RESUMEN
Soluble dietary fibers promote metabolic benefits on body weight and glucose control, but underlying mechanisms are poorly understood. Recent evidence indicates that intestinal gluconeogenesis (IGN) has beneficial effects on glucose and energy homeostasis. Here, we show that the short-chain fatty acids (SCFAs) propionate and butyrate, which are generated by fermentation of soluble fiber by the gut microbiota, activate IGN via complementary mechanisms. Butyrate activates IGN gene expression through a cAMP-dependent mechanism, while propionate, itself a substrate of IGN, activates IGN gene expression via a gut-brain neural circuit involving the fatty acid receptor FFAR3. The metabolic benefits on body weight and glucose control induced by SCFAs or dietary fiber in normal mice are absent in mice deficient for IGN, despite similar modifications in gut microbiota composition. Thus, the regulation of IGN is necessary for the metabolic benefits associated with SCFAs and soluble fiber.
Asunto(s)
Gluconeogénesis , Mucosa Intestinal/metabolismo , Intestinos/inervación , Animales , Encéfalo/metabolismo , Grasas de la Dieta/metabolismo , Fibras de la Dieta/metabolismo , Ácidos Grasos Volátiles/metabolismo , Glucosa/metabolismo , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/metabolismo , Homeostasis , Resistencia a la Insulina , Ratones , Microbiota , Obesidad/metabolismo , Oligosacáridos/metabolismo , RatasRESUMEN
Glycogen Storage Disease Type I (GSDI) is an inherited disease caused by glucose-6 phosphatase (G6Pase) deficiency, leading to a loss of endogenous glucose production and severe hypoglycemia. Moreover, most GSDI patients develop a chronic kidney disease (CKD) due to lipid accumulation in the kidney. Similar to diabetic CKD, activation of renin-angiotensin system (RAS) promotes renal fibrosis in GSDI. Here, we investigated the physiological and molecular effects of RAS blockers in GSDI patients and mice. A retrospective analysis of renal function was performed in 21 GSDI patients treated with RAS blockers. Cellular and metabolic impacts of RAS blockade were analyzed in K.G6pc-/- mice characterized by G6pc1 deletion in kidneys. GSDI patients started RAS blocker treatment at a median age of 21 years and long-term treatment reduced the progression of CKD in about 50% of patients. However, CKD progressed to kidney failure in 20% of treated patients, requiring renal transplantation. In K.G6pc-/- mice, CKD was associated with an impairment of autophagy and ER stress. RAS blockade resulted in a rescue of autophagy and decreased ER stress, concomitantly with decreased fibrosis and improved renal function, but without impact on glycogen and lipid contents. In conclusion, these data confirm the partial beneficial effect of RAS blockers in the prevention of CKD in GSDI. Mechanistically, we show that these effects are linked to a reduction of cell stress, without affecting metabolism.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo I , Insuficiencia Renal Crónica , Animales , Femenino , Glucosa/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo I/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Humanos , Lípidos , Masculino , Ratones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/genética , Sistema Renina-Angiotensina/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: The role of hepatoportal glucose sensors is poorly understood in the context of insulin resistance. OBJECTIVES: We assessed the effects of glucose infusion in the portal vein on insulin tolerance in 2 rat models of insulin resistance, and the role of capsaicin sensitive nerves in this signal. METHODS: Male Wistar rats, 8 weeks old, weighing 250-275 g, were used. Insulin and glucose tolerance were assessed following a 4-hour infusion of either glucose or saline through catheterization in the portal vein in 3 paradigms. In experiment 1, for diet-induced insulin resistance, rats were fed either a control diet (energy content: proteins = 22.5%, carbohydrates = 64.1%, and lipids = 13.4%) or a high-fat diet (energy content: proteins = 15.3%, carbohydrates = 40.3%, and lipids =44.4%) for 4 months. In experiment 2, for centrally induced peripheral insulin resistance, catheters were inserted in the carotid artery to deliver either an emulsion of triglycerides [intralipid (IL)] or saline towards the brain for 24 hours. In experiment 3, for testing the role of capsaicin-sensitive nerves, experiment 2 was repeated following a periportal treatment with capsaicin or vehicle. RESULTS: In experiment 1, when compared to rats fed the control diet, rats fed the high-fat diet exhibited decreased insulin and glucose tolerance (P ≤ 0.05) that was restored with a glucose infusion in the portal vein (P ≤ 0.05). In experiment 2, infusion of a triglyceride emulsion towards the brain (IL rats) decreased insulin and glucose tolerance and increased hepatic endogenous production when compared to saline-infused rats (P ≤ 0.05). Glucose infusion in the portal vein in IL rats restored insulin and glucose tolerance, as well as hepatic glucose production, to controls levels (P ≤ 0.05). In experiment 3, portal infusion of glucose did not increase insulin tolerance in IL rats that received a periportal pretreatment with capsaicin. CONCLUSIONS: Stimulation of hepatoportal glucose sensors increases insulin tolerance in rat models of insulin resistance and requires the presence of capsaicin-sensitive nerves.
Asunto(s)
Resistencia a la Insulina , Insulina , Animales , Glucemia/metabolismo , Capsaicina/metabolismo , Capsaicina/farmacología , Emulsiones/metabolismo , Glucosa/metabolismo , Insulina/metabolismo , Insulina Regular Humana/farmacología , Hígado/metabolismo , Masculino , Fibras Nerviosas/metabolismo , Vena Porta/metabolismo , Ratas , Ratas Wistar , Triglicéridos/metabolismoRESUMEN
The excessive endogenous glucose production (EGP) induced by glucagon participates in the development of type 2 diabetes. To further understand this hormonal control, we studied the short-term regulation by cyclic adenosine monophosphate (cAMP) of the glucose-6-phosphatase (G6Pase) enzyme, which catalyzes the last reaction of EGP. In gluconeogenic cell models, a 1-h treatment by the adenylate cyclase activator forskolin increased G6Pase activity and glucose production independently of any change in enzyme protein amount or G6P content. Using specific inhibitors or protein overexpression, we showed that the stimulation of G6Pase activity involved the protein kinase A (PKA). Results of site-directed mutagenesis, mass spectrometry analyses, and in vitro phosphorylation experiments suggested that the PKA stimulation of G6Pase activity did not depend on a direct phosphorylation of the enzyme. However, the temperature-dependent induction of both G6Pase activity and glucose release suggested a membrane-based mechanism. G6Pase is composed of a G6P transporter (G6PT) and a catalytic unit (G6PC). Surprisingly, we demonstrated that the increase in G6PT activity was required for the stimulation of G6Pase activity by forskolin. Our data demonstrate the existence of a post-translational mechanism that regulates G6Pase activity and reveal the key role of G6PT in the hormonal regulation of G6Pase activity and of EGP.
Asunto(s)
Antiportadores/genética , AMP Cíclico/farmacología , Células Epiteliales/efectos de los fármacos , Glucagón/farmacología , Glucosa-6-Fosfatasa/genética , Glucosa/biosíntesis , Proteínas de Transporte de Monosacáridos/genética , Adenovirus Humanos/genética , Adenovirus Humanos/metabolismo , Animales , Antiportadores/metabolismo , Células CACO-2 , Línea Celular , Colforsina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Regulación de la Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Glucosa-6-Fosfatasa/metabolismo , Glucosa-6-Fosfato/metabolismo , Células Hep G2 , Humanos , Proteínas de Transporte de Monosacáridos/metabolismo , Mutagénesis Sitio-Dirigida , Fosforilación , Biosíntesis de Proteínas , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Ratas , Transducción de SeñalRESUMEN
OBJECTIVE: To evaluate the role of bile routing modification on the beneficial effects of gastric bypass surgery on glucose and energy metabolism. BACKGROUND: Gastric bypass surgery (GBP) promotes early improvements in glucose and energy homeostasis in obese diabetic patients. A suggested mechanism associates a decrease in hepatic glucose production to an enhanced intestinal gluconeogenesis. Moreover, plasma bile acids are elevated after GBP and bile acids are inhibitors of gluconeogenesis. METHODS: In male Sprague-Dawley rats, we performed bile diversions from the bile duct to the midjejunum or the mid-ileum to match the modified bile delivery in the gut occurring in GBP. Body weight, food intake, glucose tolerance, insulin sensitivity, and food preference were analyzed. The expression of gluconeogenesis genes was evaluated in both the liver and the intestine. RESULTS: Bile diversions mimicking GBP promote an increase in plasma bile acids and a marked improvement in glucose control. Bile bioavailability modification is causal because a bile acid sequestrant suppresses the beneficial effects of bile diversions on glucose control. In agreement with the inhibitory role of bile acids on gluconeogenesis, bile diversions promote a blunting in hepatic glucose production, whereas intestinal gluconeogenesis is increased in the gut segments devoid of bile. In rats fed a high-fat-high-sucrose diet, bile diversions improve glucose control and dramatically decrease food intake because of an acquired disinterest in fatty food. CONCLUSIONS: This study shows that bile routing modification is a key mechanistic feature in the beneficial outcomes of GBP.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Bilis/fisiología , Glucemia/metabolismo , Metabolismo Energético , Derivación Gástrica , Animales , Biomarcadores/metabolismo , Preferencias Alimentarias/fisiología , Regulación de la Expresión Génica , Gluconeogénesis/genética , Homeostasis , Íleon/cirugía , Resistencia a la Insulina , Mucosa Intestinal/metabolismo , Yeyuno/cirugía , Hígado/metabolismo , Masculino , Obesidad/metabolismo , Obesidad/cirugía , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Deregulation of hepatic glucose production is a key driver in the pathogenesis of diabetes, but its short-term regulation is incompletely deciphered. According to textbooks, glucose is produced in the endoplasmic reticulum by glucose-6-phosphatase (G6Pase) and then exported in the blood by the glucose transporter GLUT2. However, in the absence of GLUT2, glucose can be produced by a cholesterol-dependent vesicular pathway, which remains to be deciphered. Interestingly, a similar mechanism relying on vesicle trafficking controls short-term G6Pase activity. We thus investigated whether Caveolin-1 (Cav1), a master regulator of cholesterol trafficking, might be the mechanistic link between glucose production by G6Pase in the ER and glucose export through a vesicular pathway. METHODS: Glucose production from fasted mice lacking Cav1, GLUT2 or both proteins was measured in vitro in primary culture of hepatocytes and in vivo by pyruvate tolerance tests. The cellular localization of Cav1 and the catalytic unit of glucose-6-phosphatase (G6PC1) were studied by western blotting from purified membranes, immunofluorescence on primary hepatocytes and fixed liver sections and by in vivo imaging of chimeric constructs overexpressed in cell lines. G6PC1 trafficking to the plasma membrane was inhibited by a broad inhibitor of vesicular pathways or by an anchoring system retaining G6PC1 specifically to the ER membrane. RESULTS: Hepatocyte glucose production is reduced at the step catalyzed by G6Pase in the absence of Cav1. In the absence of both GLUT2 and Cav1, gluconeogenesis is nearly abolished, indicating that these pathways can be considered as the two major pathways of de novo glucose production. Mechanistically, Cav1 colocalizes but does not interact with G6PC1 and controls its localization in the Golgi complex and at the plasma membrane. The localization of G6PC1 at the plasma membrane is correlated to glucose production. Accordingly, retaining G6PC1 in the ER reduces glucose production by hepatic cells. CONCLUSIONS: Our data evidence a pathway of glucose production that relies on Cav1-dependent trafficking of G6PC1 to the plasma membrane. This reveals a new cellular regulation of G6Pase activity that contributes to hepatic glucose production and glucose homeostasis.
Asunto(s)
Glucosa-6-Fosfatasa , Glucosa , Animales , Ratones , Caveolina 1/metabolismo , Colesterol/metabolismo , Glucosa/metabolismo , Glucosa-6-Fosfatasa/metabolismo , Hígado/metabolismoRESUMEN
Intestinal gluconeogenesis (IGN), gastric bypass (GBP) and gut microbiota positively regulate glucose homeostasis and diet-induced dysmetabolism. GBP modulates gut microbiota, whether IGN could shape it has not been investigated. We studied gut microbiota and microbiome in wild type and IGN-deficient mice, undergoing GBP or not, and fed on either a normal chow (NC) or a high-fat/high-sucrose (HFHS) diet. We also studied fecal and urine metabolome in NC-fed mice. IGN and GBP had a different effect on the gut microbiota of mice fed with NC and HFHS diet. IGN inactivation increased abundance of Deltaproteobacteria on NC and of Proteobacteria such as Helicobacter on HFHS diet. GBP increased abundance of Firmicutes and Proteobacteria on NC-fed WT mice and of Firmicutes, Bacteroidetes and Proteobacteria on HFHS-fed WT mice. The combined effect of IGN inactivation and GBP increased abundance of Actinobacteria on NC and the abundance of Enterococcaceae and Enterobacteriaceae on HFHS diet. A reduction was observed in the amounf of short-chain fatty acids in fecal (by GBP) and in both fecal and urine (by IGN inactivation) metabolome. IGN and GBP, separately or combined, shape gut microbiota and microbiome on NC- and HFHS-fed mice, and modify fecal and urine metabolome.
Asunto(s)
Derivación Gástrica/métodos , Microbioma Gastrointestinal/fisiología , Gluconeogénesis/fisiología , Intestinos/metabolismo , Metaboloma , Estómago/metabolismo , Actinobacteria/clasificación , Actinobacteria/genética , Actinobacteria/aislamiento & purificación , Animales , ADN Bacteriano/genética , Enterobacteriaceae/clasificación , Enterobacteriaceae/genética , Enterobacteriaceae/aislamiento & purificación , Enterococcaceae/clasificación , Enterococcaceae/genética , Enterococcaceae/aislamiento & purificación , Ácidos Grasos Volátiles/metabolismo , Firmicutes/clasificación , Firmicutes/genética , Firmicutes/aislamiento & purificación , Intestinos/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Filogenia , Proteobacteria/clasificación , Proteobacteria/genética , Proteobacteria/aislamiento & purificación , Estómago/microbiología , Estómago/cirugíaRESUMEN
Protein feeding is known to decrease hunger and subsequent food intake in animals and humans. It has also been suggested that glucose appearance into portal vein, as occurring during meal assimilation, may induce comparable effects. Here, we connect these previous observations by reporting that intestinal gluconeogenesis (i.e., de novo synthesis of glucose) is induced during the postabsorptive time (following food digestion) in rats specifically fed on protein-enriched diet. This results in glucose release into portal blood, counterbalancing the lowering of glycemia resulting from intestinal glucose utilization. Comparable infusions into the portal vein of control postabsorptive rats (fed on starch-enriched diet) decrease food consumption and activate the hypothalamic nuclei regulating food intake. Similar hypothalamic activation occurs on protein feeding. All these effects are absent after denervation of the portal vein. Thus, portal sensing of intestinal gluconeogenesis may be a novel mechanism connecting the macronutrient composition of diet to food intake.
Asunto(s)
Proteínas en la Dieta , Ingestión de Alimentos , Gluconeogénesis , Glucosa-6-Fosfatasa/biosíntesis , Glutaminasa/biosíntesis , Intestino Delgado/metabolismo , Fosfoenolpiruvato Carboxiquinasa (GTP)/biosíntesis , Animales , Conducta Animal , Carbohidratos de la Dieta , Inducción Enzimática , Glucosa/metabolismo , Hipotálamo/metabolismo , Vena Porta/inervación , Vena Porta/metabolismo , Periodo Posprandial , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Factores de TiempoRESUMEN
OBJECTIVE: Roux-en-Y gastric surgery (RYGB) promotes a rapid and sustained weight loss and amelioration of glucose control in obese patients. A high number of molecular hypotheses were previously tested using duodenal-jejunal bypass (DJB) performed in various genetic models of mice with knockouts for various hormones or receptors. The data were globally negative or inconsistent. Therefore, the mechanisms remained elusive. Intestinal gluconeogenesis is a gut function that has been suggested to contribute to the metabolic benefits of RYGB in obese patients. METHODS: We studied the effects of DJB on body weight and glucose control in obese mice fed a high fat-high sucrose diet. Wild type mice and mice with a genetic suppression of intestinal gluconeogenesis were studied in parallel using glucose- and insulin-tolerance tests. Fecal losses, including excretion of lipids, were studied from the feces recovered in metabolic cages. RESULTS: DJB induced a dramatic decrease in body weight and improvement in glucose control (glucose- and insulin-tolerance) in obese wild type mice fed a high calorie diet, for 25 days after the surgery. The DJB-induced decrease in food intake was transient and resumed to normal in 7-8 days, suggesting that decreased food intake could not account for the benefits. Total fecal losses were about 5 times and lipid losses 7 times higher in DJB-mice than in control (sham-operated and pair-fed) mice, and could account for the weight loss of mice. The results were comparable in mice with suppression of intestinal gluconeogenesis. There was no effect of DJB on food intake, body weight or fecal loss in lean mice fed a normal chow diet. CONCLUSIONS: DJB in obese mice fed a high calorie diet promotes dramatic fecal loss, which could account for the dramatic weight loss and metabolic benefits observed. This could dominate the effects of the mouse genotype/phenotype. Thus, fecal energy loss should be considered as an essential process contributing to the metabolic benefits of DJB in obese mice.
Asunto(s)
Derivación Gástrica , Obesidad/metabolismo , Obesidad/cirugía , Animales , Peso Corporal , Masculino , Ratones , Ratones Endogámicos C57BL , Pérdida de PesoRESUMEN
OBJECTIVE: The respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut-brain-liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation. METHODS: We studied mice whose glucose-6-phosphatase (G6Pase) catalytic subunit (G6PC) is specifically knocked down in the kidneys (K-G6pc-/- mice) during fasting. We also examined the additional effects of intestinal G6pc deletion, renal denervation and vitamin D administration on the altered glucose metabolism in K-G6pc-/- mice. RESULTS: Compared with WT mice, K-G6pc-/- mice exhibited (1) lower glycemia, (2) enhanced intestinal but not hepatic G6Pase activity, (3) enhanced hepatic glucokinase (GK encoded by Gck) activity, (4) increased hepatic glucose-6-phosphate and (5) hepatic glycogen spared from exhaustion during fasting. Increased hepatic Gck expression in the post-absorptive state could be dependent on the enhancement of insulin signal (AKT phosphorylation) in K-G6pc-/- mice. In contrast, the increase in hepatic GK activity was not observed in mice with both kidney- and intestine-knockout (KI-G6pc-/- mice). Hepatic Gck gene expression and hepatic AKT phosphorylation were reduced in KI-G6pc-/- mice. Renal denervation by capsaicin did not induce any effect on glucose metabolism in K-G6pc-/- mice. Plasma level of 1,25 (OH)2 D3, an active form of vitamin D, was decreased in K-G6pc-/- mice. Interestingly, the administration of 1,25 (OH)2 D3 prevented the enhancement of intestinal gluconeogenesis and hepatic GK activity and blocked the accumulation of hepatic glycogen otherwise observed in K-G6pc-/- mice during fasting. CONCLUSIONS: A diminution in renal gluconeogenesis that is accompanied by a decrease in blood vitamin D promotes a novel repartition of EGP among glucose producing organs during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Our data suggest a possible involvement of a crosstalk between the kidneys and intestine (via the vitamin D system) and the intestine and liver (via a neural gut-brain axis), which might take place in the situations of deficient renal glucose production, such as chronic kidney disease.
Asunto(s)
Gluconeogénesis/fisiología , Glucosa/biosíntesis , Riñón/fisiología , Animales , Glucemia/metabolismo , Ayuno/fisiología , Glucosa/metabolismo , Glucosa-6-Fosfatasa/metabolismo , Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I , Hipoglucemia/metabolismo , Insulina/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Glucógeno Hepático/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vitamina D/metabolismoRESUMEN
Roux-en-Y gastric bypass (RYGB) induces remission or substantial improvement of type 2 diabetes mellitus (T2D) but underlying mechanisms are still unclear. The beneficial effects of dietary proteins on energy and glucose homeostasis are mediated by the antagonist effects of peptides toward mu-opioid receptors (MORs), which are highly expressed in the distal gut. We hypothesized that the beneficial effects of RYGB could depend at least in part on the interaction of peptides from food with intestinal MORs. Duodenal-jejunal bypass (DJB) was performed in obese and lean wild-type (WT) or MOR deficient (MOR-/-) mice. Food intake and body weight was monitored daily during 3 weeks. Glucose homeostasis was assessed from glucose and insulin tolerance tests. In obese WT and MOR-/- mice, DJB induced a rapid and sustained weight loss partly independent of food intake, and a rapid improvement in glycaemic parameters. Weight loss was a major determinant of the improvements observed. In lean WT and MOR-/- mice, DJB had no effect on weight loss but significantly enhanced glucose tolerance. We found that MORs are not essential in the metabolic beneficial effects of DJB, suggesting that protein sensing in the distal gut is not a link in the metabolic benefits of gastric surgery.
Asunto(s)
Proteínas en la Dieta/metabolismo , Duodeno/fisiología , Derivación Gástrica , Yeyuno/fisiología , Animales , Metabolismo Energético , Derivación Gástrica/métodos , Masculino , Ratones , Ratones Noqueados , Obesidad/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Pérdida de PesoRESUMEN
To date, glyceroneogenesis has only been described in mammals but we demonstrate in this paper that it could exist in the invertebrate Schistosoma mansoni, the parasitic helminth transmitted by fresh water molluscs and responsible for the major human endemic disease, schistosomiasis. Glyceroneogenesis is a phosphoenolpyruvate carboxykinase (PEPCK)-dependent process by which glycerol can be produced from precursors like glutamine and therefore represents a truncated gluconeogenic pathway. We have previously demonstrated the possible central role of glutamine in mollusc-schistosome interactions. In this work, we show that glutamine effectively promotes in vitro survival and protein synthesis in sporocysts, the intramolluscan larval stages of S. mansoni, possibly through its role as an energy source. However, the demonstration that PEPCK is massively expressed in these larval forms as compared to adult parasites, together with the observation that 3-mercaptopicolinate, a specific inhibitor of PEPCK, significantly reduces the effect of glutamine on sporocyst growth, suggest that glutamine could also be used for glucose or glycerol production. Results of [14C] glutamine incorporation confirmed that neosynthesis of glucose and mainly of glycerol occurred in sporocysts and was dependent on PEPCK activity. Therefore, our results strongly indicate that glyceroneogenesis could exist in schistosomes. Several hypotheses can be proposed concerning the importance of glycerol for the adaptation of this helminth to its host osmotic and energetic environment.
Asunto(s)
Glutamina/metabolismo , Glicerol/metabolismo , Oocistos/metabolismo , Schistosoma mansoni/metabolismo , Animales , Biomphalaria/parasitología , Cricetinae , Medios de Cultivo , Glucosa/metabolismo , Interacciones Huésped-Parásitos , Mesocricetus/parasitología , Oocistos/enzimología , Oocistos/crecimiento & desarrollo , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Schistosoma mansoni/enzimología , Schistosoma mansoni/crecimiento & desarrolloRESUMEN
It has been recently suggested that the small intestine (SI) has the capacity to contribute to endogenous glucose production (EGP), in addition to the liver and kidney. The aim of this work was: (1) to estimate the role of SI glucose fluxes in glucose homeostasis in insulin resistance states (induced by high-fat (HF) feeding); (2) to assess the effect of metformin, an anti-diabetic molecule, on these fluxes. Rats were fed for 6 weeks on a HF-diet, supplemented or not with metformin (HF-Met) at a daily dosage of 50 mg/kg during the last week. We combined arterio-venous glucose balance measurements and isotopic dilution techniques to separate basal intestinal glucose uptake (IGU) and release (IGR). Contrary to what was observed in control starch-fed rats, IGU was negligible in HF-fed rats: 0.6 +/- 2.4 micromol/kg min (mean +/- S.E.M., n = 9). It was restored to a level close to that of control rats in the HF-Met group: 13.0 +/- 6.7 micromol/kg min (mean +/- S.E.M., n = 9, p < 0.05 compared to the non-treated group). Similarly, IGR was close to zero in HF-fed rats (-3.8 +/- 2.6 micromol/kg min), but was significant in HF-Met rats (7.4 +/- 4.4 micromol/kg min, p < 0.05 compared to non-treated rats). These data strongly suggest that the impairment of glucose uptake in the SI might be a crucial feature of insulin resistance states and that a key beneficial effect of metformin in these situations might be to restore a normal glucose metabolism in this tissue.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Intestinos/efectos de los fármacos , Metformina/farmacología , Animales , Mucosa Intestinal/metabolismo , Intestinos/enzimología , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
It has been recently suggested that the small intestine (SI) has the capacity to contribute to endogenous glucose production (EGP), in addition to the liver and kidney. The aim of this work was: (1) to estimate the role of SI glucose fluxes in glucose homeostasis in insulin resistance states (induced by high-fat (HF) feeding); (2) to assess the effect of metformin, an anti-diabetic molecule, on these fluxes. Rats were fed for 6 weeks on a HF-diet, supplemented or not with metformin (HF-Met) at a daily dosage of 50 mg/kg during the last week. We combined arterio-venous glucose balance measurements and isotopic dilution techniques to separate basal intestinal glucose uptake (IGU) and release (IGR). Contrary to what was observed in control starch-fed rats, IGU was negligible in HF-fed rats: 0.6+/-2.4 micromol/kg/min (mean+/-S.E.M., n=9). It was restored to a level close to that of control rats in the HF-Met group: 13.0+/-6.7 micromol/kg/min (mean+/-S.E.M., n=9, p<0.05 compared to the non-treated group). Similarly, IGR was close to zero in HF-fed rats (-3.8+/-2.6 micromol/kg/min), but was significant in HF-Met rats (7.4+/-4.4 micromol/kg/min, p<0.05 compared to non-treated rats). These data strongly suggest that the impairment of glucose uptake in the SI might be a crucial feature of insulin resistance states and that a key beneficial effect of metformin in these situations might be to restore a normal glucose metabolism in this tissue.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Intestinos/efectos de los fármacos , Metformina/farmacología , Animales , Mucosa Intestinal/metabolismo , Intestinos/enzimología , Hígado/enzimología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The liver is considered the main contributor of endogenous glucose production (EGP) in the postabsorptive (PA) state in mammals. However, it has been shown that the kidney, in PA and fasting states, and the intestine, in insulinopenia states, could make significant contributions to EGP. Using glucose tracer dilution combined to a vessel ligaturing approach, we studied the respective role of these organs in glucose turnover under various nutritional conditions in the rat (Rattus norvegicus). Both organs constitute key sites of glucose disposal in all situations in the non-moving rat. The kidney makes a small (12%) contribution to EGP in the PA state (9.6+/-1.3 micromol/kg min, means+/-SEM, n=5), which is dramatically increased (p<0.01) in 24 h-fasting (18.8+/-1.0 micromol/kg min) or streptozotocin diabetes (48+/-3 micromol/kg min). The small intestine contributes to EGP via two ways: a direct glucose contribution that may only take place in fasting and diabetes; an indirect contribution via the supply of alanine and lactate to liver gluconeogenesis that may account for up to 5 micromol/kg min in both PA and fasted states in the rat. These data emphasize the coordinate interactions among the three gluconeogenic organs in glucose homeostasis when nutritional conditions are changing.
Asunto(s)
Glucosa/metabolismo , Mucosa Intestinal/metabolismo , Riñón/metabolismo , Estado Nutricional , Animales , Diabetes Mellitus Experimental/metabolismo , Ayuno/metabolismo , Homeostasis , Ratas , Ratas Sprague-DawleyRESUMEN
Beneficial effects of dietary fiber on glucose and energy homeostasis have long been described, focusing mostly on the production of short-chain fatty acids by the gut commensal bacteria. However, bacterial fermentation of dietary fiber also produces large amounts of succinate and, to date, no study has focused on the role of succinate on host metabolism. Here, we fed mice a fiber-rich diet and found that succinate was the most abundant carboxylic acid in the cecum. Dietary succinate was identified as a substrate for intestinal gluconeogenesis (IGN), a process that improves glucose homeostasis. Accordingly, dietary succinate improved glucose and insulin tolerance in wild-type mice, but those effects were absent in mice deficient in IGN. Conventional mice colonized with the succinate producer Prevotella copri exhibited metabolic benefits, which could be related to succinate-activated IGN. Thus, microbiota-produced succinate is a previously unsuspected bacterial metabolite improving glycemic control through activation of IGN.
Asunto(s)
Gluconeogénesis/efectos de los fármacos , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Mucosa Intestinal/metabolismo , Microbiota , Ácido Succínico/farmacología , Animales , Ciego/efectos de los fármacos , Ciego/metabolismo , Conducta Alimentaria/efectos de los fármacos , Genotipo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Microbiota/efectos de los fármacos , Oligosacáridos/farmacología , Prevotella/efectos de los fármacos , Prevotella/metabolismoRESUMEN
OBJECTIVES: Certain nutrients positively regulate energy homeostasis via intestinal gluconeogenesis (IGN). The objective of this study was to evaluate the impact of a deficient IGN in glucose control independently of nutritional environment. METHODS: We used mice deficient in the intestine glucose-6 phosphatase catalytic unit, the key enzyme of IGN (I-G6pc (-/-) mice). We evaluated a number of parameters involved in energy homeostasis, including insulin sensitivity (hyperinsulinemic euglycaemic clamp), the pancreatic function (insulin secretion in vivo and in isolated islets) and the hypothalamic homeostatic function (leptin sensitivity). RESULTS: Intestinal-G6pc (-/-) mice exhibit slight fasting hyperglycaemia and hyperinsulinemia, glucose intolerance, insulin resistance and a deteriorated pancreatic function, despite normal diet with no change in body weight. These defects evoking type 2 diabetes (T2D) derive from the basal activation of the sympathetic nervous system (SNS). They are corrected by treatment with an inhibitor of α-2 adrenergic receptors. Deregulation in a key target of IGN, the homeostatic hypothalamic function (highlighted here through leptin resistance) is a mechanistic link. Hence the leptin resistance and metabolic disorders in I-G6pc (-/-) mice are corrected by rescuing IGN by portal glucose infusion. Finally, I-G6pc (-/-) mice develop the hyperglycaemia characteristic of T2D more rapidly under high fat/high sucrose diet. CONCLUSIONS: Intestinal gluconeogenesis is a mandatory function for the healthy neural control of glucose homeostasis.
RESUMEN
Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes.
RESUMEN
The activation of glucose-6-phosphatase (G6Pase), a key enzyme of endogenous glucose production, is correlated with type 2 diabetes. Type 2 diabetes is characterized by sustained hyperglycemia leading to glucotoxicity. We investigated whether glucotoxicity mechanisms control the expression of the G6Pase catalytic unit (G6pc). We deciphered the transcriptional regulatory mechanisms of the G6pc promoter by glucotoxicity in a hepatoma cell line then in primary hepatocytes and in the liver of diabetic mice. High glucose exposure induced the production of reactive oxygen species (ROS) and, in parallel, induced G6pc promoter activity. In hepatocytes, glucose induced G6pc gene expression and glucose release. The decrease of ROS concentrations by antioxidants eliminated all the glucose-inductive effects. The induction of G6pc promoter activity by glucose was eliminated in the presence of small interfering RNA, targeting either the hypoxia-inducible factor (HIF)-1α or the CREB-binding protein (CBP). Glucose increased the interaction of HIF-1α with CBP and the recruitment of HIF-1 on the G6pc promoter. The same mechanism might occur in hyperglycemic mice. We deciphered a new regulatory mechanism induced by glucotoxicity. This mechanism leading to the induction of HIF-1 transcriptional activity may contribute to the increase of hepatic glucose production during type 2 diabetes.