Shivaprakash Jagalur Mutt

Vitamin D and adipose tissue-more than storage.

The pandemic increase in obesity is inversely associated with vitamin D levels. While a higher BMI was causally related to lower 25-hydroxyvitamin D (25(OH)D), no evidence was obtained for a BMI lowering effect by higher 25(OH)D. Some of the physiological functions of 1,25(OH)2D3 (1,25-dihydroxycholecalciferol or calcitriol) via its receptor within the adipose tissue have been investigated such as its effect on energy balance, adipogenesis, adipokine, and cytokine secretion. Adipose tissue inflammation has been recognized as the key component of metabolic disorders, e.g., in the metabolic syndrome. The adipose organ secretes more than 260 different proteins/peptides. However, the molecular basis of the interactions of 1,25(OH)2D3, vitamin D binding proteins (VDBPs) and nuclear vitamin D receptor (VDR) after sequestration in adipose tissue and their regulations are still unclear. 1,25(OH)2D3 and its inactive metabolites are known to inhibit the formation of adipocytes in mouse 3T3-L1 cell line. In humans, 1,25(OH)2D3 promotes preadipocyte differentiation under cell culture conditions. Further evidence of its important functions is given by VDR knock out (VDR−/−) and CYP27B1 knock out (CYP27B1 −/−) mouse models: Both VDR−/− and CYP27B1−/− models are highly resistant to the diet induced weight gain, while the specific overexpression of human VDR in adipose tissue leads to increased adipose tissue mass. The analysis of microarray datasets from human adipocytes treated with macrophage-secreted products up-regulated VDR and CYP27B1 genes indicating the capacity of adipocytes to even produce active 1,25(OH)2D3. Experimental studies demonstrate that 1,25(OH)2D3 has an active role in adipose tissue by modulating inflammation, adipogenesis and adipocyte secretion. Yet, further in vivo studies are needed to address the effects and the effective dosages of vitamin D in human adipose tissue and its relevance in the associated diseases.

Inhibition of cytokine secretion from adipocytes by 1,25-dihydroxyvitamin D3 via the NF-κB pathway

Adipose tissue inflammation is an important pathological process in obese people, associated with diabetes and cardiovascular disease. We hypothesized that 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] inhibits cytokine secretion from adipocytes via direct inhibition of transcription factor nuclear factor‐κB (NF‐κB). We utilized two different human models. Bone marrow‐derived human mesenchymal stromal cells (hMSCs) differentiated into adipocytes, and adipocytes isolated from biopsies stimulated with lipopolysaccharide (LPS) were treated with or without 1,25(OH)2D3. Expression and secretion of interleukin‐6 (IL‐6) were measured by quantitative RT‐PCR analysis and ELISA. Assessment of NF‐κB nuclear translocation, DNA binding activity was performed by immunofluorescence (IF) and electrophoretic mobility assay (EMSA). Inhibitor κB (IκB) and its phosphorylation were detected by Western blot (WB) analysis. Simultaneous 1,25(OH)2D3 cotreatment significantly reduced LPS‐stimulated (10 ng/ml) IL‐6 secretion dose dependently by 15% at 10–10 M and 26% at 10–7 M (P<0.05) in hMSCs, while preincubation with 1,25(OH)2D3 (10–7 M) for 24 h reduced IL‐6 secretion by 24 and 35% (P<0.001) and mRNA levels by 34 and 30% (P<0.05) in hMSCs and isolated adipocytes, respectively. 1,25(OH)2D3 suppressed LPS‐stimulated IκB phosphorylation‐mediated NF‐κB translocation into the nucleus were evident from WB, IF, and EMSA. 1,25(OH)2D3 inhibits LPS‐stimulated IL‐6 secretion in two human adipocyte models via interference with NF‐κB signaling.—Mutt, S. J., Karhu, T., Lehtonen, S., Lehenkari, P., Carlberg, C., Saarnio, J., Sebert, S., Hyppönen, E., Järvelin, M.‐R., Herzig, K.‐H. Inhibition of cytokine secretion from adipocytes by 1,25‐dihydroxyvitamin D3 via the NF‐κB pathway. FASEB J. 26, 4400–4407 (2012). www.fasebj.org

Vitamin D deficiency at admission is not associated with 90-day mortality in patients with severe sepsis or septic shock: Observational FINNAKI cohort study

Abstract Introduction Low levels of vitamin D have been associated with increased mortality in patients that are critically ill. This study explored whether vitamin D levels were associated with 90-day mortality in severe sepsis or septic shock. Methods Plasma vitamin D levels were measured on admission to the intensive care unit (ICU) in a prospective multicentre observational study. Results 610 patients with severe sepsis were included; of these, 178 (29%) had septic shock. Vitamin D deficiency (<50 nmol/L) was present in 333 (55%) patients. The 90-day mortality did not differ among patients with or without vitamin D deficiency (28.3% vs. 28.5%, p = 0.789). Diabetes was more common among patients deficient compared to those not deficient in vitamin D (30% vs. 18%, p < 0.001). Hospital-acquired infections at admission were more prevalent in patients with a vitamin D deficiency (31% vs. 16%, p < 0.001). A multivariable adjusted Cox regression model showed that low vitamin D levels could not predict 90-day mortality (<50 nmol/L: hazard ratio (HR) 0.99 (95% CI: 0.72–1.36), p > 0.9; and <25 nmol/L: HR 0.44 (95% CI: 0.22–0.87), p = 0.018). Conclusions Vitamin D deficiency detected upon ICU admission was not associated with 90-day mortality in patients with severe sepsis or septic shock. Key messages In severe sepsis and septic shock, a vitamin D deficiency upon ICU admission was not associated with increased mortality. Compared to patients with sufficient vitamin D, patients with deficient vitamin D more frequently exhibited diabetes, elevated C-reactive protein levels, and hospital-acquired infections upon ICU admission, and they more frequently developed acute kidney injury.

Concentrated Arabinoxylan but Not Concentrated β-Glucan in Wheat Bread Has Similar Effects on Postprandial Insulin as Whole-Grain Rye in Porto-arterial Catheterized Pigs

The acute glycemic effects of concentrated dietary fibers (DF) versus whole-grain rye were studied in porto-arterial catheterized pigs. Two white wheat breads with wheat arabinoxylan (AX) or oat β-glucan (BG), two rye breads with intact rye kernels (RK) or milled rye (GR), and a low DF white wheat bread were fed to six pigs in a randomized crossover design. Blood profiles were collected for 4 h after feeding. Glucose absorption was reduced in pigs fed the AX bread at 60 min postprandial (3.1 mmol/min for AX compared to 9.4 mmol/min for WF, P = 0.02) and insulin secretion was lowered at 30 min postprandial for AX and GR (74.4 and 129 pmol/min for AX and GR, respectively, compared to 738 pmol/min for WF, P < 0.04). In conclusion, the GR and AX breads were most effective in improving insulin economy, suggesting that arabinoxylan from wheat and rye induces similar outcomes in the metabolic response.

Postprandial PYY increase by resistant starch supplementation is independent of net portal appearance of short-chain fatty acids in pigs

Increased dietary fiber (DF) fermentation and short-chain fatty acid (SCFA) production may stimulate peptide tyrosine-tyrosine (PYY) secretion. In this study, the effects of hindgut SCFA production on postprandial PYY plasma levels were assessed using different experimental diets in a porto-arterial catheterized pig model. The pigs were fed experimental diets varying in source and levels of DF for one week in 3×3 Latin square designs. The DF sources were whole-wheat grain, wheat aleurone, rye aleurone-rich flour, rye flakes, and resistant starch. Postprandial blood samples were collected from the catheters and analyzed for PYY levels and net portal appearance (NPA) of PYY was correlated to NPA of SCFA. No significant effects of diets on NPA of PYY were observed (P > 0.05), however, resistant starch supplementation increased postprandial NPA of PYY levels by 37 to 54% compared with rye-based and Western-style control diets (P = 0.19). This increase was caused by higher mesenteric artery and portal vein PYY plasma levels (P < 0.001) and was independent of SCFA absorption (P > 0.05). The PYY levels were higher in response to the second daily meal compared with the first daily meal (P < 0.001), but similar among diets (P > 0.10). In conclusion, the increased postprandial PYY responses in pigs fed with different levels and sources of DF are not caused by an increased SCFA absorption and suggest that other mechanisms such as neural reflexes and possibly an increased flow of digesta in the small intestine may be involved. The content of DF and SCFA production did not affect PYY levels.

Decreased preoperative serum 25-Hydroxyvitamin D levels in colorectal cancer are associated with systemic inflammation and serrated morphology.

Deficiency of vitamin D is associated with increased risk of several types of cancer including colorectal cancer (CRC). However, factors contributing to low levels of 25-hydroxyvitamin D [25(OH)D] in CRC are not clear. Therefore, in this study serum 25(OH)D levels in 117 CRC patients and 86 controls were analyzed and correlated with the clinicopathological data including morphological subtype (serrated or conventional), quantity of tumor infiltrating immune cells, levels of systemic inflammatory markers, and disease outcome. We found that the patients had lower serum 25(OH)D levels compared to the controls. Interestingly, among the patients mismatch repair deficiency, serrated morphology, and high body mass index associated with lowest serum 25(OH)D levels. In addition, patients operated in summer or autumn had higher serum 25(OH)D levels. Furthermore, serum 25(OH)D levels inversely correlated with several systemic inflammatory markers, e.g. serum C reactive protein, but did not associate with prognosis. Mechanism leading to vitamin D deficiency in these patients are not clear but could be related to the effects of systemic inflammation. Longitudinal studies are warranted to assess vitamin D deficiency as a potential risk factor for serrated colorectal polyps and adenocarcinoma.

Adipokines and inflammatory markers in elderly subjects with high risk of type 2 diabetes and cardiovascular disease

Inflammation plays a significant role in pathogenesis of diabetes and atherosclerosis. Increased adiposity with an upregulation of cytokines in prediabetes has been associated with vascular inflammation and considered a leading causal factor for type 2 diabetes (T2D). Information on adipokines and inflammatory markers in prediabetes, defined by hemoglobin A1C (HbA1c) 5.7–6.4% in addition to impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), are sparse. We conducted a population–based cross-sectional study (part of a follow-up study) of inhabitants of Oulu, Finland, born in 1935. Inflammatory markers and traditional risk markers of 367 subjects were measured. The glucose status was determined by an oral glucose tolerance test (OGTT) and HbA1c. Inflammatory markers and glycemic levels were analysed using analysis of covariance (ANCOVA). Of the participants, 193 were normoglycemic, 82 had prediabetes and 40 T2D. Inflammatory cytokines were significantly higher in subjects with prediabetes as compared to normoglycemic subjects: IL-4 (14.9 vs 5.9 pg/ml, p = 0.041), IP-10 (251 vs 209 pg/ml, p = 0.05), TNF-α (10.4 vs 6.9 pg/ml, p = 0.027), RANTES (43.3 vs 33.1 pg/ml, p = 0.009), CD40L (3708 vs 1671 pg/ml, p = 0.010) and VEGF (269 vs 174 pg/ml, p = 0.013). These inflammatory cytokines remained significant even after adjustment for waist circumference. The differences in inflammatory markers in prediabetic and T2D subjects were not statistically significant. Prediabetes was associated with low-grade inflammation with increased inflammatory cytokine levels, while the levels in prediabetic subjects were comparable to those in T2D subjects. The associations were independent of visceral adiposity.