IntroductionBoth obesity and a poor diet are considered major risk factors for triggering insulin resistance syndrome (IRS) and the development of type 2 diabetes mellitus (T2DM). Owing to the impact of low-carbohydrate diets, such as the keto diet and the Atkins diet, on weight loss in individuals with obesity, these diets have become an effective strategy for a healthy lifestyle. However, the impact of the ketogenic diet on IRS in healthy individuals of a normal weight has been less well researched. This study presents a cross-sectional observational study that aimed to investigate the effect of low carbohydrate intake in healthy individuals of a normal weight with regard to glucose homeostasis, inflammatory, and metabolic parameters.MethodsThe study included 120 participants who were healthy, had a normal weight (BMI 25 kg/m2), and had no history of a major medical condition. Self-reported dietary intake and objective physical activity measured by accelerometry were tracked for 7 days. The participants were divided into three groups according to their dietary intake of carbohydrates: the low-carbohydrate (LC) group (those consuming <45% of their daily energy intake from carbohydrates), the recommended range of carbohydrate (RC) group (those consuming 45–65% of their daily energy intake from carbohydrates), and the high-carbohydrate (HC) group (those consuming more than 65% of their daily energy intake from carbohydrates). Blood samples were collected for the analysis of metabolic markers. HOMA of insulin resistance (HOMA-IR) and HOMA of β-cell function (HOMA-β), as well as C-peptide levels, were used for the evaluation of glucose homeostasis.ResultsLow carbohydrate intake (<45% of total energy) was found to significantly correlate with dysregulated glucose homeostasis as measured by elevations in HOMA-IR, HOMA-β% assessment, and C-peptide levels. Low carbohydrate intake was also found to be coupled with lower serum bicarbonate and serum albumin levels, with an increased anion gap indicating metabolic acidosis. The elevation in C-peptide under low carbohydrate intake was found to be positively correlated with the secretion of IRS-related inflammatory markers, including FGF2, IP-10, IL-6, IL-17A, and MDC, but negatively correlated with IL-3.DiscussionOverall, the findings of the study showed that, for the first time, low-carbohydrate intake in healthy individuals of a normal weight might lead to dysfunctional glucose homeostasis, increased metabolic acidosis, and the possibility of triggering inflammation by C-peptide elevation in plasma.

Toll-like receptors (TLRs) have been targeted for therapeutic drug development for several disorders, including cardiovascular diseases (CVD), and diabetes mellitus. Daily levels physical activity (PA) has been purported to influence the systemic circulation of cytokines, affecting the overall activation of TLRs and influencing the inflammatory milieu. Objective and self-reported daily PA was tracked in 69 normal-weight adults. Freedson's cut-offs categorized daily PA intensity into the 25th lowest, medium, and top percentiles. Monocytic TLR2 expression was quantified by flow cytometry in fresh whole blood. Cross-sectional associations between flow cytometry measured TLR2+ subsets and clinical biomarkers were evaluated. PA increased circulation of TLR2+ monocytes. TLR2 expression was adversely corelated with reduced diastolic blood pressure (DBP), triglyceride (TG), and matrix metallopeptidase 9 (MMP9) levels. However, regression analysis indicated that only TG levels were independently linked with TLR2+ subsets in circulation in active participants. Higher daily levels of physical activity are associated with improved cardiovascular blood markers and elevated circulatory monocytic TLR2+ subsets. These findings suggest that TLR2 may play a role in modulating CVD risk factors in individuals leading physically active lifestyles.

Background Toll-like receptors (TLRs) have been targeted for therapeutic drug development for several disorders, including cardiovascular diseases, and diabetes mellitus. Daily levels physical activity (PA) has been purported to influence the systemic circulation of cytokines, affecting the overall activation of TLRs and influencing the inflammatory milieu.Methods Objective and self-reported daily PA was tracked in 69 normal-weight adults. Freedson's cut-offs categorized daily PA intensity into the 25th lowest, medium, and top percentiles. Monocytic TLR2 expression was quantified by flow cytometry in fresh whole blood. Cross-sectional associations between flow cytometry measured TLR2+ subsets and clinical biomarkers were evaluated.Results PA increased circulation of TLR2+ monocytes. TLR2 expression was adversely corelated with reduced diastolic blood pressure (DBP), triglyceride (TG), and matrix metallopeptidase 9 (MMP9) levels. However, regression analysis indicated that only TG levels were independently linked with TLR2+ subsets in circulation in active participants.Conclusions Higher daily PA levels improve cardiovascular health by upregulating monocytic TLR2+ subsets in circulation, indicating that TLR2 may modulate inflammatory cytokines under physically active lifestyles.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor of type-2 diabetes and cardiovascular disease. Obesity induced by various high-fat diets from different sources results in different types of meta-inflammatory derangements, including NAFLD. Fats are a central part of healthy diets, however, the impact of various dietary fats, lacking in sucrose, on liver fat accumulation and expression of lipogenic and inflammatory markers remains unclear. To study this, C57BL/6J mice were fed sucrose-free HFDs comprising fat from diverse sources, including cocoa butter (c-HFD), sunflower oil (s-HFD), soybean oil (so-HFD), and fish oil (f-HFD). Mice fed c-HFD or so-HFD developed more severe liver steatosis, compared with those fed s-HFD or f-HFD. Liver histopathology displayed high levels of lobular inflammation in mice fed c-HFD, so-HFD, and s-HFD. Kupffer cell counts were higher in mice fed c-HFD and s-HFD. Hepatic fibrosis was seen in mice fed s-HFD or so-HFD. Of note, there was no hepatic fibrosis in mice fed f-HFD. None of the diet had a significant impact on total body weight. However, liver weight was slightly increased in mice fed c-HFD or s-HFD. Mice fed c-HFD, s-HFD, and so-HFD displayed insulin resistance. Expression of the key genes of glycolysis (Pklr), de novo lipogenesis (Acaca, Fasn, Scd1), fatty acid oxidation (Cpt1a, Ppar-α), inflammation (Tnf-α) was upregulated in mice fed c-HFD or s-HFD. No significant difference was seen regarding genes of fatty acid uptake (Cd36, Fabp2), and chemokine-associated inflammation (Ccl2). Interestingly, hepatic IL-1β and IL-6 were elevated only in mice fed c-HFD. Taken together, these findings indicate that mice fed the sucrose-free HFDs comprising lipids from various dietary sources may have differential effects on hepatic steatosis at levels of de novo lipogenesis, hepatic inflammation, and whole-body insulin resistance. Disclosure R. Ahmad: None. T.K. Jacob: None. S.P. Kochumon: None. R.S. Thomas: None. S. Shenouda: None. N. Akhter: None. A. Wilson: None. F. Bahman: None. A. Hasan: None. F. Alrashed: None. H. Arefanian: None. A. Al Madhoun: None. F. Almulla: None. S.T.K. Sindhu: None. Funding Kuwait Foundation for the Advancement of Sciences (RAAM-2016-007)

Nonalcoholic fatty liver disease (NAFLD) represents a global healthcare challenge; it is the hepatic manifestation of metabolic syndrome and is strongly associated with developing type 2diabetes mellitus (T2DM). Liver fat accumulation is the first step of disease progression that triggers hepatic lipotoxicity. The role of ceramides in inducing deleterious effects on hepatic metabolism is now well-accepted. Yet, the specific role of stress responsive sphingomyelinase activation under lipotoxic conditions remains under-investigated. The complexity of NAFLD pathogenesis contributes to lack of proper investigatory model, limiting progression in developing and testing novel treatment and prevention strategies. Here, we first report a convenient in-vitro human cell-based model with great resemblance to in-vivo NAFLD hallmarks. Neutral Sphingomyelinase (nSMase2) expression and activity was found to be elevated in both the liver of high fat steatosis mouse models and in HepG2-steatosis cell models. Meanwhile, the functional inhibition of nSMase2 prevented hepatotoxicity-induced pathologies by significantly reducing intracellular lipid accumulation and prevented the upregulation of TNF-α triggered inflammation. Furthermore, inhibition of nSMase2 showed significant increase in PPARα at both gene and protein levels, while PPARα reduction was observed under the stimulation of nSMase2 activity by its agonist daunorubicin (DNR). Together the presented data highlight the role of nSMase2 in the pathogenesis of NAFLD and other disorders linked to hepatic steatosis, providing a novel therapeutic target. Disclosure F. Alrashed: None. H. Arefanian: None. S.T. Sindhu: None. F. Bahman: None. H. AlSaeed: None. A. Al Madhoun: None. F. Alzaid: None. F. Al-Mulla: None. R. Ahmad: None. Funding Kuwait Foundation for the Advancement of Sciences (RA0402021)