Type 2 Diabetes Mellitus (T2DM) is a rapidly growing global health issue characterized by insulin resistance and chronic inflammation. Beyond regulating glucose homeostasis, insulin plays a pivotal role in modulating immune cell function, linking metabolic dysregulation with immune responses. This review examines the intricate relationship between insulin resistance and immune dysfunction in T2DM, focusing on how impaired insulin signaling pathways, particularly PI3K/Akt and MAPK, contribute to immune cell activation, proliferation, and chronic inflammation. Insulin resistance impacts immune cells such as T cells, B cells, macrophages, and neutrophils, leading to an imbalance between pro-inflammatory and anti-inflammatory responses. Elevated pro-inflammatory cytokines (eg, TNF-α, IL-6) and adipokines (eg, leptin, resistin) exacerbate insulin resistance, promoting a vicious cycle of metabolic and immune dysregulation. This interplay contributes to the chronic low-grade inflammation that underlies T2DM pathogenesis, further impairing insulin signaling and glucose metabolism. Restoration of insulin sensitivity is, therefore, a critical step toward correcting immune imbalance in insulin-resistant states like T2DM. Therapeutic approaches that reduce inflammation could also support improvements in insulin sensitivity, addressing both metabolic and immune disturbances simultaneously. The review also explores therapeutic strategies, including insulin therapy, targeting insulin signaling pathways, and lifestyle interventions. Insulin therapy can reduce pro-inflammatory cytokine production and enhance anti-inflammatory responses, although challenges such as potential immune suppression and hyperinsulinemia remain. Targeting key signaling pathways and transcription factors offers promising avenues for modulating immune responses, while lifestyle interventions, such as dietary modifications, physical activity, and weight management, can improve insulin sensitivity and reduce inflammation. By understanding the dual role of insulin in regulating both metabolic and immune functions, this review underscores the importance of addressing immune dysfunction as part of comprehensive T2DM management. Targeting the interconnected pathways of insulin signaling and immune regulation could lead to more effective therapeutic approaches, ultimately improving patient outcomes and reducing disease complications.

Glucagon plays a central role in hepatic adaptation during fasting, with the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) traditionally associated with increased gluconeogenesis. However, recent experimental models and clinical studies have challenged this view, suggesting a more complex interplay between PCK1 and glucagon, which extends beyond gluconeogenesis and has broader implications for metabolic regulation in health and disease.

This review provides a comprehensive overview of the current evidence on the multifaceted roles of PCK1 in glucagon-dependent hepatic adaptation during fasting, which is crucial for maintaining systemic homeostasis not only of glucose, but also of lipids and amino acids. We explore the relationship between PCK1 deficiency and glucagon resistance in metabolic disorders, including inherited PCK1 deficiency and metabolic dysfunction-associated steatotic liver disease (MASLD), and compare findings from experimental animal models with whole-body or tissue-specific ablation of PCK1 or the glucagon receptor. We propose new research platforms to advance the therapeutic potential of targeting PCK1 in metabolic diseases.

We propose that hepatic PCK1 deficiency might be an acquired metabolic disorder linking alterations in lipid metabolism with impaired glucagon signaling. Our findings highlight interesting links between glycerol, PCK1 deficiency, elevated plasma alanine levels and glucagon resistance. We conclude that the roles of PCK1 and glucagon in metabolic regulation are more complex than previously assumed. In this (un)expected scenario, hepatic PCK1 deficiency and glucagon resistance appear to exert limited control over glycemia, but have broader metabolic effects related to lipid and amino acid dysregulation. Given the shift in glucagon research from receptor inhibition to activation, we propose that a similar paradigm shift is needed in the study of hepatic PCK1. Understanding PCK1 expression and activity in the glucagon-dependent hepatic adaptation to fasting might provide new perspectives and therapeutic opportunities for metabolic diseases.

Adipose triglyceride lipase (ATGL) is an attractive therapeutic target in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the effects of pharmacological ATGL inhibition on the development of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in mice.

Streptozotocin-injected male mice were fed a high-fat diet to induce MASH. Mice receiving the ATGL inhibitor atglistatin (ATGLi) were compared to controls using liver histology, lipidomics, metabolomics, 16s rRNA, and RNA sequencing. Human ileal organoids, HepG2 cells, and Caco2 cells treated with the human ATGL inhibitor NG-497, HepG2 ATGL knockdown cells, gel-shift, and luciferase assays were analysed for mechanistic insights. We validated the benefits of ATGLi on steatohepatitis and fibrosis in a low-methionine choline-deficient mouse model.

ATGLi improved serum liver enzymes, hepatic lipid content, and histological liver injury. Mechanistically, ATGLi attenuated PPARα signalling, favouring hydrophilic bile acid (BA) synthesis with increased Cyp7a1, Cyp27a1, Cyp2c70, and reduced Cyp8b1 expression. Additionally, reduced intestinal Cd36 and Abca1, along with increased Abcg5 expression, were consistent with reduced levels of hepatic triacylglycerol species containing polyunsaturated fatty acids, like linoleic acid, as well as reduced cholesterol levels in the liver and plasma. Similar changes in gene expression associated with PPARα signalling and intestinal lipid transport were observed in ileal organoids treated with NG-497. Furthermore, HepG2 ATGL knockdown cells revealed reduced expression of PPARα target genes and upregulation of genes involved in hydrophilic BA synthesis, consistent with reduced PPARα binding and luciferase activity in the presence of the ATGL inhibitors.

Inhibition of ATGL attenuates PPARα signalling, translating into hydrophilic BA composition, interfering with dietary lipid absorption, and improving metabolic disturbances. Validation with NG-497 opens a new therapeutic perspective for MASLD.

Despite the recent approval of drugs novel mechanistic insights and pathophysiology-oriented therapeutic options for MASLD (metabolic dysfunction-associated steatotic liver disease) are still urgently needed. Herein, we show that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis, using atglistatin (ATGLi), improves MASH (metabolic dysfunction-associated steatohepatitis), fibrosis, and key features of metabolic dysfunction in mouse models of MASH and liver fibrosis. Mechanistically, we demonstrated that attenuation of PPARα signalling in the liver and gut favours hydrophilic bile acid composition, ultimately interfering with dietary lipid absorption. One of the drawbacks of ATGLi is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition using the human inhibitor NG-497 in human primary ileum-derived organoids, Caco2 cells, and HepG2 cells translated into therapeutic mechanisms similar to ATGLi. Collectively, these findings reveal a possible new avenue for MASLD treatment.

Tripterygium wilfordii is a traditional Chinese medicine used to treat rheumatic diseases, with properties such as clearing heat, detoxifying, dispelling wind, and relieving pain. In recent years, its active compound, celastrol, garnered significant attention for its potential therapeutic effects on metabolic diseases. Celastrol exhibits bioactivities such as regulating metabolic functions and anti-inflammatory effects, positioning it as a promising candidate for the treatment of obesity, diabetes, atherosclerosis (AS), and non-alcoholic fatty liver disease (NAFLD).

This review aims to explore the pharmacological mechanisms of celastrol in metabolic diseases, focusing on its anti-inflammatory mechanisms and metabolic regulation effects, providing theoretical support for further investigation of its therapeutic potential in metabolic diseases.

Literature was retrieved from PubMed, Web of Science, Scopus, Cochrane, and Google Scholar. This review primarily focuses on anti-inflammatory mechanisms of celastrol, its metabolic regulation, and toxicity studies, by systematically analyzing its effects in obesity, diabetes, AS, and NAFLD, providing scientific evidence for its potential clinical applications.

Celastrol regulates multiple signaling pathways, particularly inhibiting NF-κB and activating AMPK, reducing the production of pro-inflammatory cytokines and improving insulin sensitivity, enhancing its therapeutic potential in metabolic diseases. Additionally, celastrol regulates adipogenesis and energy metabolism by influencing key transcription factors such as PPARγ and SREBP-1c. Numerous studies highlight its role in alleviating oxidative stress and improving mitochondrial function, further enhancing its metabolic benefits.

In summary, celastrol holds great promise as a multi-target therapeutic agent for metabolic diseases, offering anti-inflammatory, metabolic regulatory, and antioxidative benefits. Despite these, challenges remain for the clinical application of celastrol due to its poor bioavailability and potential toxicity. Advanced formulation strategies and targeted delivery systems are urgently needed to overcome challenges related to bioavailability and clinical translation.

BACKGROUNDThis study examined the underlying cellular mechanisms associated with insulin resistance (IR) and metabolic disease risk within subcutaneous adipose tissue (SAT) in youth with obesity and IR compared with those without IR.METHODSThirteen adolescents who were insulin sensitive (IS) and 17 adolescents with IR and obesity underwent a 3-hour oral glucose tolerance test and MRI to measure abdominal fat distribution and liver fat content. Lipolysis was determined by glycerol turnover ([2H5]-glycerol infusion) and adipose triglyceride lipase (ATGL) phosphorylation (Western blot) from SAT samples biopsied prior to and 30-minutes following insulin infusion during a hyperinsulinemic-euglycemic clamp (HEC).RESULTSGlycerol turnover suppression during the HEC (first step) was lower in participants with IR compared with those with IS. Prior to insulin infusion, activated ATGL (reflected by the p-ATGL (Ser406)-to-ATGL ratio) was greater in participants with IR compared with those with IS and suppressed in response to a 30-minute insulin exposure in participants with IS, but not in those with IR. Lastly, greater ATGL inactivation is associated with greater glycerol suppression and lower liver fat.CONCLUSIONSInsulin-mediated inhibition of adipose tissue lipolysis via ATGL is dysregulated among adolescents with IR compared with those with IS, thereby serving as a vital mechanism linking glucose and insulin dysregulation and ectopic lipid storage within the liver.FUNDINGThis work was supported by funding from the NIH (R01-HD028016-25A1, T32- DK-007058, R01-DK124272, RO1-DK119968, R01MD015974, RO1-DK113984, P3-DK045735, RO1-DK133143, and RC2-DK120534) and the Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award.

The liver acts as a central metabolic hub, integrating signals from the gastrointestinal tract and adipose tissue to regulate carbohydrate, lipid, and amino acid metabolism. Gut-derived metabolites, such as acetate and ethanol and non-esterified fatty acids from white adipose tissue (WAT), influence hepatic processes, which rely on mitochondrial function to maintain systemic energy balance. Metabolic dysregulation from obesity, insulin resistance, and type 2 diabetes disrupt these pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). This review explores the metabolic fluxes within the gut-adipose tissue-liver axis, focusing on the pivotal role of de novo lipogenesis (DNL), dietary substrates like glucose and fructose, and changes in mitochondrial function during MASLD progression. It highlights the contributions of white adipose tissue insulin resistance and impaired mitochondrial dynamics to hepatic lipid accumulation. Further understanding how the interplay between substrate flux from the gastro-intestinal tract integrates with adipose tissue and intersects with structural and functional alterations to liver mitochondria will be important to identify novel therapeutic targets and advance the treatment of MASLD and MASH.

Prediabetes is a highly prevalent and increasingly common condition affecting a significant proportion of the global population. The heterogeneous nature of prediabetes presents a challenge in identifying individuals who particularly benefit from lifestyle or other therapeutic interventions aiming at preventing type 2 diabetes (T2D) and associated comorbidities. The phenotypic characteristics of individuals at risk for diabetes are associated with both specific risk profiles for progression and a differential potential to facilitate prediabetes remission and reduce the risk of future T2D. This review examines the current definition and global prevalence of prediabetes and evaluates the potential of prediabetes remission to reduce the alarming increase in the global burden of T2D.

Type 2 diabetes mellitus (T2DM) is a global health burden, with hyperglycemia as the main hallmark. This review commences with a concise overview of the intricate mechanisms underlying glucose uptake and utilization in organisms. Notably, we emphasize that T2DM management strategies pivot on delaying carbohydrate digestion, augmenting insulin secretion, and enhancing insulin sensitivity in target tissues. Unfortunately, the drugs currently available in the market for the treatment of T2DM have unpleasant side effects, spurring an urgent quest for safer and more efficacious alternatives. Flavonoids, emerging as a promising class of bioactive compounds derived from plants, offer a multi-faceted approach to diabetes treatment. Specifically, they potently inhibit enzymes such as α-amylase, α-glucosidase, dipeptidyl peptidase-4 (DPP-4), glycogen phosphorylase (GP) and protein-tyrosine phosphatase-1B (PTP1B). Through an in-depth analysis, this review not only summarizes these inhibitory actions but also establishes the structure-activity relationship (SAR), providing a blueprint for rational drug design. However, the clinical translation of flavonoids has been hampered by their suboptimal water solubility and bioavailability, attributable to the characteristic carbonyl and hydroxyl groups. Ingeniously, this chemical quirk has been harnessed to engineer metal chelates, which exhibit enhanced pharmacokinetic profiles. Herein, we offer an exhaustive overview of the latest advancements in flavonoid metal complexes research, spotlighting their potential as next-generation diabetes therapeutics. Available data are poised to galvanize the development of novel flavonoid derivatives, be it as potent drugs or functional foods, for combating T2DM.

Physiological adaptations to fasting enable humans to survive for prolonged periods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization of fatty acids and glycerol from adipocyte lipid stores by canonical neutral lipases, including the rate limiting adipose triglyceride lipase (Pnpla2/ATGL), is critical to the adaptive fasting response. Here we discovered an alternative mechanism of lipolysis in adipocytes involving a lysosomal program. We functionally tested lysosomal lipolysis with pharmacological and genetic approaches in mice and in murine and human adipocyte and adipose tissue explant culture, establishing dependency on lysosomal acid lipase (LIPA/LAL) and the microphthalmia/transcription factor E (MiT/TFE) family. Our study establishes a model whereby the canonical pathway is critical for rapid lipolytic responses to adrenergic stimuli operative in the acute stage of fasting, while the alternative lysosomal pathway dominates with prolonged fasting.

Skin epithelial stem cells correct aberrancies induced by oncogenic mutations. Oncogenes invoke different strategies of epithelial tolerance; while wild-type cells outcompete β-catenin-gain-of-function (βcatGOF) cells, HrasG12V cells outcompete wild-type cells. Here we ask how metabolic states change as wild-type stem cells interface with mutant cells and drive different cell-competition outcomes. By tracking the endogenous redox ratio (NAD(P)H/FAD) with single-cell resolution in the same mouse over time, we discover that βcatGOF and HrasG12V mutations, when interfaced with wild-type epidermal stem cells, lead to a rapid drop in redox ratios, indicating more oxidized cellular redox. However, the resultant redox differential persists through time in βcatGOF, whereas it is flattened rapidly in the HrasG12Vmodel. Using 13C liquid chromatography-tandem mass spectrometry, we find that the βcatGOF and HrasG12V mutant epidermis increase the fractional contribution of glucose through the oxidative tricarboxylic acid cycle. Treatment with metformin, a modifier of cytosolic redox, inhibits downstream mutant phenotypes and reverses cell-competition outcomes of both mutant models.

Carbohydrates can be converted into fatty acids via de novo lipogenesis (DNL). Although DNL is considered inefficient, these endogenous fatty acids contribute substantially to the esterification pathway in adipose tissue, together with fatty acids of feeding. This article revisited the concepts of DNL and aimed to discuss the clinical magnitude of carbohydrate overfeeding and fat mass accumulation. Although fat storage resulting from fat intake is more favorable for fat mass accrual than carbohydrates due to molecule structure and metabolism (e.g., oxidation and thermic effect), carbohydrates can substantially participate in lipogenesis and esterification under excess carbohydrate intake over time. Regarding only monosaccharide overfeeding, glucose and fructose favor the subcutaneous and visceral adipose tissue, respectively. While fructose and sucrose are considered villains in nonalcoholic fatty liver disease, energy surplus from carbohydrates, regardless of sources, can be considered an underlying cause of obesity. Interestingly, some degree of DNL in adipocytes may be favorable to mitigate a high deposition of fatty acids in the liver, conferring a physiological role. Although "fat burns in the flame of carbohydrate" is a praiseworthy phrase that has helped describe basic concepts in biochemistry for many decades, it appears to be overvalued and extrapolated even nowadays. DNL cannot be neglected. It is time to consider DNL an efficient biochemical process in health and disease.

Globally, diabetes mellitus (DM) and its complications are considered among the most significant public health problems. According to numerous scientific studies, Plants and their bioactive compounds may reduce inflammation and oxidative stress (OS), leading to a reduction in the progression of DM. Moringa oleifera (MO), widely used in Ayurvedic and Unani medicine for centuries because of its health-promoting characteristics, particularly its ability to control DM and its related complications. MO is a multi-purpose plant that has an impressive range of nutritional components including proteins, amino acids (Essential and non-essential amino acids), carbs, fats, fiber, vitamins, and phenolic compounds. In the modern era, scientists have paid close attention to the anti-diabetic, anti-oxidative and anti-inflammatory attributes and other medicinal properties, of MO leaves and seeds. MO leaves and seeds have modulatory effects on DM that are likely influenced by multiple mechanisms. Some of these mechanisms include direct effects, but other mechanisms involve inhibition the production of inflammatory markers, modulation of the gut microbiome, reduction of OS, enhancement of glucose metabolism through hexokinase and glucose 6-phosphate dehydrogenase, improve insulin sensitivity and glucose uptake in the liver and muscles. Overall, these findings suggest that MO may play a role in lowering the risk of DM and its related outcomes. The purpose of this review is to provide a comprehensive overview of the nutritional and bioactive profiles of MO leaves and seeds, as well as to investigate their possible anti-diabetic effects by modulating oxidative stress and inflammation. Our results indicate that MO may be a beneficial natural resource for management of DM and related issues by lowering oxidative stress and inflammation. Furthermore, studies on MO has yielded promising findings in diabetic animal models, indicating antioxidant and anti-inflammatory properties. However, human trials have shown less solid results, most likely due to a lack of studies, different techniques, and dosages. More clinical research is needed to fully understand MO's anti-diabetic potential, notably in lowering oxidative stress and inflammation, both of which are critical in controlling diabetes complications.

Adipose tissue (AT) metabolism involves coordinating various cells and cellular processes to regulate energy storage, release, and overall metabolic homeostasis. Therein, macrophage and its cytokine are important in controlling tissue homeostasis. Among cytokines, the role of transforming growth factor-β1 (Tgf-β1), a cytokine abundantly expressed in CD206+ M2-like macrophage and correlated with the expansion of AT and fibrosis, in AT metabolism, remains unknown. We used CD206CreERT2; Tgf-β1f/f mouse model in which the Tgf-β1 gene was conditionally deleted in CD206+ M2-like macrophages followed by tamoxifen administration, to investigate the role of the Tgf-β1 gene in glucose and insulin metabolism. Our data demonstrated that lack of CD206+ M2-like macrophages derived Tgf-β1 gene improved glucose metabolism and insulin sensitivity by enhancing adipogenesis via hyperplasia. The Tgf-β1 gene, specifically from CD206+ M2-like macrophages, deletion stimulated APs' proliferation and differentiation, leading to the generation of smaller mature adipocytes, therefore enhancing insulin sensitivity and improving glucose metabolism under normal chow conditions. Our study brings a new perspective that Tgf-β1 gene deletion specific from CD206+ M2-like macrophage promotes adipocyte hyperplasia, improving glucose homeostasis and insulin sensitivity in the lean state.

ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.

This study aimed to investigate the association of IL-6 with steatotic liver disease (SLD) and liver fibrosis (LF) in rheumatoid arthritis (RA) patients at a rheumatology center in Cartagena de Indias, Colombia.

This was a cross-sectional study that included RA and non-RA cases. The level of cellular expression of interleukin 6 (IL-6) was evaluated by flow cytometry in peripheral blood leukocytes, and the presence of SLD and LF was detected by elastosonography. The main outcome was to establish the association between the levels of cellular expression of IL-6 and the development of SLD and LF.

This study included 47 cases of RA and 34 cases on-RA, with a mean age of 54 and 55 years, respectively. The frequency of SLD was 55.3% in RA and 38.2% in non-RA. The frequency of LF was 12.8% in RA and 14.7% in non-RA, with no statistical difference. The levels of cellular expression of IL-6 were significantly higher in RA compared to non-RA. Cellular expression of IL-6 was associated with the presence of SLD (54% vs. 30.3%; p = 0.002). This association was not maintained in RA cases (49.5% vs. 47.6%; p = 0.571). No association was found between cellular expression of IL-6 and LF in the total population (43.8% vs. 42.7%; p = 0.813) nor in RA cases (59.41% vs. 48.3%; p = 0.526).

IL-6 levels were related to SLD in the evaluated sample, and RA was not a risk factor for SLD or LF. The prognostic role of IL-6 for SLD in patients with RA requires further studies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-2H2-glucose, U-2H5-glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2-F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH.

Hepatic insulin resistance (IR) is often said to be "pathway-selective" with preserved insulin stimulation of de novo lipogenesis (DNL) despite attenuated insulin signaling toward glucose metabolism. However, DNL has not been assessed in models of liver-specific IR. We studied mice with differential tissue-specific lipid-induced IR achieved by different durations of high-fat diet (HFD) feeding. Mice with isolated hepatic IR demonstrated markedly reduced DNL, with a rebound seen in mice with whole-body IR. Insr T1150A mice (protected against diacylglycerol-PKCε-induced hepatic IR) maintained normal DNL with HFD feeding. During hyperinsulinemic clamps, hepatic IR reduced DNL, but hyperglycemia augmented DNL in both resistant and sensitive animals. Regulation through SREBP1c did not consistently correlate with changes in DNL. These results demonstrate that hepatic IR is not pathway-selective, highlighting the primacy of lipogenic substrate in stimulation of DNL. Future therapeutics to reduce lipogenesis should target substrate drivers of DNL rather than targeting plasma insulin levels.

Insulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism.

We utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism.

Hx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway.

This study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications.

Disturbances in carbohydrate metabolism are suggested to be the early symptoms of pancreatic ductal adenocarcinoma (PDAC). The accumulated data suggests that endocrine function-related biomarkers may represent a breakthrough in the early detection of PDAC. Factors which may predispose one to the development of PDAC are insulin resistance and hyperinsulinemia. Elevated insulin levels induce the onset of carcinogenesis by altering the differentiation and function of islet cells through stimulating growth factors, including insulin-like growth factors (IGFs). Impaired β cell function, along with the impact of PDAC-released factors (e.g., adrenomedullin (ADM), IGF-1, and macrophage inhibitory factor (MIF) on pancreatic islets, may contribute to the induction of diabetes associated with PDAC. Recently, exosomes have attracted worldwide attention due to their role in varied features of cell function, particularly in cancer progression. Exosomes comprise of small extracellular vesicles produced by almost all cells. These vesicles contain a vast array of biomolecules, including proteins and microRNAs. Exosomes participate in cancer growth and promote angiogenesis. They promote tumorigenesis and metastasis, and are associated with the acquisition of cancer cells resistant to chemotherapy. Data have been accumulating recently on the role of exosomes in the rapid recognition, prognosis and potential therapy of pancreatic cancer.

We assessed in vivo rates of hepatic mitochondrial oxidation, gluconeogenesis, and β-hydroxybutyrate (β-OHB) turnover by positional isotopomer NMR tracer analysis (PINTA) in individuals with metabolic-dysfunction-associated steatotic liver (MASL) (fatty liver) and MASL disease (MASLD) (steatohepatitis) compared with BMI-matched control participants with no hepatic steatosis. Hepatic fat content was quantified by localized 1H magnetic resonance spectroscopy (MRS). We found that in vivo rates of hepatic mitochondrial oxidation were unaltered in the MASL and MASLD groups compared with the control group. A physiological increase in plasma glucagon concentrations increased in vivo rates of hepatic mitochondrial oxidation by 50%-75% in individuals with and without MASL and increased rates of glucose production by ∼50% in the MASL group, which could be attributed in part to an ∼30% increase in rates of mitochondrial pyruvate carboxylase flux. These results demonstrate that (1) rates of hepatic mitochondrial oxidation are not substantially altered in individuals with MASL and MASLD and (2) glucagon increases rates of hepatic mitochondrial oxidation.

To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.

Glucose tolerance improves significantly upon consuming a second, identical meal later in the day (second meal phenomenon). We previously established that morning hyperinsulinemia primes the liver for increased afternoon hepatic glucose uptake (HGU). Although the route of insulin delivery is an important determinant of the mechanisms by which insulin regulates liver glucose metabolism (direct hepatic vs indirect insulin action), it is not known if insulin's delivery route affects the second meal response. To determine whether morning peripheral insulin delivery (as occurs clinically (subcutaneous)) can enhance afternoon HGU, conscious dogs were treated in the morning with insulin delivered via the portal vein, or peripherally (leg vein), while glucose was infused to maintain euglycemia. Consequently, arterial insulin levels increased similarly in both groups, but relative hepatic insulin deficiency occurred when insulin was delivered peripherally. In the afternoon, all animals were challenged with the same hyperinsulinemic-hyperglycemic clamp to simulate identical postprandial-like conditions. The substantial enhancement of HGU in the afternoon caused by morning portal vein insulin delivery was lost when insulin was delivered peripherally. This indicates that morning insulin does not cause the second meal phenomenon via its indirect actions on the liver, but rather through direct activation of hepatic insulin signaling.

Coenzyme A (CoA) is synthesized from pantothenate, L-cysteine and adenosine triphosphate (ATP), and plays a vital role in diverse physiological processes. Protein acylation is a common post-translational modification (PTM) that modifies protein structure, function and interactions. It occurs via the transfer of acyl groups from acyl-CoAs to various amino acids by acyltransferase. The characteristics and effects of acylation vary according to the origin, structure, and location of the acyl group. Acetyl-CoA, formyl-CoA, lactoyl-CoA, and malonyl-CoA are typical acyl group donors. The major acyl donor, acyl-CoA, enables modifications that impart distinct biological functions to both histone and non-histone proteins. These modifications are crucial for regulating gene expression, organizing chromatin, managing metabolism, and modulating the immune response. Moreover, CoA and acyl-CoA play significant roles in the development and progression of neurodegenerative diseases, cancer, cardiovascular diseases, and other health conditions. The goal of this review was to systematically describe the types of commonly utilized acyl-CoAs, their functions in protein PTM, and their roles in the progression of human diseases.

The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.

By providing a concise overview of adipose tissue types, elucidating the regulation of adipose thermogenic capacity in both physiological contexts and chronic wasting diseases (a protracted hypermetabolic state that precipitates sustained catabolism and consequent progressive corporeal atrophy), and most importantly, delving into the ongoing discourse regarding the role of adipose tissue thermogenic activation in chronic wasting diseases, this review aims to provide researchers with a comprehensive understanding of the field.

Adipose tissue, traditionally classified as white, brown, and beige (brite) based on its thermogenic activity and potential, is intricately regulated by complex mechanisms in response to exercise or cold exposure. This regulation is adipose depot-specific and dependent on the duration of exposure. Excessive thermogenic activation of adipose tissue has been observed in chronic wasting diseases and has been considered a pathological factor that accelerates disease progression. However, this conclusion may be confounded by the detrimental effects of excessive lipolysis. Recent research also suggests that such activation may play a beneficial role in the early stages of chronic wasting disease and provide potential therapeutic effects. A more comprehensive understanding of the changes in adipose tissue thermogenesis under physiological and pathological conditions, as well as the underlying regulatory mechanisms, is essential for the development of novel interventions to improve health and prevent disease.

The root cause of type 2 diabetes (T2D) is insulin resistance (IR), defined by the failure of cells to respond to circulating insulin to maintain lipid and glucose homeostasis. While the causes of whole-body insulin resistance are multifactorial, a major contributing factor is dysregulation of liver and adipose tissue function. Adipose dysfunction, particularly adipose tissue-IR (adipo-IR), plays a crucial role in the development of hepatic insulin resistance and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) in the context of T2D. In this review, we will focus on molecular mechanisms of hepatic insulin resistance and its association with adipose tissue function. A deeper understanding of the pathophysiological mechanisms of the transition from a healthy state to insulin resistance, impaired glucose tolerance, and T2D may enable us to prevent and intervene in the progression to T2D.

Psoriasis (PsO) is a chronic inflammatory dermatosis that often presents with erythematous, sharply demarcated lesions. Although psoriasis is primarily a dermatological disease, its immune-mediated pathogenesis produces systemic effects and is closely associated with various comorbid conditions such as cardiovascular disease (CVD), metabolic syndrome (MetS), and diabetes mellitus type II (DMII). Apremilast, an oral phosphodiesterase 4 (PDE-4) inhibitor, has shown promise in treating moderate-to-severe psoriasis and is associated with potential cardiometabolic benefits. In a 12-month prospective observational study involving 137 patients with moderate-to-severe psoriasis, we assessed changes in psoriasis clinimetric scores and metabolic profiles from baseline (T0) to 52 weeks (T1) to evaluate the efficacy of apremilast. After 52 weeks of apremilast treatment, we documented a statistically significant decrease in low-density lipoprotein (LDL) and total cholesterol, triglycerides, and glucose levels. Our findings even suggest a potential synergistic effect among patients treated with apremilast, alongside concomitant statin and/or insulin therapy. Although the results of our study must be validated on a larger scale, the use of apremilast in the treatment of psoriatic patients with cardio-metabolic comorbidities yields promising results.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent and significant global public health issue. Nonalcoholic steatohepatitis (NASH) represents an advanced stage of NAFLD in terms of pathology. However, the intricate mechanisms underlying the progression from NAFLD to NASH remain elusive. Ferroptosis, characterized by iron-dependent cell death and distinguished from other forms of cell death based on morphological, biochemical, and genetic criteria, has emerged as a potential participant with a pivotal role in driving NAFLD progression. Nevertheless, its precise mechanism remains poorly elucidated. In this review article, we comprehensively summarize the pathogenesis of NAFLD/NASH and ferroptosis while highlighting recent advances in understanding the mechanistic involvement of ferroptosis in NAFLD/NASH.

Diabetes mellitus, a hyperglycemic condition associated with multitudinous organ dysfunction, is a hallmark of the metabolic disorder. This life-threatening condition affects millions of individuals globally, harming them financially, physically and psychologically in the course of therapy.

The course therapy for illnesses has undergone ground-breaking transformations due to recent technical advances and insights. Alternatively, the administration of hyperglycemia-reducing agents results in several complications, including severe cardiovascular disease, kidney failure, hepatic problems, and several dermatological conditions. Consideration of alternate diabetic therapy having minimal side effects or no adverse reactions has been driven by such problems.

An extensive literature study was conducted in authoritative scientific databases such as PubMed, Scopus, and Web of Science to identify the studies elucidating the bioactivities of terpenoids in diabetic conditions.

Keywords including 'terpenoids', 'monoterpenes', 'diterpenes', 'sesquiterpenes', 'diabetes', 'diabetes mellitus', 'clinical trials', 'preclinical studies', and 'increased blood glucose' were used to identify the relevant research articles. The exclusion criteria, such as English language, duplication, open access, abstract only, and studies not involving preclinical and clinical research, were set. Based on these criteria, 937 relevant articles were selected for further evaluation.

Triterpenes can serve as therapeutic agents for diabetic retinopathy, peripheral neuropathy, and kidney dysfunction by inhibiting several pathways linked to hyperglycemia and its complications. Therefore, it is essential to draw special attention to these compounds' therapeutic effectiveness and provide scientific professionals with novel data.

This study addressed recent progress in research focussing on mechanisms of terpenoid, its by-products, physiological actions, and therapeutic applications, particularly in diabetic and associated disorders.

Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown.

The constructed ASGR1 knockout mice and ASGR1-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro.

ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis.

The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.

Adipose progenitor cells (APCs) are heterogeneous stromal cells and help to maintain metabolic homeostasis. However, the influence of obesity on human APC heterogeneity and the role of APC subpopulations on regulating glucose homeostasis remain unknown. Here, we find that APCs in human visceral adipose tissue contain four subsets. The composition and functionality of APCs are altered in patients with type 2 diabetes (T2D). CD9+CD55low APCs are the subset which is significantly increased in T2D patients. Transplantation of these cells from T2D patients into adipose tissue causes glycemic disturbance. Mechanistically, CD9+CD55low APCs promote T2D development through producing bioactive proteins to form a detrimental niche, leading to upregulation of adipocyte lipolysis. Depletion of pathogenic APCs by inducing intracellular diphtheria toxin A expression or using a hunter-killer peptide improves obesity-related glycemic disturbance. Collectively, our data provide deeper insights in human APC functionality and highlights APCs as a potential therapeutic target to combat T2D. All mice utilized in this study are male.

Diabetes and obesity are risk factors for kidney disease. Whereas renal glucose production increases in diabetes, recent data suggest that gluconeogenic and oxidative capacity decline in kidney disease. Thus, metabolic dysregulation caused by diet-induced insulin resistance may sensitize the kidney for a loss in function. Here, we examined how diet-induced insulin resistance disrupts mitochondrial metabolic fluxes in the renal cortex in vivo. C57BL/6J mice were rendered insulin resistant through high-fat (HF) feeding; anaplerotic, cataplerotic, and oxidative metabolic fluxes in the cortex were quantified through 13C-isotope tracing during a hyperinsulinemic-euglycemic clamp. As expected, HF-fed mice exhibited increased body weight, gluconeogenesis, and systemic insulin resistance compared with chow-fed mice. Relative to the citric acid cycle, HF feeding increased metabolic flux through pyruvate carboxylation (anaplerosis) and phosphoenolpyruvate carboxykinase (cataplerosis) and decreased flux through the pyruvate dehydrogenase complex in the cortex. Furthermore, the relative flux from nonpyruvate sources of acetyl-CoA profoundly increased in the cortex of HF-fed mice, correlating with a marker of oxidative stress. The data demonstrate that HF feeding spares pyruvate from dehydrogenation at the expense of increasing cataplerosis, which may underpin renal gluconeogenesis during insulin resistance; the results also support the hypothesis that dysregulated oxidative metabolism in the kidney contributes to metabolic disease.

Smokers are at increased risk of type 2 diabetes (T2D), but the underlying mechanisms are unclear. We investigated if the smoking-T2D association is mediated by alterations in the metabolome and assessed potential interaction with genetic susceptibility to diabetes or insulin resistance.

In UK Biobank (n = 93,722), cross-sectional analyses identified 208 metabolites associated with smoking, of which 131 were confirmed in Mendelian Randomization analyses, including glycoprotein acetyls, fatty acids, and lipids. Elastic net regression was applied to create a smoking-related metabolic signature. We estimated hazard ratios (HR) of incident T2D in relation to baseline smoking/metabolic signature and calculated the proportion of the smoking-T2D association mediated by the signature. Additive interaction between the signature and genetic risk scores for T2D (GRS-T2D) and insulin resistance (GRS-IR) on incidence of T2D was assessed as relative excess risk due to interaction (RERI).

The HR of T2D was 1·73 (95% confidence interval (CI) 1·54 - 1·94) for current versus never smoking, and 38·3% of the excess risk was mediated by the metabolic signature. The metabolic signature and its mediation role were replicated in TwinGene. The metabolic signature was associated with T2D (HR: 1·61, CI 1·46 - 1·77 for values above vs. below median), with evidence of interaction with GRS-T2D (RERI: 0·81, CI: 0·23 - 1·38) and GRS-IR (RERI 0·47, CI: 0·02 - 0·92).

The increased risk of T2D in smokers may be mediated through effects on the metabolome, and the influence of such metabolic alterations on diabetes risk may be amplified in individuals with genetic susceptibility to T2D or insulin resistance.

Physical activity is integral to metabolic health, particularly in addressing insulin resistance and related disorders such as type 2 diabetes mellitus (T2DM). Studies consistently demonstrate a strong association between physical activity levels and insulin sensitivity. Regular exercise interventions were shown to significantly improve glycemic control, highlighting exercise as a recommended therapeutic strategy for reducing insulin resistance. Physical inactivity is closely linked to islet cell insufficiency, exacerbating insulin resistance through various pathways including ER stress, mitochondrial dysfunction, oxidative stress, and inflammation. Conversely, physical training and exercise preserve and restore islet function, enhancing peripheral insulin sensitivity. Exercise interventions stimulate β-cell proliferation through increased circulating levels of growth factors, further emphasizing its role in maintaining pancreatic health and glucose metabolism. Furthermore, sedentary lifestyles contribute to elevated oxidative stress levels and ceramide production, impairing insulin signaling and glucose metabolism. Regular exercise induces anti-inflammatory responses, enhances antioxidant defenses, and promotes mitochondrial function, thereby improving insulin sensitivity and metabolic efficiency. Encouraging individuals to adopt active lifestyles and engage in regular exercise is crucial for preventing and managing insulin resistance and related metabolic disorders, ultimately promoting overall health and well-being.

Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent chronic liver diseases worldwide in recent decades. Metabolic diseases like excessive blood glucose, central obesity, dyslipidemia, hypertension, and liver function abnormalities cause NAFLD. NAFLD significantly increases the likelihood of liver cancer, heart disease, and mortality, making it a leading cause of liver transplants. Non-alcoholic steatohepatitis (NASH) is a more advanced form of the disease that causes scarring and inflammation of the liver over time and can ultimately result in cirrhosis and hepatocellular carcinoma. In this review, we briefly discuss NAFLD's pathogenic mechanisms, their progression into NASH and afterward to NASH-related cirrhosis. It also covers disease epidemiology, metabolic mechanisms, glucose and lipid metabolism in the liver, macrophage dysfunction, bile acid toxicity, and liver stellate cell stimulation. Additionally, we consider the contribution of intestinal microbiota, genetics, epigenetics, and ecological factors to fibrosis progression and hepatocellular carcinoma risk in NAFLD and NASH patients.

Age-related visceral obesity could contribute to the development of cardiometabolic complications. The pathogenesis of visceral fat mass accumulation during the aging process remains complex and largely unknown. Interleukin-6 (IL-6) has emerged as one of the prominent inflammaging markers which are elevated in circulation during aging. However, the precise role of IL-6 in regulating age-related visceral adipose tissue accumulation remains uncertain.

A cross-sectional study including 77 older adults (≥65 years of age) was initially conducted. There was a significant positive association between serum IL-6 levels and visceral fat mass. We subsequently validated a modest but significant elevation in serum IL-6 levels in aged mice. Furthermore, we demonstrated that compared to wildtype control, IL-6 deficiency (IL-6 KO) significantly attenuated the accumulation of visceral adipose tissue during aging. Further metabolic characterization suggested that IL-6 deficiency resulted in improved lipid metabolism parameters and energy expenditure in aged mice. Moreover, histological examinations of adipose depots revealed that the absence of IL-6 ameliorated adipocyte hypertrophy in visceral adipose tissue of aged mice. Mechanically, the ablation of IL-6 could promote the PKA-mediated lipolysis and consequently mitigate lipid accumulation in adipose tissue in aged mice.

Our findings identify a detrimental role of IL-6 during the aging process by promoting visceral adipose tissue accumulation through inhibition of lipolysis. Therefore, strategies aimed at preventing or reducing IL-6 levels may potentially ameliorate age-related obesity and improve metabolism during aging.