Insulin Sensitivity In Peripheral Tissues Research Articles

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

Beyond Glucose: The Dual Assault of Oxidative and ER Stress in Diabetic Disorders.

Diabetes mellitus, a prevalent global health concern, is characterized by hyperglycemia. However, recent research reveals a more intricate landscape where oxidative stress and endoplasmic reticulum (ER) stress orchestrate a dual assault, profoundly impacting diabetic disorders. This review elucidates the interplay between these two stress pathways and their collective consequences on diabetes. Oxidative stress emanates from mitochondria, where reactive oxygen species (ROS) production spirals out of control, leading to cellular damage. We explore ROS-mediated signaling pathways, which trigger β-cell dysfunction, insulin resistance, and endothelial dysfunction the quintessential features of diabetes. Simultaneously, ER stress unravels, unveiling how protein folding disturbances activate the unfolded protein response (UPR). We dissect the UPR's dual role, oscillating between cellular adaptation and apoptosis, significantly influencing pancreatic β-cells and peripheral insulin-sensitive tissues. Crucially, this review exposes the synergy between oxidative and ER stress pathways. ROS-induced UPR activation and ER stress-induced oxidative stress create a detrimental feedback loop, exacerbating diabetic complications. Moreover, we spotlight promising therapeutic strategies that target both stress pathways. Antioxidants, molecular chaperones, and novel pharmacological agents offer potential avenues for diabetes management. As the global diabetes burden escalates, comprehending the dual assault of oxidative and ER stress is paramount. This review not only unveils the intricate molecular mechanisms governing diabetic pathophysiology but also advocates a holistic therapeutic approach. By addressing both stress pathways concurrently, we may forge innovative solutions for diabetic disorders, ultimately alleviating the burden of this pervasive health issue.

Shouldn’t Stage 4 And 5 Chronic Kidney Disease Patients Use Metformin?

Metformin tip 2 diyabetes mellitus (DM) tanılı hastaların tedavisi için birçok kılavuzda yaşam tarzı değişikliği ile birlikte ilk sırada önerilen anti diyabetik ajandır. İlacın etki mekanizması periferik dokuda insülin duyarlılığını arttırması ve karaciğerden glukoz salınımını azaltmasıdır. Metformin düşük maliyetli, etkin ve güvenilir bir ilaçtır. Sık yan etkisi gastrointestinal yan etkiler olması yanında en korkulan yan etkisi laktik asidozdur. Bu yan etkisi nedeniyle kronik böbrek hastalığı (KBH) tanılı hastalarda birçok klavuzda kullanımı sınırlandırılmıştır. Biz bu yazıda KBH’nin her evresinde metformin kullanımını inceledik. Metfomin ilişkili laktik asidoz (MALA) gelişim sıklığını araştırdık. Evre 4 ve evre 5 KBH hastaları metformin kullanmamalı mı? Sorusuna cevap aradık. Sonuç olarak MALA gibi yan etkilerin son derece nadir olduğuna karar verdik. Bu yan etkilerin daha çok enfeksiyon, ciddi kardiyovasküler olay, hipotansiyon gibi doku perfüzyonunun bozulduğu hastalıklar varlığında ortaya çıktığını gözlemledik. Dolayısıyla metformin kullanımının MALA gibi yan etkilerden ziyade hastanın klinik durumunun stabil olmadığı durumlarda ve ilacın artmış birikim riski nedeniyle özellikle evre 5 hastalarda kontrendike olabileceği kanaatine vardık.vre 4 ve evre 5 KBY’li hastalarda çok da korkmadan kar zarar ilişkisi göz önünde bulundurularak kullanılması gerekliliği kanaatine vardık.

Evaluation of leptin hormone and Tumor necrosis factor levels in patients with type two diabetes mellites

: Type 2 diabetes mellitus (T2DM) is a leading cause of mortality and morbidity worldwide. Leptin, an adipokine with the primary function of regulating energy balance, is found to mediate insulin secretion and sensitivity in peripheral tissues. Aims: Hence, we aimed to determine the role of leptin in the development of insulin resistance (IR) in newly diagnosed T2DM patients and determine tumor necrosis factoralpha (TNF-α). Materials and methods: A case control study a total of 80 patients and 50 control groups, used Cobas E311 device to measure glucose, whereas HbA1c used D-10 hemoglobin Hba1c device whereas other parameters used ELISA methods were used to analyses 130 samples Results: Highly significant increase level of Fasting blood sugar, hemoglobin A1c, Insulin, Leptin and HOMA- insulin resistance whereas significant decrease level of TNF alpha and , Plasminogen activator inhibitors -1 in patient type two diabetes mellitus compared to the control group. Conclusion: increased the level of leptin levels while TNF-α levels were decreased in type 2 diabetes patients.

Mulberry extract ameliorates T2DM-related symptoms via AMPK pathway in STZ-HFD-induced C57BL/6J mice

Ethnopharmacological relevanceMulberry (Morus alba L.) is not only a tasty food but also a beneficial medicinal substance that has been historically used to treat diabetes, as recorded in Tang Ben Cao. Recent research on animal models has shown that the ethyl acetate extract of Morus alba L. fruits (EMF) has hypoglycemic and hypolipidemic properties. However, there is a lack of documentation on the specific mechanisms through which EMF exerts its hypoglycemic effects. Objective of the studyThis study aimed to investigate the impact of EMF on L6 cells and C57/BL6J mice and to elucidate the potential mechanisms underlying its effects. The findings of this study can contribute to the existing evidence for the application of EMF as a therapeutic drug or dietary supplement in the management of type 2 diabetes mellitus (T2DM). Materials and methodsThe UPLC-Q-TOF-MS technique was utilized to gather MS data. Masslynx 4.1 software in conjunction with the SciFinder database and other relevant references were used to analyze and identify the chemical composition of EMF. A series of in vitro investigations including MTT assay, glucose uptake assay and Western blot analysis were performed using an L6 cell model stably expressing IRAP-mOrange after EMF treatment. In vivo investigations were performed on a STZ-HFD co-induced T2DM mouse model, which included assessments of body composition, biochemical tests, histopathological analysis, and Western blot analysis. ResultsMTT results revealed that EMF had no toxic effects on the cells at various concentrations. When EMF was administered to L6 cells, there was an increase in glucose transporter type 4 (GLUT4) translocation activity and a significant dose-dependent enhancement of glucose uptake by L6 myotubes. EMF treatment led to a marked increase in P-AMPK levels and GLUT4 expression in the cells, but these effects were reversed by an AMPK inhibitor (Compound C). In diabetic mice with STZ-HFD-induced diabetes, EMF treatment improved oral glucose tolerance, hyperglycemia, and hyperinsulinemia. Furthermore, EMF supplementation significantly reduced insulin resistance (IR) in diabetic mice, as evaluated using a steady-state model of the insulin resistance index. Histopathological sections demonstrated that acute EMF treatment reduced hepatic steatosis, pancreatic damage, and adipocyte hypertrophy. Western blot analysis demonstrated that EMF treatment also reduced abnormally high PPARγ expression, elevated the level of p-AMPK and p-ACC, and augmented the abundance of GLUT4 in insulin-sensitive peripheral tissues. SummaryThe results suggest that EMF may exert beneficial effects on T2DM through the AMPK/GLUT4 and AMPK/ACC pathways, as well as by regulating PPARγ expression.

Pioglitazone - the forgotten drug with multidirectional action

Introduction: Pioglitazone (PG) which belongs to thiazolidinedione class is a drug used in the treatment of type 2 diabetes. PG increases the insulin sensitivity of peripheral tissues. Type 2 diabetes mellitus (T2DM) is one of the most common and fastest developing diseases. The antihyperglycemic effect of pioglitazone (PG) is not its only one. This drug has a number of other metabolically beneficial effects. Many outcome trials indicate a positive impact of PG on the functioning of other systems.
 Aim of the study: The aim of this study is to summarize the current knowledge on the effectiveness and safety of pioglitazone based on the available scientific literature.
 Materials and methods: Literature review based on PubMed, Google Scholar database using the following phrases: pioglitazone, type 2 diabetes, pioglitazone in non-alcoholic fatty liver disease (NAFLD) therapy, pioglitazone and cardiovascular risk, pioglitazone nephroprotective effect, pioglitazone safety profile.
 State of knowledge: Pioglitazone is an oral antidiabetic drug used in the therapy of T2DM. PG belongs to the ‘insulin- sensitizers’. It is included in the treatment in the case of intolerance, contraindications to metformin or as part of combination therapy.
 Conclusions: Recently, interest in pioglitazone has waned due to the perception of significant side effects. The analysis of the papers showed a positive effect of PG on the cardiovascular system, central nervous system, NAFLD and nephroprotection. The acceptable safety profile of pioglitazone with the appropriate selection of patients as well as its multidirectional action and effectiveness mean that clinicians should reconsider the use of this drug guided by the balance of profits and losses.

Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease.

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZDs) which regulate the expression of genes involved in glucose and lipid metabolism as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZDs have shown anti-fibrogenic and anti-inflammatory effectsin vitro and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells.

Роль вітаміну D у розвитку, перебігу та лікуванні артеріальної гіпертензії

The literature review considers the new universal molecule empagliflozin, which managed to change the glucose‑centric approach in endocrinology to an organoprotective one. The results of the pivotal clinical trials conducted with empagliflozin (EMPA‑REG‑OUTCOME, EMPEROR‑REDUCED, EMPEROR‑PRESERVED and EMPULSE) strongly support the ability of empagliflozin to reduce rates of cardiovascular death or hospitalization for heart failure and to slow down the progression of chronic kidney disease. Among the confirmed and potentially favorable metabolic consequences of empagliflozin administration, the following should be emphasized: a selective antihyperglycemic effect only in conditions of hyperglycemia/glucosuria, which does not depend either on insulin production or sensitivity of peripheral tissues to insulin but is limited only by the glomerular filtration rate. This effect allows avoiding hypoglycemia even in patients without diabetes. The drug is one of the most durable among oral hypoglycemic agents and allows to maintain the achieved HbA1c values for 6 — 8 years, delaying the initiation of insulin therapy in patients with type 2 diabetes mellitus. Empagliflozin was superior to placebo in preventing death from cardiovascular disease, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus. This effect resulted from the significant reduction in the risk of cardiovascular mortality without significant changes in nonfatal myocardial infarction or nonfatal stroke. Combination with other oral and injectable hypoglycemic drugs is possible. In case of combination with sulfonylurea drugs or insulin, the dose of the latter needs to be adjusted in the direction of its decrease. Weight loss of up to 2 — 3 kg against the background of empagliflozin is an expected phenomenon that can modify blood pressure indicators and insulin resistance. Empagliflozin has the ability to reduce steatosis and improve liver fibrosis scores in patients with NAFLD without type 2 diabetes mellitus.

The intestinal microbiome associated with lipid metabolism and obesity in humans and animals.

Intestinal microbiota is considered to play an integral role in maintaining health of host by modulating several physiological functions including nutrition, metabolism and immunity. Accumulated data from human and animal studies indicate that intestinal microbes can affect lipid metabolism in host through various direct and indirect biological mechanisms. These mechanisms include the production of various signalling molecules by the intestinal microbiome, which exert a strong effect on lipid metabolism, bile secretion in the liver, reverse transport of cholesterol and energy expenditure and insulin sensitivity in peripheral tissues. This review discusses the findings of recent studies suggesting an emerging role of intestinal microbiota and its metabolites in regulating lipid metabolism and the association of intestinal microbiota with obesity. Additionally, we discuss the controversies and challenges in this research area. However, intestinal micro-organisms are also affected by some external factors, which in turn influence the regulation of microbial lipid metabolism. Therefore, we also discuss the effects of probiotics, prebiotics, diet structure, exercise and other factors on intestinal microbiological changes and lipid metabolism regulation.

Liver Fetuin-A at Initiation of Insulin Resistance

Hepatokines (liver secreted proteins with possible distant action) are emerging potential players in insulin resistance in type 2 diabetic patients. Here, we explored the effect of a high-fat diet on the expression of fetuin-A, one of those candidate liver proteins, and its relationship with liver macrophage activation. Mice were fed a normal diet or a high-fat diet for 3 days, known to initiate steatosis and liver insulin resistance. A preventive liver macrophage depletion was obtained by intravenous injection of clodronate-loaded liposomes. The mRNA and protein expression of fetuin-A was evaluated by qPCR, Western blot and immunofluorescence on different insulin-sensitive tissues (liver, adipose tissue, and muscle). Short-term high-fat diet-induced steatosis, liver macrophage activation, and hepatic insulin resistance together with a significantly increased expression of liver AHSG (α2-HS glycoprotein/fetuin-A) mRNA and serum fetuin-A concentration. On immunofluorescence, fetuin-A was mostly expressed in centrilobular hepatocytes. This increase in fetuin-A under high-fat diet was not evidenced in other peripheral insulin-sensitive tissues (skeletal muscle and adipose tissue). The mRNA expression of α2-HS glycoprotein was 800 times higher within the liver compared with the adipose tissue or the muscle. Liver macrophage depletion that significantly ameliorated insulin sensitivity was associated with a significant decrease in α2-HS glycoprotein mRNA expression. In conclusion, this study demonstrated liver fetuin-A overexpression at the initiation of high-fat diet feeding, concurrent with hepatic steatosis and insulin resistance. Targeting liver macrophages in this setting reduced liver α2-HS glycoprotein expression suggesting that fetuin-A acts as an hepatokine with proinsulin resistance effects.

The Different Insulin-Sensitising and Anti-Inflammatory Effects of Palmitoleic Acid and Oleic Acid in a Prediabetes Model.

Introduction Monounsaturated fatty acids (MUFA) are understood to have therapeutic and preventive effects on chronic complications associated with type 2 diabetes mellitus (T2DM); however, there are differences between individual MUFAs. Although the effects of palmitoleic acid (POA) are still debated, POA can regulate glucose homeostasis, lipid metabolism, and cytokine production, thus improving metabolic disorders. In this study, we investigated and compared the metabolic effects of POA and oleic acid (OA) supplementation on glucose and lipid metabolism, insulin sensitivity, and inflammation in a prediabetic model, the hereditary hypertriglyceridemic rat (HHTg). HHTg rats exhibiting genetically determined hypertriglyceridemia, insulin resistance, and impaired glucose tolerance were fed a standard diet. POA and OA were each administered intragastrically at a dose of 100 mg/kg b.wt. for four weeks. Results Supplementation with both MUFAs significantly elevated insulin and glucagon levels, but only POA decreased nonfasting glucose. POA-treated rats showed elevated circulating NEFA associated with increased lipolysis, lipoprotein lipase gene expression, and fatty acid reesterification in visceral adipose tissue (VAT). The mechanism of improved insulin sensitivity of peripheral tissues (measured as insulin-stimulated lipogenesis and glycogenesis) in POA-treated HHTg rats could contribute increased circulating adiponectin and omentin levels together with elevated FADS1 gene expression in VAT. POA-supplemented rats exhibited markedly decreased proinflammatory cytokine production by VAT, which can alleviate chronic inflammation. OA-supplemented rats exhibited decreased arachidonic acid (AA) profiles and decreased proinflammatory AA-derived metabolites (20-HETE) in membrane phospholipids of peripheral tissues. Slightly increased FADS1 gene expression after OA along with increased adiponectin production by VAT was reflected in slightly ameliorated adipose tissue insulin sensitivity (increased insulin-stimulated lipogenesis). Conclusions Our results show that POA served as a lipokine, ameliorating insulin sensitivity in peripheral tissue and markedly modulating the metabolic activity of VAT including cytokine secretion. OA had a beneficial effect on lipid metabolism and improved inflammation by modulating AA metabolism.

Irisin and the fibronectin type III domain-containing family: structure, signaling and role in female reproduction.

Dietary stress such as obesity and short-term changes in energy balance can disrupt ovarian function leading to infertility. Adipose tissue secretes hormones (adipokines), such as leptin and adiponectin, that are known to alter ovarian function. Muscles can also secrete endocrine factors, and one such family of myokines, the eleven Fibronectin type III domain-containing (FNDC) proteins, is emerging as important for energy sensing and homeostasis. In this review, we summarize the known roles the FNDC proteins play in energy homeostasis and explore potential impacts on fertility in females. The most well-known member, FNDC5, is the precursor of the 'exercise hormone', irisin, secreted by both muscle and adipose tissue. The receptors for irisin are integrins, and it has recently been shown to alter steroidogenesis in ovarian granulosa cells although the effects appear to be species or context specific, and irisin may improve uterine and placental function in women and rodent models. Another member, FNDC4, is also cleaved to release a bioactive protein that modulates insulin sensitivity in peripheral tissues and whose receptor, ADGRF5, is expressed in the ovary. As obese women and farm animals in negative energy balance (NEB) both have altered insulin sensitivity, secreted FNDC4 may impact ovarian function. We propose a model in which NEB or dietary imbalance alters plasma irisin and secreted FNDC4 concentrations, which then act on the ovary through their cognate receptors to reduce granulosa cell proliferation and follicle health. Research into these molecules will increase our understanding of energy sensing and fertility and may lead to new approaches to alleviate post-partum infertility. In Brief: Hormones secreted by muscle cells (myokines) are involved in the adaptive response to nutritional and metabolic changes. In this review, we discuss how one family of myokines may alter fertility in response to sudden changes in energy balance.

Ser/Thr phosphatases: One of the key regulators of insulin signaling.

Protein phosphorylation is an important post-translational modification that regulates several cellular processes including insulin signaling. The evidences so far have already portrayed the importance of balanced actions of kinases and phosphatases in regulating the insulin signaling cascade. Therefore, elucidating the role of both kinases and phosphatases are equally important. Unfortunately, the role of phosphatases is less studied as compared to kinases. Since brain responds to insulin and insulin signaling is reported to be crucial for many neuronal processes, it is important to understand the role of neuronal insulin signaling regulators. Ser/Thr phosphatases seem to play significant roles in regulating neuronal insulin signaling. Therefore, in this review, we discussed the involvement of Ser/Thr phosphatases in regulating insulin signaling and insulin resistance in neuronal system at the backdrop of the same phosphatases in peripheral insulin sensitive tissues.

Participation of Magnesium in the Secretion and Signaling Pathways of Insulin: an Updated Review.

Several studies have demonstrated the participation of various minerals in mechanisms involving insulin. Magnesium, in particular, plays an important role in the secretion and action of this hormone. Therefore, this review aimed to examine the latest insights into the biochemical and molecular aspects of the participation of magnesium in insulin sensitivity. Magnesium plays a vital role in the activity of intracellular proteins involved in insulin secretion in β-pancreatic cells, such as glucokinase, ATPase, and protein kinase C. In addition, evidence suggests that this mineral participates directly in insulin sensitivity and signaling in peripheral tissues, acting in the phosphorylation of the receptor tyrosine kinase and the insulin receptor substrates 1, insulin receptor substrates 2, phosphatidylinositol 3-kinase, and protein kinase B, and indirectly by reducing oxidative stress and chronic low-grade inflammation, which also lead to insulin resistance. Thus, magnesium deficiency is associated with glucose intolerance, while magnesium supplementation stimulates insulin secretion in pancreatic cells and improves insulin sensitivity in peripheral tissues. However, studies must consider assess short- and long-term nutritional status of mineral before performing intervention, the relevance of the balance of other nutrients that influence hormone secretion and sensibility, and health status of the assessed population.

Beneficial effects of carvedilol modulating potassium channels on the control of glucose.

The increased prevalence of hypertensive patients with type 2 diabetes mellitus (T2DM) is evident worldwide, leading to a higher risk of cardiovascular disease onset, which is substantially associated with disabilities and mortality in the clinic. In order to achieve the satisfyingly clinical outcomes and prognosis, the comprehensive therapies have been conducted with a beneficial effect on both blood pressure and glucose homeostasis, and clinical trials reveal that some kind of antihypertensive drugs such as angiotensin converting enzyme inhibitors (ACE-I) may, at least in part, meet the dual requirement during the disease management. As a nonselective β-blocker, carvedilol is employed for treating many cardiovascular diseases in clinical practice, including hypertension, angina pectoris and heart failure, and also exhibit the effectiveness for glycemic control and insulin resistance. Apart from alleviating sympathetic nervous system activity, several causes, such as lowering oxygen reactive species, may contribute to the effects of carvedilol on controlling plasma glucose levels, suggesting a feature of this drug having multiple targets. Interestingly, numerous distinct K+ channels expressed in pancreatic β-cells and peripheral insulin-sensitive tissues, which play a sentential role in glucose metabolism, are subjected to extensive modulation of carvdilol, establishing a linkage between K+ channels and drug's effects on the control of glucose. A variety of evidence shows that the impact of carvedilol on different K+ channels, including Kv, KAch, KATP and K2P, can lead to positive influences for glucose homeostasis, contributing to its clinical beneficial effectiveness in treatment of hypertensive patients with T2DM. This review focus on the control of plasma glucose conferred by carvedilol modulation on K+ channels, providing the novel mechanistic explanation for drug's actions.

Effect of adrenalectomy and insulin resistance on non‐shivering thermogenesis in the corpulent rat

Glucocorticoid hormones have been reported to impede optimal insulin sensitivity and glucose uptake in peripheral tissues via interactions with GLUT transporters, leading to insulin resistance and impaired glucose uptake via GLUT transporters. The LA/Ntul//‐cp rat expresses obesity in 25% of the offspring by 5 to 6 weeks of age but remains non diabetic throughout much if not all of its lifespan when normally reared. Groups of congenic lean and obese LA/Ntul//‐cp rats were fed low glycemic Purina Chow diets from 6 to 9 weeks of age or overfed with a high energy cafeteria diet (Café) from 9 until 12 weeks of age. Subgroups of obese animals were adrenalectomized (ADX) at 6 weeks of age (WoA) and subjected to the same dietary regimen to determine if the Café overfeeding could enhance the normal thermic response to norepinephrine (NE) in the obese phenotype and to determine if ADX would result in a restoration of glycemic status and NE‐induced thermogenesis in the obese phenotype. Measures of Oral Glucose Tolerance (OGT), Area under the glucose curve (AUC), and NE‐stimulated VO2 were determined (NE, 200 µg, s.c.) at 6, 9 and 12 WoA in all treatment groups and Insulin:Glucose ratios (I:G) at 12 WoA. Obese animal demonstrated hyperphagia at all ages studied, and Obese ADX hyperphagia from 9 to 12 WoA. OGT and AUC indicated modest glucose intolerance in the obese phenotype, and which was restored following ADX at 6 and 9 WoA. NE resulted in a progressive increase in VO2 in lean rats at each age studied, but NE‐stimulated VO2 was lower in the obese phenotype and decreased further after the Café feeding regimen. ADX was associated with a restoration of OGT, I:G and NE stimulated VO2 equivalent to that observed in lean animals at 12 weeks of age. These results are consistent with adrenocorticoid‐mediated insulin resistance likely due to a receptor level defect in insulin sensitivity as a contributory factor in the impairment in OGT and NST in the obese phenotype of this strain.

Deep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control

Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. Using proteomic approaches, we interrogate hepatocyte protein secretion in two models of murine NASH to understand how liver-derived factors modulate lipid metabolism and insulin sensitivity in peripheral tissues. We reveal striking hepatokine remodelling that is associated with insulin resistance and maladaptive lipid metabolism, and identify arylsulfatase A (ARSA) as a hepatokine that is upregulated in NASH and type 2 diabetes. Mechanistically, hepatic ARSA reduces sulfatide content and increases lysophosphatidylcholine (LPC) accumulation within lipid rafts and suppresses LPC secretion from the liver, thereby lowering circulating LPC and lysophosphatidic acid (LPA) levels. Reduced LPA is linked to improvements in skeletal muscle insulin sensitivity and systemic glycemic control. Hepatic silencing of Arsa or inactivation of ARSA’s enzymatic activity reverses these effects. Together, this study provides a unique resource describing global changes in hepatokine secretion in NASH, and identifies ARSA as a regulator of liver to muscle communication and as a potential therapeutic target for type 2 diabetes.

Homeostatic and Pathophysiological Regulation of Toll-like Receptor 4 Signaling by GM3 Ganglioside Molecular Species

Chronic inflammation plays an important role in the pathogenesis of obesity and metabolic disorders. In obesity, pattern-recognition receptors in innate immune system, such as Toll-like receptor 4 (TLR4), cause chronic inflammation through prolonged activation by various endogenous ligands, including fatty acids and its metabolites. Gangliosides and other glycosphingolipids are important metabolites of fatty acids and saccharides. GM3, the simplest ganglioside comprising α2,3-sialyllactose, is expressed in insulin-sensitive peripheral tissues such as liver and adipose tissue, and furthermore secreted abundantly into serum. It has been shown that GM3 regulates the signal transduction of insulin receptor in adipose tissue as a component of membrane microdomains, and elevation in GM3 level causes insulin resistance. However, the homeostatic and pathophysiological functions of extracellularly secreted GM3 are poorly understood. We recently reported that GM3 species with differing fatty acid structures act as pro- and anti-inflammatory endogenous TLR4 ligands. GM3 with very long-chain fatty acid (VLCFA) and α-hydroxyl VLCFA strongly enhanced TLR4 activation. Conversely, GM3 with long-chain fatty acid (LCFA) and ω-9 unsaturated VLCFA inhibited TLR4 activation, counteracting the VLCFA species. GM3 interacted with the extracellular complex of TLR4 and promoted dimerization/oligomerization. In obesity and metabolic disorders, VLCFA species were increased in serum and adipose tissue, whereas LCFA species was relatively decreased; their imbalances were correlated to disease progression. Our findings suggest that GM3 species are disease-related endogenous TLR4 ligands, and "glycosphingolipid sensing" by TLR4 controls the homeostatic and pathological roles of innate immune signaling.

Regulatory Effects of N-3 PUFAs on Pancreatic β-cells and Insulin-sensitive Tissues.

The N-3 polyunsaturated fatty acids (PUFAs) have a wide range of health benefits, including antiinflammatory effects, improvements in lipids metabolism and promoting insulin secretion, as well as reduction of cancer risk. Numerous studies support that N-3 PUFAs have the potentials to improve many metabolic diseases, such as diabetes, nonalcoholic fatty liver disease and obesity, which are attributable to N-3 PUFAs mediated enhancement of insulin secretion by pancreatic β-cells and improvements in insulin sensitivity and metabolic disorders in peripheral insulin-sensitive tissues such as liver, muscles, and adipose tissue. In this review, we summarized the up-to-date clinical and basic studies on the regulatory effects and molecular mechanisms of N-3 PUFAs mediated benefits on pancreatic β-cells, adipose tissue, liver, and muscles in the context of glucose and/or lipid metabolic disorders. We also discussed the potential factors involved in the inconsistent results from different clinical researches of N-3 PUFAs.

A combination of melatonin and moderate-intensity aerobic exercise improves pancreatic beta-cell function and glycemic homeostasis in type 2 diabetic model of animals

Nocturnal melatonin secretion is important for preservation of ß-cell mass and function. Knowing that type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia caused by the elevated resistance of peripheral tissues to insulin, reduction in pineal melatonin and disturbances of insulin secretion by pancreatic ß-cells. In this context, exercise is considered one of the most valuable non-pharmacological approaches for treatment of T2DM. Considering the beneficial role of melatonin on glycemic metabolism in physical exercise, we investigated the effects of moderate-intensity aerobic exercise plus melatonin on glycemic homeostasis, the morphology and architecture of pancreas in spontaneous T2DM animals [Goto-Kakizaki (GK) rats]. The results confirmed that melatonin alone reduced the mass of epididymal white adipose tissue (WAT); however, only the combination of melatonin and physical exercise significantly reduced caloric intake, body weight, WAT and improved glucose tolerance and insulin sensitivity in T2DM rats. This combination also reduced apoptosis of cells in pancreatic islets. We observed either melatonin or the combination was able to reduce insulinemia. However, only the combination improved the morphology of the pancreatic islets. Thus, we conclude that in GK rats, melatonin plays a crucial role in the functionality of the pancreas to improve insulin sensitivity of peripheral tissues and, consequently, to maintain the glucose homeostasis. In addition, the combination is more efficiency to improve glucose tolerance and integrity of pancreatic islets in GK rats than melatonin alone.