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1.
Adv Exp Med Biol ; 1275: 195-227, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33539017

RESUMEN

Type 2 diabetes (T2D) is a worldwide serious public health problem. Insulin resistance and ß-cell failure are the two major components of T2D pathology. In addition to defective endoplasmic reticulum (ER) stress signaling due to glucolipotoxicity, ß-cell dysfunction or ß-cell death initiates the deleterious vicious cycle observed in T2D. Although the primary cause is still unknown, overnutrition that contributes to the induction of the state of low-grade inflammation, and the activation of various protein kinases-related metabolic pathways are main factors leading to T2D. In this chapter following subjects, which have critical checkpoints regarding ß-cell fate and protein kinases pathways are discussed; hyperglycemia-induced ß-cell failure, chronic accumulation of unfolded protein in ß-cells, the effect of intracellular reactive oxygen species (ROS) signaling to insulin secretion, excessive saturated free fatty acid-induced ß-cell apoptosis, mitophagy dysfunction, proinflammatory responses and insulin resistance, and the reprogramming of ß-cell for differentiation or dedifferentiation in T2D. There is much debate about selecting proposed therapeutic strategies to maintain or enhance optimal ß-cell viability for adequate insulin secretion in T2D. However, in order to achieve an effective solution in the treatment of T2D, more intensive clinical trials are required on newer therapeutic options based on protein kinases signaling pathways.


Asunto(s)
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Estrés Oxidativo , Proteínas Quinasas/metabolismo
2.
Nat Commun ; 12(1): 213, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431899

RESUMEN

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.


Asunto(s)
Dieta Alta en Grasa , Exosomas/metabolismo , Resistencia a la Insulina/genética , Fosfatidilcolinas/metabolismo , Regulación hacia Arriba/genética , Tejido Adiposo/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Dislipidemias/complicaciones , Dislipidemias/genética , Dislipidemias/patología , Células Epiteliales/metabolismo , Hígado Graso/complicaciones , Hígado Graso/genética , Hígado Graso/patología , Heces , Regulación de la Expresión Génica , Intolerancia a la Glucosa , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Insulina/metabolismo , Interleucina-6/sangre , Intestinos/citología , Lípidos/química , Hígado/metabolismo , Hígado/patología , Activación de Macrófagos , Ratones Endogámicos C57BL , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Tetraspanina 30/metabolismo , Factor de Necrosis Tumoral alfa/sangre
3.
Nat Commun ; 12(1): 547, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33483510

RESUMEN

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.


Asunto(s)
Glucemia/metabolismo , Enfermedad de la Arteria Coronaria/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Metabolismo de los Lípidos , Modelos Biológicos , Animales , Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Femenino , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Ratones Endogámicos C57BL , Polimorfismo de Nucleótido Simple
4.
Nat Commun ; 12(1): 183, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420039

RESUMEN

We have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived ß-cells (hiPSC-ß-cells) and diminishes oligomer-mediated apoptosis of ß-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated ß-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3. MSL-7 improves glucose tolerance and ß-cell function of hIAPP+ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and ß-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated ß-cell death and the development of diabetes are also significantly reduced by ß-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.


Asunto(s)
Amiloide/metabolismo , Proteínas Amiloidogénicas/metabolismo , Autofagia/fisiología , Diabetes Mellitus Tipo 2/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Animales , Apoptosis/fisiología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Técnicas de Inactivación de Genes , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Secretoras de Insulina , Macroautofagia/fisiología , Ratones , Ratones Transgénicos
5.
Nat Commun ; 12(1): 650, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510172

RESUMEN

Hepatic inflammation is the driving force for the development and progression of NASH. Treatment targeting inflammation is believed to be beneficial. In this study, adoptive transfer of CD4+ T cells converted double negative T cells (cDNT) protects mice from diet-induced liver fat accumulation, lobular inflammation and focal necrosis. cDNT selectively suppress liver-infiltrating Th17 cells and proinflammatory M1 macrophages. IL-10 secreted by M2 macrophages decreases the survival and function of cDNT to protect M2 macrophages from cDNT-mediated lysis. NKG2A, a cell inhibitory molecule, contributes to IL-10 induced apoptosis and dampened suppressive function of cDNT. In conclusion, ex vivo-generated cDNT exert potent protection in diet induced obesity, type 2 diabetes and NASH. The improvement of outcome is due to the inhibition on liver inflammatory cells. This study supports the concept and the feasibility of potentially utilizing this autologous immune cell-based therapy for the treatment of NASH.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Inflamación/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Traslado Adoptivo/métodos , Animales , Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Dieta Alta en Grasa/efectos adversos , Progresión de la Enfermedad , Perfilación de la Expresión Génica/métodos , Inflamación/genética , Interleucina-10/metabolismo , Hígado/patología , Macrófagos/clasificación , Macrófagos/inmunología , Masculino , Ratones Endogámicos C57BL , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/terapia , Obesidad/etiología , Obesidad/metabolismo , Obesidad/terapia
6.
Nat Commun ; 12(1): 674, 2021 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-33514698

RESUMEN

Transcriptionally mature and immature ß-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in ß-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH ß-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH ß-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the ß-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in ß-cell maturity, might be important for the maintenance of islet function.


Asunto(s)
Secreción de Insulina/fisiología , Células Secretoras de Insulina/metabolismo , Animales , Calcio/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Femenino , Técnicas de Sustitución del Gen , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Factores de Transcripción Maf de Gran Tamaño/genética , Factores de Transcripción Maf de Gran Tamaño/metabolismo , Masculino , Ratones , Ratones Transgénicos , Modelos Animales , Cultivo Primario de Células , Transactivadores/genética , Transactivadores/metabolismo
7.
Nat Med ; 27(1): 58-65, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33398160

RESUMEN

White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear1,2. Here we retrospectively categorized 134,529 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans from 52,487 patients, by presence or absence of BAT, and used propensity score matching to assemble a study cohort. Scans in the study population were initially conducted for indications related to cancer diagnosis, treatment or surveillance, without previous stimulation. We report that individuals with BAT had lower prevalences of cardiometabolic diseases, and the presence of BAT was independently correlated with lower odds of type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure and hypertension. These findings were supported by improved blood glucose, triglyceride and high-density lipoprotein values. The beneficial effects of BAT were more pronounced in individuals with overweight or obesity, indicating that BAT might play a role in mitigating the deleterious effects of obesity. Taken together, our findings highlight a potential role for BAT in promoting cardiometabolic health.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Enfermedades Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucemia/metabolismo , Dislipidemias/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos
8.
Metabolism ; 114: 154390, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33039407

RESUMEN

BACKGROUND: Endothelial dysfunction is an early pathogenic event in the progression of cardiovascular disease in patients with Type 2 Diabetes (T2D). Endothelial KCa2.3 and KCa3.1 K+ channels are important regulators of arterial diameter, and we thus hypothesized that SKA-31, a small molecule activator of KCa2.3 and KCa3.1, would positively influence agonist-evoked dilation in myogenically active resistance arteries in T2D. METHODOLOGY: Arterial pressure myography was utilized to investigate endothelium-dependent vasodilation in isolated cremaster skeletal muscle resistance arteries from 22 to 24 week old T2D Goto-Kakizaki rats, age-matched Wistar controls, and small human intra-thoracic resistance arteries from T2D subjects. Agonist stimulated changes in cytosolic free Ca2+ in acutely isolated, single endothelial cells from Wistar and T2D Goto-Kakizaki cremaster and cerebral arteries were examined using Fura-2 fluorescence imaging. MAIN FINDINGS: Endothelium-dependent vasodilation in response to acetylcholine (ACh) or bradykinin (BK) was significantly impaired in isolated cremaster arteries from T2D Goto-Kakizaki rats compared with Wistar controls, and similar results were observed in human intra-thoracic arteries. In contrast, inhibition of myogenic tone by sodium nitroprusside, a direct smooth muscle relaxant, was unaltered in both rat and human T2D arteries. Treatment with a threshold concentration of SKA-31 (0.3 µM) significantly enhanced vasodilatory responses to ACh and BK in arteries from T2D Goto-Kakizaki rats and human subjects, whereas only modest effects were observed in non-diabetic arteries of both species. Mechanistically, SKA-31 enhancement of evoked dilation was independent of vascular NO synthase and COX activities. Remarkably, SKA-31 treatment improved agonist-stimulated Ca2+ elevation in acutely isolated endothelial cells from T2D Goto-Kakizaki cremaster and cerebral arteries, but not from Wistar control vessels. In contrast, SKA-31 treatment did not affect intracellular Ca2+ release by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor cyclopiazonic acid. CONCLUSIONS: Collectively, our data demonstrate that KCa channel modulation can acutely restore endothelium-dependent vasodilatory responses in T2D resistance arteries from rats and humans, which appears to involve improved endothelial Ca2+ mobilization.


Asunto(s)
Arterias/metabolismo , Calcio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotelio Vascular/metabolismo , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/metabolismo , Acetilcolina/farmacología , Animales , Arterias/efectos de los fármacos , Bradiquinina/farmacología , Endotelio Vascular/efectos de los fármacos , Humanos , Músculo Esquelético/irrigación sanguínea , Ratas , Ratas Wistar , Vasodilatación/efectos de los fármacos
9.
Metabolism ; 114: 154404, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33069810

RESUMEN

BACKGROUND: Recent studies have considered the obesity-related lipid environment as the potential cause for M1 macrophage polarization in type 2 diabetes. However, the specific regulatory mechanism is still unclear. Here, we investigated the role and molecular mechanism of histone methyltransferases G9a in lipids-induced M1 macrophage polarization in type 2 diabetes. METHODS: We used saturated fatty acid palmitate to induce macrophage polarization, and performed real-time PCR, western blot, flow cytometry and CHIP assay to study the function and molecular mechanism of G9a. Additionally, we isolated the peripheral blood mononuclear cells (PBMCs) from 187 patients with type 2 diabetes and 68 healthy individuals, and analyzed the expression level of G9a. RESULTS: The palmitate treatment induced the macrophage M1 polarization, and decreased the expression of G9a. The deficiency of G9a could promote the palmitate-induced M1 macrophage polarization, whereas, over-expressing G9a notably suppressed this process. Meanwhile, we observed the regulatory role of G9a on the ER stress which could contribute to M1 macrophage. Furthermore, we identified the fatty acid transport protein CD36 as the potential target of G9a. Dependent on the methyltransferase activity, G9a could negatively regulate the expression of CD36 induced by palmitate. The CD36 inhibitor SSO could significantly attenuate the regulatory effect of G9a on M1 macrophage polarization and ER stress. Importantly, G9a was decreased, and suppressed CD36 and M1 macrophage genes in the PBMCs from individuals with type 2 diabetes. CONCLUSIONS: Our studies demonstrate that G9a plays critical roles in lipid-induced M1 macrophage polarization via negatively regulating CD36.


Asunto(s)
Antígenos CD36/metabolismo , Polaridad Celular/fisiología , Diabetes Mellitus Tipo 2/metabolismo , Histona Metiltransferasas/metabolismo , Macrófagos/metabolismo , Animales , Polaridad Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Leucocitos Mononucleares/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Ácido Palmítico/farmacología , Células RAW 264.7
10.
Metabolism ; 114: 154414, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33129839

RESUMEN

AIMS/HYPOTHESIS: Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the "disappearance" of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. METHODS: Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. RESULTS: The islets of diabetic subjects were 3 times more innervated than controls (0.91 ±â€¯0.21 vs 0.32 ±â€¯0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = -0.84; p = 0.01), incremental second-phase insulin secretion (r = -0.84, p = 0.03) and arginine-stimulated insulin secretion (r = -0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). CONCLUSIONS/INTERPRETATION: Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.


Asunto(s)
Neuronas Adrenérgicas/fisiología , Desdiferenciación Celular/fisiología , Diabetes Mellitus Tipo 2/metabolismo , Gliburida/metabolismo , Secreción de Insulina/fisiología , Células Secretoras de Insulina/metabolismo , Fibras Nerviosas/fisiología , Anciano , Glucemia/metabolismo , Femenino , Intolerancia a la Glucosa/metabolismo , Humanos , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Masculino , Persona de Mediana Edad
11.
Metabolism ; 114: 154416, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33137378

RESUMEN

CONTEXT: In this study, we aimed to identify the determinants of mitochondrial dysfunction in skeletal muscle (SKLM) of subjects with type 2 diabetes (T2DM), and to evaluate the effect of pioglitazone (PIO) on SKLM mitochondrial proteome. METHODS: Two different groups of adults were studied. Group I consisted of 8 individuals with normal glucose tolerance (NGT) and 8 with T2DM, subjected to SKLM mitochondrial proteome analysis by 2D-gel electrophoresis followed by mass spectrometry-based protein identification. Group II included 24 individuals with NGT and 24 with T2DM, whose SKLM biopsies were subjected to immunoblot analysis. Of the 24 subjects with T2DM, 20 were randomized to receive placebo or PIO (15 mg daily) for 6 months. After 6 months of treatment, SKLM biopsy was repeated. RESULTS: Mitochondrial proteomic analysis on Group I revealed that several mitochondrial proteins involved in oxidative metabolism were differentially expressed between T2DM and NGT groups, with a downregulation of ATP synthase alpha chain (ATP5A), electron transfer flavoprotein alpha-subunit (ETFA), cytochrome c oxidase subunit VIb isoform 1 (CX6B1), pyruvate dehydrogenase protein X component (ODPX), dihydrolipoamide dehydrogenase (DLDH), dihydrolipoamide-S-succinyltransferase (DLST), and mitofilin, and an up-regulation of hydroxyacyl-CoA-dehydrogenase (HCDH), 3,2-trans-enoyl-CoA-isomerase (D3D2) and delta3,5-delta2,4-dienoyl-CoA-isomerase (ECH1) in T2DM as compared to NGT subjects. By immunoblot analysis on SKLM lysates obtained from Group II we confirmed that, in comparison to NGT subjects, those with T2DM exhibited lower protein levels of ATP5A (-30%, P = 0.006), ETFA (-50%, P = 0.02), CX6B1 (-30%, P = 0.03), key factors for ATP biosynthesis, and of the structural protein mitofilin (-30%, P = 0.01). T2DM was associated with a reduced abundance of the enzymes involved in the Krebs cycle DLST and ODPX (-20%, P ≤ 0.05) and increased levels of HCDH and ECH1, enzymes implicated in the fatty acid catabolism (+30%, P ≤ 0.05). In subjects with type 2 diabetes treated with PIO for 6 months we found a restored SKLM protein abundance of ATP5A, ETFA, CX6B1, and mitofilin. Moreover, protein levels of HCDH and ECH1 were reduced by -10% and - 15% respectively (P ≤ 0.05 for both) after PIO treatment. CONCLUSION: Type 2 diabetes is associated with reduced levels of mitochondrial proteins involved in oxidative phosphorylation and an increased abundance of enzymes implicated in fatty acid catabolism in SKLM. PIO treatment is able to improve SKLM mitochondrial proteomic profile in subjects with T2DM.


Asunto(s)
Adenosina Trifosfato/biosíntesis , Diabetes Mellitus Tipo 2/metabolismo , Mitocondrias Musculares/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/efectos de los fármacos , Pioglitazona/farmacología , Adulto , Femenino , Glucosa/metabolismo , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Fosforilación Oxidativa , Proteómica
12.
Metabolism ; 114: 154415, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33137379

RESUMEN

BACKGROUND AND AIMS: The reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects. METHODS: We used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the ß-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data. RESULTS: a) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion. CONCLUSION: We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/administración & dosificación , Péptido 1 Similar al Glucagón/administración & dosificación , Incretinas/administración & dosificación , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Polipéptido Inhibidor Gástrico/uso terapéutico , Péptido 1 Similar al Glucagón/uso terapéutico , Prueba de Tolerancia a la Glucosa , Humanos , Incretinas/uso terapéutico , Células Secretoras de Insulina/metabolismo , Modelos Teóricos
13.
Nat Rev Endocrinol ; 17(1): 11-30, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33188364

RESUMEN

Initial studies found increased severity of coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in patients with diabetes mellitus. Furthermore, COVID-19 might also predispose infected individuals to hyperglycaemia. Interacting with other risk factors, hyperglycaemia might modulate immune and inflammatory responses, thus predisposing patients to severe COVID-19 and possible lethal outcomes. Angiotensin-converting enzyme 2 (ACE2), which is part of the renin-angiotensin-aldosterone system (RAAS), is the main entry receptor for SARS-CoV-2; although dipeptidyl peptidase 4 (DPP4) might also act as a binding target. Preliminary data, however, do not suggest a notable effect of glucose-lowering DPP4 inhibitors on SARS-CoV-2 susceptibility. Owing to their pharmacological characteristics, sodium-glucose cotransporter 2 (SGLT2) inhibitors might cause adverse effects in patients with COVID-19 and so cannot be recommended. Currently, insulin should be the main approach to the control of acute glycaemia. Most available evidence does not distinguish between the major types of diabetes mellitus and is related to type 2 diabetes mellitus owing to its high prevalence. However, some limited evidence is now available on type 1 diabetes mellitus and COVID-19. Most of these conclusions are preliminary, and further investigation of the optimal management in patients with diabetes mellitus is warranted.


Asunto(s)
/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , /antagonistas & inhibidores , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Manejo de la Enfermedad , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/metabolismo , Factores de Riesgo
15.
Gene ; 766: 145155, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32950634

RESUMEN

Expression of browning genes are lower in both humans and animals with type 2 diabetes (T2D). This study aims at determining effects of long-term nitrate administration on protein and mRNA levels of uncoupling protein 1 (UCP1), peroxisome proliferator activated receptor gamma (PPAR-γ), and PPAR-γ coactivator 1 alpha (PGC1-α) in epididymal adipose tissue (eAT) of rats with T2D. Male Wistar rats were divided into 4 groups (n = 6/group): Control, diabetes, control + nitrate (CN), and diabetes + nitrate (DN). T2D was induced using high fat diet combined with a low-dose of streptozotocin (30 mg/kg body weight). Sodium nitrate was administrated at a dose of 100 mg/L for 6 months in nitrate-treated rats. Fasting serum glucose and insulin concentrations were measured at months 0 (i.e. at start of the protocol), 3, and 6. At month 6, protein and mRNA levels of UCP1, PPAR-γ, and PGC1-α were measured in eAT samples. In addition, tissue concentration of cyclic guanosine monophosphate (cGMP) was measured and histological analyses were done at month 6. In rats with T2D, 6-month administration of nitrate decreased serum glucose and insulin concentrations by 13% and 23%, respectively and increased cGMP level by 85%. Rats with T2D had lower mRNA and protein levels of PPAR-γ (62%, P < 0.0001 and 18%, P = 0.0472), PGC1-α (49%, P = 0.0019 and 21%, P = 0.0482), and UCP1 (35%, P = 0.0613 and 30%, P = 0.0031) in eAT; 6-month nitrate administration restored these decreased levels to near control values. In addition, nitrate increased adipocyte density by 193% and decreased adipocyte area by 53% in rats with T2D. In conclusion, long-term low-dose nitrate administration increased mRNA and protein expressions of browning genes in white adipose tissue of male rats with T2D; these findings partly explain favorable metabolic effects of nitrate administration in diabetes.


Asunto(s)
Adipocitos Marrones/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Epidídimo/efectos de los fármacos , Nitratos/administración & dosificación , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Epidídimo/metabolismo , Glucosa/metabolismo , Insulina/sangre , Masculino , PPAR gamma/genética , PPAR gamma/metabolismo , ARN Mensajero/genética , Ratas , Ratas Wistar , Estreptozocina/farmacología
16.
PLoS One ; 15(12): e0240873, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33382706

RESUMEN

BACKGROUND: Sorghum bicolor (SB) is rich in protective phytoconstituents with health benefits and regarded as a promising source of natural anti-diabetic substance. However, its comprehensive bioactive compound(s) and mechanism(s) against type-2 diabetes mellitus (T2DM) have not been exposed. Hence, we implemented network pharmacology to identify its key compounds and mechanism(s) against T2DM. METHODS: Compounds in SB were explored through GC-MS and screened by Lipinski's rule. Genes associated with the selected compounds or T2DM were extracted from public databases, and the overlapping genes between SB-compound related genes and T2DM target genes were identified using Venn diagram. Then, the networking between selected compounds and overlapping genes was constructed, visualized, and analyzed by RStudio. Finally, affinity between compounds and genes was evaluated via molecular docking. RESULTS: GC-MS analysis of SB detected a total of 20 compounds which were accepted by the Lipinski's rule. A total number of 16 compounds-related genes and T2DM-related genes (4,763) were identified, and 81 overlapping genes between them were selected. Gene set enrichment analysis exhibited that the mechanisms of SB against T2DM were associated with 12 signaling pathways, and the key mechanism might be to control blood glucose level by activating PPAR signaling pathway. Furthermore, the highest affinities were noted between four main compounds and six genes (FABP3-Propyleneglyco monoleate, FABP4-25-Oxo-27-norcholesterol, NR1H3-Campesterol, PPARA-ß-sitosterol, PPARD-ß-sitosterol, and PPARG-ß-sitosterol). CONCLUSION: Our study overall suggests that the four key compounds detected in SB might ameliorate T2DM severity by activating the PPAR signaling pathway.


Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Hipoglucemiantes/química , Fitoquímicos/química , Sorghum/química , Esteroles/química , Sitios de Unión , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteína 3 de Unión a Ácidos Grasos/antagonistas & inhibidores , Proteína 3 de Unión a Ácidos Grasos/genética , Proteína 3 de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/farmacología , Receptores X del Hígado/antagonistas & inhibidores , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Simulación del Acoplamiento Molecular , PPAR alfa/antagonistas & inhibidores , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR delta/antagonistas & inhibidores , PPAR delta/genética , PPAR delta/metabolismo , PPAR gamma/antagonistas & inhibidores , PPAR gamma/genética , PPAR gamma/metabolismo , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Extractos Vegetales/química , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Transducción de Señal , Esteroles/aislamiento & purificación , Esteroles/farmacología , Relación Estructura-Actividad
17.
PLoS One ; 15(12): e0243638, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33332405

RESUMEN

BACKGROUND: Albuminuria develops in ~40% of subjects with Type 2 Diabetes Mellitus (T2DM), and is often associated with malnutrition, severe comorbidities and decreased life expectancy. The association between albuminuria and altered whole body protein turnover in T2DM is currently unknown. OBJECTIVE: To assess whole body protein degradation and synthesis in type 2 diabetes with and without albuminuria. METHODS: Fourteen T2DM male subjects, with either increased [AER+] or normal [AER-] urinary albumin excretion rate, and eleven age-matched male healthy controls, were infused with phenylalanine [Phe] and tyrosine [Tyr] tracers. Post-absorptive rates of appearance (Ra) of Phe (= protein degradation) and Tyr, Phe hydroxylation to Tyr (Hy) (catabolic pathway), and Phe disposal to protein synthesis [PS], were determined. RESULTS: Phe and Tyr Ra were not different among the groups. However, in T2DM [AER+], the fraction of Phe disposal to hydroxylation was ~50% and ~25% greater than that of both controls and T2DM [AER-] (p<0.006 and p = 0.17, respectively). Conversely, as compared to controls, the fractional Phe disposal to PS was ~10% lower in T2DM [AER+] (p<0.006), and not different from that in T2DM [AER-]. As a consequence, in T2DM [AER+], the ratio between the fractional Phe disposal to hydroxylation and that to PS was ~70% greater (p = 0.005) than that in healthy controls, whereas in the T2DM [AER-] this ratio was ~30% greater than in controls (p = 0.19). CONCLUSIONS: On the basis of the kinetics of the essential amino acid phenylalanine, T2DM subjects with increased AER exhibit a catabolic pattern of whole body protein turnover.


Asunto(s)
Albuminuria/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Proteolisis , Adulto , Albuminuria/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenilalanina/metabolismo , Biosíntesis de Proteínas
18.
BMC Bioinformatics ; 21(Suppl 17): 508, 2020 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-33308172

RESUMEN

BACKGROUND: The aim of a recent research project was the investigation of the mechanisms involved in the onset of type 2 diabetes in the absence of familiarity. This has led to the development of a computational model that recapitulates the aetiology of the disease and simulates the immunological and metabolic alterations linked to type-2 diabetes subjected to clinical, physiological, and behavioural features of prototypical human individuals. RESULTS: We analysed the time course of 46,170 virtual subjects, experiencing different lifestyle conditions. We then set up a statistical model able to recapitulate the simulated outcomes. CONCLUSIONS: The resulting machine learning model adequately predicts the synthetic dataset and can, therefore, be used as a computationally-cheaper version of the detailed mathematical model, ready to be implemented on mobile devices to allow self-assessment by informed and aware individuals. The computational model used to generate the dataset of this work is available as a web-service at the following address: http://kraken.iac.rm.cnr.it/T2DM .


Asunto(s)
Diabetes Mellitus Tipo 2/patología , Aprendizaje Automático , Adulto , Anciano , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Riesgo , Interfaz Usuario-Computador , Dispositivos Electrónicos Vestibles
19.
Nat Commun ; 11(1): 5611, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33154349

RESUMEN

Fine-tuning of insulin release from pancreatic ß-cells is essential to maintain blood glucose homeostasis. Here, we report that insulin secretion is regulated by a circular RNA containing the lariat sequence of the second intron of the insulin gene. Silencing of this intronic circular RNA in pancreatic islets leads to a decrease in the expression of key components of the secretory machinery of ß-cells, resulting in impaired glucose- or KCl-induced insulin release and calcium signaling. The effect of the circular RNA is exerted at the transcriptional level and involves an interaction with the RNA-binding protein TAR DNA-binding protein 43 kDa (TDP-43). The level of this circularized intron is reduced in the islets of rodent diabetes models and of type 2 diabetic patients, possibly explaining their impaired secretory capacity. The study of this and other circular RNAs helps understanding ß-cell dysfunction under diabetes conditions, and the etiology of this common metabolic disorder.


Asunto(s)
Secreción de Insulina/genética , Insulina/genética , Intrones , ARN Circular/metabolismo , Animales , Señalización del Calcio , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Regulación de la Expresión Génica , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ratones , ARN Circular/genética , Ratas
20.
Nat Commun ; 11(1): 5225, 2020 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-33067434

RESUMEN

Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy individuals and patients with T2D. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from Cxcr3-/- mice do not exhibit this metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhances immunogenicity and protective efficacy against M. tuberculosis challenge. Collectively, these results demonstrate an important function of CD8+ T cells in metformin-derived host metabolic-fitness towards M. tuberculosis infection.


Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Animales , Vacuna BCG/administración & dosificación , Vacuna BCG/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Cobayas , Humanos , Masculino , Ratones , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/fisiología , Tuberculosis/etiología , Tuberculosis/inmunología , Tuberculosis/microbiología , Tuberculosis/prevención & control
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