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1.
Eur J Endocrinol ; 185(4): R93-R101, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34370694

RESUMO

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.


Assuntos
Hormônios Peptídicos/fisiologia , Animais , Regulação do Apetite/efeitos dos fármacos , Regulação do Apetite/genética , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/genética , Humanos , Hipertensão/genética , Hipertensão/terapia , Contração Muscular/efeitos dos fármacos , Contração Muscular/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Obesidade/genética , Obesidade/terapia , Hormônios Peptídicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Somatostatina/química , Somatostatina/farmacologia , Somatostatina/fisiologia
2.
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
3.
Eur J Endocrinol ; 185(1): 23-32, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33886497

RESUMO

Aims/hypothesis: Metabolic effects of intermittent unhealthy lifestyle in young adults are poorly studied. We investigated the gluco-metabolic and hepatic effects of participation in Roskilde Festival (1 week of binge drinking and junk food consumption) in young, healthy males. Methods: Fourteen festival participants (FP) were studied before, during and after 1 week's participation in Roskilde Festival. Fourteen matched controls (CTRL) who did not participate in Roskilde Festival or change their lifestyle in other ways were investigated along a similar timeline. Results: The FP group consumed more alcohol compared to their standard living conditions (2.0 ± 3.9 vs 16.3 ± 8.3 units/day, P < 0.001). CTRLs did not change their alcohol consumption. AUC for glucose during OGTT did not change in either group. C-peptide responses increased in the FP group (206 ± 24 vs 236 ± 17 min × nmol/L, P = 0.052) and the Matsuda index of insulin sensitivity decreased (6.2 ± 2.4 vs 4.7 ± 1.4, P = 0.054). AUC for glucagon during oral glucose tolerance test (OGTT) increased in the FP group (1037 ± 90 vs 1562 ± 195 min × pmol/L, P = 0.003) together with fasting fibroblast growth factor 21 (FGF21) (62 ± 30 vs 132 ± 72 pmol/L, P < 0.001), growth differentiation factor 15 (GDF5) (276 ± 78 vs 330 ± 83 pg/mL, P = 0.009) and aspartate aminotransferase (AST) levels (37.6 ± 6.8 vs 42.4 ± 11 U/L, P = 0.043). Four participants (29%) developed ultrasound-detectable steatosis and a mean strain elastography-assessed liver stiffness increased (P = 0.026) in the FP group. Conclusions/Interpretation: Participation in Roskilde Festival did not affect oral glucose tolerance but was associated with a reduction in insulin sensitivity, increases in glucagon, FGF21, GDF15 and AST and lead to increased liver stiffness and, in 29% of the participants, ultrasound-detectable hepatic steatosis.


Assuntos
Aspartato Aminotransferases/metabolismo , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Glicemia/metabolismo , Dieta , Fast Foods , Fígado Gorduroso/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Adulto , Peptídeo C/metabolismo , Proteína C-Reativa/metabolismo , Dinamarca , Técnicas de Imagem por Elasticidade , Fígado Gorduroso/diagnóstico por imagem , Glucagon/metabolismo , Teste de Tolerância a Glucose , Férias e Feriados , Humanos , Resistência à Insulina , Fígado/diagnóstico por imagem , Masculino , Adulto Jovem
4.
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
5.
Endocr Connect ; 9(12): 1221-1232, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33252353

RESUMO

The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.

6.
J Clin Med ; 9(10)2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33036179

RESUMO

Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group (p = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (-28 (-44;-11) vs. 2 (-13;18) dB/m, p < 0.01) and body weight (-4.7 (-6.4;-2.9) vs. -1.4 (-3;0.3) kg, p < 0.01). One-year's liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP.

7.
Nutrients ; 12(10)2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32987824

RESUMO

Postprandial glucose excursions are postulated to increase the risk for diabetes complications via the production of advanced glycation end products (AGEs). The soluble receptor of AGEs (sRAGE) likely acts as a decoy receptor, mopping up AGEs, diminishing their capacity for pro-inflammatory and pro-apoptotic signaling. Recent evidence suggests that AGEs and soluble receptor for AGEs (sRAGE) may be altered under postprandial and fasting conditions. Here, we investigated the effects of increasing oral glucose loads during oral glucose tolerance tests (OGTT) and matched isoglycaemic intravenous (i.v.) glucose infusions (IIGI) on circulating concentrations of sRAGE. Samples from eight individuals with type 2 diabetes and eight age-, gender-, and body mass index (BMI)-matched controls, all of whom underwent three differently dosed OGTTs (25 g, 75 g, and 125 g), and three matched IIGIs were utilised (NCT00529048). Serum concentrations of sRAGE were measured over 240 min during each test. For individuals with diabetes, sRAGE area under the curve (AUC0-240min) declined with increasing i.v. glucose dosages (p < 0.0001 for trend) and was lower during IIGI compared to OGTT at the 125 g dosage (p = 0.004). In control subjects, sRAGE AUC0-240min was only lower during IIGI compared to OGTT at the 25 g dose (p = 0.0015). sRAGE AUC0-240min was negatively correlated to AUC0-240min for the incretin hormone glucagon-like peptide -1 (GLP-1) during the 75 g OGTT and matched IIGI, but only in individuals with type 2 diabetes. These data suggest that gastrointestinal factors may play a role in regulating sRAGE concentrations during postprandial glucose excursions, thus warranting further investigation.


Assuntos
Complicações do Diabetes/complicações , Diabetes Mellitus Tipo 2/metabolismo , Glucose/administração & dosagem , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Administração Oral , Idoso , Glicemia , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Teste de Tolerância a Glucose , Homeostase , Humanos , Incretinas , Masculino , Pessoa de Meia-Idade
8.
Diabetes ; 69(6): 1090-1099, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31974144

RESUMO

Glucagon secretion is regulated by circulating glucose, but it has turned out that amino acids also play an important role and that hepatic amino acid metabolism and glucagon are linked in a mutual feedback cycle, the liver-α-cell axis. On the basis of this knowledge, we hypothesized that hepatic steatosis might impair glucagon's action on hepatic amino acid metabolism and lead to hyperaminoacidemia and hyperglucagonemia. We subjected 15 healthy lean and 15 obese steatotic male participants to a pancreatic clamp with somatostatin and evaluated hepatic glucose and amino acid metabolism when glucagon was at basal levels and at high physiological levels. The degree of steatosis was evaluated from liver biopsy specimens. Total RNA sequencing of liver biopsy specimens from the obese steatotic individuals revealed perturbations in the expression of genes predominantly involved in amino acid metabolism. This group was characterized by fasting hyperglucagonemia, hyperaminoacidemia, and no lowering of amino acid levels in response to high levels of glucagon. Endogenous glucose production was similar between lean and obese individuals. Our results suggest that hepatic steatosis causes resistance to the effect of glucagon on amino acid metabolism. This results in increased amino acid concentrations and increased glucagon secretion, providing a likely explanation for fatty liver-associated hyperglucagonemia.


Assuntos
Aminoácidos/sangue , Fígado Gorduroso/metabolismo , Glucagon/metabolismo , Obesidade/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/metabolismo , Glicemia , Hormônios/farmacologia , Humanos , Hiperamonemia/sangue , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Pâncreas/efeitos dos fármacos , Somatostatina/farmacologia
9.
Front Endocrinol (Lausanne) ; 11: 617400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33488526

RESUMO

The hormones amylin and calcitonin interact with receptors within the same family to exert their effects on the human organism. Calcitonin, derived from thyroid C cells, is known for its inhibitory effect on osteoclasts. Calcitonin of mammalian origin promotes insulin sensitivity, while the more potent calcitonin extracted from salmon additionally inhibits gastric emptying, promotes gallbladder relaxation, increases energy expenditure and induces satiety as well as weight loss. Amylin, derived from pancreatic beta cells, regulates plasma glucose by delaying gastric emptying after meal ingestion, and modulates glucagon secretion and central satiety signals in the brain. Thus, both hormones seem to have metabolic effects of relevance in the context of non-alcoholic fatty liver disease (NAFLD) and other metabolic diseases. In rats, studies with dual amylin and calcitonin receptor agonists have demonstrated robust body weight loss, improved glucose tolerance and a decreased deposition of fat in liver tissue beyond what is observed after a body weight loss. The translational aspects of these preclinical data currently remain unknown. Here, we describe the physiology, pathophysiology, and pharmacological effects of amylin and calcitonin and review preclinical and clinical findings alluding to the future potential of amylin and calcitonin-based drugs for the treatment of obesity and NAFLD.


Assuntos
Peso Corporal/fisiologia , Calcitonina/uso terapêutico , Fígado Gorduroso/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/uso terapêutico , Obesidade/metabolismo , Agonistas dos Receptores da Amilina/farmacologia , Agonistas dos Receptores da Amilina/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Calcitonina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Obesidade/tratamento farmacológico
10.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443356

RESUMO

The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/biossíntese , Receptores dos Hormônios Gastrointestinais/agonistas , Animais , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos
11.
Am J Physiol Gastrointest Liver Physiol ; 316(4): G462-G472, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653341

RESUMO

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over nonalcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared with healthy normal-weight and obese individuals. RNA sequencing and quantitative histomorphometry of liver fat, inflammation and fibrosis were performed on liver biopsies obtained from healthy normal-weight ( n = 14) and obese ( n = 12) individuals, NAFL ( n = 15) and NASH ( n = 16) patients. Normal-weight and obese subjects showed normal liver histology and comparable gene expression profiles. Liver transcriptome signatures were largely overlapping in NAFL and NASH patients, however, clearly separated from healthy normal-weight and obese controls. Most marked pathway perturbations identified in both NAFL and NASH were associated with markers of lipid metabolism, immunomodulation, extracellular matrix remodeling, and cell cycle control. Interestingly, NASH patients with positive Sonic hedgehog hepatocyte staining showed distinct transcriptome and histomorphometric changes compared with NAFL. In conclusion, application of immunohistochemical markers of hepatocyte injury may serve as a more objective tool for distinguishing NASH from NAFL, facilitating improved resolution of hepatic molecular changes associated with progression of NAFLD. NEW & NOTEWORTHY Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. NAFLD is associated with the metabolic syndrome and can progress to the more serious form, nonalcoholic steatohepatitis (NASH), and ultimately lead to irreversible liver damage. Using gold standard molecular and histological techniques, this study demonstrates that the currently used diagnostic tools are problematic for differentiating mild NAFLD from NASH and emphasizes the marked need for developing improved histological markers of NAFLD progression.


Assuntos
Tecido Adiposo , Perfilação da Expressão Gênica/métodos , Inflamação , Cirrose Hepática , Fígado , Hepatopatia Gordurosa não Alcoólica , Obesidade , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Índice de Massa Corporal , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Inflamação/imunologia , Inflamação/patologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/diagnóstico , Obesidade/metabolismo
12.
Metab Syndr Relat Disord ; 16(10): 530-536, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30325692

RESUMO

BACKGROUND: Fasting hyperglucagonemia can be detrimental to glucose metabolism in patients with type 2 diabetes (T2D) and may contribute to metabolic disturbances in obese and/or prediabetic subjects. However, the mechanisms underlying fasting hyperglucagonemia remain elusive. METHODS: We evaluated the interrelationship between fasting hyperglucagonemia and demographic and biochemical parameters in 106 patients with T2D (31% female, age: 57 ± 9 years [mean ± standard deviation; body mass index (BMI): 30.1 ± 4.4 kg/m2; fasting plasma glucose (FPG): 9.61 ± 2.39 mM; hemoglobin A1c (HbA1c): 57.1 ± 13.1 mmol/mol] and 163 nondiabetic control subjects (29% female; age: 45 ± 17 years; BMI: 25.8 ± 4.1 kg/m2; FPG: 5.2 ± 0.4 mM; and HbA1c: 35.4 ± 3.8 mmol/mol). Multiple linear regression analysis was applied using a stepwise approach with fasting plasma glucagon as dependent parameter and BMI, waist-to-hip ratio (WHR), blood pressure, hemoglobin A1c, FPG, and insulin concentrations as independent parameters. RESULTS: Fasting plasma glucagon concentrations were significantly higher among patients with T2D (13.5 ± 6.3 vs. 8.5 ± 3.8 mM, P < 0.001) together with HbA1c (P < 0.001), FPG (P < 0.001), and insulin (84.9 ± 56.4 vs. 57.7 ± 35.3 mM, P < 0.001). When adjusted for T2D, HbA1c and insulin were significantly positive determinants for fasting plasma glucagon concentrations. Furthermore, WHR comprised a significant positive determinant. CONCLUSIONS: We confirm that fasting plasma glucagon concentrations are abnormally high in patients with T2D, and show that fasting plasma glucagon concentrations are influenced by WHR (in addition to glycemic control and fasting plasma insulin concentrations), which may point to visceral fat deposition as an important determinant of increased fasting plasma glucagon concentrations.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Glucagon/sangue , Glucose/metabolismo , Adulto , Idoso , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Jejum , Feminino , Teste de Tolerância a Glucose , Hemoglobina A Glicada/análise , Humanos , Insulina/sangue , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Regressão
13.
Diabetes Obes Metab ; 20(8): 1937-1943, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29654643

RESUMO

AIM: To evaluate the relationship between plasma dipeptidyl-peptidase 4 (DPP-4) activity and its protection of glucagon-like peptide-1 (GLP-1) using the DPP-4 inhibitor sitagliptin. METHODS: On four separate days, patients with type 2 diabetes (T2D) (n = 8; age: 59.9 ±10.8 [mean ±SD] years; body mass index [BMI]: 28.8 ±4.6 kg/m2 ; glycated haemoglobin A1c [HbA1c]: 43.1 ±0.5 mmol/mol [6.6% ±1.7%]) received a 380-minute continuous intravenous infusion of GLP-1 (1.0 pmol × kg bodyweight-1 × minutes-1 ) and a double-blind, single-dose oral administration of sitagliptin in doses of 0 (placebo), 25, 100 and 200 mg. RESULTS: Plasma DPP-4 activity decreased compared to baseline (placebo) with increasing doses of sitagliptin (P < .01), reaching a maximal inhibition with the 100 mg dose. Levels of intact GLP-1 increased with increasing doses of sitagliptin from placebo to 100 mg (area under curve [AUC] 7.2 [95%, CI; 12.1, 16.4] [placebo], 10.7 [16.1, 21.4] [25 mg], 11.7 [17.8, 23.6] [100 mg] nmol/L × 360 minutes [P < .01]), but no further increase in intact GLP-1 levels was observed with 200 mg of sitagliptin (11.5 [17.6, 23.4] nmol/L × 360 minutes) (P = .80). CONCLUSION: Our findings suggest that the sitagliptin dose of 100 mg is sufficient to inhibit both plasma and membrane-bound DPP-4 activity, presumably also leading to complete protection of endogenous GLP-1 in patients with T2D.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/sangue , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/farmacocinética , Hiperglicemia/prevenção & controle , Incretinas/farmacocinética , Fragmentos de Peptídeos/farmacocinética , Fosfato de Sitagliptina/administração & dosagem , Administração Oral , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/sangue , Hemoglobina A Glicada/análise , Humanos , Inativação Metabólica/efeitos dos fármacos , Incretinas/administração & dosagem , Incretinas/sangue , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Sobrepeso/complicações , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/sangue , Fosfato de Sitagliptina/uso terapêutico
14.
Diabetes Care ; 41(6): 1260-1267, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29602793

RESUMO

OBJECTIVE: Epidemiological studies suggest that smoking increases the risk of type 2 diabetes. We hypothesized that smoking-derived nicotine and ensuing activation of nicotinic cholinergic receptors in the gastrointestinal tract and the autonomic nervous system would have a detrimental effect on postprandial glucose metabolism and, thus, potentially constitute a link between smoking and the development of type 2 diabetes. RESEARCH DESIGN AND METHODS: We subjected 11 male heavy smokers to two identical 4-h liquid mixed-meal tests: one with concomitant cigarette smoking (immediately before and after meal intake) and one without smoking. Twelve age-, sex-, and BMI-matched nonsmokers underwent an identical meal test without smoking. RESULTS: The smokers were characterized by higher fasting plasma concentrations of glucagon compared with the nonsmokers. Among smokers, cigarette smoking before and after the meal significantly reduced postprandial plasma glucose excursions. There were no differences in gut or pancreatic hormone concentrations between the test days in the smoking group, and the responses were similar to those in the control group. CONCLUSIONS: Our results suggest that smoking in association with meal intake decreases the postprandial plasma glucose concentrations, possibly through decreased gastric emptying, and that elevated fasting glucagon concentrations rather than smoking-induced alterations in postprandial glucose and hormone responses may be associated with the elevated risk of type 2 diabetes in chronic smokers.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucagon/sangue , Fumar/efeitos adversos , Fumar/metabolismo , Adulto , Sistema Nervoso Autônomo/metabolismo , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Esvaziamento Gástrico/fisiologia , Trato Gastrointestinal/metabolismo , Glucagon/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial/fisiologia , Receptores Nicotínicos/metabolismo , Fumar/sangue
15.
Basic Clin Pharmacol Toxicol ; 121(4): 290-297, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28374974

RESUMO

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play an important role in glucose homeostasis by potentiating glucose-induced insulin secretion. Furthermore, GLP-1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP-1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP-1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP-1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP-1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Intestino Delgado/metabolismo , Modelos Biológicos , Adulto , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Esvaziamento Gástrico , Peptídeo 1 Semelhante ao Glucagon/antagonistas & inibidores , Glucose/administração & dosagem , Teste de Tolerância a Glucose , Antagonistas de Hormônios/farmacologia , Humanos , Absorção Intestinal , Intestino Delgado/efeitos dos fármacos , Cinética , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
16.
Diabetologia ; 60(7): 1344-1353, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28364253

RESUMO

AIMS/HYPOTHESIS: We investigated whether a reduced incretin effect, as observed in patients with type 2 diabetes, can be detected in high-risk individuals, such as women with prior gestational diabetes mellitus (pGDM). METHODS: In this cross-sectional study, 102 women without diabetes with pGDM and 15 control participants without pGDM and with normal glucose tolerance (NGT) underwent a 4 h 75 g OGTT and an isoglycaemic i.v. glucose infusion (IIGI). Women with pGDM were classified as having NGT or prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Insulin sensitivity was assessed using the Matsuda index and HOMA2-IR and the incretin effect was calculated from insulin responses during the study (100% × [AUCinsulin,OGTT - AUCinsulin,IIGI]/AUCinsulin,OGTT). RESULTS: Sixty-three of the 102 women with pGDM (62%) had prediabetes (median [interquartile range]: age, 38.3 [6.5] years; BMI, 32.1 [5.8] kg/m2) and 39 women (38%) had NGT (age, 39.5 [5.6] years; BMI, 31.0 [6.7] kg/m2). Control participants (n = 15) were not significantly different from the pGDM group with regards to age (39.2 [7.4] years) and BMI (28.8 [9.2] kg/m2). Compared with women with NGT and control participants, women with prediabetes had lower insulin sensitivity, as measured by the Matsuda index (3.0 [2.4] vs 5.0 [2.6] vs 1.5 [1.8], respectively; p < 0.001). The incretin effect was 55.3% [27.8], 73.8% [19.0] and 76.7% [24.6] in women with prediabetes, women with normal glucose tolerance and control participants, respectively (p < 0.01). CONCLUSION/INTERPRETATION: Prediabetes was highly prevalent in women with pGDM, and alterations in the incretin effect were detected in this group before the development of type 2 diabetes. TRIAL REGISTRATION: clinicaltrialsregister.eu 2012-001371-37-DK.


Assuntos
Diabetes Gestacional/sangue , Diabetes Gestacional/fisiopatologia , Incretinas/sangue , Estado Pré-Diabético/sangue , Estado Pré-Diabético/fisiopatologia , Adulto , Área Sob a Curva , Glicemia/análise , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos Transversais , Dinamarca , Diabetes Mellitus Tipo 2 , Método Duplo-Cego , Feminino , Glucagon/análise , Peptídeo 1 Semelhante ao Glucagon/análise , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Gravidez , Prevalência
17.
J Clin Endocrinol Metab ; 101(11): 4377-4384, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27533305

RESUMO

CONTEXT: Oral glucose ingestion elicits a larger insulin response and delayed suppression of glucagon compared to isoglycemic IV glucose infusion (IIGI). OBJECTIVE: We studied whether these differences translate into effects on endogenous glucose production (EGP) and glucose disposal in patients with type 2 diabetes and nondiabetic control subjects. DESIGN: This was a single-blinded, randomized, crossover study. SETTING: The study was conducted at a specialized research unit. PARTICIPANTS: Ten patients with type 2 diabetes (age, [mean ± SD] 57.1 ± 6.7 years; body mass index, 29.0 ± 4.3 kg/m2; hemoglobin A1c, 53.8 ± 11.0 mmol/mol; duration of diabetes, 9.2 ± 5.0 years) and 10 matched nondiabetic control subjects (age, 56.0±10.7 years; body mass index, 29.8 ± 2.9 kg/m2; hemoglobin A1c, 33.8 ± 5.5 mmol/mol) participated. INTERVENTIONS: Three experimental days: 75 g-oral glucose tolerance test (OGTT), IIGI, and IIGI+glucagon (IIGI with a concomitant IV glucagon infusion [0.8 ng/kg/min from 0 to 25 minutes] designed to mimic portal glucagon concentrations during OGTT in the type 2 diabetic group) were undertaken. MAIN OUTCOME MEASURES: Glucose kinetics were assessed by tracer methodology. RESULTS: Glucose rate of disappearance was higher during the OGTT vs IIGI in the control group, but similar on all days in the diabetic group. Surprisingly, in both groups, EGP was more suppressed during IIGI than during OGTT, and exogenous glucagon infusion during IIGI did not restore EGP to the levels observed during OGTT. CONCLUSION: EGP was less suppressed during OGTT than during IIGI in both patients with type 2 diabetes and in nondiabetic control subjects. Based on the present experimental design, it was not possible to attribute this difference to the delayed glucagon suppression observed in the initial phase of the OGTT.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Glucagon/metabolismo , Glucose/metabolismo , Avaliação de Processos e Resultados em Cuidados de Saúde , Glicemia/análise , Estudos Cross-Over , Feminino , Glucagon/administração & dosagem , Glucose/administração & dosagem , Teste de Tolerância a Glucose , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Método Simples-Cego
19.
Diabetes ; 65(3): 585-97, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26672094

RESUMO

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.


Assuntos
Trato Gastrointestinal/metabolismo , Glucagon/metabolismo , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Pancreatite/cirurgia , Idoso , Glicemia/metabolismo , Estudos de Casos e Controles , Colecistocinina/metabolismo , Cromatografia Líquida , Ensaio de Imunoadsorção Enzimática , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Gastrinas/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células Secretoras de Glucagon/metabolismo , Glucose/farmacologia , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Proteômica , Radioimunoensaio , Espectrometria de Massas em Tandem
20.
Med Hypotheses ; 86: 100-3, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26547273

RESUMO

For more than a century type 2 diabetes has been looked upon mainly as an insulin-related disease and it is well-acknowledged that insulin resistance and beta cell dysfunction play important roles in the pathophysiology of the disease. During the last couple of decades, glucagon has also been recognised to play a significant role in type 2 diabetic pathophysiology. However, the mechanisms underlying disturbances in the regulation of glucagon remain unclear. Glucagon constitutes the primary stimulus for hepatic glucose production and, thus, upholds adequate blood glucose levels during fasting conditions. Many - but not all - patients with type 2 diabetes are characterised by inappropriately elevated plasma levels of glucagon contributing to their hyperglycaemic state. We believe that phenotypical dissimilarities within this group of patients may determine the presence and degree of hyperglucagonaemia. Results from our group show that both normoglycaemic individuals and patients with type 2 diabetes with non-alcoholic fatty liver disease (NAFLD) exhibit fasting hyperglucagonaemia compared to similarly grouped individuals without NAFLD. Therefore, we speculate that NAFLD - and not type 2 diabetes per se - is the main driver behind fasting hyperglucagonaemia. We hypothesise that in the majority of type 2 diabetic individuals hepatic sensitivity to glucagon is compromised due to hepatic steatosis, and that this provides a feedback mechanism acting at the level of pancreatic alpha cells, leading to elevated levels of glucagon. Here we present our hypothesis and propose a way to test it. If our hypothesis holds true, hepatic glucagon resistance would constitute a parallel to the obesity-induced insulin resistance in muscle and liver tissue, and underpin a central role for glucagon in the pathogenesis of type 2 diabetes. This would provide a crucial step forward in understanding the interaction between NAFLD and the alpha cell in the pathophysiology underlying type 2 diabetes.


Assuntos
Anemia/etiologia , Anemia/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Glucagon/metabolismo , Modelos Biológicos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Glucagon/metabolismo , Humanos
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