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1.
Diabetes Obes Metab ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34617375

RESUMO

AIMS: Glucagon-like peptide 1 (GLP-1) receptor agonists induce body weight loss, and body weight loss may reduce bone mineral density. An antiresorptive potential of long-acting GLP-1 receptor agonists has been observed in both type 1 and type 2 diabetes, but the effects of short-acting GLP-1 receptor agonism on bone metabolism have never been investigated in type 1 diabetes. The MAG1C trial evaluated the efficacy of short-acting exenatide added to insulin therapy in type 1 diabetes on bone mineral density and bone turnover markers as prespecified, secondary endpoints. MATERIALS AND METHODS: In a randomized, double-blinded, parallel-group trial, 108 individuals with type 1 diabetes aged ≥18 years on basal-bolus therapy with HbA1c 59-88 mmol/mol (7.5-10.0%) and body mass index >22.0 kg/m2 were randomized (1:1) to preprandial subcutaneous injection of 10 µg exenatide (Byetta®) before breakfast, lunch and dinner over 26 weeks as add-on treatment to regular insulin therapy. RESULTS: Exenatide elicited a 4.4 kg body weight reduction compared with placebo, but no between-group differences in bone mineral density as assessed by whole-body, hip, lumbar and forearm dual-energy X-ray absorptiometry following 26 weeks' treatment were observed. Fasting plasma levels of C-terminal telopeptides of type I collagen, a marker of bone resorption, and amino-terminal propeptide of type I procollagen, a marker of bone formation, were unchanged by exenatide compared with placebo after 26 weeks. CONCLUSIONS: Despite an exenatide-induced body weight reduction, no changes in bone metabolism were observed with exenatide added to insulin therapy in type 1 diabetes after 26 weeks. This article is protected by copyright. All rights reserved.

2.
Blood Purif ; : 1-9, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34583354

RESUMO

INTRODUCTION: The accuracy of hemoglobin A1c (HbA1c) as a glycemic marker in patients with type 2 diabetes (T2D) receiving hemodialysis (HD) remains unknown. To assess accuracy, we compared HbA1c and fructosamine levels with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with T2D receiving HD. METHODS: Thirty patients in the HD group and 36 patients in the control group (T2D and an estimated glomerular filtration rate >60 mL/min/1.73 m2) completed the study period of 17 weeks. CGM (Ipro2®, Medtronic) was performed 5 times for periods of up to 7 days (with 4-week intervals) during a 16-week period. HbA1c (mmol/mol), the estimated mean plasma glucose from HbA1c (eMPGA1c [mmol/L]) and fructosamine (µmol/L) was measured at week 17 and compared with mean sensor glucose levels from CGM. FINDINGS: In the HD group, mean sensor glucose was 1.4 mmol/L (95% confidence interval [CI]: 1.0-1.8) higher than the eMPGA1c, whereas the difference for controls was 0.1 mmol/L (95% CI: -0.1-[0.4]; p < 0.001). Adjusted for mean sensor glucose, HbA1c was lower in the HD group (-7.3 mmol/mol, 95% CI: -10.0-[-4.7]) than in the control group (p < 0.001), with no difference detected for fructosamine (p = 0.64). DISCUSSION: HbA1c evaluated by CGM underestimates plasma glucose levels in patients receiving HD. The underestimation represents a clinical challenge in optimizing glycemic control in the HD population. Fructosamine is unaffected by the factors affecting HbA1c and appears to be more accurate for glycemic monitoring. CGM or fructosamine could thus complement HbA1c in obtaining more accurate glycemic control in this patient group.

3.
Acta Psychiatr Scand ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34587287

RESUMO

Psychotic disorders such as schizophrenia are closely related to the development of obesity and metabolic perturbations. Antipsychotic medication is the mainstay of treatment of psychosis, but the drugs are associated with marked risk of metabolic side effects1 . The onset of psychotic disorders typically occurs in early adulthood, and as the course of illness is often chronic, long-term or even lifelong treatment with antipsychotic medication will often be needed.

4.
Diabetes Obes Metab ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34490741

RESUMO

Glucose-dependent insulinotropic polypeptide (GIP) plays an important role in the glucose and lipid metabolism. We investigated the effects of exogenous GIP on lipid metabolism during time of stable insulin levels. Ten male patients with type 1 diabetes without endogenous insulin secretion (C-peptide-negative, mean [±SD] age 26 ± 4years, body mass index 24 [±2] kg/m2 , glycated haemoglobin 56 [±8] mmol/mol or 7.3 [±0.8]%) were studied in a randomized, double-blind, placebo-controlled, crossover study with continuous intravenous infusions of GIP (4 pmol/kg/min) or placebo (saline), during two separate 90-minute hyperglycaemic (12 mmol/L) clamps with basal insulin substitution (0.1-0.2 mU/kg/min). Plasma glycerol concentrations increased from baseline during GIP infusion and decreased during placebo infusion (baseline-subtracted area under the curve [bsAUC] 703 ± 407 vs. -262 ± 240 µmol/L × min, respectively; P < 0.001). Free fatty acids (FFAs) increased during GIP infusions (bsAUC 5505 ± 2170 µEq/L × min) and remained unchanged during placebo infusion (bsAUC -74 ± 2363 µEq/L × min), resulting in a significant difference between GIP and placebo infusions (P < 0.001). Plasma concentrations of glucose, insulin, glucagon-like peptide-1 and glucagon were similar during GIP and placebo infusions. GIP increased plasma glycerol and FFAs in patients with type 1 diabetes during hyperglycaemia and stable basal insulin levels. This supports a direct lipolytic effect of GIP at high glucose and low levels of plasma insulin.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34505899

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and represents a wide spectrum ranging from mild steatosis over non-alcoholic steatohepatitis with and without fibrosis to overt cirrhosis. Patients with NAFLD have a high risk of developing cardiovascular disease and chronic kidney disease (CKD). So far, there is scarce evidence of the prevalence of NAFLD among patients with CKD. We investigated the prevalence of moderate-to-severe hepatic steatosis graded according to the definition of NAFLD in a cohort of patients with CKD. METHODS: Hepatic liver fat content was evaluated by computed tomography (CT) scan in 291 patients from the Copenhagen Chronic Kidney Disease Cohort Study and in 866 age- and sex-matched individuals with normal kidney function from the Copenhagen General Population Study. Liver attenuation density <48 Hounsfield units was used as cut-off value for moderate-to-severe hepatic steatosis. RESULTS: The prevalence of moderate-to-severe hepatic steatosis was 7.9% and 10.7% (P = 0.177) among patients with CKD and controls, respectively. No association between liver fat content and CKD stage was found. In the pooled data set from both cohorts, adjusted odds ratios for moderate-to-severe hepatic steatosis among persons with diabetes, overweight and obesity amounted to 3.1 (95% confidence interval (CI) 1.6-5.9), 14.8 (95% CI 4.6-47.9) and 42.0 (95% CI 12.9-136.6), respectively. CONCLUSIONS: In a cohort of 291 patients with CKD, kidney function was not associated with the prevalence of moderate-to-severe hepatic steatosis as assessed by CT scan.

6.
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
7.
Neurogastroenterol Motil ; : e14210, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34378827

RESUMO

OBJECTIVE: Neurotensin (NT) is released from enteroendocrine cells and lowers food intake in rodents. We evaluated postprandial NT secretion in humans after surgeries associated with accelerated small intestinal nutrient delivery, and after Roux-en-Y gastric bypass (RYGB) when glucagon-like peptide-1 (GLP-1) signalling and dipeptidyl peptidase 4 (DPP-4) were inhibited, and during pharmacological treatments influencing entero-pancreatic functions. METHODS: We measured NT concentrations in plasma from meal studies: (I) after truncal vagotomy with pyloroplasty (TVP), cardia resection +TVP (CTVP), and matched controls (n = 10); (II) after RYGB, sleeve gastrectomy (SG), and in matched controls (n = 12); (III) after RYGB (n = 11) with antagonism of GLP-1 signalling using exendin(9-39) and DPP-4 inhibition using sitagliptin; (IV) after RYGB (n = 11) during a run-in period and subsequent treatment with, sitagliptin, liraglutide (GLP-1 receptor agonist), verapamil (calcium antagonist), acarbose (alpha glucosidase inhibitor), and pasireotide (somatostatin analogue), respectively. RESULTS: (I) NT secretion was similar after TVP/CTVP (p = 0.9), but increased vs. controls (p < 0.0001). (II) NT secretion was increased after RYGB vs. SG and controls (p < 0.0001). NT responses were similar in SG and controls (p = 0.3), but early postprandial NT concentrations were higher after SG (p < 0.05). (III) Exendin (9-39) and sitagliptin did not change NT responses vs placebo (p > 0.2), but responses were lower during sitagliptin vs. exendin(9-39) (p = 0.03). (IV) Pasireotide suppressed NT secretion (p = 0.004). Sitagliptin tended to lower NT secretion (p = 0.08). Liraglutide, verapamil, and acarbose had no effect (p > 0.9). CONCLUSION: Neurotensin secretion is increased after surgeries associated with accelerated gastric emptying and lowered by pasireotide.

8.
Diabetologia ; 64(11): 2425-2431, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34405256

RESUMO

AIMS/HYPOTHESIS: Type 1 diabetes is characterised by reduced glucagon response to hypoglycaemia, increasing the risk of insulin treatment-associated hypoglycaemia known to hamper glycaemic control. We previously reported a glucagonotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) during insulin-induced hypoglycaemia in individuals with type 1 diabetes. Here we investigate the effect of a 6-day s.c. GIP infusion on time in glycaemic range as assessed by continuous glucose monitoring (CGM) in individuals with type 1 diabetes. METHODS: In a randomised, placebo-controlled, double-blind crossover study, time in glycaemic range (assessed by double-blinded CGM) was evaluated in 20 men with type 1 diabetes (18-75 years, stable insulin treatment ≥3 months, diabetes duration 2-15 years, fasting plasma C-peptide below 200 pmol/l, BMI 20-27 kg/m2, HbA1c <69 mmol/mol [8.5%]) during two × 6 days of continuous s.c. GIP (6 pmol kg-1 min-1) and placebo (saline [154 mmol/l NaCl]) infusion, respectively, with an interposed 7-day washout period. The primary outcome was glycaemic time below range, time in range and time above range. RESULTS: There were no significant differences in time below range (<3.9 mmol/l, p = 0.53) or above range (>10 mmol/l, p = 0.32) during night-time or daytime, in mean glucose, or in hypoglycaemic events as assessed by CGM. GIP altered neither self-reported hypoglycaemia nor safety measures. Compared with placebo, GIP significantly increased time in tight range (3.9-7.8 mmol/l) during daytime (06:00-23:59 hours) by [mean ± SEM] 11.2 ± 5.1% [95% CI 0.41, 21.9] (p = 0.02). CONCLUSIONS/INTERPRETATION: Six-day s.c. GIP infusion in men with type 1 diabetes did not procure convincing effect on overall time in range, but increased time in tight glycaemic range during daytime by ~2 h per day. TRIAL REGISTRATION: ClinicalTrials.gov NCT03734718. FUNDING: The study was funded by grants from The Leona M. and Harry B. Helmsley Charitable Trust and Aase og Ejnar Danielsens Fond.

9.
Expert Opin Pharmacother ; : 1-15, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34420454

RESUMO

Introduction: The number of individuals under 18 years of age with type 2 diabetes is increasing at an alarming rate worldwide. These patients are often characterized by obesity and they often experience a more rapid disease progression than adults with type 2 diabetes. Thus, focus on prevention and management of complications and comorbidities is imperative. With emphasis on weight loss and optimal glycemic control, treatment includes lifestyle changes and pharmacotherapy, which in this patient group is limited to metformin, liraglutide and insulin. In selected cases, bariatric surgery is indicated.Areas covered: This perspective article provides an overview of the literature covering pathophysiology, diagnosis, characteristics and treatment of pediatric type 2 diabetes, and outlines the gaps in our knowledge where further research is needed. The paper draws on both mechanistic studies, large scale intervention trials, epidemiological studies and international consensus statements.Expert opinion: Type 2 diabetes in pediatric patients is an increasing health care problem, and the current treatment strategies do not successfully meet the many challenges and obstacles in this patient group. Treatments must be early, intensive, multifaceted and durable. Also, prevention of obesity and type 2 diabetes in at-risk children should be addressed and prioritized on all levels.

10.
Diabet Med ; 38(10): e14655, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34291491

RESUMO

AIMS: The once-weekly administered glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) semaglutide, has, in clinical trials, demonstrated significant reductions in glycated haemoglobin A1c (HbA1c ) and body weight in persons with type 2 diabetes. We evaluated the real-world clinical effects of semaglutide once weekly in a hospital-based diabetes out-patient clinic. METHODS: This retrospective observational cohort study included persons with type 2 diabetes (n = 119) on a broad range of antidiabetic medicine: GLP-1RA naïve persons (n = 37) and GLP-1RA-experienced persons (n = 82). Person characteristics at inclusion: age [median (quartiles)]: 65 (57, 72) years; body weight 99 (86, 118) kg; body mass index (BMI) 33 (29, 38) kg/m²; HbA1c 61 (54, 69) mmol/mol/(7.7 (7.1, 8.5) %). Data were collected at baseline and after 3, 6 and 12 months of semaglutide treatment. Data were analysed using a general linear mixed model for repeated measurements. RESULTS: After 12 months, the reductions in HbA1c were (mean [95% confidence interval]: GLP-1RA naïve: -12.8 [-17.0, -8.5] mmol/mol/ -1.2 [-1.6, -0.8]% (p < 0.01) and GLP-1RA experienced: -6.4 [-9.0, -3.8] mmol/mol/ -0.6 [-0.8, -0.4]% (p < 0.01), respectively. Body weight reductions in GLP-1RA naïve: -5 [-6.9, -3.1] kg (p < 0.01) and GLP-1RA experienced: -3.2 [-4.4, -2.0] kg (p < 0.01), respectively. Seventy-five percent received 1 mg QW semaglutide. CONCLUSION: We observed effects of semaglutide once weekly on HbA1c and body weight comparable with the effects observed in clinical studies with fewer persons in our cohort receiving maximum dose of semaglutide.

11.
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
12.
J Clin Endocrinol Metab ; 106(8): 2164-2170, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34036343

RESUMO

BACKGROUND: Cholecystokinin (CCK) is a gut hormone originally known for its effects on gallbladder contraction and release of digestive enzymes. CCK, however, also mediates satiety and stimulate insulin secretion. Knowledge of the distribution of CCK-producing enteroendocrine cells (I cells) in humans is sparse. The general notion, based on animal data, is that I cells are present mainly in the proximal small intestine. We examined the occurrence of I cells (immunohistochemically) and the expression of CCK messenger RNA (mRNA) as well as CCK1 and CCK2 receptor mRNA along the intestines in healthy individuals and patients with type 2 diabetes. METHODS: Mucosal biopsies collected with 30-cm intervals in the small intestine and from seven anatomical locations in the large intestine (using double-balloon enteroscopy) from 12 patients with type 2 diabetes and 12 gender-, age-, and body mass index-matched healthy individuals were analyzed using mRNA sequencing and immunohistochemical staining. RESULTS: We observed a gradual decrease in CCK mRNA expression and density of CCK-immunoreactive cells from duodenum to ileum. Very few CCK-immunoreactive cells and nearly undetectable CCK mRNA expression were found in the large intestine. No significant differences were seen between the groups. Expression of CCK receptors was observed in the duodenum of both groups. CONCLUSIONS: Both density of CCK cells and expression of CCK mRNA decreased through the small intestine in both groups with low levels in the large intestine. Patients with type 2 diabetes did not have altered density of CCK cells or expression of CCK mRNA in intestinal mucosa.

15.
Eur J Endocrinol ; 185(1): 33-45, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33886495

RESUMO

Objective: The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved. Design: A randomized, double-blinded, placebo-controlled, crossover study. Methods: Ten patients with overweight/obesity and type 2 diabetes (mean±s.d.; HbA1c 52 ± 11 mmol/mol; BMI 32.5 ± 4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1200 pmol/kg/min), or placebo (saline) during two separate, 230-min, standardized, liquid mixed meal tests followed by a meal ad libitum. Subcutaneous adipose tissue biopsies were analyzed. Results: Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide% ± s.e.m.; -14 ± 6%, P = 0.021) and peak glucagon (Δ% ± s.e.m.; -11 ± 6%, P = 0.046) but had no effect on plasma glucose (P = 0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX; ±s.e.m.; -4.9 ± 2 ng/mL × min, P = 0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, meal consumption ad libitum or adipose tissue triglyceride content. Conclusions: Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycaemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.


Assuntos
Glicemia/metabolismo , Reabsorção Óssea/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Secreção de Insulina/fisiologia , Obesidade/metabolismo , Triglicerídeos/metabolismo , Adulto , Idoso , Glicemia/efeitos dos fármacos , Colágeno Tipo I/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Comportamento Alimentar/efeitos dos fármacos , Polipeptídeo Inibidor Gástrico/farmacologia , Humanos , Secreção de Insulina/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/farmacologia , Peptídeos/efeitos dos fármacos , Peptídeos/metabolismo , Período Pós-Prandial , Distribuição Aleatória , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo
16.
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
17.
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
18.
Commun Biol ; 4(1): 416, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772116

RESUMO

A high fat diet and obesity have been linked to the development of metabolic dysfunction and the promotion of multiple cancers. The causative cellular signals are multifactorial and not yet completely understood. In this report, we show that Inositol Polyphosphate-4-Phosphatase Type II B (INPP4B) signaling protects mice from diet-induced metabolic dysfunction. INPP4B suppresses AKT and PKC signaling in the liver thereby improving insulin sensitivity. INPP4B loss results in the proteolytic cleavage and activation of a key regulator in de novo lipogenesis and lipid storage, SREBP1. In mice fed with the high fat diet, SREBP1 increases expression and activity of PPARG and other lipogenic pathways, leading to obesity and non-alcoholic fatty liver disease (NAFLD). Inpp4b-/- male mice have reduced energy expenditure and respiratory exchange ratio leading to increased adiposity and insulin resistance. When treated with high fat diet, Inpp4b-/- males develop type II diabetes and inflammation of adipose tissue and prostate. In turn, inflammation drives the development of high-grade prostatic intraepithelial neoplasia (PIN). Thus, INPP4B plays a crucial role in maintenance of overall metabolic health and protects from prostate neoplasms associated with metabolic dysfunction.


Assuntos
Síndrome Metabólica/terapia , Monoéster Fosfórico Hidrolases/genética , Substâncias Protetoras/farmacologia , Transdução de Sinais , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Monoéster Fosfórico Hidrolases/metabolismo , Monoéster Fosfórico Hidrolases/farmacologia
19.
Diabetes Obes Metab ; 23(7): 1666-1671, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33764641

RESUMO

Data-driven tools are needed to inform individualized treatment decisions for people with type 2 diabetes (T2D). To show how treatment might be individualized, an interactive outline tool was developed to predict treatment outcomes. Individualized predictions were generated for change in HbA1c and body weight after initiation of newer antidiabetes drugs recommended by current guidelines. These predictions were based on data from randomized controlled trials of glucose-lowering drugs. The data included patient demographics and clinical characteristics (sex, age, body mass index, weight, diabetes duration, HbA1c level, current diabetes treatment and renal function). Predicted outcomes were determined using prespecified statistical models from original trial protocols and estimated coefficients for selected baseline characteristics. This prototype illustrates how evidence-based individualized treatment might be facilitated in the clinic for people with T2D. Further and ongoing development is required to improve the tool's prognostic value, including the addition of disease co-morbidities and patient-orientated outcomes. Patient engagement and data-sharing by sponsors of clinical trials, as well as real-world evidence, are needed to provide reliable predicted outcomes to inform shared patient-physician decision-making.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobina A Glicada/análise , Humanos
20.
BMJ Open ; 11(2): e044711, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558360

RESUMO

INTRODUCTION: Bile acid malabsorption (BAM) is a socially debilitating disease characterised by high stool frequency and urgency caused by a spillover of bile acids into the colon. Bile acid sequestrants (BASs) have limited therapeutic effect but represent the only available treatment option. Cases reporting total remission of BAM-related symptoms after treatment with liraglutide, a glucagon-like peptide 1 analogue, prompted us to design a clinical trial investigating the therapeutic effect of this compound in patients with BAM. METHODS AND ANALYSIS: Fifty adult individuals with moderate or severe BAM as assessed by the 75selenium-homotaurocholic acid test (SeHCAT) will, after a run-in period of 10 days with no BAM treatment, be randomised to either treatment with the BAS colesevelam or liraglutide (double blinded) for 6 weeks. Daily symptom diaries and questionnaires will be filled in. Blood and faecal samples will be collected and SeHCAT will be performed at baseline, after week 3 and at end of trial. The primary endpoint is change in daily stool frequency. Secondary endpoints include changes from baseline in questionnaires, biochemistry, SeHCAT and faecal bile acid content and microbial composition. ETHICS AND DISSEMINATION: The study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Regional Scientific Ethics Committee of the Capital Region of Denmark and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark's good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: EudraCA: 2018-003575-34; Pre-results.


Assuntos
Ácidos e Sais Biliares , Liraglutida , Adulto , Cloridrato de Colesevelam , Método Duplo-Cego , Peptídeo 1 Semelhante ao Glucagon , Humanos , Hipolipemiantes , Liraglutida/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
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