RESUMEN
BACKGROUND: The bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes. METHODS: We conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomised, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes. FINDINGS: Human colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in faecal BA was associated with weight loss and with decreased fructosamine. INTERPRETATIONS: In humans, BA signalling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. ClinicalTrials.gov number, NCT02871882, NCT02033876. FUNDING: Research support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology.
Asunto(s)
Ácidos y Sales Biliares/administración & dosificación , Glucemia/metabolismo , Colon/efectos de los fármacos , Diabetes Mellitus Tipo 2/terapia , Íleon/efectos de los fármacos , Obesidad/terapia , Administración Oral , Ácidos y Sales Biliares/química , Ácidos y Sales Biliares/metabolismo , Transporte Biológico , Cápsulas , Línea Celular , Colestenonas/sangre , Colon/metabolismo , Colon/patología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Cámaras de Difusión de Cultivos , Células Enteroendocrinas/citología , Células Enteroendocrinas/efectos de los fármacos , Células Enteroendocrinas/metabolismo , Ayuno/fisiología , Factores de Crecimiento de Fibroblastos/sangre , Fructosamina/sangre , Expresión Génica , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/genética , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Humanos , Íleon/metabolismo , Íleon/patología , Insulina/sangre , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Periodo Posprandial , Cultivo Primario de Células , Receptores Acoplados a Proteínas G/sangre , Receptores Acoplados a Proteínas G/genéticaRESUMEN
BACKGROUND: Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). METHODS: Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). RESULTS: Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6-3.2 times higher in HVs (643.73-1239.3 µmol/24 h) and ~8 times higher in T2DM (1786.0 µmol/24 h) than with placebo (HVs: 386.93 µmol/24 h; T2DM: 220.00 µmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3-5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. CONCLUSIONS: Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).
Asunto(s)
Benzotiepinas/administración & dosificación , Benzotiepinas/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glicósidos/administración & dosificación , Glicósidos/efectos adversos , Glicoproteínas de Membrana/antagonistas & inhibidores , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Simportadores/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Benzotiepinas/farmacocinética , Ácidos y Sales Biliares/análisis , Ácidos y Sales Biliares/metabolismo , Glucemia/metabolismo , Colestenonas/sangre , Diabetes Mellitus Tipo 2/metabolismo , Método Doble Ciego , Heces/química , Femenino , Glicósidos/farmacocinética , Homeostasis , Humanos , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Combination therapy is being increasingly used as a treatment paradigm for metabolic diseases such as diabetes and obesity. In the peptide therapeutics realm, recent work has highlighted the therapeutic potential of chimeric peptides that act on two distinct receptors, thereby harnessing parallel complementary mechanisms to induce additive or synergistic benefit compared to monotherapy. Here, we extend this hypothesis by linking a known anti-diabetic peptide with an anti-obesity peptide into a novel peptide hybrid, which we termed a phybrid. We report on the synthesis and biological activity of two such phybrids (AC164204 and AC164209), comprised of a glucagon-like peptide-1 receptor (GLP1-R) agonist, and exenatide analog, AC3082, covalently linked to a second generation amylin analog, davalintide. Both molecules acted as full agonists at their cognate receptors in vitro, albeit with reduced potency at the calcitonin receptor indicating slightly perturbed amylin agonism. In obese diabetic Lep(ob)/Lep (ob) mice sustained infusion of AC164204 and AC164209 reduced glucose and glycated haemoglobin (HbA1c) equivalently but induced greater weight loss relative to exenatide administration alone. Weight loss was similar to that induced by combined administration of exenatide and davalintide. In diet-induced obese rats, both phybrids dose-dependently reduced food intake and body weight to a greater extent than exenatide or davalintide alone, and equal to co-infusion of exenatide and davalintide. Phybrid-mediated and exenatide + davalintide-mediated weight loss was associated with reduced adiposity and preservation of lean mass. These data are the first to provide in vivo proof-of-concept for multi-pathway targeting in metabolic disease via a peptide hybrid, demonstrating that this approach is as effective as co-administration of individual peptides.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Glucosa/metabolismo , Obesidad/tratamiento farmacológico , Péptidos/farmacología , Animales , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatología , Receptor del Péptido 1 Similar al Glucagón , Hemoglobina Glucada/metabolismo , Masculino , Ratones , Ratones Obesos , Obesidad/metabolismo , Obesidad/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores de Glucagón/agonistas , Receptores de Glucagón/metabolismoRESUMEN
Bile acids are recognized as metabolic modulators. The present study was aimed at evaluating the effects of a potent Asbt inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasis in Zucker Diabetic Fatty (ZDF) rats. Oral administration of 264W94 for two wk increased fecal bile acid concentrations and elevated non-fasting plasma total Glp-1. Treatment of 264W94 significantly decreased HbA1c and glucose, and prevented the drop of insulin levels typical of ZDF rats in a dose-dependent manner. An oral glucose tolerance test revealed up to two-fold increase in plasma total Glp-1 and three-fold increase in insulin in 264W94 treated ZDF rats at doses sufficient to achieve glycemic control. Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in small intestines and the liver but co-administration of a Fxr agonist (GW4064) did not attenuate 264W94 induced glucose lowering effects. In summary, our results demonstrate that inhibition of Asbt increases bile acids in the distal intestine, promotes Glp-1 release and may offer a new therapeutic strategy for type 2 diabetes mellitus.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Hipoglucemiantes/uso terapéutico , Absorción Intestinal/efectos de los fármacos , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Simportadores/antagonistas & inhibidores , Tiazepinas/uso terapéutico , Animales , Ácidos y Sales Biliares/análisis , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Heces/química , Regulación de la Expresión Génica/efectos de los fármacos , Péptido 1 Similar al Glucagón/sangre , Hipoglucemiantes/administración & dosificación , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Isoxazoles/administración & dosificación , Isoxazoles/uso terapéutico , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Zucker , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Tiazepinas/administración & dosificaciónRESUMEN
The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol·kg(-1)·day(-1)) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1ß, IL-2, IL-6, MCP-1, IFNγ, and TNFα) and pancreatitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or lipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN- or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Páncreas/efectos de los fármacos , Pancreatitis/tratamiento farmacológico , Péptidos/farmacología , Ponzoñas/farmacología , Análisis de Varianza , Animales , Área Bajo la Curva , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Exenatida , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Ratones , Páncreas/metabolismo , Páncreas/patología , Pancreatitis/inducido químicamente , Pancreatitis/complicaciones , Pancreatitis/patología , Péptidos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Ponzoñas/uso terapéuticoRESUMEN
Exenatide is a 39-amino acid peptide incretin mimetic approved for adjunctive treatment of type 2 diabetes. It shares several glucoregulatory activities with the mammalian hormone, glucagon-like peptide-1 (GLP-1). In clinical use, subcutaneous exenatide injections demonstrate glucoregulatory and weight loss effects with sustained plasma concentrations in the 50-100 pM range. We investigated the pharmacokinetics of exenatide in normoglycemic rats and biological activity in diabetic db/db mice after delivery to various epithelial surfaces of the intestinal and respiratory tracts. In rats, elimination kinetics were similar for all routes of administration (median k(e) 0.017 min(-1)). Bioavailability (versus intravenous administration) and C(max) per unit dose differed markedly. For gastrointestinal administration, sublingual administration invoked the highest bioavailability (0.37%); in db/db mice, potentially therapeutic concentrations were obtainable. In contrast, intraduodenal bioavailability was low (0.0053%). In regard to respiratory surfaces, bioavailability of intratracheal exenatide was up to 13.6%, and for nasal administration, 1.68%. Both routes of administration produced therapeutic plasma concentrations and glucose-lowering in db/db mice. At high doses, aerosolized exenatide also achieved effective concentrations and glucose-lowering. In summary, the intestinal tract seems to have limited potential as a route of exenatide administration, with sublingual being most promising. In contrast, the respiratory tract appears to be more viable, comparing favorably with the clinically approved subcutaneous route. Despite little optimization of the delivery formulation, exenatide bioavailability compared favorable to that of several commercially available bioactive peptides.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Péptidos/administración & dosificación , Ponzoñas/administración & dosificación , Aerosoles , Animales , Disponibilidad Biológica , Glucemia/efectos de los fármacos , Vías de Administración de Medicamentos , Exenatida , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Ratones , Péptidos/farmacocinética , Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Ponzoñas/farmacocinética , Ponzoñas/farmacologíaRESUMEN
Exenatide, the active ingredient of BYETTA (exenatide injection), is an incretin mimetic that has been developed for the treatment of patients with type 2 diabetes. Exenatide binds to and activates the known GLP-1 receptor with a potency comparable to that of the mammalian incretin GLP-1(7-36), thereby acting as a glucoregulatory agent. AC3174 is an analog of exenatide with leucine substituted for methionine at position 14, [Leu(14)]exendin-4. The purpose of these studies was to evaluate the glucoregulatory activity and pharmacokinetics of AC3174. In RINm5f cell membranes, the potency of AC3174 for the displacement of [(125)I]GLP-1 and activation of adenylate cyclase was similar to that of exenatide and GLP-1. In vivo, AC3174, administered as a single IP injection, significantly decreased plasma glucose concentration and glucose excursion following the administration of an oral glucose challenge in both non-diabetic (C57BL/6) and diabetic db/db mice (P<0.05 vs. vehicle-treated). The magnitude of glucose lowering of AC3174 was comparable to exenatide. The ED(50) values of AC3174 for glucose lowering (60 minute post-dose) were 1.2 microg/kg in db/db mice and 1.3 microg/kg in C57BL/6 mice. AC3174 has insulinotropic activity in vivo. Administration of AC3174 resulted in a 4-fold increase in insulin concentrations in normal mice following an IP glucose challenge. AC3174 was also shown to inhibit food intake and decrease gastric emptying in rodent models. AC3174 was stable in human plasma (>90% of parent peptide was present after 5 h of incubation). In rats, the in vivo half-life of AC3174 was 42-43 min following SC administration. In summary, AC3174 is an analog of exenatide that binds to the GLP-1 receptor in vitro and shares many of the biological and glucoregulatory activities of exenatide and GLP-1 in vivo.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Péptidos/sangre , Péptidos/farmacocinética , Ponzoñas/sangre , Ponzoñas/farmacocinética , Adenilil Ciclasas/metabolismo , Animales , Glucemia/análisis , Línea Celular Tumoral , Membrana Celular/metabolismo , Estabilidad de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Exenatida , Vaciamiento Gástrico/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Semivida , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Insulina/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Péptidos/administración & dosificación , Péptidos/química , Péptidos/metabolismo , Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Ponzoñas/administración & dosificación , Ponzoñas/química , Ponzoñas/metabolismo , Ponzoñas/farmacologíaRESUMEN
Amylin is a 37-amino acid polypeptide co-secreted with insulin from the pancreatic beta-cells. It complements insulin's stimulation of the rate of glucose disappearance (Rd) by slowing the rate of glucose appearance (Ra) through several mechanisms, including an inhibition of mealtime glucagon secretion and a slowing of gastric emptying. To determine if endogenous amylin tonically inhibits these processes, we studied the effects of the amylin receptor blocker AC187 upon glucagon secretion during euglycemic, hyperinsulinemic clamps in Sprague-Dawley (HSD) rats, upon gastric emptying in HSD rats, and upon gastric emptying and plasma glucose profile in hyperamylinemic, and genetically obese, Lister Albany/NIH rats during a glucose challenge. Amylin blockade increased glucagon concentration, accelerated gastric emptying of liquids, and resulted in an exaggerated post-challenge glycemia. These data collectively indicate a physiologic role for amylin in glucose homeostasis via mechanisms that include regulation of glucagon secretion and gastric emptying.
Asunto(s)
Amiloide/antagonistas & inhibidores , Amiloide/fisiología , Vaciamiento Gástrico/efectos de los fármacos , Vaciamiento Gástrico/fisiología , Glucagón/metabolismo , Fragmentos de Péptidos/farmacología , Animales , Glucemia/metabolismo , Glucagón/sangre , Homeostasis , Polipéptido Amiloide de los Islotes Pancreáticos , Masculino , Obesidad/sangre , Obesidad/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores de Polipéptido Amiloide de Islotes Pancreáticos , Receptores de Péptidos/antagonistas & inhibidoresRESUMEN
In rodents, weight reduction after peptide YY[3-36] (PYY[3-36]) administration may be due largely to decreased food consumption. Effects on other processes affecting energy balance (energy expenditure, fuel partitioning, gut nutrient uptake) remain poorly understood. We examined whether s.c. infusion of 1 mg/(kg x d) PYY[3-36] (for up to 7 d) increased metabolic rate, fat combustion, and/or fecal energy loss in obese mice fed a high-fat diet. PYY[3-36] transiently reduced food intake (e.g., 25-43% lower at d 2 relative to pretreatment baseline) and decreased body weight (e.g., 9-10% reduction at d 2 vs. baseline) in 3 separate studies. Mass-specific metabolic rate in kJ/(kg x h) in PYY[3-36]-treated mice did not differ from controls. The dark cycle respiratory quotient (RQ) was transiently decreased. On d 2, it was 0.747 +/- 0.008 compared with 0.786 +/- 0.004 for controls (P < 0.001); light cycle RQ was reduced throughout the study in PYY[3-36]-treated mice (0.730 +/- 0.006) compared with controls (0.750 +/- 0.009; P < 0.001). Epididymal fat pad weight in PYY[3-36]-treated mice was approximately 50% lower than in controls (P < 0.01). Fat pad lipolysis ex vivo was not stimulated by PYY[3-36]. PYY[3-36] decreased basal gallbladder emptying in nonobese mice. Fecal energy loss was negligible ( approximately 2% of ingested energy) and did not differ between PYY[3-36]-treated mice and controls. Thus, negative energy balance after PYY[3-36] administration in diet-induced obese mice results from reduced food intake with a relative maintenance of mass-specific energy expenditure. Fat loss and reduced RQ highlight the potential for PYY[3-36] to drive increased mobilization of fat stores to help meet energy requirements in this model.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Grasas de la Dieta/efectos adversos , Metabolismo Energético/efectos de los fármacos , Obesidad/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Péptido YY/farmacología , Tejido Adiposo/metabolismo , Animales , Calorimetría , Grasas de la Dieta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiologíaRESUMEN
BACKGROUND AND AIMS: The neuroendocrine hormone amylin, cosecreted with insulin from pancreatic beta-cells in response to nutrient ingestion, has several physiologic actions to limit the rate of nutrient uptake, including the slowing of gastric emptying. METHODS: To investigate whether amylin might modulate digestive enzyme secretion from the exocrine pancreas, anesthetized Sprague Dawley rats were cannulated via the pancreatic duct and the secretory response (flow, amylase and lipase) to cholecystokinin (1 microg s.c.) was measured in the absence and in the presence of 0.1, 0.3 and 1 microg s.c. doses of amylin. RESULTS: Amylin alone did not affect pancreatic secretion, but it dose-dependently inhibited cholecystokinin-stimulated amylase secretion by up to 58% and lipase secretion by up to 67%. The ED50's for these responses were 0.21 microg+/-0.18 log and 0.11 microg+/-0.05 log, respectively, doses that result in excursions of plasma amylin concentration that are within the reported physiological range. Amylin did not evoke cell signalling in the Ar42j model of pancreatic acinar cells, and responses to amylin were not observed in either Ar42j cells or isolated pancreatic acini in a microphysiometer indicating that the effect of amylin was indirect. CONCLUSIONS: Inhibition of stimulated pancreatic enzyme secretion is likely to be a physiological, extrapancreatic, action of amylin. Amylinergic mechanisms modulating both gastric emptying and pancreatic enzyme secretion may thus match, respectively, the appearance of substrate and enzymes in the gut lumen.
Asunto(s)
Amilasas/metabolismo , Amiloide/química , Colecistoquinina/farmacología , Lipasa/metabolismo , Amiloide/metabolismo , Amiloide/farmacología , Animales , Colecistoquinina/metabolismo , Relación Dosis-Respuesta a Droga , Vaciamiento Gástrico , Insulina/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos , Masculino , Páncreas/citología , Páncreas/enzimología , Pancreatitis/metabolismo , Péptidos/química , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factores de TiempoRESUMEN
The effects of the incretin mimetic exenatide (exendin-4) on metabolic parameters, insulin sensitivity, and beta-cell mass were examined in nondiabetic, insulin-resistant obese fa/fa Zucker rats. After 6 wk of treatment, ad libitum-fed exenatide-treated (EX) and pair-fed vehicle control (PF) rats had comparable food intake, body weight, hemoglobin A(1c) (HbA(1c)), and fasting plasma concentrations of glucose, insulin, and lipids. Concurrent decreases in food intake and weight gain were observed in EX and PF rats, compared with ad libitum-fed vehicle control (CON) rats (P < 0.001). The increases in HbA(1c) and fasting plasma insulin concentrations that occur during the normal progression of this disease model were significantly reduced in EX and PF rats, compared with CON rats (P < 0.001). The insulin sensitivity index (ISI; glucose infusion rate to plasma insulin concentration) measured during a hyperinsulinemic euglycemic clamp was 224% higher in EX rats than CON rats (P < 0.001) and 61% higher in EX rats than PF rats (P < 0.004). The latter difference was despite comparable HbA(1c), fasting glucose, fasting insulin, total cholesterol, high-density lipoprotein, and daily food consumption between EX and PF animals. In the absence of exenatide, beta-cell mass was hyperbolically related to ISI (beta-cell mass * ISI was constant). Analogous to the disposition index, the beta-cell mass * ISI product was 63% greater in EX than PF rats (P < 0.05). Thus, exenatide increased beta-cell mass to a greater extent than would be expected in animals of comparable insulin resistance, suggesting a direct trophic effect on islet neogenesis in obese fa/fa rats independent of body weight and glycemia.