Improvement of Insulin Sensitivity by Isoenergy High Carbohydrate Traditional Asian Diet: A Randomized Controlled Pilot Feasibility Study

The prevalence of diabetes is rising dramatically among Asians, with increased consumption of the typical Western diet as one possible cause. We explored the metabolic responses in East Asian Americans (AA) and Caucasian Americans (CA) when transitioning from a traditional Asian diet (TAD) to a typical Western diet (TWD), which has not been reported before. This 16-week randomized control pilot feasibility study, included 28AA and 22CA who were at risk of developing type 2 diabetes. Eight weeks of TAD were provided to all participants, followed by 8 weeks of isoenergy TWD (intervention) or TAD (control). Anthropometric measures, lipid profile, insulin resistance and inflammatory markers were assessed. While on TAD, both AA and CA improved in insulin AUC (−960.2 µU/mL×h, P = 0.001) and reduced in weight (−1.6 kg; P<0.001), body fat (−1.7%, P<0.001) and trunk fat (−2.2%, P<0.001). Comparing changes from TAD to TWD, AA had a smaller weight gain (−1.8 to 0.3 kg, P<0.001) than CA (−1.4 to 0.9 kg, P = 0.001), but a greater increase in insulin AUC (AA: −1402.4 to 606.2 µU/mL×h, P = 0.015 vs CA: −466.0 to 223.5 µU/mL×h, P = 0.034) and homeostatic static model assessment-insulin resistance (HOMA-IR) (AA: −0.3 to 0.2, P = 0.042 vs CA: −0.1 to 0.0, P = 0.221). Despite efforts to maintain isoenergy state and consumption of similar energy, TAD induced weight loss and improved insulin sensitivity in both groups, while TWD worsened the metabolic profile. Trial Registration: ClinicalTrials.gov NCT0037954

Interleukin-33 Primes Mast Cells for Activation by IgG Immune Complexes

Mast cells (MCs) are heterogeneous cells whose phenotype is modulated by signals received from the local microenvironment. Recent studies have identified the mesenchymal-derived cytokine IL-33 as a potent direct activator of MCs, as well as regulator of their effector phenotype, and have implicated this activity in the ability of mast cells to contribute to murine experimental arthritis. We explored the hypothesis that IL-33 enables participation of synovial MCs in murine K/BxN arthritis by promoting their activation by IgG immune complexes. Compared to wild-type (WT) control mice, transgenic animals lacking the IL-33 receptor ST2 exhibited impaired MC-dependent immune complex-induced vascular permeability (flare) and attenuated K/BxN arthritis. Whereas participation of MCs in this model is mediated by the activating IgG receptor FcγRIII, we pre-incubated bone marrow-derived MCs with IL-33 and found not only direct induction of cytokine release but also a marked increase in FcγRIII-driven production of critical arthritogenic mediators including IL-1β and CXCL2. This “priming” effect was associated with mRNA accumulation rather than altered expression of Fcγ receptors, could be mimicked by co-culture of WT but not ST2−/− MCs with synovial fibroblasts, and was blocked by antibodies against IL-33. In turn, WT but not ST2−/− MCs augmented fibroblast expression of IL-33, forming a positive feedback circuit. Together, these findings confirm a novel role for IL-33 as an amplifier of IgG immune complex-mediated inflammation and identify a potential MC-fibroblast amplification loop dependent on IL-33 and ST2

Physiological Responses to Different Diets in Intervention Group, including drop-outs (Intent-to-treat) (N = 41).

a<p>BP, blood pressure; CRP, C-reactive protein; HOMA-IR, Homeostatic model assessment-insulin resistance; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1; % B, endothelium-mediated dilation; % N, non-endothelium-mediated dilation; IL, interleukin; TAD, traditional Asian diet; TNF-α, tumor necrosis factor-alpha; TWD, typical Western diet.</p>b<p>P-value of the changes observed before and after 8 weeks of TAD (Visit 3-Visit 2).</p>c<p>P-value of the changes observed before and after 8 weeks of TWD (Visit 4-Visit 3).</p>d<p>P-value of the Visit 4-Visit 3 and Visit 3-Visit 2.</p><p>Physiological Responses to Different Diets in Intervention Group, including drop-outs (Intent-to-treat) (N = 41).</p

Flow of participants throughout the study.

<p>^aAA, Asian Americans; CA, Caucasian Americans.</p

Physiological Responses to Different Diets among Asian Americans and Caucasian Americans in Intervention Group, including drop-outs (Intent-to-treat).

a<p>BP, blood pressure; CRP, C-reactive protein; HOMA-IR, Homeostatic model assessment-insulin resistance; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1; % B, endothelium-mediated dilation; % N, non-endothelium-mediated dilation; IL, interleukin; TAD, traditional Asian diet; TNF-α, tumor necrosis factor-alpha; TWD, typical Western diet.</p>b<p>P-value of the changes observed before and after 8 weeks of TAD (Visit 3-Visit 2).</p>c<p>P-value of the changes observed before and after 8 weeks of TWD (Visit 4-Visit 3).</p>d<p>P-value of the Visit 4-Visit 3 and Visit 3-Visit 2.</p><p>Physiological Responses to Different Diets among Asian Americans and Caucasian Americans in Intervention Group, including drop-outs (Intent-to-treat).</p

Baseline Profile for all participants enrolled Asian Americans vs Caucasian Americans (N = 50).

a<p>BP, blood pressure; CRP, C-reactive protein; HbA_1c, glycosylated hemoglobin; HOMA-IR, Homeostatic model assessment-insulin resistance; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1; % B, endothelium-mediated dilation; % N, non-endothelium-mediated dilation; IL, interleukin; TNF-α, tumor necrosis factor-alpha.</p><p>Baseline Profile for all participants enrolled Asian Americans vs Caucasian Americans (N = 50).</p

ST2 deficiency attenuates K/BxN arthritis.

<p>Arthritis was initiated in ST2^−/− mice and their WT littermates via intraperitoneal administration of K/BxN mouse serum on days 0 and 2 (n = 5/group). (A) Clinical score on a 0–12 scale, <i>P</i><0.0001, WT versus ST2^−/−. (B) Change in ankle thickness, <i>P</i><0.0001, WT versus ST2^−/−. (C) Histomorphometric quantification of arthritic tissue (5 ankles/group). (D) Cytokine mRNA in ankle lysates (10 ankles/group from two separate experiments) at day 8 or 10 arthritis. (E) Acute change in wrist and ankle thickness (“flare”) measured 30 minutes after initial serum administration (n = 5/group). Results shown are the mean ± SEM. Panels A–C&E reflect 1 of 2 experiments with similar results. *<i>P</i><0.05, **<i>P</i><0.01, WT versus ST2^−/−.</p

IL-33 enhances FcγRIII-mediated cytokine production by mast cells.

<p>(A–C) FcγRII^−/− or WT B6 mBMMCs were pre-incubated with or without IL-33 (10 ng/ml) for 4 hours, and then cells in pre-incubation media were spun onto plates pre-coated with anti-FcγRII/III Ab (2.4G2). Supernatants were harvested at 16 hours and assayed for IL-6 (A&B) and the granule mediator β-hexosaminidase (C). Differences in baseline IL-6 production were reproducibly observed between FcγRII^−/− and B6 mBMMCs, and may reflect divergent genetic backgrounds or other factors. (D) FcγRII^−/− mBMMCs incubated with or without IL-33 for 4 hours were activated by plate-bound 2.4G2 Ab (10 µg/ml) for 16 hours and assayed by multiplex cytokine array. (E) Quantitation of optical density of selected mediators from D (mean of 2 dots). (F) Assay of mediators identified in D-E via specific ELISA in separate experiments employing an identical experimental design (IL-1β performed on lysates). (G) To determine whether IL-33 induced intracellular accumulation of cytokine, B6 mBMMCs were stimulated with IL-33 (10 ng/ml) for the intervals indicated, washed×2 in ice-cold PBS, and lysed in the presence of protease inhibitors. All results representative of at least 2 independent experiments. *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001.</p

IL-33 mediates a MC-FLS amplification loop.

<p>MCs were cultured with or without FLS for 1–2 weeks in the upper and lower chambers, respectively, of a transwell apparatus. (A) Cytokine mRNA expression in WT and ST2^−/− MCs after co-culture with FLS. (B) Cytokine mRNA levels in MCs with or without anti-IL-33 Ab treatment (10 µg/ml q4d). Data represent 2 independent experiments with similar results. (C–D) Cytokine mRNA levels in FLS. n = 2 wells per condition, reflective of 2–5 pooled experiments. *<i>P</i><0.05, **<i>P</i><0.01, N.S., not significant.</p