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1.
Am J Physiol Endocrinol Metab ; 319(2): E410-E426, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32663101

RESUMO

Diabetes is a chronic, progressive disease that calls for longitudinal data and analysis. We introduce a longitudinal mathematical model that is capable of representing the metabolic state of an individual at any point in time during their progression from normal glucose tolerance to type 2 diabetes (T2D) over a period of years. As an application of the model, we account for the diversity of pathways typically followed, focusing on two extreme alternatives, one that goes through impaired fasting glucose (IFG) first and one that goes through impaired glucose tolerance (IGT) first. These two pathways are widely recognized to stem from distinct metabolic abnormalities in hepatic glucose production and peripheral glucose uptake, respectively. We confirm this but go beyond to show that IFG and IGT lie on a continuum ranging from high hepatic insulin resistance and low peripheral insulin resistance to low hepatic resistance and high peripheral resistance. We show that IFG generally incurs IGT and IGT generally incurs IFG on the way to T2D, highlighting the difference between innate and acquired defects and the need to assess patients early to determine their underlying primary impairment and appropriately target therapy. We also consider other mechanisms, showing that IFG can result from impaired insulin secretion, that non-insulin-dependent glucose uptake can also mediate or interact with these pathways, and that impaired incretin signaling can accelerate T2D progression. We consider whether hyperinsulinemia can cause insulin resistance in addition to being a response to it and suggest that this is a minor effect.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etiologia , Progressão da Doença , Jejum , Glucose/biossíntese , Intolerância à Glucose , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/fisiopatologia , Incretinas/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Fígado/metabolismo , Modelos Teóricos , Transdução de Sinais/fisiologia
2.
Expert Opin Pharmacother ; 21(13): 1565-1578, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32521177

RESUMO

INTRODUCTION: Recent advances in anti-diabetic medications and glucose monitoring have led to a paradigm shift in diabetes care. Newer anti-diabetic medications such as DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1RAs), and SGLT2 inhibitors have enabled optimal glycemic control to be achieved without increasing the risk of hypoglycemia and weight gain. Treatment with GLP-1RAs and SGLT2 inhibitors has been demonstrated to improve cardiorenal outcomes, positioning these agents as the mainstay of treatment for patients with type 2 diabetes (T2DM). The development of these newer agents has also prompted a paradigm shift in the concept of T2DM, highlighting the importance of beta cell dysfunction in the pathophysiology of T2DM. AREAS COVERED: Recent advances in pharmacotherapy for diabetes are summarized with a focus on the role of incretin-based drugs and SGLT2 inhibitors. The importance of a paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM is also discussed, given from an Asian perspective. EXPERT OPINION: Management of T2DM including lifestyle modification as well as pharmacotherapy should be focused on reducing beta cell workload, to preserve functional beta cell mass. A paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM enhances the implementation of person-centered diabetes care.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Glicemia/análise , Automonitorização da Glicemia , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucose/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Incretinas/metabolismo , Insulina/uso terapêutico , Células Secretoras de Insulina/metabolismo , Medicina de Precisão , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico
3.
Rev Med Suisse ; 16(697): 1186-1190, 2020 Jun 10.
Artigo em Francês | MEDLINE | ID: mdl-32520456

RESUMO

DPP-4 inhibitors are a well-established treatment for type 2 diabetes. They act by improving glycemic control through the incretin system. This class of molecules are well-tolerated and are associated with a low risk of hypoglycemia. Yet, their efficacy in glycemic control is rather moderate and they don't offer a benefit in terms of cardiovascular or renal protection. Even if they have a good safety profile, it is important to pay attention to the risk of cardiac failure and pancreatitis. This article provides an overview of the use of DPP-4 inhibitors in 2020.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/metabolismo
4.
J Nutr ; 150(8): 2101-2111, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470979

RESUMO

BACKGROUND: Dietary polyphenols including anthocyanins target multiple organs. OBJECTIVE: We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G). METHODS: Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2). RESULTS: In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P < 0.05). In Exp. 2, Cy3G attenuated HFD-induced body-weight gain (20.3% at week 16), and improved glucose tolerance (26.5% at week 15) but not insulin tolerance. Although Cy3G had no effect on glucose tolerance in LFD mice, LFD/Cy3G/AB mice showed better glucose tolerance than LFD/Cy3G mice (23%). In contrast, HFD/Cy3G/AB mice showed worse glucose tolerance compared with HFD/Cy3G mice (15%). Beneficial effects of Cy3G in HFD mice were not associated with changes in plasma leptin, insulin or GLP-1 concentrations. However, Cy3G increased hepatic Fgf21 expression in mice in Exp. 1 by 4-fold and attenuated Fgf21 overexpression in HFD mice (Exp. 2, 22%), associated with increased expression of genes that encode FGFR1 and ß-klotho (>3-fold, P < 0.05). CONCLUSIONS: Dietary Cy3G may reduce body weight and exert metabolic homeostatic effects in mice via changes in hepatic FGF21.


Assuntos
Antocianinas/farmacologia , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/administração & dosagem , Fatores de Crescimento de Fibroblastos/metabolismo , Intolerância à Glucose , Glucosídeos/farmacologia , Ganho de Peso/efeitos dos fármacos , Animais , Gorduras na Dieta/efeitos adversos , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Incretinas/genética , Incretinas/metabolismo , Leptina/metabolismo , Fígado , Masculino , Camundongos , Distribuição Aleatória , Perda de Peso/efeitos dos fármacos
5.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G23-G35, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421358

RESUMO

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells (EECs) in response to nutrient ingestion and lower blood glucose levels by stimulation of insulin secretion and thus are defined as incretins. GLP-1 receptor (GLP-1R) expression has been identified on enteric neurons that include intrinsic afferent neurons, extrinsic spinal, and vagal sensory afferents but has not been shown to have an incretin effect through these nerves. GLP-1 and GIP enter the mesenteric lymphatic fluid (MLF) after a meal via the interstitial fluid (IF) from local tissue secretion and/or blood capillaries. We tested if MLF could induce diet-dependent intransient increases in intracellular calcium ([Ca2+]i) in cultured sensory neurons. Postprandial rat MLF, collected from the superior mesenteric lymphatic duct, induced a significant twofold higher intransient increase in [Ca2+]i in primary-cultured sensory neurons than MLF from fasted rats. Inhibition of transient receptor potential vanilloid 1 (TRPV1) and TRPV1 and ankyrin 1 cation channels (TRPA1) with ruthenium red eliminated the difference. Substance P (SP) (a peptide that stimulates insulin secretion) sensor cells cocultured with sensory neurons showed both the GLP-1R agonist exendin-4 (Ex-4) and GIP induced transient increases in [Ca2+]i directly coupled to SP secretion in the sensory nerves. Ex-4-induced release of SP required expression of either TRPA1 or TRPV1. These data identify unrecognized actions of GLP-1 and GIP as incretins by acting as neurolymphocrines and suggest a mechanism for sensory nerves to respond to the postprandial state through MLF.NEW & NOTEWORTHY Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted upon eating to lower blood sugar. GLP-1 and GIP were found to induce the secretion of substance P (SP) from cultured sensory nerves. SP enhances insulin secretion. Mesenteric lymphatic fluid (MLF) also stimulates sensory neurons in a diet-dependent manner. These studies identify new actions of GLP-1 and GIP as incretins and suggest a mechanism for sensory nerves to respond to diet through MLF.


Assuntos
Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Substância P/metabolismo , Canal de Cátion TRPA1/metabolismo , Animais , Glicemia/metabolismo , Células Enteroendócrinas/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Incretinas/metabolismo , Período Pós-Prandial , Ratos , Receptores dos Hormônios Gastrointestinais
6.
Am J Physiol Endocrinol Metab ; 318(6): E956-E964, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32182123

RESUMO

Enhanced meal-related enteroendocrine secretion, particularly of glucagon-like peptide-1 (GLP-1), contributes to weight-loss and improved glycemia after Roux-en-Y gastric bypass (RYGB). Dietary glucose drives GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion postoperatively. Understanding how glucose triggers incretin secretion following RYGB could lead to new treatments of diabetes and obesity. In vitro, incretin release depends on glucose absorption via sodium-glucose cotransporter 1 (SGLT1). We investigated the importance of SGLT1/SGLT2 for enteropancreatic hormone concentrations and glucose metabolism after RYGB in a randomized, controlled, crossover study. Ten RYGB-operated patients ingested 50 g of oral glucose with and without acute pretreatment with 600 mg of the SGLT1/SGLT2-inhibitor canagliflozin. Paracetamol and 3-O-methyl-d-glucopyranose (3-OMG) were added to the glucose drink to evaluate rates of intestinal entry and absorption of glucose, respectively. Blood samples were collected for 4 h. The primary outcome was 4-h plasma GLP-1 (incremental area-under the curve, iAUC). Secondary outcomes included glucose, GIP, insulin, and glucagon. Canagliflozin delayed glucose absorption (time-to-peak 3-OMG: 50 vs. 132 min, P < 0.01) but did not reduce iAUC GLP-1 (6,067 vs. 7,273·min·pmol-1·L-1, P = 0.23), although peak GLP-1 concentrations were lowered (-28%, P = 0.03). Canagliflozin reduced GIP (iAUC -28%, P = 0.01; peak concentrations -57%, P < 0.01), insulin, and glucose excursions, whereas plasma glucagon (AUC 3,216 vs. 4,160 min·pmol·L-1, P = 0.02) and amino acids were increased. In conclusion, acute SGLT1/SGLT2-inhibition during glucose ingestion did not reduce 4-h plasma GLP-1 responses in RYGB-patients but attenuated the early rise in GLP-1, GIP, and insulin, whereas late glucagon concentrations were increased. The results suggest that SGLT1-mediated glucose absorption contributes to incretin hormone secretion after RYGB.


Assuntos
Canagliflozina/farmacologia , Derivação Gástrica , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Transportador 1 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peptídeo C/efeitos dos fármacos , Peptídeo C/metabolismo , Estudos Cross-Over , Polipeptídeo Inibidor Gástrico/efeitos dos fármacos , Glucagon/efeitos dos fármacos , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos , Teste de Tolerância a Glucose , Humanos , Incretinas/metabolismo , Insulina/metabolismo , Pessoa de Meia-Idade , Polipeptídeo Pancreático/efeitos dos fármacos , Polipeptídeo Pancreático/metabolismo , Transportador 1 de Glucose-Sódio/antagonistas & inibidores
7.
Endocrinology ; 161(2)2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913472

RESUMO

Myeloid-derived growth factor (MYDGF), which is produced by bone marrow-derived cells, mediates cardiac repair following myocardial infarction by inhibiting cardiac myocyte apoptosis to subsequently reduce the infarct size. However, the function of MYDGF in the incretin system of diabetes is still unknown. Here, loss-of-function and gain-of-function experiments in mice revealed that MYDGF maintains glucose homeostasis by inducing glucagon-like peptide-1 (GLP-1) production and secretion and that it improves glucose tolerance and lipid metabolism. Treatment with recombinant MYDGF increased the secretion and production of GLP-1 in STC-1 cells in vitro. Mechanistically, the positive effects of MYDGF are potentially attributable to the activation of protein kinase A/glycogen synthase kinase 3ß/ß-catenin (PKA/GSK-3ß/ß-catenin) and mitogen-activated protein kinase (MAPK) kinases/extracellular regulated protein kinase (MEK/ERK) pathways. Based on these findings, MYDGF promotes the secretion and production of GLP-1 in intestinal L-cells and potentially represents a potential therapeutic medication target for type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Incretinas/metabolismo , Interleucinas/sangue , Adulto , Idoso , Animais , Estudos de Casos e Controles , Linhagem Celular , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Knockout , Pessoa de Meia-Idade
8.
Ann N Y Acad Sci ; 1461(1): 104-126, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31392745

RESUMO

Incretins are hormones secreted from enteroendocrine cells after nutrient intake that stimulate insulin secretion from ß cells in a glucose-dependent manner. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the only two known incretins. Dysregulation of incretin secretion and actions are noted in diseases such as obesity and diabetes. In this review, we first summarize our traditional understanding of the physiology of GIP and GLP-1, and our current knowledge of the relationships between GIP and GLP-1 and obesity and diabetes. Next, we present the results from major randomized controlled trials on the use of GLP-1 receptor agonists for managing type 2 diabetes, and emerging data on treating obesity and prediabetes. We conclude with a glimpse of the future with possible complex interactions between nutrients, gut microbiota, the endocannabinoid system, and enteroendocrine cells.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Incretinas/metabolismo , Obesidade/metabolismo , Animais , Endocanabinoides/metabolismo , Microbioma Gastrointestinal , Guias como Assunto , Humanos
9.
Diabetes Res Clin Pract ; 158: 107928, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31734225

RESUMO

OBJECTIVE: To compare basal insulin and mTOR signaling in subcutaneous fat of obese T2DM vs. obese subjects with normal glucose tolerance (NGT), and correlate it with clinical parameters of carbohydrate metabolism and incretin secretion profiles. METHODS: Recruited were 22 patients with long (>10 years) and morbid (BMI > 35 kg/m2) obesity, 12 of which had NGT and 10 had T2DM. Hyperinsulinemic-euglycemic clamp test and HOMA-IR were used to measure insulin resistance. Blood samples taken at 0, 30 and 120 min of food load test were used to assess incretin profile, insulin and glucose levels. Amount of total and visceral fat was determined by bioelectrical impedance analysis. Subcutaneous fat biopsies were obtained during bariatric surgery for all patients and analyzed by western blots. RESULTS: As assessed by western blots of insulin receptor substrate (IRS), Akt, Raptor, Rictor, mTOR and S6K1, the basal insulin signaling and mTORC activities were comparable in NGT and T2DM groups, whereas phosphorylation of AS160 was significantly lower and that of serum and glucocorticoid-induced kinase (SGK) was significantly higher in T2DM group. Various correlations were found between the degree of insulin resistance and amount of visceral fat, changes in incretin profile, glucose metabolic parameters and phosphorylation level of AS160, incretin secretion profile and phosphorylated levels of AS160 or SGK1. CONCLUSION: Altered phosphorylation of AS160 and SGK1 is associated with obese T2DM phenotype.


Assuntos
Tecido Adiposo/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Incretinas/metabolismo , Insulina/sangue , Fosforilação/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Nature ; 574(7776): 63-68, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554967

RESUMO

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.


Assuntos
Receptor gp130 de Citocina/metabolismo , Citocinas/síntese química , Citocinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ligação Competitiva , Citocinas/química , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , Fígado Gorduroso/prevenção & controle , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Incretinas/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Obesidade/metabolismo , Pâncreas/metabolismo , Fosfoproteínas/metabolismo , Engenharia de Proteínas , Receptores de Interleucina-6/metabolismo , Transdução de Sinais , Fatores de Transcrição , Ganho de Peso/efeitos dos fármacos
12.
J Clin Invest ; 129(9): 3786-3791, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31403469

RESUMO

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.


Assuntos
Hipotálamo/metabolismo , Incretinas/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Proteínas rap1 de Ligação ao GTP/metabolismo , Adiposidade/genética , Animais , Incretinas/genética , Leptina/genética , Camundongos , Obesidade/genética , Receptores dos Hormônios Gastrointestinais/genética , Receptores dos Hormônios Gastrointestinais/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteínas rap1 de Ligação ao GTP/genética
13.
Nutrients ; 11(8)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412576

RESUMO

This review aimed to describe the potential mechanisms by which incretin hormones could mediate the relationship between glycemic index and cardiometabolic diseases. A body of evidence from many studies suggests that low glycemic index (GI) diets reduces the risk for type 2 diabetes and coronary heart disease. In fact, despite the extensive literature on this topic, the mechanisms underlying unfavorable effects of high GI foods on health remain not well defined. The postprandial and hormonal milieu could play a key role in the relationship between GI and cardiovascular risk. Incretin hormones, glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important regulators of postprandial homeostasis by amplifying insulin secretory responses. Response of GIP and GLP-1 to GI have been studied more in depth, also by several studies on isomaltulose, which have been taken as an ideal model to investigate the kinetics of incretin secretion in response to foods' GI. In addition, extrapancreatic effects of these incretin hormones were also recently observed. Emerging from this have been exciting effects on several targets, such as body weight regulation, lipid metabolism, white adipose tissue, cardiovascular system, kidney, and liver, which may importantly affect the health status.


Assuntos
Glicemia/metabolismo , Carboidratos da Dieta/metabolismo , Metabolismo Energético , Índice Glicêmico , Cardiopatias/metabolismo , Incretinas/metabolismo , Doenças Metabólicas/metabolismo , Animais , Carboidratos da Dieta/efeitos adversos , Cardiopatias/sangue , Cardiopatias/fisiopatologia , Humanos , Incretinas/sangue , Doenças Metabólicas/sangue , Doenças Metabólicas/fisiopatologia , Estado Nutricional
14.
Eur J Pharmacol ; 859: 172521, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31276666

RESUMO

Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent the degradation of glucagon-like peptide-1 (GLP-1) and improve glycemic control. The GLP-1 insulinotropic effect involves a pathway through vagus nerve GLP-1 receptors in the gut, in addition to a direct effect on the pancreas. Therefore, this study verified whether DPP-4 inhibition in the gut contributed to the improvement of glycemic control. Anagliptin, a DPP-4 inhibitor, was administered orally or subcutaneously (with or without passing through the gastrointestinal tract, respectively) to mice. The association between blood glucose suppression following oral glucose challenge and DPP-4 inhibition in the small intestine and plasma was assessed. Oral administration of anagliptin (0.03-0.3 mg/kg) in normal mice significantly suppressed blood glucose, which was associated with an increase in insulin secretion at a dose of ≥0.1 mg/kg (P < 0.05). Subcutaneous administration of anagliptin (0.01-0.1 mg/kg) produced similar results. However, plasma DPP-4 inhibition following oral administration was weaker than that following subcutaneous administration; blood glucose suppression was significantly correlated with small intestinal DPP-4 inhibition (r = 0.949, P < 0.01), but not with plasma DPP-4 inhibition. Additionally, similar results were observed in a type 2 diabetes model (r = 0.975, P < 0.001). Thus, these results demonstrated that an improvement in glycemic control was dependent upon small intestinal DPP-4 inhibition. As these effects were accompanied by the elevation of intact GLP-1 in the portal, this suggests that improvement in glucose tolerance after anagliptin treatment might be related to an increase in GLP-1 receptor signaling in the small intestine and portal vein.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Incretinas/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , Animais , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/metabolismo , Teste de Tolerância a Glucose , Incretinas/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirimidinas/farmacologia
15.
Metabolism ; 98: 121-135, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31173757

RESUMO

Incretins have risen to the forefront of therapies for obesity and related metabolic complications, primarily because of their efficacy and relatively few side effects. Importantly, their efficacy in altering energy balance and decreasing body weight is apparently through actions in the central nervous system (CNS); the latter may have implications beyond obesity per se, i.e. in other disease states associated with obesity including CNS-related disorders. Here, we first describe the role of the CNS in energy homeostasis and then the current state of knowledge in terms of incretin physiology, pathophysiology and efficacy in preclinical and clinical studies. In the future, more clinical studies are needed to fully map mechanistic pathways underlying incretin actions and outcomes in the human CNS. Additionally, future research will likely lead to the discovery of additional novel incretins and/or more efficacious medications with less side effects through the improvement of current compounds with properties that would allow them to have more favorable pharmacokinetic and pharmacodynamic profiles and/or by combining known and novel incretins into safe and more efficacious combination therapies leading ultimately to more tangible benefits for our patients.


Assuntos
Sistema Nervoso Central/fisiologia , Incretinas/metabolismo , Incretinas/fisiologia , Animais , Fármacos Antiobesidade/farmacologia , Sistema Nervoso Central/metabolismo , Humanos , Incretinas/farmacologia , Camundongos
16.
Am J Physiol Endocrinol Metab ; 317(2): E244-E249, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31112407

RESUMO

It is unknown whether activation of hepato-portal vein (PV) glucose sensors plays a role in incretin hormone amplification of oral glucose-stimulated insulin secretion (GSIS). In previous studies, PV glucose infusion increased GSIS through unknown mechanisms, perhaps neural stimulation of pancreatic ß-cells and/or stimulation of gut incretin hormone release. Thus, there could be a difference in the incretin effect when comparing GSIS with portal rather than leg vein (LV) glucose infusion. Plasma insulin and incretin hormones were studied in six overnight-fasted dogs. An oral glucose tolerance test (OGTT) was administered, and then 1 and 2 wk later the arterial plasma glucose profile from the OGTT was mimicked by infusing glucose into either the PV or a LV. The arterial glucose levels were nearly identical between groups (AUCs within 1% of each other). Oral glucose administration increased arterial GLP-1 and GIP levels by more than sixfold, whereas they were not elevated by PV or LV glucose infusion. Oral glucose delivery was associated with only a small incretin effect (arterial insulin and C-peptide were 21 ± 23 and 24 ± 17% greater, respectively, during the 1st hour with oral compared with PV glucose and 14 ± 37 and 13 ± 35% greater, respectively, in oral versus LV; PV versus LV responses were not significantly different from each other). Thus, following an OGTT incretin hormone release did not depend on activation of PV glucose sensors, and the insulin response was not greater with PV compared with LV glucose infusion in the dog. The small incretin effect points to species peculiarities, which is perhaps related to diet.


Assuntos
Glucose/farmacologia , Incretinas/metabolismo , Veia Porta/metabolismo , Animais , Glicemia/análise , Peptídeo C/sangue , Cães , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucose/administração & dosagem , Teste de Tolerância a Glucose , Membro Posterior/irrigação sanguínea , Infusões Intravenosas , Insulina/sangue , Insulina/metabolismo , Masculino , Veia Porta/química , Fluxo Sanguíneo Regional , Veias
17.
Ann Biol Clin (Paris) ; 77(3): 261-271, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30998190

RESUMO

Type 2 diabetes (T2DM) associated with non-alcoholic fatty liver disease (NAFLD) increases cardiovascular risk. Complex and subtle connections are established between hepatic dysfunction and adipose tissue hyperactivity. This relationship is mediated by insulin resistance, dyslipidemia and inflammation. Recently incretins have been involved in this connection including GLP-1 (glucagon-like peptide-1). The aim of this study is to establish interactions between the GLP-1 plasma levels and metabolic syndrome clusters and adipocytokines profile (leptin, adiponectin, resistin, TNFα and IL-6) in diabetic subjects with or without NAFLD. The study was undertaken on 320 adult subjects divided into four groups: NAFLD, DT2, NAFLD+DT2 and control. In all subjects, the metabolic syndrome clusters was investigated according to the NCEP/ATPIII criteria. Insulin resistance was evaluated by the Homa-IR model. The metabolic parameters were determined on Cobas® automated biochemical analysis. The adipocytokines are determined by immunoassay method on Elisa human reader - Biotek ELX 800. The NAFLD has been confirmed by abdominal ultrasound and by histology. Feeding and fasting plasma GLP-1 was assessed by Elisa method. The data revealed that insulin resistance (Homa-IR) is present in all groups. Homa-IR is negatively associated with plasma GLP-1 depletion in the NAFLD, DT2 and NAFLD+DT2 groups. Adiponectin levels are decreased in all groups as for GLP-1. At the opposite, leptin, resistin, TNFα and IL-6 levels show an inverse correlation with GLP-1. This study suggests that plasma GLP-1 can be considered as a transition and evolution biomarker between NAFLD and T2D. GLP-1 accurately reflects metabolic and inflammatory status, both in subjects with NAFLD only or with T2D only, before the diabetes - steatosis stage.


Assuntos
Adipocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Incretinas/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Adipocinas/análise , Adipocinas/metabolismo , Adulto , Biomarcadores/análise , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Feminino , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Humanos , Incretinas/análise , Incretinas/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Fígado/patologia , Masculino , Redes e Vias Metabólicas/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações
18.
Nat Commun ; 10(1): 1029, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833673

RESUMO

Enteroendocrine cells are specialised sensory cells located in the intestinal epithelium and generate signals in response to food ingestion. Whilst traditionally considered hormone-producing cells, there is evidence that they also initiate activity in the afferent vagus nerve and thereby signal directly to the brainstem. We investigate whether enteroendocrine L-cells, well known for their production of the incretin hormone glucagon-like peptide-1 (GLP-1), also release other neuro-transmitters/modulators. We demonstrate regulated ATP release by ATP measurements in cell supernatants and by using sniffer patches that generate electrical currents upon ATP exposure. Employing purinergic receptor antagonists, we demonstrate that evoked ATP release from L-cells triggers electrical responses in neighbouring enterocytes through P2Y2 and nodose ganglion neurones in co-cultures through P2X2/3-receptors. We conclude that L-cells co-secrete ATP together with GLP-1 and PYY, and that ATP acts as an additional signal triggering vagal activation and potentially synergising with the actions of locally elevated peptide hormone concentrations.


Assuntos
Trifosfato de Adenosina/metabolismo , Enterócitos/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Intestinos , Neurônios Aferentes/metabolismo , Vias Aferentes , Animais , Linhagem Celular , Ingestão de Alimentos , Células Enteroendócrinas/metabolismo , Feminino , Cistos Glanglionares/metabolismo , Cistos Glanglionares/patologia , Incretinas/metabolismo , Mucosa Intestinal/inervação , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Gânglio Nodoso/metabolismo , Gânglio Nodoso/patologia , Peptídeo YY/metabolismo , Receptores Purinérgicos P2X2/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Nervo Vago/metabolismo
19.
Front Biosci (Landmark Ed) ; 24: 688-699, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844705

RESUMO

Numerous micro-organisms naturally reside in the human body assuming a symbiotic, or, at times, even a dysbiotic relationship with the host. These microbial populations are referred to as the human microbiota. Host microbial populations are an important mediator of gastro-intestinal mucosal permeability, bile acid metabolism, short-chain fatty acids synthesis, fermentation of dietary polysaccharides and FXR/TGR5 signaling. Variations in the composition and function of gut microbiota have been observed in type 2 diabetes mellitus, insulin resistance and obesity, as well as in inflammatory bowel diseases. The microbial imbalance induced by such pathological processes is described as dysbiosis. In this review, we describe the pathophysiological links between type 2 diabetes mellitus and gut microbiota, explore the effect of anti-diabetic drugs on gut microbiota and suggest possible therapeutic targets.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus Tipo 2/microbiologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Disbiose/induzido quimicamente , Fermentação , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Incretinas/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Metformina/farmacologia , Camundongos , Obesidade/metabolismo , Permeabilidade , Polissacarídeos/metabolismo , Transdução de Sinais , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , alfa-Glucosidases/metabolismo
20.
Nutrients ; 11(3)2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30813546

RESUMO

Diminished postprandial secretion of incretins and insulin represents one of the key pathophysiological mechanisms behind type 2 diabetes (T2D). We tested the effects of two energy- and macronutrient-matched meals: A standard meat (M-meal) and a vegan (V-meal) on postprandial incretin and insulin secretion in participants with T2D. A randomized crossover design was used in 20 participants with T2D. Plasma concentrations of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), amylin, and gastric inhibitory peptide (GIP) were determined at 0, 30, 60, 120, and 180 min. Beta-cell function was assessed with a mathematical model, using C-peptide deconvolution. Repeated-measures ANOVA was used for statistical analysis. Postprandial plasma glucose responses were similar after both test meals (p = 0.64). An increase in the stimulated secretion of insulin (by 30.5%; 95% CI 21.2 to 40.7%; p < 0.001), C-peptide (by 7.1%; 95% CI 4.1 to 9.9%; p < 0.001), and amylin (by 15.7%; 95% CI 11.8 to 19.7%; p < 0.001) was observed following consumption of the V-meal. An increase in stimulated secretion of GLP-1 (by 19.2%; 95% CI 12.4 to 26.7%; p < 0.001) and a decrease in GIP (by -9.4%; 95% CI -17.3 to -0.7%; p = 0.02) were observed after the V-meal. Several parameters of beta-cell function increased after the V-meal, particularly insulin secretion at a fixed glucose value 5 mmol/L, rate sensitivity, and the potentiation factor. Our results showed an increase in postprandial incretin and insulin secretion, after consumption of a V-meal, suggesting a therapeutic potential of plant-based meals for improving beta-cell function in T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Incretinas/metabolismo , Insulina/metabolismo , Refeições , Adulto , Estudos Cross-Over , Diabetes Mellitus Tipo 2/dietoterapia , Dieta Vegana , Ingestão de Energia , Humanos , Masculino , Carne , Pessoa de Meia-Idade , Nutrientes , Verduras
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