T3-L1 adipocytes. Involvement of cAMP, phosphorylated extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (PKB), adenosine 5' monophosphateactivated protein kinase (AMPK) and Jun-amino-terminal kinase (JNK) in MCR mediated lipolysis were studied. Interestingly, results obtained in 3T3-L1 cells suggest that lipolysis stimulated by a-MSH, NDPa- MSH, MT-II, SHU9119 and PG-901 is mediated through MC5R in a cAMP independent manner. Finally, we identify essential differences in MCR mediated lipolysis when using 3T3-L1 cells compared to primary adipocytes

α-MSH stimulates glucose uptake in mouse muscle and phosphorylates Rab-GTPase-activating protein TBC1D1 independently of AMPK

The melanocortin system includes five G-protein coupled receptors (family A) defined as MC1R-MC5R, which are stimulated by endogenous agonists derived from proopiomelanocortin (POMC). The melanocortin system has been intensely studied for its central actions in body weight and energy expenditure regulation, which are mainly mediated by MC4R. The pituitary gland is the source of various POMC-derived hormones released to the circulation, which raises the possibility that there may be actions of the melanocortins on peripheral energy homeostasis. In this study, we examined the molecular signaling pathway involved in α-MSH-stimulated glucose uptake in differentiated L6 myotubes and mouse muscle explants. In order to examine the involvement of AMPK, we investigate -MSH stimulation in both wild type and AMPK deficient mice. We found that -MSH significantly induces phosphorylation of TBC1 domain (TBC1D) family member 1 (S237 and T596), which is independent of upstream PKA and AMPK. We find no evidence to support that -MSH-stimulated glucose uptake involves TBC1D4 phosphorylation (T642 and S704) or GLUT4 translocation

α-MSH (100 nM) stimulated 2-Deoxy Glucose uptake and TBC1D1 S237, T596 and S700 phosphorylation +/- H89 in dissected soleus explants from WT mice.

<p>A: Soleus muscle was dissected, stimulated and 2-DG was measured as described (n indicated in the individual bars). B: Phosphorylation of TBC1D1 was measured in soleus muscle using WB as described. TBC1D1 S237, T596 and S700 phosphorylation is normalized to total TBC1D1. Findings are shown as a representative immunoblot and pooled data quantified in bar graphs as arbitrary units. 2-way RM ANOVA was used to calculate statistical significance (*p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle). ^# indicates a significant effect of genotype (^#p < 0.05, ^##p < 0.01, ^###p < 0.001). Data generated in the experiment are only obtained from experiment day 4.</p

α-MSH (100 nM) stimulated TBC1D1 S237 and T596 phosphorylation in WT and AMPK KD mice.

<p>TBC1D1 S237 and T596 phosphorylation sites were measured in soleus muscle using WB as described (n indicated in the individual bars). Phosphorylation of TBC1D1 S237 and T596 is normalized to total TBC1D1. Findings are shown as representative immunoblots and pooled data is quantified in bar graphs as arbitrary units. 2-way RM ANOVA was used to calculate statistical significance (*p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle). ^# indicates a significant effect of genotype (^#p < 0.05, ^##p < 0.01, ^###p < 0.001).</p

α-MSH induced phosphorylation of AMPK in differentiated L6 myotubes and in soleus explants dissected from lean and diet-induced obese (DIO) mice.

<p>A: Phosphorylation of AMPK in lean and DIO mice in basal conditions in soleus muscle explants (n=4). 2.B: α-MSH-phosphorylation of AMPK in lean and DIO soleus muscle explants (n=6). 2.C: Phosphorylation of AMPK after α-MSH-stimulation (100 nM) in differentiated L6 myotubes (n=4). AMPK phosphorylation is normalized to total AMPK. Unpaired one-tailed t-test was used to calculate statistical significance (*p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle)</p