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1.
Nutrients ; 13(8)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34444986

RESUMO

Postprandial hypotension (PPH) is an important and under-recognised disorder resulting from inadequate compensatory cardiovascular responses to meal-induced splanchnic blood pooling. Current approaches to management are suboptimal. Recent studies have established that the cardiovascular response to a meal is modulated profoundly by gastrointestinal factors, including the type and caloric content of ingested meals, rate of gastric emptying, and small intestinal transit and absorption of nutrients. The small intestine represents the major site of nutrient-gut interactions and associated neurohormonal responses, including secretion of glucagon-like peptide-1, glucose-dependent insulinotropic peptide and somatostatin, which exert pleotropic actions relevant to the postprandial haemodynamic profile. This review summarises knowledge relating to the role of these gut peptides in the cardiovascular response to a meal and their potential application to the management of PPH.


Assuntos
Pressão Sanguínea , Polipeptídeo Inibidor Gástrico/sangue , Fármacos Gastrointestinais/farmacologia , Peptídeo 1 Semelhante ao Glucagon/sangue , Hipotensão , Período Pós-Prandial , Somatostatina/sangue , Acarbose/farmacologia , Acarbose/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Fármacos Gastrointestinais/uso terapêutico , Glucagon/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1/sangue , Humanos , Hipotensão/tratamento farmacológico , Hipotensão/fisiopatologia , Insulina/sangue , Peptídeos , Circulação Esplâncnica
2.
Biomed Res Int ; 2021: 9920826, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34341763

RESUMO

Background: Abrus precatorius is used in folk medicine across Afro-Asian regions of the world. Earlier, glucose lowering and pancreato-protective effects of Abrus precatorius leaf extract (APLE) was confirmed experimentally in STZ/nicotinamide-induced diabetic rats; however, the underlying mechanism of antidiabetic effect and pancreato-protection remained unknown. Objective: This study elucidated antidiabetic mechanisms and pancreato-protective effects of APLE in diabetic rats. Materials and Methods: APLE was prepared by ethanol/Soxhlet extraction method. Total phenols and flavonoids were quantified calorimetrically after initial phytochemical screening. Diabetes mellitus (DM) was established in adult Sprague-Dawley rats (weighing 120-180 g) of both sexes by daily sequential injection of nicotinamide (48 mg/kg; ip) and Alloxan (120 mg/kg; ip) over a period of 7 days. Except control rats which had fasting blood glucose (FBG) of 4.60 mmol/L, rats having stable FBG (16-21 mmol/L) 7 days post-nicotinamide/Alloxan injection were considered diabetic and were randomly reassigned to one of the following groups (model, APLE (100, 200, and 400 mg/kg, respectively; po) and metformin (300 mg/kg; po)) and treated daily for 18 days. Bodyweight and FBG were measured every 72 hours for 18 days. On day 18, rats were sacrificed under deep anesthesia; organs (kidney, liver, pancreas, and spleen) were isolated and weighed. Blood was collected for estimation of serum insulin, glucagon, and GLP-1 using a rat-specific ELISA kit. The pancreas was processed, sectioned, and H&E-stained for histological examination. Effect of APLE on enzymatic activity of alpha (α)-amylase and α-glucosidase was assessed. Antioxidant and free radical scavenging properties of APLE were assessed using standard methods. Results: APLE dose-dependently decreased the initial FBG by 68.67%, 31.07%, and 4.39% compared to model (4.34%) and metformin (43.63%). APLE (100 mg/kg) treatment restored weight loss relative to model. APLE increased serum insulin and GLP-1 but decreased serum glucagon relative to model. APLE increased both the number and median crosssectional area (×106 µm2) of pancreatic islets compared to that of model. APLE produced concentration-dependent inhibition of α-amylase and α-glucosidase relative to acarbose. APLE concentration dependently scavenged DPPH and nitric oxide (NO) radicals and demonstrated increased ferric reducing antioxidant capacity (FRAC) relative to standards. Conclusion: Antidiabetic effect of APLE is mediated through modulation of insulin and GLP-1 inversely with glucagon, noncompetitive inhibition of α-amylase and α-glucosidase, free radical scavenging, and recovery of damaged/necro-apoptosized pancreatic ß-cells.


Assuntos
Abrus/química , Diabetes Mellitus Experimental/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucagon/sangue , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , Aloxano , Animais , Antioxidantes/metabolismo , Compostos de Bifenilo/química , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Feminino , Flavonoides/análise , Sequestradores de Radicais Livres/farmacologia , Cobaias , Concentração Inibidora 50 , Insulina/sangue , Ferro/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Cinética , Masculino , Niacinamida , Fenóis/análise , Compostos Fitoquímicos/análise , Picratos/química , Extratos Vegetais/farmacologia , Ratos Sprague-Dawley
3.
Nutrients ; 13(6)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208508

RESUMO

Obesity and ageing are current issues of global concern. Adaptive homeostasis is compromised in the elderly, who are more likely to suffer age-related health issues, such as obesity, metabolic syndrome, and cardiovascular disease. The current worldwide prevalence of obesity and higher life expectancy call for new strategies for treating metabolic disorders. Grape-seed proanthocyanidin extract (GSPE) is reported to be effective in ameliorating these pathologies, especially in young animal models. In this study, we aimed to test the effectiveness of GSPE in modulating obesity-related pathologies in aged rats fed an obesogenic diet. To do so, 21-month-old rats were fed a high-fat/high-sucrose diet (cafeteria diet) for 11 weeks. Two time points for GSPE administration (500 mg/kg body weight), i.e., a 10-day preventive GSPE treatment prior to cafeteria diet intervention and a simultaneous GSPE treatment with the cafeteria diet, were assayed. Body weight, metabolic parameters, liver steatosis, and systemic inflammation were analysed. GSPE administered simultaneously with the cafeteria diet was effective in reducing body weight, total adiposity, and liver steatosis. However, the preventive treatment was effective in reducing only mesenteric adiposity in these obese, aged rats. Our results confirm that the simultaneous administration of GSPE improves metabolic disruptions caused by the cafeteria diet also in aged rats.


Assuntos
Extrato de Sementes de Uva/uso terapêutico , Obesidade/tratamento farmacológico , Proantocianidinas/uso terapêutico , Adiposidade/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Modelos Animais de Doenças , Fígado Gorduroso/tratamento farmacológico , Feminino , Glucagon/sangue , Insulina/sangue , Obesidade/metabolismo , Ratos , Ratos Wistar , Perda de Peso/efeitos dos fármacos
4.
Nutrients ; 13(7)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209137

RESUMO

D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.


Assuntos
Hipotálamo/metabolismo , Inositol/análogos & derivados , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Administração Oral , Animais , Glicemia/metabolismo , Ativação Enzimática/efeitos dos fármacos , Glucagon/sangue , Homeostase , Hipotálamo/efeitos dos fármacos , Inositol/administração & dosagem , Inositol/sangue , Inositol/química , Inositol/farmacologia , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
5.
Eur J Endocrinol ; 185(2): 343-353, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34085953

RESUMO

Objective: Hypoglycemia is associated with an increased risk of cardiovascular disease including cardiac arrhythmias. We investigated the effect of hypoglycemia in the setting of acute glycemic fluctuations on cardiac rhythm and cardiac repolarization in insulin-treated patients with type 2 diabetes compared with matched controls without diabetes. Design: A non-randomized, mechanistic intervention study. Methods: Insulin-treated patients with type 2 diabetes (n = 21, age (mean ± s.d.): 62.8 ± 6.5 years, BMI: 29.0 ± 4.2 kg/m2, HbA1c: 6.8 ± 0.5% (51.0 ± 5.4 mmol/mol)) and matched controls (n = 21, age: 62.2 ± 8.3 years, BMI 29.2 ± 3.5 kg/m2, HbA1c: 5.3 ± 0.3% (34.3 ± 3.3 mmol/mol)) underwent a sequential hyperglycemic and hypoglycemic clamp with three steady-states of plasma glucose: (i) fasting plasma glucose, (ii) hyperglycemia (fasting plasma glucose +10 mmol/L) and (iii) hyperinsulinemic hypoglycemia (plasma glucose < 3.0 mmol/L). Participants underwent continuous ECG monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained. Results: Both groups experienced progressively increasing heart rate corrected QT (Fridericia's formula) interval prolongations during hypoglycemia ((∆mean (95% CI): 31 ms (16, 45) and 39 ms (24, 53) in the group of patients with type 2 diabetes and controls, respectively) with similar increases from baseline at the end of the hypoglycemic phase (P = 0.43). The incidence of ventricular premature beats increased significantly in both groups during hypoglycemia (P = 0.033 and P < 0.0001, respectively). One patient with type 2 diabetes developed atrial fibrillation during recovery from hypoglycemia. Conclusions: In insulin-treated patients with type 2 diabetes and controls without diabetes, hypoglycemia causes clinically significant and similar increases in cardiac repolarization that might increase vulnerability for serious cardiac arrhythmias and sudden cardiac death.


Assuntos
Arritmias Cardíacas/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Hipoglicemia/fisiopatologia , Idoso , Arritmias Cardíacas/sangue , Pressão Sanguínea/fisiologia , Diabetes Mellitus Tipo 2/sangue , Eletrocardiografia , Feminino , Glucagon/sangue , Hormônio do Crescimento/sangue , Frequência Cardíaca/fisiologia , Humanos , Hidrocortisona/sangue , Hipoglicemia/sangue , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , Potássio/sangue
6.
Nutrients ; 13(5)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064996

RESUMO

(1) Background: Whey protein lowers postprandial blood glucose in health and type 2 diabetes, by stimulating insulin and incretin hormone secretion and slowing gastric emptying. The branched-chain amino acids, leucine, isoleucine and valine, abundant in whey, may mediate the glucoregulatory effects of whey. We investigated the comparative effects of intragastric administration of leucine, isoleucine and valine on the plasma glucose, C-peptide and glucagon responses to and gastric emptying of a mixed-nutrient drink in healthy men. (2) Methods: 15 healthy men (27 ± 3 y) received, on four separate occasions, in double-blind, randomised fashion, either 10 g of leucine, 10 g of isoleucine, 10 g of valine or control, intragastrically, 30 min before a mixed-nutrient drink. Plasma glucose, C-peptide and glucagon concentrations were measured before, and for 2 h following, the drink. Gastric emptying of the drink was quantified using 13C-acetate breath-testing. (3) Results: Amino acids alone did not affect plasma glucose or C-peptide, while isoleucine and valine, but not leucine, stimulated glucagon (p < 0.05), compared with control. After the drink, isoleucine and leucine reduced peak plasma glucose compared with both control and valine (all p < 0.05). Neither amino acid affected early (t = 0-30 min) postprandial C-peptide or glucagon. While there was no effect on overall gastric emptying, plasma glucose at t = 30 min correlated with early gastric emptying (p < 0.05). (4) Conclusion: In healthy individuals, leucine and isoleucine lower postprandial blood glucose, at least in part by slowing gastric emptying, while valine does not appear to have an effect, possibly due to glucagon stimulation.


Assuntos
Aminoácidos de Cadeia Ramificada/farmacologia , Glicemia/metabolismo , Peptídeo C/sangue , Esvaziamento Gástrico/efeitos dos fármacos , Glucagon/sangue , Isoleucina/farmacologia , Leucina/farmacologia , Valina/farmacologia , Adulto , Diabetes Mellitus Tipo 2 , Método Duplo-Cego , Polipeptídeo Inibidor Gástrico/sangue , Humanos , Insulina , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial/efeitos dos fármacos , Proteínas do Soro do Leite/farmacologia , Adulto Jovem
7.
Nutr Diabetes ; 11(1): 13, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859173

RESUMO

BACKGROUND/OBJECTIVES: Different infant formulas, varying in protein type and quantity, are available for infants who are not breastfed or are partially breastfed. Postprandial insulinemic and glycemic responses to intact vs partially hydrolyzed protein in infant formula are unclear. To compare the effect of different forms (partially hydrolyzed vs non-hydrolyzed) and levels of protein in infant formula compared with a human milk reference subgroup on insulin response in adults. SUBJECTS/METHODS: In a randomized, double-blinded, cross-over study, 35 healthy adults consumed 600 ml of three different infant formulas: Intact protein-based formula (INTACT) (1.87 g protein/100 kcal; whey/casein ratio of 70/30; 63 kcal/100 ml), partially hydrolyzed whey-based formula (PHw) (1.96 g protein/100 kcal; 100% whey; 63 kcal/100 ml), a high-protein partially hydrolyzed whey-based formula (HPPHw) (2.79 g protein/100 kcal; 100%whey; 73 kcal/100 ml) and a subgroup also consumed human milk (HM) (n = 11). Lipid and carbohydrate (lactose) contents were similar (5.1-5.5 and 10.5-11.6 g/100 kcal, respectively). Venous blood samples were taken after overnight fasting and at different intervals for 180 min post-drink for insulin, glucose, blood lipids, GLP-1, glucagon, and C-peptide. RESULTS: Twenty-nine subjects (eight consuming HM) adhered to the protocol. INTACT and PHw groups had similar postprandial insulinemia and glycaemia (Cmax and iAUC) that were not different from those of the HM subgroup. HPPHw resulted in higher postprandial insulin responses (iAUC) relative to all other groups (p < 0.001, p < 0.001, p = 0.002 for the comparison with INTACT, PHw, HM, respectively). HPPHw resulted in a higher glucose response compared to INTACT and PHw (iAUC: p = 0.003, p = 0.001, respectively), but was not different from HM (p = 0.41). CONCLUSION: This study in adults demonstrates similar postprandial insulinemia and glycaemia between INTACT and PHw, close to that of HM, but lower than HPPHw, which had a higher protein content compared to the other test milks. The findings remain to be confirmed in infants. CLINICAL TRIAL REGISTRATION: This study is registered at clinicaltrials.gov, identifier NCT04332510.


Assuntos
Glicemia/análise , Proteínas na Dieta/administração & dosagem , Fórmulas Infantis , Insulina/sangue , Leite Humano , Adulto , Peptídeo C/sangue , Estudos Cross-Over , Método Duplo-Cego , Feminino , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Voluntários Saudáveis , Humanos , Lactente , Lipídeos/sangue , Masculino , Período Pós-Prandial , Triglicerídeos/sangue , Proteínas do Soro do Leite/administração & dosagem , Adulto Jovem
8.
Vet J ; 271: 105652, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33840485

RESUMO

Metabolic and endocrine disorders, such as dyslipidemia, are common in donkeys. Negative energy balance due to fasting, stressful conditions, or disease is a major trigger for fat mobilization often leading to dyslipidemia. The hormonal response to fasting has not been well characterized in donkeys. Therefore, this work aimed to study variations in insulin, glucagon, leptin, total adiponectin, ghrelin, and insulin-like growth factor-1 concentrations, insulin-to-glucagon (IGR) and glucagon-to-insulin (GIR) molar ratios, and lipid and carbohydrate parameters during a 66 h fasting period in 8 adult donkeys, and to determine differences depending on body condition. Obese donkeys developed earlier lipid mobilization (increased plasma total triglyceride and total cholesterol concentrations) compared to non-obese donkeys. Plasma glucose and leptin concentrations decreased in obese animals. After 60 h fasting, obese donkeys showed a significant increase in glucagon and decrease in leptin. GIR significantly increased, while insulin and IGR decreased in both groups. These findings support faster lipid mobilization in response to negative energy status in obese donkeys during fasting, which could be linked to greater glucagonemia and could explain the predisposition of these animals to dyslipidemia.


Assuntos
Dislipidemias/veterinária , Metabolismo Energético/fisiologia , Equidae/sangue , Jejum/sangue , Obesidade/veterinária , Adiponectina/sangue , Animais , Glicemia/análise , Dislipidemias/sangue , Dislipidemias/etiologia , Feminino , Grelina/sangue , Glucagon/sangue , Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Leptina/sangue , Lipídeos/sangue , Obesidade/sangue
9.
Nutrients ; 13(4)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810265

RESUMO

The endocrine pancreas plays a key role in metabolism. Procyanidins (GSPE) targets ß-cells and glucagon-like peptide-1 (GLP-1)-producing cells; however, there is no information on the effects of GSPE on glucagon. We performed GSPE preventive treatments administered to Wistar rats before or at the same time as they were fed a cafeteria diet during 12 or 17 weeks. We then measured the pancreatic function and GLP-1 production. We found that glucagonemia remains modified by GSPE pre-treatment several weeks after the treatment has finished. The animals showed a higher GLP-1 response to glucose stimulation, together with a trend towards a higher GLP-1 receptor expression in the pancreas. When the GSPE treatment was administered every second week, the endocrine pancreas behaved differently. We show here that glucagon is a more sensitive parameter than insulin to GSPE treatments, with a secretion that is highly linked to GLP-1 ileal functionality and dependent on the type of treatment.


Assuntos
Glucagon/metabolismo , Extrato de Sementes de Uva/farmacologia , Insulina/metabolismo , Proantocianidinas/farmacologia , Animais , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Extrato de Sementes de Uva/administração & dosagem , Ilhotas Pancreáticas/metabolismo , Proantocianidinas/administração & dosagem , Ratos , Ratos Wistar
10.
Diabetes ; 70(6): 1347-1356, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33722838

RESUMO

Hyperglucagonemia is a well-known contributor to diabetic hyperglycemia, and glucagon-like peptide 1 (GLP-1) suppresses glucagon secretion. Reduced inhibitory effects of glucose and GLP-1 on glucagon secretion may contribute to the hyperglucagonemia in diabetes and influence the success of GLP-1 receptor agonist therapy. We examined the dose-response relationship for GLP-1 on glucose-induced glucagon suppression in healthy individuals and patients with type 2 and type 1 diabetes. In randomized order, 10 healthy individuals with normal glucose tolerance, 10 patients with type 2 diabetes, and 9 C-peptide-negative patients with type 1 diabetes underwent 4 separate stepwise glucose clamps (five 30-min steps from fasting level to 15 mmol/L plasma glucose) during simultaneous intravenous infusions of saline or 0.2, 0.4, or 0.8 pmol GLP-1/kg/min. In healthy individuals and patients with type 2 diabetes, GLP-1 potentiated the glucagon-suppressive effect of intravenous glucose in a dose-dependent manner. In patients with type 1 diabetes, no significant changes in glucagon secretion were observed during the clamps whether with saline or GLP-1 infusions. In conclusion, the glucagonostatic potency of GLP-1 during a stepwise glucose clamp is preserved in patients with type 2 diabetes, whereas our patients with type 1 diabetes were insensitive to the glucagonostatic effects of both glucose and GLP-1.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Glicemia/metabolismo , Dinamarca , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Relação Dose-Resposta a Droga , Jejum/sangue , Feminino , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Técnica Clamp de Glucose , Hemoglobina A Glicada/efeitos dos fármacos , Hemoglobina A Glicada/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
11.
J Clin Endocrinol Metab ; 106(5): 1398-1409, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33524152

RESUMO

AIM: To examine the relationship between plasma glucagon levels and insulin sensitivity and insulin secretion in obese subjects. METHODS: Suppression of plasma glucagon was examined in 275 obese Hispanic Americans with varying glucose tolerance. All subjects received a 2-hour oral glucose tolerance test (OGTT) and a subset (n = 90) had euglycemic hyperinsulinemic clamp. During OGTT, we quantitated suppression of plasma glucagon concentration, Matsuda index of insulin sensitivity, and insulin secretion/insulin resistance (disposition) index. Plasma glucagon suppression was compared between quartiles of insulin sensitivity and beta-cell function. RESULTS: Fasting plasma glucagon levels were similar in obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D), but the fasting glucagon/insulin ratio decreased progressively from NGT to prediabetes to T2D (9.28 ± 0.66 vs 6.84 ± 0.44 vs 5.84 ± 0.43; P < 0.001). Fasting and 2-hour plasma glucagon levels during OGTT progressively increased and correlated positively with severity of insulin resistance (both Matsuda index and euglycemic hyperinsulinemic clamp). The fasting glucagon/insulin ratio declined with worsening insulin sensitivity and beta-cell function, and correlated with whole-body insulin sensitivity (Matsuda index, r = 0.81; P < 0.001) and beta-cell function (r = 0.35; P < 0.001). The glucagon/insulin ratio also correlated and with beta-cell function during OGTT at 60 and 120 minutes (r = -0.47; P < 0.001 and r = -0.32; P < 0.001). CONCLUSION: Insulin-mediated suppression of glucagon secretion in obese subjects is impaired with increasing severity of glucose intolerance and parallels the severity of insulin resistance and beta-cell dysfunction.


Assuntos
Glucagon/metabolismo , Intolerância à Glucose/metabolismo , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Jejum/sangue , Feminino , Glucagon/sangue , Técnica Clamp de Glucose , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Hispano-Americanos , Humanos , Insulina/metabolismo , Secreção de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/fisiopatologia , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/fisiopatologia , Estados Unidos , Veteranos
12.
J Ethnopharmacol ; 272: 113949, 2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-33610707

RESUMO

ETHNO-PHARMACOLOGICAL RELEVANCE: The genus Aloe has a long history of usage in medicine. Aloe barbadensis Miller, commonly known as Aloe vera, is said to possess anti-diabetic, anti-inflammatory, anti-cancer, anti-microbial, immunomodulation, wound healing properties. AIM OF THE STUDY: In diabetes mellitus, loss in intestinal permeability is observed with high levels of zonulin and low levels of glucagon-like peptide-1 (GLP-1) leading to hyperglycemia. The aim of the study was to understand the role of peptide/polypeptide fraction (PPF) of Aloe vera in the alleviation of diabetes through maintaining the intestinal permeability by regulating the zonulin and GLP-1 levels. MATERIALS AND METHODS: The PPF of Aloe vera was obtained through trichloroacetic acid precipitation. The anti-diabetic potential of the PPF was tested through DPP-IV inhibition, glucose diffusion assay, and by using Rin-m5F cells. The anti-diabetic potential of the PPF was tested at a dose of 0.450 mg/kg bw in vivo using streptozotocin-induced diabetic Wistar rats. The effect of PPF on fasting plasma glucose, insulin, glucagon, Zonulin, GLP-1, DPP-IV, levels were studied in diabetic rats. The histopathological studies of the pancreas, small intestine, and liver were carried out for organ-specific effects. RESULTS: PPF has the ability to reduce fasting plasma glucose levels with concomitant increase in insulin levels in streptozotocin-induced diabetic rats. It was also observed that increase in GLP-1 levels with a decrease in DPP-IV and zonulin levels thereby mitigating the loss of intestinal permeability. These findings correlate with the small intestine's histopathological observation where the excessive proliferation of epithelium in the small intestine of diabetic rats was reduced after PPF treatment. CONCLUSION: These results suggest that the PPF of Aloe vera alleviates diabetes through islet cell rejuvenation via GLP-1/DPP-IV pathway and thereby suggesting the usage of PPF as an alternate medicine for diabetes mellitus with the possibility to reduce the intestinal permeability and zonulin levels.


Assuntos
Aloe/química , Diabetes Mellitus Experimental/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Haptoglobinas/metabolismo , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Precursores de Proteínas/metabolismo , Animais , Glicemia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Glucagon/sangue , Glucose-6-Fosfato/metabolismo , Glicogênio/metabolismo , Hexoquinase/metabolismo , Hipoglicemiantes/uso terapêutico , Inflamação/metabolismo , Insulina/sangue , Intestino Delgado/patologia , Fígado/patologia , Óxido Nítrico/metabolismo , Pâncreas/patologia , Extratos Vegetais/uso terapêutico , Ratos Wistar , Estreptozocina
13.
Vet J ; 269: 105610, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33593492

RESUMO

Alpha-2-adrenoceptor agonists are sedatives that can cause fluctuations in serum insulin and blood glucose (BG) concentrations in horses. The objectives of this study were to investigate the effects of detomidine and vatinoxan on BG, insulin, and glucagon concentrations in horses with and without insulin dysregulation (ID). In a blinded cross-over design, eight horses with ID and eight horses without ID were assigned to each of four treatments: detomidine (0.02 mg/kg; DET), vatinoxan (0.2 mg/kg; VAT), detomidine + vatinoxan (DET + VAT), and saline control (SAL). Blood samples were taken at 0, 1, 2, 4, 6, and 8 h. Change from baseline was used as the response in modelling, and the differences between treatments were evaluated with repeated measures analysis of covariance. P values ≤0.05 were considered significant. Comparing DET vs. SAL and DET vs. DET + VAT, insulin was higher at 2 h in the non-ID group and 2 and 4 h in the ID group. There was no difference in insulin between SAL and DET + VAT or VAT. Comparing DET vs. SAL, BG was higher at 1 and 2 h then was lower at 4 h in both ID and non-ID groups. At 1 h in both groups, BG after DET + VAT was lower than after DET but higher than after SAL. Comparing DET vs. SAL, glucagon was lower at 1 h in the ID group and 1 and 2 h in the non-ID group. Vatinoxan was effective in preventing detomidine-induced hyperglycaemia as well as the subsequent insulin increase in horses with ID.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Glicemia/análise , Glucagon/sangue , Cavalos/sangue , Insulina/sangue , Animais , Interações Medicamentosas , Feminino , Hipnóticos e Sedativos/farmacologia , Imidazóis/farmacologia , Resistência à Insulina/fisiologia , Masculino , Quinolizinas/farmacologia
14.
J Nutr ; 151(4): 921-929, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33561274

RESUMO

BACKGROUND: The potential of a ketone monoester (ß-hydroxybutyrate; KEßHB) supplement to rapidly mimic a state of nutritional ketosis offers a new therapeutic possibility for diabetes prevention and management. While KEßHB supplementation has a glucose-lowering effect in adults with obesity, its impact on glucose control in other insulin-resistant states is unknown. OBJECTIVES: The primary objective was to investigate the effect of KEßHB-supplemented drink on plasma glucose in adults with prediabetes. The secondary objective was to determine its impact on plasma glucoregulatory peptides. METHODS: This randomized controlled trial [called CETUS (Cross-over randomizEd Trial of ß-hydroxybUtyrate in prediabeteS)] included 18 adults [67% men, mean age = 55 y, mean BMI (kg/m2) = 28.4] with prediabetes (glycated hemoglobin between 5.7% and 6.4% and/or fasting plasma glucose between 100 and 125 mg/dL). Participants were randomly assigned to receive KEßHB-supplemented and placebo drinks in a crossover sequence (washout period of 7-10 d between the drinks). Blood samples were collected from 0 to 150 min, at intervals of 30 min. Paired-samples t tests were used to investigate the change in the outcome variables [ß-hydroxybutyrate (ßHB), glucose, and glucoregulatory peptides] after both drinks. Repeated measures analyses were conducted to determine the change in concentrations of the prespecified outcomes over time. RESULTS: Blood ßHB concentrations increased to 3.5 mmol/L within 30 minutes after KEßHB supplementation. Plasma glucose AUC was significantly lower after KEßHB supplementation than after the placebo [mean difference (95% CI): -59 (-85.3, -32.3) mmol/L × min]. Compared with the placebo, KEßHB supplementation led to significantly greater AUCs for plasma insulin [0.237 (0.044, 0.429) nmol/L × min], C-peptide [0.259 (0.114, 0.403) nmol/L × min], and glucose-dependent insulinotropic peptide [0.243 (0.085, 0.401) nmol/L × min], with no significant differences in the AUCs for amylin, glucagon, and glucagon-like peptide 1. CONCLUSIONS: Ingestion of the KEßHB-supplemented drink acutely increased the blood ßHB concentrations and lowered the plasma glucose concentrations in adults with prediabetes. Further research is needed to investigate the dynamics of repeated ingestions of a KEßHB supplement by individuals with prediabetes, with a view to preventing new-onset diabetes. This trial was registered at www.clinicaltrials.gov as NCT03889210.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Glicemia/metabolismo , Cetose/etiologia , Estado Pré-Diabético/sangue , Estado Pré-Diabético/dietoterapia , Ácido 3-Hidroxibutírico/sangue , Adulto , Idoso , Peptídeo C/sangue , Estudos Cross-Over , Suplementos Nutricionais , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Insulina/sangue , Polipeptídeo Amiloide das Ilhotas Pancreáticas/sangue , Cetose/sangue , Masculino , Pessoa de Meia-Idade , Método Simples-Cego
15.
Nutr Diabetes ; 11(1): 3, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33414406

RESUMO

BACKGROUND: The rate of gastric emptying and glucoregulatory hormones are key determinants of postprandial glycaemia. Intragastric administration of L-tryptophan slows gastric emptying and reduces the glycaemic response to a nutrient drink in lean individuals and those with obesity. We investigated whether tryptophan decreases postprandial glycaemia and slows gastric emptying in type 2 diabetes (T2D). METHODS: Twelve men with T2D (age: 63 ± 2 years, HbA1c: 49.7 ± 2.5 mmol/mol, BMI: 30 ± 1 kg/m2) received, on three separate occasions, 3 g ('Trp-3') or 1.5 g ('Trp-1.5') tryptophan, or control (0.9% saline), intragastrically, in randomised, double-blind fashion, 30 min before a mixed-nutrient drink (500 kcal, 74 g carbohydrates), containing 3 g 3-O-methyl-D-glucose (3-OMG) to assess glucose absorption. Venous blood samples were obtained at baseline, after tryptophan, and for 2 h post-drink for measurements of plasma glucose, C-peptide, glucagon and 3-OMG. Gastric emptying of the drink was quantified using two-dimensional ultrasound. RESULTS: Tryptophan alone stimulated C-peptide (P = 0.002) and glucagon (P = 0.04), but did not affect fasting glucose. In response to the drink, Trp-3 lowered plasma glucose from t = 15-30 min and from t = 30-45 min compared with control and Trp-1.5, respectively (both P < 0.05), with no differences in peak glucose between treatments. Gastric emptying tended to be slower after Trp-3, but not Trp-1.5, than control (P = 0.06). Plasma C-peptide, glucagon and 3-OMG increased on all days, with no major differences between treatments. CONCLUSIONS: In people with T2D, intragastric administration of 3 g tryptophan modestly slows gastric emptying, associated with a delayed rise, but not an overall lowering of, postprandial glucose.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Esvaziamento Gástrico/efeitos dos fármacos , Triptofano/administração & dosagem , 3-O-Metilglucose/sangue , Idoso , Bebidas , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Vias de Administração de Medicamentos , Glucagon/sangue , Glucose/metabolismo , Humanos , Insulina/sangue , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Nutrientes , Obesidade/tratamento farmacológico , Período Pós-Prandial
16.
J Clin Endocrinol Metab ; 106(5): e2151-e2161, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33491091

RESUMO

CONTEXT: Altered satiety hormones in women with polycystic ovarian syndrome (PCOS) may contribute to obesity. Diets with a low glycemic load (GL) may influence appetite-regulating hormones including glucagon and ghrelin. OBJECTIVE: To test the hypothesis that following a 4-week, eucaloric low vs high GL diet habituation, a low vs high GL meal will increase glucagon and decrease ghrelin to reflect greater satiety and improve self-reported fullness. METHODS: Secondary analysis of a randomized crossover trial. PARTICIPANTS: Thirty women diagnosed with PCOS. INTERVENTION: Participants were provided low (41:19:40% energy from carbohydrate:protein:fat) and high (55:18:27) GL diets for 8 weeks each. At each diet midpoint, a solid meal test was administered to examine postprandial ghrelin, glucagon, glucose, insulin, and self-reported appetite scores. RESULTS: After 4 weeks, fasting glucagon was greater with the low vs high GL diet (P = .035), and higher fasting glucagon was associated with lesser feelings of hunger (P = .009). Significant diet effects indicate 4-hour glucagon was higher (P < .001) and ghrelin was lower (P = .009) after the low vs high GL meal. A trending time × diet interaction (P = .077) indicates feelings of fullness were greater in the early postprandial phase after the high GL meal, but no differences were observed the late postprandial phase. CONCLUSION: These findings suggest after low GL diet habituation, a low GL meal reduces ghrelin and increases glucagon in women with PCOS. Further research is needed to determine the influence of diet composition on ad libitum intake in women with PCOS.


Assuntos
Dieta , Ingestão de Energia , Grelina/sangue , Glucagon/sangue , Carga Glicêmica , Síndrome do Ovário Policístico/fisiopatologia , Resposta de Saciedade/fisiologia , Adulto , Estudos Cross-Over , Feminino , Seguimentos , Humanos , Fome , Masculino , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/sangue , Prognóstico , Adulto Jovem
17.
Nutrients ; 13(2)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499025

RESUMO

Whey protein is an insulinotropic fraction of dairy that reduces postprandial glucose levels in patients with type 2 diabetes mellitus (T2DM). We have recently shown that ß-lactoglobulin (BLG), the largest protein fraction of whey, elevates insulin concentrations compared with iso-nitrogenous whey protein isolate (WPI) in healthy individuals. We therefore hypothesized that BLG pre-meals would lower glucose levels compared with WPI in patients with T2DM. We investigated 16 participants with T2DM using a randomized double-blinded cross-over design with two pre-meal interventions, (i) 25 g BLG and (ii) 25 g WPI prior to an oral glucose tolerance test (OGTT), followed by four days of continuous glucose monitoring (CGM) at home. BLG increased concentrations of insulin with 10%, glucagon with 20%, and glucose with 10% compared with WPI after the OGTT (all p < 0.05). Both BLG and WPI reduced the interstitial fluid (ISF) glucose concentrations (using CGM) with 2 mM and lowered glycemic variability with 10-15%, compared with tap-water (p < 0.05), and WPI lowered the ISF glucose with 0.5 mM compared with BLG from 120 min and onwards (p < 0.05). In conclusion, BLG pre-meals resulted in higher insulin, glucagon, and glucose concentrations compared with WPI in participants with T2DM. Pre-meal servings of WPI remains the most potent protein in terms of lowering postprandial glucose excursions.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/sangue , Lactoglobulinas/uso terapêutico , Adulto , Idoso , Automonitorização da Glicemia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Glucagon/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Proteínas do Soro do Leite
18.
Nutrients ; 13(1)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429977

RESUMO

Sugar consumption is associated with a whole range of negative health effects and should be reduced and the natural sweetener xylitol might be helpful in achieving this goal. The present study was conducted as a randomized, placebo-controlled, double-blind, cross-over trial. Twelve healthy, lean volunteers received intragastric solutions with 7, 17 or 35 g xylitol or tap water on four separate days. We examined effects on: gut hormones, glucose, insulin, glucagon, uric acid, lipid profile, as well as gastric emptying rates, appetite-related sensations and gastrointestinal symptoms. We found: (i) a dose-dependent stimulation of cholecystokinin (CCK), active glucagon-like peptide-1 (aGLP-1), peptide tyrosine tyrosine (PYY)-release, and decelerated gastric emptying rates, (ii) a dose-dependent increase in blood glucose and insulin, (iii) no effect on motilin, glucagon, or glucose-dependent insulinotropic peptide (GIP)-release, (iv) no effect on blood lipids, but a rise in uric acid, and (v) increased bowel sounds as only side effects. In conclusion, low doses of xylitol stimulate the secretion of gut hormones and induce a deceleration in gastric emptying rates. There is no effect on blood lipids and only little effect on plasma glucose and insulin. This combination of properties (low-glycemic sweetener which stimulates satiation hormone release) makes xylitol an attractive candidate for sugar replacement.


Assuntos
Esvaziamento Gástrico/efeitos dos fármacos , Hormônios Gastrointestinais/metabolismo , Edulcorantes/farmacologia , Xilitol/farmacologia , Adulto , Glicemia/metabolismo , Colecistocinina/sangue , Estudos Cross-Over , Dipeptídeos/sangue , Método Duplo-Cego , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Hormônios Gastrointestinais/sangue , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Insulina/sangue , Lipídeos/sangue , Masculino , Edulcorantes/administração & dosagem , Ácido Úrico/sangue , Xilitol/administração & dosagem , Adulto Jovem
19.
Diabetes ; 70(2): 477-491, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33239450

RESUMO

Elevation of glucagon levels and increase in α-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR complex 1 (mTORC1) regulation that controls glucagon secretion and α-cell mass. In the current studies we investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in α-cells (αTSC2KO). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of α-cell proliferation, cell size, and mass expansion. Hyperglucagonemia in αTSC2KO was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in αTSC2KO mice was characterized by reduced expression of the glucagon receptor (GCGR), PEPCK, and genes involved in amino acid metabolism and urea production. Glucagon resistance in αTSC2KO mice was associated with improved glucose levels in streptozotocin-induced ß-cell destruction and high-fat diet-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.


Assuntos
Glicemia/metabolismo , Células Secretoras de Glucagon/metabolismo , Glucagon/sangue , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Animais , Peso Corporal/fisiologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Ingestão de Alimentos/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Intolerância à Glucose/metabolismo , Insulina/sangue , Secreção de Insulina/fisiologia , Camundongos , Receptores de Glucagon/metabolismo , Transdução de Sinais/fisiologia , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
20.
Biochim Biophys Acta Gen Subj ; 1865(3): 129811, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33309687

RESUMO

BACKGROUND: There is growing evidence to support beneficial effects of the hypothalamic synthesised hormone, oxytocin, on metabolism. However, the biological half-life of oxytocin is short and receptor activation profile unspecific. METHODS: We have characterised peptide-based oxytocin analogues with structural modifications aimed at improving half-life and receptor specificity. Following extensive in vitro and in vivo characterisation, antidiabetic efficacy of lead peptides was examined in high fat fed (HFF) mice. RESULTS: Following assessment of stability against enzymatic degradation, insulin secretory activity, receptor activation profile and in vivo bioactivity, analogues 2 N (Ac-C ˂YIQNC >PLG-NH2) and D7R ((d-C)YIQNCYLG-NH2) were selected as lead peptides. Twice daily injection of either peptide for 22 days reduced body weight, energy intake, plasma glucose and insulin and pancreatic glucagon content in HFF mice. In addition, both peptides reduced total- and LDL-cholesterol, with concomitant elevations of HDL-cholesterol, and D7R also decreased triglyceride levels. The two oxytocin analogues improved glucose tolerance and insulin responses to intraperitoneal, and particularly oral, glucose challenge on day 22. Both oxytocin analogues enhanced insulin sensitivity, reduced HOMA-IR and increased bone mineral density. In terms of pancreatic islet histology, D7R reversed high fat feeding induced elevations of islet and beta cell areas, which was associated with reductions in beta cell apoptosis. Islet insulin secretory responsiveness was improved by 2 N, and especially D7R, treatment. CONCLUSION: Novel, enzymatically stable oxytocin analogues exert beneficial antidiabetic effects in HFF mice. GENERAL SIGNIFICANCE: These observations emphasise the, yet untapped, therapeutic potential of long-acting oxytocin-based agents for obesity and type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Obesidade/tratamento farmacológico , Oligopeptídeos/farmacologia , Ocitocina/farmacologia , Animais , Glicemia/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Ingestão de Energia/genética , Feminino , Glucagon/sangue , Meia-Vida , Hipoglicemiantes/síntese química , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Obesidade/sangue , Obesidade/etiologia , Obesidade/patologia , Oligopeptídeos/síntese química , Ocitocina/análogos & derivados , Ocitocina/síntese química , Estabilidade Proteica , Triglicerídeos/sangue
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