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Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease.
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VCA Colonial Animal Hospital, Ithaca, New York, USA
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Weill Cornell College of Medicine, New York, New York, USA
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Fate Therapeutics, San Diego, California, USA
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Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, California, USA
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Glucagon plays a central role in amino acid (AA) homeostasis. The dog is an established model of glucagon biology, and recently, metabolomic changes in people associated with glucagon infusions have been reported. Glucagon also has effects on the kidney; however, changes in urinary AA concentrations associated with glucagon remain under investigation. Therefore, we aimed to fill these gaps in the canine model by determining the effects of glucagon on the canine plasma metabolome and measuring urine AA concentrations. Employing two constant rate glucagon infusions (CRI) – low-dose (CRI-LO: 3 ng/kg/min) and high-dose (CRI-HI: 50 ng/kg/min) on five research beagles, we monitored interstitial glucose and conducted untargeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) on plasma samples and urine AA concentrations collected pre- and post-infusion. The CRI-HI induced a transient glucose peak (90–120 min), returning near baseline by infusion end, while only the CRI-LO resulted in 372 significantly altered plasma metabolites, primarily reductions (333). Similarly, CRI-HI affected 414 metabolites, with 369 reductions, evidenced by distinct clustering post-infusion via data reduction (PCA and sPLS-DA). CRI-HI notably decreased circulating AA levels, impacting various AA-related and energy-generating metabolic pathways. Urine analysis revealed increased 3-methyl-l-histidine and glutamine, and decreased alanine concentrations post-infusion. These findings demonstrate glucagon’s glucose-independent modulation of the canine plasma metabolome and highlight the dog’s relevance as a translational model for glucagon biology. Understanding these effects contributes to managing dysregulated glucagon conditions and informs treatments impacting glucagon homeostasis.
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist used for the treatment of T2D, has been shown to alleviate diabetic cardiomyopathy (DbCM) in experimental T2D, which was associated with increased myocardial glucose oxidation. To determine whether this increase in glucose oxidation is necessary for cardioprotection, we hypothesized that liraglutide’s ability to alleviate DbCM would be abolished in mice with cardiomyocyte-specific deletion of pyruvate dehydrogenase (PDH; Pdha1 CM−/− mice), the rate-limiting enzyme of glucose oxidation. Male Pdha1 CM−/− mice and their α-myosin heavy chain Cre expressing littermates (αMHCCre mice) were subjected to experimental T2D via 10 weeks of high-fat diet supplementation, with a single low-dose injection of streptozotocin (75 mg/kg) provided at week 4. All mice were randomized to treatment with either vehicle control or liraglutide (30 µg/kg) twice daily during the final 2.5 weeks, with cardiac function assessed via ultrasound echocardiography. As expected, liraglutide treatment improved glucose homeostasis in both αMHCCre and Pdha1 CM−/− mice with T2D, in the presence of mild weight loss. Parameters of systolic function were unaffected by liraglutide treatment in both αMHCCre and Pdha1 CM−/− mice with T2D. However, liraglutide treatment alleviated diastolic dysfunction in αMHCCre mice, as indicated by an increase and decrease in the e′/a′ and E/e′ ratios, respectively. Conversely, liraglutide failed to rescue these indices of diastolic dysfunction in Pdha1 CM−/− mice. Our findings suggest that increases in glucose oxidation are necessary for GLP-1R agonist mediated alleviation of DbCM. As such, strategies aimed at increasing PDH activity may represent a novel approach for the treatment of DbCM.
Department of Obstetrics and Gynecology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
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Department of Obstetrics and Gynecology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
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Polycystic ovary syndrome (PCOS) is a condition resulting from the interaction between environmental factors and hereditary components, profoundly affecting offspring development. Although the etiology of this disease remains unclear, aberrant in utero androgen exposure is considered one of the pivotal pathogenic factors. Herein, we demonstrate the intergenerational inheritance of PCOS-like phenotypes in F2 female offspring through F1 males caused by maternal testosterone exposure in F0 mice. We found impaired serum hormone expression and reproductive system development in prenatal testosterone-treated F1 male and F2 female mice (PTF1 and PTF2). In addition, downregulated N6-methyladenosine (m6A) methyltransferase and binding proteins induced mRNA hypomethylation in the PTF1 testis, including frizzled-6 (Fzd6). In the PTF2 ovary, decreased FZD6 protein expression inhibited the mammalian target of rapamycin (mTOR) signaling pathway and activated Forkhead box O3 (FoxO3) phosphorylation, which led to impaired follicular development. These data indicate that epigenetic modification of the mTOR signaling pathway could be involved in the intergenerational inheritance of maternal testosterone exposure-induced impairments in the PTF2 ovary through male PTF1 mice.
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Non-alcoholic fatty liver disease (NAFLD) is the fastest growing cause of liver-associated death globally. Whole-body knockout (KO) of Na+/H+ exchanger 1 (NHE1, SLC9A1) was previously proposed to protect against high fat diet-induced liver damage, however, mechanistic insight was lacking. The aim of the present work was to address this question in vitro to determine how NHE1 specifically in hepatocytes impacts lipid overload-induced inflammation, fibrosis, and hepatocyte- hepatic stellate cell (HSC) crosstalk. We induced palmitate (PA)-based steatosis in AML12 and HepG2 hepatocytes, manipulated NHE1 activity pharmacologically and by CRISPR-Cas knockout (KO) and -overexpression, and measured intracellular pH (pHi), steatosis-associated inflammatory and fibrotic mediators and cell death. PA treatment increased NHE1 mRNA levels but modestly reduced NHE1 protein expression and hepatocyte pHi. NHE1 KO in hepatocytes did not alter lipid droplet accumulation but reduced inflammatory signaling (p38 MAPK activity), lipotoxicity (4-HNE accumulation) and apoptosis (PARP cleavage). Conditioned medium from PA-treated hepatocytes increased expression of NHE1 and of the fibrosis regulator tissue inhibitor of matrix metalloproteases-2 (TIMP2) in LX-2 HSCs, in a manner abolished by NHE1 KO in hepatocytes. We conclude that NHE1 is regulated in NAFLD in vitro and contributes to the ensuing damage by aggravating hepatocyte injury and stimulating hepatocyte-HSC crosstalk.
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
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Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
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Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
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Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
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Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
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Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
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Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
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Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
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Characteristic symptoms of hyperthyroidism include weight loss, heart palpitation, and sweating. Thyroid hormones (TH) can stimulate thermogenesis through central and peripheral mechanisms. Previous studies have shown an association between dysfunction of cardiotrophin-like cytokine factor 1 (CLCF1) and cold-induced sweating syndrome, with recent research also indicating a link between CLCF1 and brown adipose tissue thermogenesis. However, it remains unclear whether CLCF1 and TH have synergistic or antagonistic effects on thermogenesis. This study aims to investigate the influence of thyroid hormone on circulating CLCF1 levels in humans and explore the potential possibilities of thyroid hormone in regulating energy metabolism by modulating Clcf1 in mice. By recruiting hyperthyroid patients and healthy subjects, we observed significantly lower serum CLCF1 levels in hyperthyroid patients compared to healthy subjects, with serum CLCF1 levels independently associated with hyperthyroidism after adjusting for potential confounders. Tissue analysis from mice treated with T3 revealed a decrease in CLCF1 expression in BAT and iWAT of C57BL/6 mice. These findings suggest that TH may play a role in regulating CLCF1 expression in adipose tissue.
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Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
Division of Endocrinology, Department of Medicine, Roudebush VA Medical Center and Indiana University School of Medicine, Indianapolis, Indiana, USA
Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
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β-Cell death contributes to β-cell loss and insulin insufficiency in type 1 diabetes (T1D), and this β-cell demise has been attributed to apoptosis and necrosis. Apoptosis has been viewed as the lone form of programmed β-cell death, and evidence indicates that β-cells also undergo necrosis, regarded as an unregulated or accidental form of cell demise. More recently, studies in non-islet cell types have identified and characterized novel forms of cell death that are biochemically and morphologically distinct from apoptosis and necrosis. Several of these mechanisms of cell death have been categorized as forms of regulated necrosis and linked to inflammation and disease pathogenesis. In this review, we revisit discoveries of β-cell death in humans with diabetes and describe studies characterizing β-cell apoptosis and necrosis. We explore literature on mechanisms of regulated necrosis including necroptosis, ferroptosis and pyroptosis, review emerging literature on the significance of these mechanisms in β-cells, and discuss experimental approaches to differentiate between various mechanisms of β-cell death. Our review of the literature leads us to conclude that more detailed experimental characterization of the mechanisms of β-cell death is warranted, along with studies to better understand the impact of various forms of β-cell demise on islet inflammation and β-cell autoimmunity in pathophysiologically relevant models. Such studies will provide insight into the mechanisms of β-cell loss in T1D and may shed light on new therapeutic approaches to protect β-cells in this disease.
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The steroidogenic acute regulatory (STAR) protein is an essential cholesterol transporter that shuttles cholesterol from the outer to the inner mitochondrial membrane in the major steroidogenic endocrine organs. It is a key player in the acute regulation of steroid hormone biosynthesis in response to tropic hormone stimulation. Its discovery thirty years ago sparked immediate interest in understanding how STAR action is controlled. Since increased STAR gene expression is a classic feature of the acute regulation of steroidogenesis, a special emphasis was placed on defining the transcriptional regulatory mechanisms that underlie its rapid induction in response to tropic hormone stimulation. These mechanisms include the effects of enhancers, the regulation of chromatin accessibility, the impact of epigenetic factors, and the role of transcription factors. Over the past three decades, understanding the transcription factors that regulate STAR gene expression has been the subject of more than 170 independent scientific publications making it one of, and if not the best, studied genes in the steroidogenic pathway. This intense research effort has led to the identification of dozens of transcription factors and their related binding sites in STAR 5' flanking (promoter) sequences across multiple species. STAR gene transcription appears to be complex in that a large number of transcription factors have been proposed to interact with either isolated or overlapping regulatory sequences that are tightly clustered over a relatively short promoter region upstream of the STAR transcription start site. Many of these transcription factors appear to work in unique combinatorial codes and are impacted by diverse hormonal and intracellular signaling pathways. This review provides a retrospective overview on the transcription factors proposed to regulate both basal and acute (hormonal) STAR gene expression, and how insights in this area have evolved over the past thirty years
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
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Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, P. R. China
Centro de Investigacion Principe Felipe, Valencia, Spain
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Obesity and diabetes represent two increasing and invalidating public health issues that often coexist. It is acknowledged that fat mass excess predisposes to insulin resistance and type 2 diabetes mellitus (T2D), with the increasing incidence of the two diseases significantly associated. Moreover, emerging evidence suggests that obesity might also accelerate the appearance of type 1 diabetes (T1D), which is now a relatively frequent comorbidity in patients with obesity. It is a common clinical finding that not all patients with obesity will develop diabetes at the same level of adiposity, with gender, genetic, and ethnic factors playing an important role in defining the timing of diabetes appearance. The adipose tissue (AT) expandability hypothesis explains this paradigm, indicating that the individual capacity to appropriately store energy surplus in the form of fat within the AT determines and prevents the toxic deposition of lipids in other organs, such as the pancreas. Thus, we posit that when the maximal storing capacity of AT is exceeded, individuals will develop T2D. In this review, we provide insight into mechanisms by which the AT controls pancreas lipid content and homeostasis in case of obesity to offer an adipocentric perspective of pancreatic lipotoxicity in the pathogenesis of diabetes. Moreover, we suggest that improving AT function is a valid therapeutic approach to fighting obesity-associated complications including diabetes.
