Treatment Of Metabolic Diseases Research Articles

Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles

GPR17 is a G-protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Such evidence is primarily drawn from mouse knockout studies and suggests GPR17 as a potential novel therapeutic target for the treatment of metabolic diseases. However, links between human GPR17 genetic variants, downstream cellular signaling, and metabolic diseases have yet to be reported. Here, we analyzed GPR17 coding sequences from control and disease cohorts consisting of individuals with adverse clinical metabolic deficits including severe insulin resistance, hypercholesterolemia, and obesity. We identified 18 nonsynonymous GPR17 variants, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, membrane localization, and downstream signaling profiles of nine GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). These nine GPR17 variants had similar protein expression and subcellular localization as wild-type GPR17; however, they showed diverse downstream signaling profiles. GPR17-G136S lost the capacity for agonist-mediated cAMP, Ca2+, and β-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT, but showed impaired Ca2+ and β-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca2+ signaling, but unaffected agonist-stimulated β-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with diverse signaling profiles, including differential signaling perturbations that resulted in GPCR signaling bias. Our findings provide a framework for structure–function relationship studies of GPR17 signaling and metabolic disease.

Monascus ruber fermented Panax ginseng ameliorates lipid metabolism disorders and modulate gut microbiota in rats fed a high-fat diet

Ethnopharmacological relevanceGinseng (Panax ginseng Meyer) is rich in a variety of biologically active ingredients, which shows good effect in the treatment of metabolic diseases. Monascus has lipid-lowering activity and one of its metabolites, lovastatin, is widely used in clinical practice. Aim of the studyThe main purpose of this study was to clarify the effects of fermented Panax ginseng by Monascus ruber (PM) on lipid metabolism and gut microbiota in rats fed a high-fat diet. Materials and methodsSPF Sprague-Dawley rats were randomly divided into 5 groups, the therapeutic effect of PM on HFD-induced obesity, hyperlipidemia, hepatic steatosis, and disordered gut microbiota were determined in rats. ResultsPM could attenuate features of obesity in rats, decrease serum TC, LDL-C and IgA levels, increase excretion of bile acids in feces. Hepatic histopathologic analysis revealed that PM decrease lipid accumulation in hepatocytes. Consistently, mRNA expression levels of cholesterol metabolism-related genes were regulated in the livers of HFD-fed rats administered with PM. In addition, PM could enhance the diversity and relative abundance of gut microbiota, reduce the Firmicutes/Bacteroidetes (F/B) ratio, increase significantly the relative abundance of Prevotella_9, and decrease these of Muribaculaceae. ConclusionsPM could regulate lipid metabolism and the structure of the gut microbiota in the HFD rats. Our findings provide valuable experience for the development of ginseng. PM could be a potentially effective strategy to prevent and treat metabolic diseases and alleviate the gut microbiota disturbance caused by it.

Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus.

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease in the world, yet there are still no approved pharmacological therapies to prevent or treat this condition. NAFLD encompasses a spectrum of severity, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Although NASH is linked to an increased risk of hepatocellular carcinoma and cirrhosis and has now become the leading cause of liver failure-related transplantation, the majority of patients with NASH will ultimately die as a result of complications of type 2 diabetes mellitus (T2DM) and cardiometabolic diseases. Importantly, NAFLD is closely linked to obesity and tightly interrelated with insulin resistance and T2DM. Thus, targeting these interconnected conditions and taking a holistic attitude to the treatment of metabolic disease could prove to be a very beneficial approach. This Review will explore the latest relevant literature and discuss the ongoing therapeutic options for NAFLD focused on targeting intermediary metabolism, insulin resistance and T2DM to remedy the global health burden of these diseases.

Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1

The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.

Berberine Ameliorates Hepatic Insulin Resistance by Regulating microRNA-146b/SIRT1 Pathway.

ObjectiveHepatic insulin resistance is a major initiating factor for type 2 diabetes mellitus. In previous study, Gegen Qinlian Decoction containing berberine could enhance hepatic insulin sensitivity by SIRT1-dependent deacetylation of FOXO1. However, it is not clear whether berberine also can improve hepatic insulin sensitivity by SIRT1/FOXO1 pathway. This study aimed to evaluate the efficacy of berberine for improving hepatic insulin resistance and the possible molecular mechanisms involved.MethodsIn vitro, HepG2 cells were induced with palmitic acid, and glycogen synthesis was examined. In vivo, a high-fat diet (HFD)-fed mouse model was established, and metabolic parameters were assessed. The expressions of miR-146b and sirtuin 1 (SIRT1) in liver were also examined. The relationship between miR-146b and SIRT1 was examined by the dual-luciferase reporter gene assay.ResultsSerum biochemical parameters, such as glucose and HOMA-IR index, were increased in HFD mice; miR-146b and SIRT1 were abnormally expressed in HFD mice and palmitic acid-treated HepG2 cells. Interestingly, berberine reduced body weight and caused a significant improvement in glucose tolerance and HOMA-IR index without altering food intake in mice. Overexpression of miR-146b abolished the protective effect of berberine on palmitic acid-induced impaired glycogen synthesis in HepG2 cells. Luciferase assay showed that miR-146b directly targeted SIRT1.ConclusionThe present findings suggest that berberine could attenuate hepatic insulin resistance through the miR-146b/SIRT1 pathway, which may represent a potential therapeutic target for the prevention and treatment of metabolic diseases, particularly diabetes.

Berteroin ameliorates lipid accumulation through AMPK-mediated regulation of hepatic lipid metabolism and inhibition of adipocyte differentiation

AimsBerteroin (5-methylthiopentyl isothiocyanate) is a naturally occurring sulforaphane analog containing a non-oxidized sulfur atom in cruciferous vegetables. The objectives of the present study were to determine the effects of berteroin on lipid metabolism in hepatocytes and adipocytes and to elucidate the mechanisms involved. Main methodsThe effect of berteroin on lipid metabolism were evaluated in liver X receptor α agonist-stimulated HepG2 cells and adipocyte differentiation-induced 3T3-L1 cells using MTT assay, western blot, real time polymerase chain reaction, oil red O staining, and triglyceride assay. Key findingsT0901317 treatment increased the expression of sterol regulatory element binding protein (SREBP)-1c, a major transcription factor that mediates lipogenesis, and berteroin pretreatment significantly inhibited the expressions of T0901317-induced SREBP-1c and lipogenic genes. Especially, berteroin had a greater inhibitory effect on T0901317-induced SREBP-1c activation than sulforaphane, AICAR, or metformin. Berteroin also markedly suppressed lipid droplet formations and triglyceride accumulations caused by both T0901317 stimulation in HepG2 hepatocytes and differentiation induction in 3T3-L1 preadipocytes. However, berteroin significantly increased the expression of mitochondrial fatty acid oxidation-related genes (carnitine palmitoyltransferase 1 (CPT-1) and peroxisome proliferator-activated receptor gamma coactivator-1α) and the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in HepG2 cells. Interestingly, effects of berteroin on the expressions of SREBP-1c protein and CPT-1 mRNA were remarkably prevented by compound C (an AMPK inhibitor). SignificanceOur results suggest berteroin-inhibited hepatic lipid accumulation and adipocyte differentiation might be mediated by AMPK activation and that berteroin might be useful for the prevention, amelioration, and treatment of metabolic diseases, including hepatic steatosis.

386-P: Chronic Treatment with the Direct AMPK Activator PXL770 Improves Cardiac, Vascular, and Renal Function in Rodents with Diabetes-Related Cardiorenal Disease

Introduction: PXL770 is a direct AMP kinase activator. In models of T2DM and NASH, PXL770 improves hyperglycemia and dyslipidemia and reduces: steatosis, inflammation, fibrogenesis. Whether these beneficial effects are associated with an improvement in diabetes-related cardiac, vascular and renal dysfunctions is unknown. Methods: Diabetic ZSF-1 rats were treated for 90 days with PXL770 (150 mg/kg BID), then cardiac function (left ventricular (LV) hemodynamics), in vitro flow-mediated dilation (FMD; arteriograph) of mesenteric artery, renal histology and function (transcutaneous GFR) were assessed. Results: Untreated ZSF-1 rats exhibited LV diastolic dysfunction, i.e., increases in LV End-Diastolic Pressure (LVEDP; 8.3±1.0 vs. 5.6±0.6 mm Hg in lean, p<.05) and LV End-Diastolic Pressure Volume Relation (LVEDPVR; 5.4±0.6 vs. 1.1±0.2 mm Hg/RVU in lean, p<.05). Myocardial tissue perfusion was reduced (4.0±0.2 vs. 7.4±0.9 ml/min/g in lean, p<.05). Untreated rats exhibited impaired mesenteric FMD (% of preconstriction; 37±11 vs. 70±7% in lean, p<.05) and renal function and structure as shown by a reduction in GFR (4.4±0.5 vs. 5.6±0.5 ml/min in lean, p<.05) and increase in glomerular score (2.3±0.2 vs. 0.6±0.1 AU in lean, p<.05). Compared to untreated ZSF-1 rats, 90-day PXL770 reduced glycaemia (-31 %, p<.05) and plasma triglycerides (-44 %, p<.05). PXL770 decreased LVEDP (-28 %) and LVEDPVR (2.7±0.2 mm Hg/RVU, p<.05) and increased LV tissue perfusion (+30 %, p<.05). PXL770 improved mesenteric FMD (64±3%, p<.05) and increased GFR (6.0±0.1 ml/min, p<.05) and reduced glomerular score (1.6±0.2, p<.05). Conclusion: In ZSF-1 rats, improvement of metabolic status induced by long-term treatment with the AMP kinase activator PXL770 is associated with an improved LV diastolic, vascular and renal function/structure. PXL770 could have therapeutic utility for the treatment of metabolic diseases and related co-morbid conditions. Disclosure Y. Stephan: None. M. Soulié: None. L. Nicol: None. P. Gluais-dagorn: Employee; Self; Poxel SA. S. Hallakou-bozec: None. P. Mulder: None. Funding Poxel SA

Natural Products in the Prevention of Metabolic Diseases: Lessons Learned from the 20th KAST Frontier Scientists Workshop.

The incidence of metabolic and chronic diseases including cancer, obesity, inflammation-related diseases sharply increased in the 21st century. Major underlying causes for these diseases are inflammation and oxidative stress. Accordingly, natural products and their bioactive components are obvious therapeutic agents for these diseases, given their antioxidant and anti-inflammatory properties. Research in this area has been significantly expanded to include chemical identification of these compounds using advanced analytical techniques, determining their mechanism of action, food fortification and supplement development, and enhancing their bioavailability and bioactivity using nanotechnology. These timely topics were discussed at the 20th Frontier Scientists Workshop sponsored by the Korean Academy of Science and Technology, held at the University of Hawaii at Manoa on 23 November 2019. Scientists from South Korea and the U.S. shared their recent research under the overarching theme of Bioactive Compounds, Nanoparticles, and Disease Prevention. This review summarizes presentations at the workshop to provide current knowledge of the role of natural products in the prevention and treatment of metabolic diseases.

Adipose Extracellular Vesicles: Messengers From and to Macrophages in Regulating Immunometabolic Homeostasis or Disorders.

Adipose tissue is comprised of heterogenous cell populations that regulate both energy metabolism and immune reactions. Macrophages play critical roles in regulating immunometabolic homeostasis or disorders through cooperation with adipocytes, adipose tissue-derived stem cells (ADSCs) or other cells in adipose tissue. Extracellular vesicles (EVs) are recently recognized as efficient messengers for intercellular communication. Emerging evidences have demonstrated that adipose EVs are actively involved in the mutual interactions of macrophages, adipocytes and ADSCs, which produce considerable influences on immunometabolism under healthy or obese conditions. Here, we will elaborate the production and the characteristics of adipose EVs that are related to macrophages under different metabolic demands or stresses, whilst discuss the roles of these EVs in regulating local or systemic immunometabolic homeostasis or disorders in the context of adipocyte-macrophage dialogue and ADSC-macrophage interaction. Particularly, we provide a profile of dynamic adipose microenvironments based on macrophages. Adipose EVs act as the messengers between ADSCs and macrophages to maintain the balance of metabolism and immunity, while drive a vicious cycle between hypertrophic adipocytes and inflammatory macrophages to cause immunometabolic imbalance. This review may provide valuable information about the physio- or pathological roles of adipose EVs and the application of adipose EVs in the diagnosis and treatment of metabolic diseases.

NTCP is a new promising target for treatment of metabolic diseases: A proof of mechanism from double-blind phase I clinical trials of Hepalatide

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Whole-brain mapping of amylin-induced neuronal activity in receptor activity-modifying protein 1/3 knockout mice.

The pancreatic hormone amylin plays a central role in regulating energy homeostasis and glycaemic control by stimulating satiation and reducing food reward, making amylin receptor agonists attractive for the treatment of metabolic diseases. Amylin receptors consist of heterodimerized complexes of the calcitonin receptor and receptor-activity modifying proteins subtype 1-3 (RAMP1-3). Neuronal activation in response to amylin dosing has been well characterized, but only in selected regions expressing high levels of RAMPs. The current study identifies global brain-wide changes in response to amylin and by comparing wild type and RAMP1/3 knockout mice reveals the importance of RAMP1/3 in mediating this response. Amylin dosing resulted in neuronal activation as measured by an increase in c-Fos labelled cells in 20 brain regions, altogether making up the circuitry of neuronal appetite regulation (e.g., area postrema (AP), nucleus of the solitary tract (NTS), parabrachial nucleus (PB), and central amygdala (CEA)). c-Fos response was also detected in distinct nuclei across the brain that typically have not been linked with amylin signalling. In RAMP1/3 knockout amylin induced low-level neuronal activation in seven regions, including the AP, NTS and PB, indicating the existence of RAMP1/3-independent mechanisms of amylin response. Under basal conditions RAMP1/3 knockout mice show reduced neuronal activity in the hippocampal formation as well as reduced hippocampal volume, suggesting a role for RAMP1/3 in hippocampal physiology and maintenance. Altogether these data provide a global map of amylin response in the mouse brain and establishes the significance of RAMP1/3 receptors in relaying this response.

Human GPR17 Nonsynonymous Variants Identified in Individuals with Metabolic Diseases Have Distinct Functional Signaling Profiles

GPR17 is a G protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Our genetic knockout studies in rodents suggest that GPR17 is a potential therapeutic target for the treatment of metabolic diseases. However, the contributions of GPR17 to human metabolism and metabolic deficits are not well understood. Here, we analyzed the human GPR17 coding sequences of individuals from control and metabolic disease cohorts that were comprised of patients with clinical phenotypes including severe insulin resistance, hypercholesterolemia, and obesity. Across cohorts, 18 nonsynonymous GPR17 variants were identified, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, cellular localization, and downstream functional signaling profiles of nine human GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). We found that the protein expression levels and subcellular localization for each of the nine GPR17 variants were similar to that of the wild type GPR17. As the endogenous GPR17 ligand is still elusive, we used a synthetic GPR17 agonist to quantitatively measure the functional signaling profiles of GPR17 variants. We found some of the variants had distinctly altered signaling profiles. GPR17-G136S lost agonist-mediated cAMP, Ca2+, and beta-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT but had impaired Ca2+ and beta-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca2+ signaling but enhanced agonist-stimulated beta-arrestin recruitment. Also, GPR17-G354V retained cAMP and Ca2+ signaling function but had attenuated beta-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with distinct signaling profiles, including differential signaling perturbations that resulted in receptor signaling bias. These results are expected to contribute to our understanding of the molecular signaling mechanisms underlying GPR17 in metabolic regulation.

Invariant NKT cells promote expansion of novel CXCR3+CCR4+CD8+ T cells in the liver following allogeneic hepatocyte transplant

Abstract Hepatocyte transplant (HcTx) is a treatment for metabolic diseases and a bridge to liver transplant but is limited by immunogenicity. Our prior work identified the critical role of CD4-dependent and CD4-independent CD8+ T cells in HcTx rejection. Herein, we evaluated the influence of invariant natural killer T cells (iNKTs), abundant in the liver, upon CD8+ T cell responses in the presence and absence of CD4+ T cells. To investigate this, C57BL/6 (wild-type; WT) or iNKT deficient Jα18 KO (H-2b) received FVB/N (H-2q) HcTx. Cohorts were depleted of CD4+ T cells and/or reconstituted with iNKTs. Recipients were evaluated for cytotoxicity, CD8+ T cell phenotype, and HcTx rejection. By comparing CD4-sufficient WT and Jα18 KO recipients, we found that the presence of iNKTs significantly enhanced in vivo CD8-mediated cytotoxicity (83±3% vs 23±3%; p<0.001) but did not affect survival (10 days vs 14 days; p=ns). However, in CD4-deficient recipients, iNKTs were critical, since without CD4+ T cells and iNKTs, CD8-mediated in vivo cytotoxicity was completely abrogated (31±3% vs 2±1%; p<0.001) and HcTx survival was significantly prolonged (14 days vs 56 days; p<0.001). iNKTs enhanced the quantity of a novel CD8+ T cell subset, CD44+IFN-γ+CXCR3+CCR4+CD8+ T cells, in the liver (2-fold) in all HcTx recipients (p<0.03 for all comparisons). CXCR3+CCR4+CD8+ T cells, when compared to CXCR3+CCR4−CD8+ T cells, express higher IFN-γ (32±3% vs 9±1%; p<0.001) and TNF-α (37±3% vs 6±1%; p<0.001). They also exhibit greater in vivo cytotoxicity (13±1% vs 5±1%; p<0.001) and mediate rapid HcTx rejection in RAG1 KO recipients (5 days vs 16 days; p=0.02). We show that iNKTs enhance the expansion of highly cytotoxic CXCR3+CCR4+CD8+ T cells that mediate rapid rejection of HcTx.

Investigation of the free fatty acid receptor 2 and its role in the treatment of type 2 diabetes mellitus

The free fatty acid receptor 2 (FFAR2) is a deorphanized G-protein coupled receptor (GPCR) that is widely expressed in various tissues in the body. Previous studies have shown that the short-chain fatty acids (SCFAs) acetate, butyrate and propionate activate FFAR2, leading to changes in cellular function. SCFAs are gut microbial metabolites important in shaping and maintaining gut homeostasis, as well as impacting other cell functions. FFAR2 is found in pancreatic islets and has led to investigational studies for the treatment of metabolic diseases. Our study focuses on FFAR2 as a potential treatment for type 2 diabetes mellitus (T2DM). FFAR2 contributes to glucose-stimulated insulin secretion (GSIS) and its potential in therapy has not been fully explored. This study focused on the effects of GPCR agonists targeting the deorphanized free fatty acid receptor 2 via intracellular calcium assays. We investigated the effects of numerous GPCR agonists on FFAR2, with a specific focus on identifying agonists or allosteric modulators. Further analysis and testing are underway to pinpoint specific agonists as potential treatment options for T2DM.

Cold‐Induced Lipokines in Metabolism

Metabolic syndrome and obesity are rapidly increasing worldwide, leading to high morbidity and mortality in type 2 diabetes, cardiovascular disease, renal failure, and cancers. Fundamental to these pathologies is adipose tissue. Besides the energy-storing white adipose tissue, brown and brown-like beige adipose tissue (BAT) are specialized for thermogenic energy expenditure. Because of the high capacity of BAT in consuming nutrients to generate heat and dissipate energy and the presence of BAT in adult humans, enhancing the quantity or activity of BAT has been regarded as an appealing approach for the treatment or prevention of obesity and its related metabolic disorders. Besides energy dissipation, at least part of BAT's beneficial effects is mediated via its secretory function and the resulting capacity to affect metabolic functions in other tissues such as muscle, WAT, and liver. BAT can produce factors, such as peptides, lipids, or other metabolites, which may act in an endocrine, paracrine, or autocrine manner to regulate physiological functions required for adaptive thermogenesis. Cold exposure is one of the most efficient ways to activate BAT and increases energy consumption. Short-term cold exposure leads to significant improvement in insulin sensitivity. By utilizing mass spectrometry-based lipidomics, we have identified novel lipid mediators (i.e., lipokines) derived from BAT, whose concentrations are increased in the circulation of cold exposed mice and humans. These lipokines act as markers and stimulators of thermogenic activity and negatively associate with body mass index and insulin sensitivity. At the molecular level, cold exposure activates the expression of key enzymes that regulate the biosynthesis of the lipokines. Mechanistic studies illustrate that cold-induced lipokines can modulate glucose and fatty acid metabolism. These findings provide novel therapeutic strategies for the treatment of metabolic diseases by producing lipokines mimicking cold exposure.

Potential Role of Propolis in the Prevention and Treatment of Metabolic Diseases.

Propolis is a resinous mixture with a complex chemical composition, produced by honeybees and stingless bees from a variety of vegetal sources. In the last decades, propolis was extensively researched, multiple studies confirming its anti-inflammatory, antioxidant, antimicrobial, and wound-healing properties. More recently, due to an exponential increase in the number of patients with metabolic diseases, there is also a growing interest in the study of antidiabetic, antihyperlipidemic, and anti-obesity effects of propolis. The aim of this review was to evaluate the potential role of propolis in the prevention and treatment of metabolic diseases like diabetes mellitus, dyslipidemia, and obesity. The preclinical in vivo and in vitro pharmacological models investigating antidiabetic, antihyperlipidemic, and anti-obesity effects of propolis were reviewed with a focus on the putative mechanisms of actions of several chemical constituents. Additionally, the available clinical studies and an evaluation of the safety profile of propolis were also presented.

Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications.

Pyruvate dehydrogenase kinase (PDK) can regulate the catalytic activity of pyruvate decarboxylation oxidation via the mitochondrial pyruvate dehydrogenase complex, and it further links glycolysis with the tricarboxylic acid cycle and ATP generation. This review seeks to elucidate the regulation of PDK activity in different species, mainly mammals, and the role of PDK inhibitors in preventing increased blood glucose, reducing injury caused by myocardial ischemia, and inducing apoptosis of tumor cells. Regulations of PDKs expression or activity represent a very promising approach for treatment of metabolic diseases including diabetes, heart failure, and cancer. The future research and development could be more focused on the biochemical understanding of the diseases, which would help understand the cellular energy metabolism and its regulation by pharmacological effectors of PDKs.

Intercellular mitochondria transfer: a new perspective for the treatment of metabolic diseases.

Intercellular mitochondria transfer: a new perspective for the treatment of metabolic diseases.

VNUT Is a Therapeutic Target for Type 2 Diabetes and NASH

ATP, used in cells as an energy currency, also acts as an extracellular signaling molecule. Studies of purinergic receptor subtypes have revealed that purinergic chemical transmission plays important roles in various cell types. The vesicular nucleotide transporter (VNUT), the ninth transporter in the SLC17 organic anion transporter family, is essential for vesicular ATP storage and its subsequent release. The VNUT is localized on the membrane of secretory vesicles and actively transports ATP into vesicles using an electrochemical gradient of protons supplied by vacuolar proton ATPase (V-ATPase) as a driving force. ATP acts as a damage-associated molecular pattern (DAMPs), contributing to the persistence of chronic inflammation. Chronic inflammation induces systemic insulin resistance, which is the underlying pathology of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). We previously demonstrated that ATP transported in insulin granules via the VNUT negatively regulates insulin secretion. We also found that hepatocytes release ATP in a VNUT-dependent manner, which elicits hepatic insulin resistance and inflammation. VNUT-knockout mice exhibited improved glucose tolerance and were resistant to the development of high fat diet-induced NAFLD. In this article, we summarize recent advances in our understanding of the mechanism of the VNUT, the development of inhibitors, and its pathological involvement in type 2 diabetes and NAFLD. The pharmacological inhibition of the VNUT may represent a potential therapeutic approach for the treatment of metabolic diseases.

Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism.

Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3-30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5-42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.