Promotes Glucose Intolerance Research Articles

Metabolic and ultrastructural renal changes in adult Wistar rats fed by a cafeteria diet.

To evaluate, by quantitative and qualitative methods, the glomerular ultrastructure in Wistar rats fed a cafeteria diet. Male Wistar rats were divided into two groups at 21 days of age: control (C, n = 10) and cafeteria diet (CAF, n = 8). The animals were followed up until 5 months of age, followed by euthanasia. The blood, kidneys, and fat deposits--epididymal, retroperitoneal, and subcutaneous--were extracted and analyzed. Data were analyzed by Student's t test, and p < 0.05 was considered statistically significant. The cafeteria diet promoted glucose intolerance, hyperglycemia (p < 0.0001), and deposition of retroperitoneal fat (p < 0.005). Scanning electron microscopy revealed that the length of the foot process was similar in both groups. The quantitative analyses by transmission electron microscopy revealed that the cafeteria diet reduced the thickness of the glomerular basement membrane (p < 0.05). The intake of lipids and simple carbohydrates were found to be associated with alteration in the glomerular ultrastructure. However, more studies are needed to evaluate not only the effects of high-protein and high-fat diets on components of the glomerular filtration barrier, but also renal physiology.

PSI-20 Trans Vaccenic Acid Does Not Improve Insulin Resistance in Diet Induced Obese Mice

Abstract Trans vaccenic acid (TVA, trans11-18:1) is a natural trans fatty acid that is exclusively found in ruminant fats such as dairy, beef, and lamb. Increased circulating concentrations of TVA and its metabolites are epidemiologically related to a reduced risk of insulin resistance and type 2 diabetes (T2D). However, direct causative evidence is lacking, and the mechanisms are poorly understood. The objective of this study was to evaluate whether TVA can alleviate insulin resistance in diet-induced obese mice when compared with oleic acid (OA, cis9-18:1, the major dietary cis 18:1 isomer) or trans10-18:1 (a major industrial trans fatty acid isomer). Forty-eight male C57BL/6J mice (7 weeks old) were fed either a low-fat diet (LFD,10% kcal total fat), a high-fat diet (HFD) enriched with OA (HFD-OA; 45% kcal total fat, 6% kcal from pure OA), an HFD enriched with TVA (HFD-TVA; 45% kcal total fat, 6% kcal from pure TVA), or an HFD enriched with trans-10 18:1 (HFD-T10; 45% kcal total fat, 6% kcal from pure trans-10 18:1) for 19 weeks. The metabolic phenotype was characterized using a glucose tolerance test (GTT) and insulin tolerance test (ITT). Insulin-sensitive tissues (muscle, liver, and adipose) were harvested and extracted for protein, which was analyzed for protein kinase B (Akt) and phosphorylated Akt (pAKT) by western blot using Vinculin as a loading control. The resulting band intensities were quantitated using the FluorChem 9900 program (Alpha Innotech). pAkt expression was normalized to Akt. Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s test. Our GTT results suggested a greater (P &amp;lt; 0.05) glucose intolerance in both HFD-TVA and HFD-T10 groups compared with the LFD group. Whereas HFD-OA-fed mice maintained their glucose tolerance and insulin sensitivity despite greater body weight and adiposity. In agreement with GTT and ITT results, we found reduced (P &amp;lt; 0.05) Akt phosphorylation in the muscle of both HFD-TVA and HFD-T10 groups compared with LFD while there was no difference in phosphorylation level in the liver and adipose. In conclusion, this work demonstrates that contrary to our initial hypothesis, a large dose of TVA (6% of calorie intake) promotes glucose intolerance and insulin resistance in HFD-fed mice. Further studies using the typical intake of TVA in humans (0.5 to 1% of calorie intake) are required to better understand the effects of TVA on glucose homeostasis.

1549-P: scEMC10 Promotes Glucose Intolerance via the Inhibition of PKA-Mediated Insulin Secretion

It has been shown recently that overexpression of the secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) impairs, whereas Emc10 knockout (KO) or antibody neutralization of circulating scEMC10 improves glucose tolerance in mice fed with high fat diet. In humans, serum scEMC10 levels correlate positively with fasting plasma glucose and HbA1c. The mechanism underlying the regulation of glucose metabolism by scEMC10 remains largely unknown. In this study, alation of EMC10 significantly improved glucose tolerance in chow diet-fed mice, which was attributed to increased glucose-stimulated insulin secretion (GSIS), but not improved insulin sensitivity evaluated by euglycemic-hyperinsulinemic clamp. Using an adeno-associated virus, either reconstitution of scEMC10 in Emc10 KO mice or overexpression of scEMC10 in wildtype mice significantly decreased glucose tolerance accompanied by blunted GSIS. Recombinant scEMC10 inhibited GSIS in both INS-1 cells and isolated primary islets in vitro. Mechanistically, we presented evidence that extracellular scEMC10 can be transported into beta cells where it binds to the catalytic subunit of PKA and inhibits phosphorylations of PKA substrates including phosphorylated CREB, along with reduced PDX-1 expression. Furthermore, antibody neutralization of circulating scEMC10 alleviated hyperglycemia in both STZ-treated mice and ob/ob mice. This work identifies scEMC10 as a suppressor of insulin secretion via the inhibition of PKA signaling in islet beta cells and suggests scEMC10 neutralizing antibody as a promising pharmaceutical agent to treat diabetes. Disclosure J.Dai: None. S.Liu: None. K.Chen: None. S.Jin: None. Y.Wang: None. L.Chen: None. X.Wang: None. Funding National Natural Science Foundation of China (81873645); Science and Technology Commission of Shanghai Municipality (22140902700)

TRIM21 ameliorates hepatic glucose and lipid metabolic disorders in type 2 diabetes mellitus by ubiquitination of PEPCK1 and FASN

Hepatic glucose and lipid metabolism disorders promote the development and progression of type 2 diabetes mellitus (T2DM), yet the underlying mechanisms are not fully understood. Here, we identify tripartite motif-containing protein 21 (TRIM21), a class IV TRIM family member, as a pivotal regulator of hepatic metabolism in T2DM for the first time. Bioinformatic analysis suggests that TRIM21 expression is significantly reduced in T2DM patients. Intriguingly, in a mouse model of obese diabetes, TRIM21 expression is predominantly reduced in the liver rather than in other metabolic organs. It is further demonstrated that hepatic overexpression of TRIM21 significantly ameliorates glucose intolerance, insulin resistance, hepatic steatosis, and dyslipidemia in obese diabetic mice. In contrast, the knockdown of TRIM21 promotes glucose intolerance, insulin resistance, and triglyceride accumulation. Mechanistically, both phosphoenolpyruvate carboxykinase 1 (PEPCK1) and fatty acid synthase (FASN) are the hepatic targets of TRIM21. We revealed that TRIM21 promotes the degradation of PEPCK1 and FASN through a direct protein–protein interaction mediated K48-linked ubiquitination. Notably, overexpression of PEPCK1 and FASN essentially abolished the beneficial effects achieved by TRIM21 overexpression in obese diabetic mice. Overall, our data demonstrate that TRIM21 is a novel regulator of hepatic metabolic disorder, and suggest TRIM21 as a promising therapeutic target for T2DM.

Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism.

There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood. Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics. Combined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism. In our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.

A pathogenic role for regulatory T cells in chronic liver disease

Abstract Current dogma holds that regulatory T (Treg) cells preserve tissue function in settings of inflammation and damage through their anti-inflammatory activity and production of epithelial growth factors – the latter of which is independent from immunosuppression. Consistent with this, we observe that Treg cells – in particular those producing the epidermal growth factor receptor (EGFR)-ligand amphiregulin (Areg) – are enriched in the livers of mice and humans with non-alcoholic steatohepatitis (NASH). Mouse and human liver Treg cells undergo substantial transcriptional changes in chronic liver damage, reflecting their increased activation; however, rather than playing a protective role, we find that Treg cell–derived Areg promotes NASH-induced liver fibrosis through the direct activation of EGFR on hepatic stellate cells. Clinically, NASH is closely linked to insulin resistance, but the mechanistic contributions of NASH-induced disease processes to insulin resistance remain unclear. We further observe that Treg cell–derived Areg promotes glucose intolerance in a NASH-dependent manner – through the induction of hepatic gluconeogenesis – a process also mediated through EGFR signaling on hepatic stellate cells. Mechanistically, Treg cell–derived Areg promotes hepatocyte gluconeogenesis through hepatocyte detection of soluble mediators produced by Areg-activated hepatic stellate cells – offering new insight into how chronic liver disease promotes insulin resistance. Taken together, we provide the first evidence that Treg cells mediate a maladaptive role in tissue injury, finding that their production of a growth factor plays a central role in liver disease and promotes liver fibrosis and glucose intolerance in NASH. This research was supported by grants from NIH (K22 AI127847, R01 HL148718, R01 CA259634, T32 GM007367, P30 CA013696, P30 DK132710) and the Searle Scholars Program (SSP-2017-2179).

191-OR: Hepatic Expression of the Branched-Chain Keto Acid Dehydrogenase Kinase Is Sufficient to Cause Glucose Intolerance in Lean Mice

Perturbed branched-chain amino acid homeostasis is a feature of obesity, insulin-resistance and type 2 diabetes. Induction of the branched-chain keto acid dehydrogenase kinase (BDK) in liver is one mechanism that is thought to contribute to elevated BCAA levels in these conditions. Whether higher levels of BDK in liver are sufficient to disturb systemic BCAA homeostasis and promote glucose intolerance in the absence of obesity or insulin resistance has never been directly tested. We treated 12 week-old C57BL6/J mice with adeno-associated virus, serotype 8 (AAV8) -BDK or control AAV8-GFP to promote long term expression of BDK specifically in liver of lean mice. Mice were then maintained on a standard low-fat chow diet for 8 weeks (n= 9 AAV8-GFP and n=AAV8-BDK) . AAV8-BDK significantly raised BDK protein and mRNA expression in liver but not adipose, skeletal muscle, or cardiac tissue compared to AAV8-GFP control mice. The higher expression of BDK in liver was associated with robust inhibitory phosphorylation of the branched-chain keto acid dehydrogenase (BCKDH) on ser293. AAV8-mediated induction of BDK expression in liver in our study was sufficient to promote significant elevations in circulating levels of the direct substrate of BCKDH, the branched chain α-keto acids as well as their cognate BCAA. There was no effect of AAV8-BDK to alter food intake, weight gain or adiposity. However, glucose tolerance measured by a 1g/kg intraperitoneal glucose tolerance test at week 7 was significantly impaired in mice receiving AAV8-BDK compared to AAV8-GFP control. These data demonstrate for the first time that induction of BDK in liver, as occurs with obesity, is sufficient to disturb systemic BCAA and glucose homeostasis in lean mice. Disclosure J.Walejko: None. R.W.Mcgarrah: None. P.J.White: None. Funding American Diabetes Association (1-16-INI-17)

Influence of Nutritional Status and Physical Exercise on Immune Response in Metabolic Syndrome

Metabolic Syndrome (MetS) is a cluster of metabolic alterations mostly related to visceral adiposity, which in turn promotes glucose intolerance and a chronic systemic inflammatory state, characterized by immune cell infiltration. Such immune system activation increases the risk of severe disease subsequent to viral infections. Strong correlations between elevated body mass index (BMI), type-2-diabetes and increased risk of hospitalization after pandemic influenza H1N1 infection have been described. Similarly, a correlation between elevated blood glucose level and SARS-CoV-2 infection severity and mortality has been described, indicating MetS as an important predictor of clinical outcomes in patients with COVID-19. Adipose secretome, including two of the most abundant and well-studied adipokines, leptin and interleukin-6, is involved in the regulation of energy metabolism and obesity-related low-grade inflammation. Similarly, skeletal muscle hormones—called myokines—released in response to physical exercise affect both metabolic homeostasis and immune system function. Of note, several circulating hormones originate from both adipose tissue and skeletal muscle and display different functions, depending on the metabolic context. This review aims to summarize recent data in the field of exercise immunology, investigating the acute and chronic effects of exercise on myokines release and immune system function.

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle.

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion

SummaryGlucose homeostasis is maintained through organ crosstalk that regulates secretion of insulin to keep blood glucose levels within a physiological range. In type 2 diabetes, this coordinated response is altered, leading to a deregulation of beta cell function and inadequate insulin secretion. Reprogramming of white adipose tissue has a central role in this deregulation, but the critical regulatory components remain unclear. Here, we demonstrate that expression of the transcriptional coregulator GPS2 in white adipose tissue is correlated with insulin secretion rate in humans. The causality of this relationship is confirmed using adipocyte-specific GPS2 knockout mice, in which inappropriate secretion of insulin promotes glucose intolerance. This phenotype is driven by adipose-tissue-secreted factors, which cause increased pancreatic islet inflammation and impaired beta cell function. Thus, our study suggests that, in mice and in humans, GPS2 controls the reprogramming of white adipocytes to influence pancreatic islet function and insulin secretion.

Exposure to Low Doses of Dechlorane Plus Promotes Adipose Tissue Dysfunction and Glucose Intolerance in Male Mice.

The prevalence of type 2 diabetes (T2D) continues to increase worldwide. It is well established that genetic susceptibility, obesity, overnutrition and a sedentary life style are risk factors for the development of T2D. However, more recently, studies have also proposed links between exposure to endocrine-disrupting chemicals (EDCs) and altered glucose metabolism. Human exposure to environmental pollutants that are suspected to have endocrine disruptor activity is ubiquitous. One such chemical is Dechlorane Plus (DP), a flame retardant, that is now detected in humans and the environment. Here we show that exposure of mice to low, environmentally relevant doses of DP promoted glucose intolerance in mice fed a high-fat diet independent of weight gain. Furthermore, DP had pronounced effects on the adipose tissue, where it induced the development of hypertrophied white adipose tissue (WAT), and increased serum levels of resistin, leptin, and plasminogen activator inhibitor-1. In addition, DP exposure induced "whitening" of brown adipose tissue (BAT), and reduced BAT uncoupling protein 1 expression. Importantly, some of these effects occurred even when the mice were fed a regular, low-fat, diet. Finally, WAT adipogenic markers were reduced with DP treatment in the WAT. We also show that DP directly inhibited insulin signaling in murine adipocytes and human primary subcutaneous adipocytes in vitro. Taken together, our results show that the exposure to low and environmentally relevant levels of DP may contribute to the development of T2D.

In Utero Dexamethasone Exposure Exacerbates Hepatic Steatosis in Rats That Consume Fructose During Adulthood.

Distinct environmental insults might interact with fructose consumption and contribute to the development of metabolic disorders. To address whether in utero glucocorticoid exposure and fructose intake modulate metabolic responses, adult female Wistar rats were exposed to dexamethasone (DEX) during pregnancy, and the offspring were administered fructose at a later time. Briefly, dams received DEX during the third period of pregnancy, while control dams remained untreated. Offspring born to control and DEX-treated mothers were defined as CTL-off and DEX-off, respectively, while untreated animals were designated CTL-off-CTL and DEX-off-CTL. CLT-off and DEX-off treated with 10% fructose in the drinking water for 8 weeks are referred to as CTL-off-FRU and DEX-off-FRU. We found that fructose promoted glucose intolerance and whole-body gluconeogenesis in both CTL-off-FRU and DEX-off-FRU animals. On the other hand, hepatic lipid accumulation was significantly stimulated in DEX-off-FRU rats when compared to the CTL-off-FRU group. The DEX-off-FRU group also displayed impaired very-low-density lipoprotein (VLDL) production and reduced hepatic expression of apoB, mttp, and sec22b. DEX-off-FRU has lower hepatic levels of autophagy markers. Taken together, our results support the unprecedented notion that in utero glucocorticoid exposure exacerbates hepatic steatosis caused by fructose consumption later in life.

Long-term exposure to bisphenol A or S promotes glucose intolerance and changes hepatic mitochondrial metabolism in male Wistar rats

The present study evaluates the effects of low-level long-term exposure to bisphenol A (BPA) and bisphenol S (BPS) on serum biochemical markers, glucose homeostasis, mitochondrial energy metabolism, biogenesis and dynamics, and redox status in livers of Wistar rats. While only the exposure to BPS induces a significant body mass gain after 21 weeks, both compounds alter serum lipid levels and lead to the development of glucose intolerance. Regarding mitochondrial metabolism, both bisphenols augment the electron entry by complex II relative to complex I in the mitochondrial respiratory chain (MRC), and reduce mitochondrial content; BPA reduces OXPHOS capacity and uncouples respiration (relative to maximal capacity of MRC) but promotes a significant increase in fatty acid oxidation. Either exposure to BPA or BPS leads to an increase in mitochondrial-derived reactive oxygen species, mainly at complex I. Additionally, BPA and BPS significantly upregulate the expression levels of dynamin-related protein 1 related to mitochondrial fission, while BPA downregulates the expression of proliferator-activated receptor gamma coactivator 1 alpha, a master regulator of mitochondrial biogenesis. In summary, our data shows that exposure to both compounds alters metabolic homeostasis and mitochondrial energy metabolism, providing new mechanisms by which BPA and BPS impair the mitochondrial metabolism.

Overproduction of endothelin-1 impairs glucose tolerance but does not promote visceral adipose tissue inflammation or limit metabolic adaptations to exercise.

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity. We found that 1) diet-induced obesity, AT inflammation, and glycemic dysregulation were not accompanied by significantly increased levels of ET-1 in AT or circulation in wild-type mice and that endothelial overexpression of ET-1 and consequently increased ET-1 levels did not cause AT inflammation yet impaired glucose tolerance; 2) reduced AT inflammation and improved glucose tolerance with voluntary wheel running was not associated with decreased levels of ET-1 in AT or circulation in obese mice nor did endothelial overexpression of ET-1 impede such exercise-induced metabolic adaptations; 3) chronic pharmacological blockade of ET-1 receptors did not suppress AT inflammation in obese mice but improved glucose tolerance; and 4) in a cohort of human subjects with a wide range of body mass indexes, ET-1 levels in AT, or circulation were not correlated with markers of inflammation in AT. In aggregate, we conclude that ET-1 signaling is not implicated in the development of visceral AT inflammation but promotes glucose intolerance, thus representing an important therapeutic target for glycemic dysregulation in conditions characterized by hyperendothelinemia. Furthermore, we show that the salutary effects of exercise on AT and systemic metabolic function are not contingent on the suppression of ET-1 signaling.

Non-Nutritive Sweeteners and Their Implications on the Development of Metabolic Syndrome.

Individuals widely use non-nutritive sweeteners (NNS) in attempts to lower their overall daily caloric intake, lose weight, and sustain a healthy diet. There are insufficient scientific data that support the safety of consuming NNS. However, recent studies have suggested that NNS consumption can induce gut microbiota dysbiosis and promote glucose intolerance in healthy individuals that may result in the development of type 2 diabetes mellitus (T2DM). This sequence of events may result in changes in the gut microbiota composition through microRNA (miRNA)-mediated changes. The mechanism(s) by which miRNAs alter gene expression of different bacterial species provides a link between the consumption of NNS and the development of metabolic changes. Another potential mechanism that connects NNS to metabolic changes is the molecular crosstalk between the insulin receptor (IR) and G protein-coupled receptors (GPCRs). Here, we aim to highlight the role of NNS in obesity and discuss IR-GPCR crosstalk and miRNA-mediated changes, in the manipulation of the gut microbiota composition and T2DM pathogenesis.

PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor.

PCSK9 loss of function genetic variants are associated with lower low-density lipoprotein cholesterol but also with higher plasma glucose levels and increased risk of Type 2 diabetes mellitus. Here, we investigated the molecular mechanisms underlying this association. Pcsk9 KO, WT, Pcsk9/Ldlr double KO (DKO), Ldlr KO, albumin AlbCre+/Pcsk9LoxP/LoxP (liver-selective Pcsk9 knock-out mice), and AlbCre-/Pcsk9LoxP/LoxP mice were used. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology, and cholesterol accumulation in pancreatic islets were studied in the different animal models. Glucose clearance was significantly impaired in Pcsk9 KO mice fed with a standard or a high-fat diet for 20 weeks compared with WT animals; insulin sensitivity, however, was not affected. A detailed analysis of pancreas morphology of Pcsk9 KO mice vs. controls revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels and decreased plasma insulin, and C-peptide levels. This phenotype was completely reverted in Pcsk9/Ldlr DKO mice implying the low-density lipoprotein receptor (LDLR) as the proprotein convertase subtilisin/kexin Type 9 (PCSK9) target responsible for the phenotype observed. Further studies in albumin AlbCre+/Pcsk9LoxP/LoxP mice, which lack detectable circulating PCSK9, also showed a complete recovery of the phenotype, thus indicating that circulating, liver-derived PCSK9, the principal target of monoclonal antibodies, does not impact beta-cell function and insulin secretion. PCSK9 critically controls LDLR expression in pancreas perhaps contributing to the maintenance of a proper physiological balance to limit cholesterol overload in beta cells. This effect is independent of circulating PCSK9 and is probably related to locally produced PCSK9.

PCSK9 Deficiency Reduces Insulin Secretion and Promotes Glucose Intolerance: the Role of the LDL Receptor

PCSK9 Deficiency Reduces Insulin Secretion and Promotes Glucose Intolerance: the Role of the LDL Receptor

Carnosic acid protects mice from high-fat diet-induced NAFLD by regulating MARCKS.

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage characterized by abnormal hepatic fat accumulation and inflammatory response. Although the molecular mechanisms responsible for the disease are not yet fully understood, the pathogenesis of NAFLD likely involves multiple signals. The identification of effective therapeutic strategies to target these signals is of utmost importance. Carnosic acid (CA), as a phenolic diterpene with anticancer, anti-bacterial, anti-diabetic and neuroprotective properties, is produced by many species of the Lamiaceae family. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a major protein kinase C (PKC) substrate in many different cell types. In the present study, wild-type C57BL/6 and MARCKS-deficient mice were randomly divided into the normal chow- or high-fat (HF) diet-fed groups. The HF diet increased the fasting glucose and insulin levels, and promoted glucose intolerance in the wild-type mice. MARCKS deficiency further upregulated intolerance, fasting glucose and insulin. The HF diet also promoted hepatic steatosis, serum alanine transaminase (ALT) and aspartate transaminase (AST) activity, inflammation and lipid accumulation in the wild-type mice. These responses were accelerated in the MARCKS-deficient mice. Importantly, increased inflammation and lipid accumulation were associated with phosphoinositide 3-kinase (PI3K)/AKT, NLR family pyrin domain containing 3 (NLRP3)/nuclear factor-κB (NF-κB) and sterol regulatory element binding protein-1c (SREBP-1c) signaling pathway activation. The mice treated with CA exhibited a significantly improved glucose and insulin tolerance. The production of pro-inflammatory cytokines and lipid accumulation were suppressed by CA. Significantly, MARCKS was reduced in mice fed the HF diet. CA treatment upregulated MARCKS expression compared to the HF group. Furthermore, the activation of the PI3K/AKT, NLRP3/NF-κB and SREBP-1c signaling pathways was inhibited by CA. Taken together, our data suggest that CA suppresses inflammation and lipogenesis in mice fed a HF diet through MARCKS regulation. Thus, CA may be prove to be a useful anti-NAFLD agent.

Diet-dependence of metabolic perturbations mediated by the endocrine disruptor tolylfluanid.

Emerging evidence implicates environmental endocrine-disrupting chemicals (EDCs) in the pathogenesis of metabolic diseases such as obesity and diabetes; however, the interactions between EDCs and traditional risk factors in disease pathogenesis remain incompletely characterized. The present study interrogates the interaction of the EDC tolylfluanid (TF) and traditional dietary stressors in the promotion of metabolic dysfunction. Eight-week-old male C57BL/6 mice were fed a high-fat, high-sucrose diet (HFHSD) or a high-sucrose diet (HSD), with or without TF supplementation at 100 μg/g, for 12 weeks. Food intake, body weight and visceral adiposity were quantified. Glucose homeostasis was interrogated by intraperitoneal glucose and insulin tolerance tests at 9 and 10 weeks of exposure, respectively. After 12 weeks of dietary exposure, metabolic cage analyses were performed to interrogate nutrient handling and energy expenditure. In the background of an HFHSD, TF promoted glucose intolerance; however, weight gain and insulin sensitivity were unchanged, and visceral adiposity was reduced. In the background of an HSD, TF increased visceral adiposity; however, glucose tolerance and insulin sensitivity were unchanged, while weight gain was reduced. Thus, these analyses reveal that the metabolic perturbations induced by dietary exposure to TF, including the directionality of alterations in body weight gain, visceral adiposity and glucose homeostasis, are influenced by dietary macronutrient composition, suggesting that populations may exhibit distinct metabolic risks based on their unique dietary characteristics.

Lead exposure, dietary magnesium and glucose homeostasis in Chinese adults

BackgroundThere is mounting evidence that pollutants, including toxic metals, contribute to the global epidemic of diabetes. Along with laboratory data suggesting that lead (Pb) exposure may disrupt insulin secretion and promote glucose intolerance, a handful of epidemiological studies have reported associations between Pb and poor glucose homeostasis. A growing literature also suggests that nutrients such as dietary magnesium (Mg)—an essential metal critical for insulin action—may delay the progression of impaired glucose regulation. Our aim was to evaluate whether this beneficial dietary metal may help to reduce the impaired glucose regulation associated with toxic metals such as Pb.MethodsWe used a subsample of more than 4000 adults aged 18–65y who provided fasting serum and toenail samples in the 2009 wave of the China Health and Nutrition Survey. We measured Pb concentrations in toenail samples using inductively coupled plasma mass spectroscopy (ICP‐MS), and measured fasting glucose using colorimetric assay methods. Dietary Mg intake was estimated from three days or 24‐h dietary recalls. We estimated the association between toenail Pb concentrations and fasting glucose levels using multivariable linear regression adjusting for age, gender, body mass index, waist circumference, physical activity, urbanicity, education level, toenail arsenic and selenium, and intakes of energy, meat and rice. Interactions with dietary Mg were examined using tertiles of intake.ResultsThe median (interquartile range) toenail Pb concentration was 1.15 (1.45) mg/kg, and the mean (SD) Mg intake was 296 (107) mg/dL. The mean fasting serum glucose level was 95.8 (24.7) mg/dL. After multivariable adjustment, among individuals in the lowest tertile of dietary Mg, there was a significant increase in fasting glucose associated with a 1‐unit increase in log‐transformed toenail Pb (β±SE 0.64±0.27 mg/dL, P&lt;0.05). However, among individuals in the highest intake tertile, toenail Pb was associated with a non‐significant reduction in fasting glucose (β±SE −0.34±0.28 mg/dL NS; interaction P&lt;0.05).ConclusionFindings suggest that exposure to Pb may promote impaired glucose homeostasis, and that dietary Mg may help to reduce the diabetogenic effects of Pb exposure. Further research is needed to determine whether essential metals such as Mg may help to mitigate the risk of diabetes associated with toxic metals such as Pb.Support or Funding InformationThis research uses data from the China Health and Nutrition Survey, funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)(R01‐HD30880). We also are grateful to the Carolina Population Center (R24 HD050924) for general support.