Metabolic Phenotype and Adipose Tissue Inflammation in Patients with Chronic Obstructive Pulmonary Disease

Potential links between metabolic derangements and adipose tissue (AT) inflammation in patients with chronic obstructive pulmonary disease (COPD) are unexplored. We investigated AT expressions of interleukin (IL)-6, tumor necrosis factor (TNF)-α, CD68 (macrophage cell surface receptor), caspase-3, and Bax, and their relationships to the metabolic phenotype in nine cachectic, 12 normal-weight, 12 overweight, and 11 obese patients with COPD (age 62.3 ± 7.2 years). With increasing body mass index, increases in AT expressions of IL-6, TNF-α, and CD68 were observed (P < .001; P = .005; P < .001, resp.), in association with reduced insulin sensitivity (P < .001). No differences were observed between cachectic and normal-weight patients in AT expressions of inflammatory or proapoptotic markers. Adipose tissue CD68 and TNF-α expressions predicted insulin sensitivity independently of known confounders (P = .005; P = .025; R2 = 0.840). Our results suggest that AT inflammation in obese COPD patients relates to insulin resistance. Cachectic patients remain insulin sensitive, with no AT upregulation of inflammatory or proapoptotic markers

Transcriptional regulation of adipocyte formation by the liver receptor homologue 1 (Lrh1) – small heterodimereization partner (Shp) network

Altered adipose tissue formation is a well-known effectors of obesity and T2D. Here, we describe the role of Lrh1 and its co-repressor Shp in the control of adipocyte formation. Expression of Lrh1 in the pre-adipocyte containing SVF is induced in obese mice models and humans while Shp expression is reduced. We demonstrate, that Lrh1 is an inhibitor of adipogenesis while Shp acts functions as an activator through repression of Lrh1 activity. This regulation is at least in part modulated by estradiol conversion through the regulation of Cyp19a1 gene expression. In vivo, loss of Lrh1 leads to induced adipogenesis, while loss of Shp causes uncontrolled activation of Lrh1 and reduced adipogenesis. As Shp expression has been linked to the development of obesity and metabolic disorders, it is possible that alterations of the Shp/Lrh1 network lead to changes in adipocyte formation, which might contribute to the development of obesity associated T2D

Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations

BACKGROUND: Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(sub ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(sub ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(sub ATP) channel by an ATP-independent route. METHODS: We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(sub ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. RESULTS: A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(sub ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. CONCLUSIONS: Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(sub ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism

Genetic analysis of single-minded 1 gene in early-onset severely obese children and adolescents

<div><p>Background</p><p>Inactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of <i>SIM1</i> mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of <i>SIM1</i> in severely obese children of Slovak and Moravian descent to determine if genetic variants within <i>SIM1</i> may influence the development of obesity in these populations.</p><p>Methods</p><p>The <i>SIM1</i> promoter region, exons and exon-intron boundaries were sequenced in 126 unrelated obese children and adolescents (2–18 years of age) and 41 adult lean controls of Slovak and Moravian origin. Inclusion criteria for the children and adolescents were a body mass index standard deviation score higher than 2 SD for an appropriate age and sex, and obesity onset at less than 5 years of age. The clinical phenotypes of the <i>SIM1</i> variant carriers were compared with clinical phenotypes of 4 <i>MC4R</i> variant carriers and with 27 unrelated <i>SIM1</i> and <i>MC4R</i> mutation negative obese controls that were matched for age and gender.</p><p>Results</p><p>Seven previously described <i>SIM1</i> variants and one novel heterozygous variant p.D134N were identified. The novel variant was predicted to be pathogenic by 7 <i>in silico</i> software analyses and is located at a highly conserved position of the SIM1 protein. The p.D134N variant was found in an 18 year old female proband (BMI 44.2kg/m²; +7.5 SD), and in 3 obese family members. Regardless of early onset severe obesity, the proband and her brother (age 16 years) did not fulfill the criteria of metabolic syndrome. Moreover, the variant carriers had significantly lower preferences for high sugar (<i>p</i> = 0.02) and low fat, low carbohydrate, high protein (<i>p</i> = 0.02) foods compared to the obese controls.</p><p>Conclusions</p><p>We have identified a novel <i>SIM1</i> variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods.</p></div

Food preference for the novel SIM1 variant p.D134N carriers (proband, her father and brother) compared to unrelated obese adult controls.

<p>A) Food preference for the low fat, low carbohydrate and high protein food and B) Food preference for the high sugar food.</p

Distribution of <i>SIM1</i> variants among carriers and <i>in silico</i> analyses.

<p>Distribution of <i>SIM1</i> variants among carriers and <i>in silico</i> analyses.</p