High-normal TSH values in obesity: is it insulin resistance or adipose tissue's guilt?

Objective: Clinical evidences reported subclinical alterations of thyroid function in obesity, although the relationship between thyroid status and obesity remains unclear. We cross-sectionally investigated the influence of metabolic features on hypothalamic-pituitary-thyroid axis in obesity. Design and methods: We enrolled 60 euthyroid subjects with no history of type 2 diabetes mellitus and assessed the relationship of thyroid function with insulin resistance, measured using euglycemic clamp, and abdominal fat volume, quantified by computed tomography scan (CT scan). Thyroid stimulating hormone (TSH) correlated with BMI (r = 0.46; P = 0.02), both visceral (r = 0.58; P = 0.02) and subcutaneous adipose tissue volumes (r = 0.43; P = 0.03) and insulin resistance (inverse relationship with insulin sensitivity-glucose uptake: r = -0.40; P = 0.04). Results: After performing multivariate regression, visceral adipose tissue volume was found to be the most powerful predictor of TSH (β = 3.05; P = 0.01), whereas glucose uptake, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, subcutaneous adipose tissue volume, and triglycerides were not. To further confirm the hypothesis that high-normal TSH values could be dependent on adipose tissue, and not on insulin resistance, we restricted our analyses to moderately obese subjects' BMI ranging 30-35 kg/m(2). This subgroup was then divided as insulin resistant and insulin sensitive according to the glucose uptake (≤ or >5 mg · kg(-1) · min(-1), respectively). We did not find any statistical difference in TSH (insulin resistant: 1.62 ± 0.65 µU/ml vs. insulin sensitive: 1.46 ± 0.48; P = not significant) and BMI (insulin resistant: 32.2 ± 1.6 kg/m(2) vs. insulin sensitive: 32.4 ± 1.4; P = not significant), thus confirming absence of correlation between thyroid function and insulin sensitivity per se. Conclusion: Our study suggests that the increase in visceral adipose tissue is the best predictor of TSH concentration in obesity, independently from the eventual concurrent presence of insulin resistance

Effects of PCSK9 inhibition on glucose metabolism and β-cell function in humans: a pilot study

BackgroundAnti-PCSK9 monoclonal antibodies are effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. PCSK9, however, is also expressed in tissues, including the pancreas, and studies on PCSK9 KO mice have shown impaired insulin secretion. Statin treatment is already known to affect insulin secretion. Our aim was to conduct a pilot study to evaluate the effect of anti-PCSK9 mAb on glucose metabolism and β-cell function in humans.MethodsFifteen non-diabetic subjects, candidates for anti-PCSK9 mAb therapy, were enrolled. All underwent OGTT at baseline and after 6 months of therapy. During OGTT, insulin secretion parameters were derived from C-peptide by deconvolution (β cell glucose sensitivity). Surrogate insulin sensitivity indices were also obtained from OGTT (Matsuda).ResultsGlucose levels during OGTT were unchanged after 6 months of anti-PCSK9 mAb treatment, as well as insulin and C-peptide levels. The Matsuda index remained unchanged, while β-cell glucose sensitivity improved post-therapy (before: 85.3 ± 65.4; after: 118.6 ± 70.9 pmol min-1m-2mM-1; p<0.05). Using linear regression, we found a significant correlation between βCGS changes and BMI (p=0.004). Thus, we compared subjects with values above and below the median (27.6 kg/m2) and found that those with higher BMI had a greater increase in βCGS after therapy (before: 85.37 ± 24.73; after: 118.62 ± 26.83 pmol min-1m-2mM-1; p=0.007). There was also a significant correlation between βCGS change and Matsuda index through linear regression (p=0.04), so we analyzed subjects who had values above and below the median (3.8). This subgroup analysis showed a slight though not significant improvement in βCGS in more insulin resistant patients, (before: 131.4 ± 69.8; after: 170.8 ± 92.7 pmol min-1m-2mM-1; p=0.066).ConclusionsOur pilot study demonstrates that six-month treatment with anti-PCSK9 mAb improves β-cell function, and does not alter glucose tolerance. This improvement is more evident in patients with greater insulin-resistance (low Matsuda) and higher BMI

IL-21 is a major negative regulator of IRF4-dependent lipolysis affecting Tregs in adipose tissue and systemic insulin sensitivity.

Obesity elicits immune cell infiltration of adipose tissue provoking chronic low-grade inflammation. Regulatory T cells (Tregs) are specifically reduced in adipose tissue of obese animals. Since interleukin (IL)-21 plays an important role in inducing and maintaining immune-mediated chronic inflammatory processes and negatively regulates Treg differentiation/activity, we hypothesized that it could play a role in obesity-induced insulin resistance. We found IL-21 and IL-21R mRNA expression upregulated in adipose tissue of high-fat diet (HFD) wild-type (WT) mice and in stromal vascular fraction from human obese subjects in parallel to macrophage and inflammatory markers. Interestingly, a larger infiltration of Treg cells was seen in the adipose tissue of IL-21 knockout (KO) mice compared with WT animals fed both normal diet and HFD. In a context of diet-induced obesity, IL-21 KO mice, compared with WT animals, exhibited lower body weight, improved insulin sensitivity, and decreased adipose and hepatic inflammation. This metabolic phenotype is accompanied by a higher induction of interferon regulatory factor 4 (IRF4), a transcriptional regulator of fasting lipolysis in adipose tissue. Our data suggest that IL-21 exerts negative regulation on IRF4 and Treg activity, developing and maintaining adipose tissue inflammation in the obesity state

Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: Evidence to date

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). Using an insulin-independent mechanism (glycosuria), they reduce glucose toxicity and improve insulin sensitivity and \uce\ub2-cell function. The promising results obtained in clinical trials show that SGLT2 significantly improves glycemic control and provides greater cardiovascular protection, combined with a reduction in body weight and blood pressure (BP). This review focuses on ertugliflozin, a new, highly selective, and reversible SGLT2 inhibitor. Clinical trials published to date show that ertugliflozin, both as a monotherapy and as an add-on to oral antidiabetic agents, is safe and effective in reducing glycosylated hemoglobin (HbA1c), body weight, and BP in T2DM patients

Advancing Diabetes Research: a novel islet isolation method from living donors.

Pancreatic islet isolation is critical for type 2 diabetes research. Although -omics approaches have shed light on islet molecular profiles, inconsistencies persist; on the other side, functional studies are essential, but they require reliable and standardized isolation methods. Here, we propose a simplified protocol applied to very small-sized samples collected from partially pancreatecto-mized living donors. Islet isolation was performed digesting tissue specimens collected during surgery within a collagenase P solution, followed by a Lympholyte density gradient separation; finally, functional assays and a staining with dithizone were carried out. Isolated pancreatic islets exhibited functional responses to glucose and arginine stimulation mirroring donors' metabolic profiles, with insulin secretion significantly decreasing in diabetic islets compared to non-diabetic islets; conversely, proinsulin secretion showed an increasing trend from non-diabetic to diabetic islets. This novel islet isolation method from living patients undergoing partial pancreatectomy offers a valuable opportunity for targeted study of islet physiology, with the primary advantage of being time-effective and successfully preserving islet viability and functionality. It enables the generation of islet preparations closely reflecting donors’ clinical profiles, simplifying the isola-tion process and eliminating the need for a Ricordi chamber. Thus, this method holds promises for advancing our understanding of diabetes and for new personalized pharmacological approaches

Prolonged pre-firing pancreatic compression with linear staplers in distal pancreatectomy: a valuable technique for post-operative pancreatic fistula prevention

Purpose: Post-operative pancreatic fistula (POPF) remains the main complication after distal pancreatectomy (DP). The aim of this study is to evaluate the potential benefit of different durations of progressive stapler closure on POPF rate and severity after DP. Methods: Patients who underwent DP between 2016 and 2023 were retrospectively enrolled and divided into two groups according to the duration of the stapler closure: those who underwent a progressive compression for < 10 min and those for ≥ 10 min. Results: Among 155 DPs, 83 (53.5%) patients underwent pre-firing compression for < 10 min and 72 (46.5%) for ≥ 10 min. As a whole, 101 (65.1%) developed POPF. A lower incidence rate was found in case of ≥ 10 min compression (34-47.2%) compared to < 10 min compression (67- 80.7%) (p = 0.001). When only clinically relevant (CR) POPFs were considered, a prolonged pre-firing compression led to a lower rate (15-20.8%) than the < 10 min cohort (32-38.6%; p = 0.02). At the multivariate analysis, a compression time of at least 10 min was confirmed as a protective factor for both POPF (OR: 5.47, 95% CI: 2.16-13.87; p = 0.04) and CR-POPF (OR: 2.5, 95% CI: 1.19-5.45; p = 0.04) development. In case of a thick pancreatic gland, a prolonged pancreatic compression for at least 10 min was significantly associated to a lower rate of CR-POPF compared to < 10 min (p = 0.04). Conclusion: A prolonged pre-firing pancreatic compression for at least 10 min seems to significantly reduce the risk of CR-POPF development. Moreover, significant advantages are documented in case of a thick pancreatic gland

Effect of Vitamin D Supplementation on Obesity-Induced Insulin Resistance: A Double-Blind, Randomized, Placebo-Controlled Trial

Objective: The aim was to investigate whether vitamin D supplementation, combined with a hypocaloric diet, could have an independent effect on insulin sensitivity in subjects with both overweight and hypovitaminosis D. Changes from baseline in anthropometric parameters, body composition, glucose tolerance, and insulin secretion were considered as secondary outcomes. Methods: Eighteen volunteers who were nondiabetic and vitamin D deficient and had BMI>25 kg/m2 were randomized (1:1) in a double-blind manner to a hypocaloric diet1either oral cholecalciferol at 25,000 IU/wk or placebo for 3 months. Hyperinsulinemic-euglycemic clamp to measure insulin sensitivity was performed at baseline and after intervention. Results: Body weight in both groups decreased significantly (27.5% in the vitamin D group and 210% in the placebo group; P<0.05 for both), with no between-group differences. Serum 25-hydroxyvitamin D levels in the vitamin D group increased considerably (from 36.7613.2 nmol/L to 74.8618.7 nmol/L; P<0.001). Insulin sensitivity in the vitamin D group improved (from 4.662.0 to 6.963.3mgkg21min21; P<0.001), whereas no changes were observed in the placebo group (from 4.961.1 to 5.160.3mgkg21min21; P50.84). Conclusions: Cholecalciferol supplementation, combined with a weight loss program, significantly improves insulin sensitivity in healthy subjects with obesity and might represent a personalized approach for insulin-resistant subjects with obesity

¿Cómo grabar una explicación gráfica con los recursos que tenemos?

En este tutorial se explica cómo grabar una explicación gráfica en video.Para acceder al video y para su mejor reproducción, hacer clic en "Enlace externo".Dirección de Educación a Distancia, Innovación en el aula y TI

Tips para generar un video

En este video se brindar consejos para generar un video propio.Para acceder al video y para su mejor reproducción, hacer clic en "Enlace externo".Dirección de Educación a Distancia, Innovación en el aula y TI

Nuclear export of FoxO1 is associated with ERK signaling in β-cells lacking insulin receptors

The insulin/insulin-like growth factor (IGF) signaling pathway plays a critical role in the regulation of islet cell biology. However, the signaling pathway(s) utilized by insulin to directly modulate β-cells is unclear. To interrogate whether insulin exerts endocrine effects in regulating proteins in the insulin/IGF-1 signaling cascade in vivo in physiological states via the insulin receptor, we designed two experimental approaches: 1) glucose gavage and 2) hyperinsulinemic intravenous infusion, for studies in either β-cell specific insulin receptor knock-out (βIRKO) or control mice. Immunostaining of sections of pancreas (collected immediately after glucose gavage or insulin infusion) from controls showed significant increases in pAKT+, p-p70S6K+, and pERK+ β-cells and a significant decrease in % nuclear FoxO1+ β-cells compared with corresponding vehicle-treated groups. In contrast, in βIRKOs, we observed no significant changes in pAKT+ or p-p70S6K+ β-cells in either experiment; however, pERK+ β-cells were significantly increased, and an attenuated decrease in % nuclear FoxO1+ β cells was evident in response to glucose gavage or insulin infusion. Treatment of control and βIRKO β-cell lines with glucose or insulin showed significantly decreased % nuclear FoxO1+ β-cells suggesting direct effects. Furthermore, blocking MAPK signaling had virtually no effect on FoxO1 nuclear export in controls, in contrast to attenuated export in βIRKO β-cells. These data suggest insulin acts on β-cells in an endocrine manner in the normal situation; and that in β-cells lacking insulin receptors, insulin and glucose minimally activate the Akt pathway, while ERK phosphorylation and FoxO1 nuclear export occur independently of insulin signaling