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1.
J Lipid Res ; 65(7): 100580, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38901559

RESUMO

This study aimed to determine whether obese men with nonalcoholic fatty liver disease (NAFLD) display differences between those with simple steatosis versus steatohepatitis (NASH) in splanchnic and hepatic FFA and VLDL-triglycerides (VLDL-TG) balances. The study involved 17 obese men with biopsy-proven NAFLD (9 with NASH and 8 with simple steatosis). We used hepatic vein catheterization in combination with [3H]palmitate and [14C]VLDL-TG tracers to measure splanchnic palmitate and VLDL-TG uptake and release rates during basal and hyperinsulinemic conditions. Indocyanine green was used to measure splanchnic plasma flow. Splanchnic palmitate uptake was similar in the two groups and significantly reduced during hyperinsulinemia (NASH: 62 (48-77) versus 38 (18-58) µmol/min; simple steatosis: 62 (46-78) versus 45 (25-65) µmol/min, mean (95% CI), basal versus clamp periods, respectively, P = 0.02 time-effect). Splanchnic palmitate release was also comparable between groups and nonsignificantly diminished during hyperinsulinemia. The percent palmitate delivered to the liver originating from visceral adipose tissue lipolysis was similar and unchanged by hyperinsulinemia. Splanchnic uptake and release of VLDL-TG were similar between groups. Hyperinsulinemia suppressed VLDL-TG release (P <0.05 time-effect) in both groups. Insulin-mediated glucose disposal was similar in the two groups (P = 0.54). Obese men with NASH and simple steatosis have similar splanchnic uptake and release of FFA and VLDL-TG and a similar proportion of FFA from visceral adipose tissue lipolysis delivered to the liver. These results demonstrate that the splanchnic balances of FFA and VLDL-TG do not differ between obese men with NASH and those with simple steatosis.


Assuntos
Insulina , Lipoproteínas VLDL , Hepatopatia Gordurosa não Alcoólica , Triglicerídeos , Humanos , Masculino , Lipoproteínas VLDL/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Pessoa de Meia-Idade , Triglicerídeos/metabolismo , Triglicerídeos/sangue , Insulina/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Ácidos Graxos não Esterificados/sangue , Adulto , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado/metabolismo , Obesidade/metabolismo , Obesidade/complicações
2.
Am J Physiol Endocrinol Metab ; 326(4): E443-E453, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38324259

RESUMO

Lactate may inhibit lipolysis and thus enhance insulin sensitivity, but there is a lack of metabolic human studies. This study aimed to determine how hyperlactatemia affects lipolysis, glucose- and protein metabolism, and insulin sensitivity in healthy men. In a single-blind, randomized, crossover design, eight healthy men were studied after an overnight fast on two occasions: 1) during a sodium-lactate infusion (LAC) and 2) during a sodium-matched NaCl infusion (CTR). Both days consisted of a 3-h postabsorptive period followed by a 3-h hyperinsulinemic-euglycemic clamp (HEC). Lipolysis rate, endogenous glucose production (EGP), and delta glucose rate of disappearance (ΔRdglu) were evaluated using [9,10-3H]palmitate and [3-3H]glucose tracers. In addition, whole body- and forearm protein metabolism was assessed using [15N]phenylalanine, [2H4]tyrosine, [15N]tyrosine, and [13C]urea tracers. In the postabsorptive period, plasma lactate increased to 2.7 ± 0.5 mmol/L during LAC vs. 0.6 ± 0.3 mmol/L during CTR (P < 0.001). In the postabsorptive period, palmitate flux was 30% lower during LAC compared with CTR (84 ± 32 µmol/min vs. 120 ± 35 µmol/min, P = 0.003). During the HEC, palmitate flux was suppressed similarly during both interventions (P = 0.7). EGP, ΔRdglu, and M value were similar during LAC and CTR. During HEC, LAC increased whole body phenylalanine flux (P = 0.02) and protein synthesis (P = 0.03) compared with CTR; LAC did not affect forearm protein metabolism compared with CTR. Lactate infusion inhibited lipolysis by 30% under postabsorptive conditions but did not affect glucose metabolism or improve insulin sensitivity. In addition, whole body phenylalanine flux was increased. Clinical trial registrations: NCT04710875.NEW & NOTEWORTHY Lactate is a decisive intermediary metabolite, serving as an energy substrate and a signaling molecule. The present study examines the effects of lactate on substrate metabolism and insulin sensitivity in healthy males. Hyperlactatemia reduces lipolysis by 30% without affecting insulin sensitivity and glucose metabolism. In addition, hyperlactatemia increases whole body amino acid turnover rate.


Assuntos
Hiperlactatemia , Resistência à Insulina , Humanos , Masculino , Glicemia/metabolismo , Estudos Cross-Over , Glucose/metabolismo , Técnica Clamp de Glucose , Insulina , Ácido Láctico/farmacologia , Palmitatos , Fenilalanina , Proteínas , Método Simples-Cego , Sódio , Tirosina
3.
Int J Mol Sci ; 25(16)2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39201693

RESUMO

In adipose tissue, reduced expression of the glycerol channel aquaporin 7 (AQP7) has been associated with increased accumulation of triglyceride. The present study determines the relative protein abundances of lipolytic enzymes, AQP7, and cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) in paired mesenteric and omental visceral adipose tissue (VAT) and abdominal and femoral subcutaneous adipose tissue (SAT) in women with either normal weight or upper-body obesity. No differences in the expression of hormone-sensitive lipase (HSL) or AQP7 were found between the two groups in the four depots. The expression of adipocyte triglyceride lipase (ATGL) and HSL were higher in omental VAT and femoral SAT than in mesenteric VAT in both groups of women. Similarly, AQP7 expression was higher in omental VAT than in mesenteric VAT. The expression of PEPCK-C was lower in omental VAT than in femoral SAT. No correlation between the expression of AQP7 and the mean adipocyte size was observed; however, the expression of PEPCK-C positively correlated with the mean adipocyte size. In conclusion, a depot-specific protein expression pattern was found for ATGL, HSL, AQP7, and PEPCK-C. The expression pattern supports that the regulation of AQP7 protein expression is at least in part linked to the lipolytic rate. Furthermore, the results support that the synthesis of glycerol-3-phosphate via glyceroneogenesis contributes to regulating triglyceride accumulation in white adipose tissue in women.


Assuntos
Aquaporinas , Glicerol , Gordura Intra-Abdominal , Obesidade , Gordura Subcutânea , Humanos , Feminino , Gordura Subcutânea/metabolismo , Aquaporinas/metabolismo , Aquaporinas/genética , Glicerol/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Adulto , Pessoa de Meia-Idade , Lipólise , Esterol Esterase/metabolismo , Esterol Esterase/genética , Lipase/metabolismo , Lipase/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Adipócitos/metabolismo , Triglicerídeos/metabolismo , Aciltransferases
4.
Diabet Med ; 40(8): e15157, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37249579

RESUMO

AIMS: The aim of our meta-analyses was to compare the effects of glucose-lowering drugs on mortality, cardiovascular and renal endpoints for a range of type 2 diabetes (T2D) subgroups defined by their specific cardiovascular risk profile. METHODS: Meta-analyses comparing drugs within the classes of GLP-1RAs and SGLT-2 inhibitors were performed and compared to sulphonylureas and DPP-4 inhibitors with available cardiovascular outcome trials. The comparison between the different classes of glucose-lowering drugs included analyses of T2D populations with low risk and high risk for cardiovascular disease including populations with established cardiovascular disease and/or kidney disease. Outcomes included mortality, major cardiovascular adverse events (MACE), hospitalisation for heart failure (HHF) and a composite renal endpoint as applied in the underlying clinical trials. RESULTS: SGLT-2 inhibitors and GLP-1RAs showed beneficial effects on mortality and MACE compared to the classes of DPP-4 inhibitors and sulphonylureas. SGLT-2 inhibitors were shown to be the most effective treatment in terms of HHF and kidney disease. Metformin was used as background therapy for the vast majority of participants in all included studies. Overall, the absolute effects of SGLT-2 inhibitors and GLP-1RAs on these important outcomes were evident for patients with established or at high risk for cardiovascular disease but limited for the low-risk subgroup. CONCLUSIONS: The findings from our analyses substantiate the relevance of treatment with SGLT-2 inhibitors or GLP-1RAs as an add-on to metformin in patients with T2D and a high risk for cardiovascular disease, and furthermore, support the recommendation for SGLT-2 inhibitor treatment in patients with T2D and heart failure or established kidney disease.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Insuficiência Cardíaca , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucose , Insuficiência Cardíaca/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Metanálise em Rede , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico
5.
Histochem Cell Biol ; 157(6): 623-639, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35235046

RESUMO

The glycerol channel AQP7 facilitates glycerol efflux from adipose tissue (AT), and AQP7 deficiency has been suggested to promote obesity. However, the release of glycerol from AT is not fully blocked in AQP7-deficient mice, which suggests that either alternative glycerol channels are present in AT or significant simple diffusion of glycerol occurs. Previous investigations of the expression of other aquaglyceroporins (AQP3, AQP9, AQP10) than AQP7 in AT are contradictory. Therefore, we here aim at determining the cellular localization of AQP3 and AQP9 in addition to AQP7 in human and mouse AT using well-characterized antibodies for immunohistochemistry (IHC) and immunoblotting as well as available single-cell transcriptomic data from human and mouse AT. We confirm that AQP7 is expressed in endothelial cells and adipocytes in human AT and find ex vivo evidence for interaction between AQP7 and perilipin-1 in adipocytes. In addition, labeling for AQP7 in human AT also includes CD68-positive cells. No labeling for AQP3 or AQP9 was identified in endothelial cells or adipocytes in human or mouse AT using IHC. Instead, in human AT, AQP3 was predominantly found in erythrocytes, whereas AQP9 expression was observed in a small number of CD15-positive cells. The transcriptomic data revealed that AQP3 mRNA was found in a low number of cells in most of the identified cell clusters, whereas AQP9 mRNA was found in myeloid cell clusters as well as in clusters likely representing mesothelial progenitor cells. No AQP10 mRNA was identified in human AT. In conclusion, the presented results do not suggest a functional overlap between AQP3/AQP9/AQP10 and AQP7 in human or mouse white AT.


Assuntos
Aquagliceroporinas , Aquaporinas , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Aquagliceroporinas/genética , Aquagliceroporinas/metabolismo , Aquaporinas/metabolismo , Células Endoteliais/metabolismo , Glicerol/metabolismo , Humanos , Camundongos , RNA Mensageiro/metabolismo
6.
Scand J Clin Lab Invest ; 82(1): 6-11, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34859720

RESUMO

Biotin is increasingly used as dietary supplement. As many immunoassays rely on a binding between biotin and streptavidin, intake of biotin may interfere with laboratory tests, leading to spurious test results. We examined the extent to which levels of aldosterone, renin, insulin-like growth factor 1 (IGF-1), growth hormone (GH) and bone alkaline phosphatase (BAP) were affected by biotin. In an experimental study performed at Aarhus University Hospital, Denmark, patient samples (plasma or serum) were pooled and spiked with biotin in increasing concentrations (0, 20, 50, 100 and 500 ng/mL). All biomarkers were analyzed using Immunodiagnostic Systems (IDS-iSYS) Multi-Discipline Automated System assays. The average bias (%) was calculated, as the difference in concentrations between the sample without biotin (reference) and the samples with increasing concentrations of biotin. Both aldosterone and renin assays showed substantial biotin interference in a dose-dependent manner, with biases up to +3484% for aldosterone and -98% for renin in the highest concentrations of biotin (100-500 ng/mL). IGF-1, GH and BAP results were generally less affected by added biotin and significant bias (>10%) was observed only when the biotin concentration was 100 ng/mL (IGF-1 and GH) or 500 ng/mL (BAP). In conclusion, biotin interfered with the IDS-iSYS immunoassays, particularly for aldosterone and renin. The assays for GH, IGF-1 and BAP were less sensitive and only with high concentrations of biotin.


Assuntos
Hormônio do Crescimento , Fator de Crescimento Insulin-Like I , Aldosterona , Fosfatase Alcalina , Biotina , Humanos , Imunoensaio/métodos , Fator de Crescimento Insulin-Like I/metabolismo , Renina
7.
Diabetologia ; 62(7): 1251-1256, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30976851

RESUMO

AIMS/HYPOTHESIS: Metformin is the endorsed first-line glucose-lowering drug for treating patients with type 2 diabetes but despite more than 50 years of use, no consensus has been reached on its mechanisms of action. In this study, we investigated the glucose-lowering effects of metformin in individuals with type 2 diabetes and non-diabetic individuals. METHODS: We performed a randomised, placebo-controlled trial in 24 individuals with recent-onset type 2 diabetes (diabetes duration 50 [48] months) who had good glycaemic control (HbA1c 48 mmol/mmol [6.5%]). The studies were conducted at Aarhus University Hospital between 2013 and 2016. Participants were randomised to receive either metformin (2000 mg/day, n = 12, MET group) or placebo (n = 12, PLA group) for 90 days, using block randomisation set up by an unblinded pharmacist. Two participants withdrew from the study prior to completion and were replaced with two new participants receiving the same treatment. In addition, we recruited a group of non-diabetic individuals with similar age and BMI (n = 12, CONT group), who were all treated with 2000 mg metformin daily. Before and after treatment all individuals underwent studies of whole-body glucose metabolism by non-steady-state [3-3H]glucose kinetics, hyperinsulinaemic-euglycaemic clamping, indirect calorimetry, metabolomics, dual x-ray absorptiometry and muscle biopsies. The primary study endpoint was the effect of metformin treatment on lipid kinetics as well as glucose rate of disappearance (Rd) and endogenous glucose production (EGP). RESULTS: One participant from the CONT group withdrew due to intolerable gastrointestinal side-effects and was excluded from analysis. As expected, metformin treatment lowered fasting plasma glucose (FPG) in the MET group (~1.5 mmol/l, p < 0.01), whereas no effect was observed in the PLA and CONT groups. Body weight and composition did not change in any of the groups. In both of the metformin-treated groups (MET and CONT), basal glucose Rd, EGP and glucagon levels increased by ~30% (p < 0.05) whereas this was not the case in the PLA group. CONCLUSIONS/INTERPRETATION: Ninety days of metformin treatment resulted in similar increases in EGP and glucose Rd in individuals with recent-onset type 2 diabetes and in non-diabetic control individuals. These results challenge the existing paradigm that metformin primarily acts in the liver by inhibiting EGP, at least in individuals with type 2 diabetes of short duration and who have discretely affected glycaemic status. Whether metformin increases basal glucose Rd by facilitating glucose uptake in other tissues such as the intestines remains to be further clarified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01729156 FUNDING: This study was supported by grants from The Danish Council for Independent Research | Medical Sciences, Aase Danielsen Fund, the Novo Nordisk Foundation, the Danish Diabetes Association and the Danish Diabetes Academy supported by the Novo Nordisk Foundation.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Humanos , Efeito Placebo
8.
Curr Opin Lipidol ; 29(1): 42-47, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29135689

RESUMO

PURPOSE OF REVIEW: Insulin resistance is closely linked to accumulation of lipid outside adipose tissue (ectopic fat storage). VLDL particles transport lipids from the liver to peripheral tissues. However, whether abnormalities in VLDL-triglyceride storage in muscle and adipose tissue exist in type 2 diabetes has previously been unknown, primarily because of methodological difficulties. Here, we review recent research on VLDL-triglyceride storage. RECENT FINDINGS: In a recent study, men with type 2 diabetes had increased skeletal muscle VLDL-triglyceride storage compared to weight-matched nondiabetic men, potentially leading to intramyocellular triglyceride accumulation. In contrast, studies of adipose tissue VLDL-triglyceride storage have shown similar storage capacity in men with and without diabetes, both in the postabsorptive and the postprandial period. In the initial submission, studies have failed to show associations between lipoprotein lipase activity, considered the rate-limiting step in storage of lipids from lipoproteins, and VLDL-TG storage in both muscle and adipose tissue. SUMMARY: Differences in muscle VLDL-triglyceride storage may lead to ectopic fat storage and contribute to the development of type 2 diabetes, whereas the ability to store VLDL-triglyceride in adipose tissue is preserved in type 2 diabetes.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Lipoproteínas VLDL/metabolismo , Músculo Esquelético/metabolismo , Triglicerídeos/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos
9.
Am J Physiol Endocrinol Metab ; 315(3): E367-E373, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29783856

RESUMO

Aquaglyceroporin 7 (AQP7) facilitates the transport of glycerol across cell membranes. In mice, fasting and refeeding regulate adipose tissue AQP7 abundance, and a role in controlling triglyceride accumulation in adipose tissue has been proposed. AQP7 is also expressed in skeletal muscle, where its function remains to be determined. Here, the abundance of AQP7 in abdominal subcutaneous adipose tissue (SAT) and skeletal muscle was evaluated in the overnight fasted and postprandial state in eight lean and eight obese men with type 2 diabetes (T2D). A biopsy from SAT and muscle was collected after an overnight fast and 2 h after ingestion of a low-fat test meal. Palmitate turnover was evaluated using a [9,10-3H] palmitate dilution technique. Tissue samples were analyzed by immunoblotting. Meal intake did not affect AQP7 expression in SAT or skeletal muscle. No association between the SAT AQP7 abundance and palmitate turnover was found. SAT AQP7 abundance was similar in lean and obese T2D men, whereas muscle AQP7 abundance was more than fourfold higher in obese T2D men. In conclusion, meal intake did not affect AQP7 protein abundance in SAT or skeletal muscle. In addition, SAT AQP7 expression does not appear to be involved in the regulation of adipose tissue lipolysis. However, in contrast to SAT AQP7, skeletal muscle AQP7 protein abundance is markedly increased in obese T2D men, potentially contributing to the excess lipid accumulation in skeletal muscle in type 2 diabetes.


Assuntos
Aquaporinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Adulto , Ingestão de Alimentos , Humanos , Lipólise , Masculino , Pessoa de Meia-Idade , Palmitatos/metabolismo , Gordura Subcutânea/metabolismo , Adulto Jovem
10.
Diabetes Obes Metab ; 20(2): 419-426, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28817248

RESUMO

AIMS: To test the hypothesis that, as well as lowering weight and increasing plasma triglyceride (TG) levels and hepatic fat compared with insulin glargine (GL) in patients with type 1 diabetes, the attenuated peripheral effects of basal insulin peglispro (BIL) may include increased free fatty acid flux to the liver, causing increased very-low-density lipoprotein (VLDL)-TG secretion and lipid oxidation, and decreased TG adipose tissue deposition. METHODS: In this open-label, randomized, 2-period crossover study, 14 patients with type 1 diabetes received once-daily, individualized, stable BIL or GL doses for 3 weeks. Palmitate flux was assessed using [9,10-3 H]palmitate infusion. VLDL-TG secretion, clearance and oxidation rate were assessed using primed-constant infusion of ex vivo labelled [1-14 C]VLDL-TG, while VLDL-TG storage rate was assessed using [9,10-3 H]VLDL-TG bolus injection. RESULTS: The VLDL-TG concentration and secretion rate, and palmitate flux were statistically significantly higher during BIL than during GL treatment (58%, 51% and 35%, respectively). The ratios of least squares (LS) geometric means for VLDL-TG clearance and oxidation were 0.92 (95% confidence interval [CI] 0.72, 1.17) and 1.31 (95% CI 0.91, 1.90), respectively. The difference in LS means for VLDL-TG storage rate was -0.36 (95% CI -0.83, 0.12). CONCLUSIONS: BIL-treated patients had higher effective lipolysis, VLDL-TG secretion and VLDL-TG concentration compared with GL-treated patients, explaining the increased plasma TG concentrations reported previously. Data support attenuated effects of BIL on lipolysis, in addition to the recently described hepato-preferential glucodynamic effects.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêutico , Insulina Lispro/análogos & derivados , Lipólise/efeitos dos fármacos , Lipoproteínas VLDL/sangue , Polietilenoglicóis/uso terapêutico , Triglicerídeos/sangue , Adulto , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Hiperglicemia/prevenção & controle , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Injeções Subcutâneas , Insulina/administração & dosagem , Insulina/efeitos adversos , Insulina/uso terapêutico , Insulina Glargina/administração & dosagem , Insulina Glargina/efeitos adversos , Insulina Lispro/administração & dosagem , Insulina Lispro/efeitos adversos , Insulina Lispro/uso terapêutico , Lipoproteínas VLDL/metabolismo , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Triglicerídeos/metabolismo , Adulto Jovem
11.
Diabetes Obes Metab ; 20(6): 1435-1444, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29405635

RESUMO

AIMS: To explore whether the pre-clinical findings that metformin improves lipid metabolism, possibly through modulation of intrahepatic partitioning of fatty acids towards oxidation and away from re-esterification and resecretion as triglycerides (TGs), can be translated to a human setting. MATERIALS AND METHODS: We performed a 3-month randomized, placebo-controlled, parallel-group clinical trial in patients with type 2 diabetes (T2D; n = 24) and healthy controls (n = 12). Patients with T2D received either placebo (placebo group) or 1000 mg metformin twice daily (metformin group), while healthy subjects were all treated with metformin (control group). Hepatic fatty acid metabolism was measured by [11 C]palmitate positron-emission tomography, hepatic TG secretion and peripheral oxidation by ex vivo labelled [1-14 C]VLDL-TG and VLDL particle size by TG/apolipoprotein B ratio. Body composition was assessed by dual-energy X-ray and whole-body lipid oxidation by indirect calorimetry. RESULTS: Metformin treatment for 3 months produced the anticipated decrease in fasting plasma glucose (FPG) in the metformin group (FPG 7.9 ± 1.8 mM [study day 1] vs 6.4 ± 1.1 mM [study day 2]), whereas patients in the placebo group and healthy controls had similar FPG levels before and after the trial (mixed model group vs time interaction; P = .003); however, contrary to our hypothesis, metformin treatment did not affect hepatic lipid metabolism or peripheral oxidation. CONCLUSION: The observed beneficial effects on lipid metabolism during metformin treatment in humans appear to be secondary to long-term alterations in body composition or glucose homeostasis.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Idoso , Glicemia/metabolismo , Composição Corporal/fisiologia , Diabetes Mellitus Tipo 2/sangue , Esquema de Medicação , Ácidos Graxos não Esterificados/metabolismo , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/metabolismo , Lipoproteínas VLDL/metabolismo , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Oxirredução/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Triglicerídeos/metabolismo
12.
Horm Metab Res ; 49(8): 604-611, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28561184

RESUMO

The aim of this study was to assess the impact of dietary control on VLDL1- and VLDL2-TG kinetics and associated metabolic parameters. Twelve overweight/obese men were randomized to a provided 3 day isocaloric diet with fixed macronutrient composition (diet group, n=6) or to their regular unrestricted diet (non-diet group, n=6). VLDL1- and VLDL2-TG turnovers were measured twice 2-4 weeks apart, using primed-constant infusion of ex vivo labeled [1-14C]VLDL1-TG and [9,10-3H]VLDL2-TG. Isocaloric diet intervention lowered the difference in the mean of both VLDL2-TG secretion and clearance rate (p<0.01), and the coefficient of variation (CV) of VLDL2-TG clearance rate (p<0.05). The difference in mean and CV of the other kinetic estimates (VLDL1-TG secretion, clearance and oxidation rate) were lowered, but not significantly. The CV's of total triglyceride, VLDL1-TG, and VLDL2-TG concentrations were significantly lowered by diet intervention compared to regular diet; total triglyceride (31%-5%, p<0.01), VLDL1-TG (42%-9%, p<0.01), and VLDL2-TG (36%-10%, p<0.01). In conclusion, VLDL1- and VLDL2-TG kinetics show great day-to-day variability, which may be diminished by diet intervention. Therefore, standardized macronutrient intake prior to study days improves the probability of demonstrating significant outcomes of cross-sectional and intervention studies of VLDL1-TG and VLDL2-TG kinetics and metabolism.


Assuntos
Dieta , Lipoproteínas VLDL/sangue , Triglicerídeos/sangue , Adulto , Idoso , Estudos Transversais , Humanos , Cinética , Masculino , Pessoa de Meia-Idade
13.
Diabetologia ; 59(4): 833-43, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26781548

RESUMO

AIMS/HYPOTHESIS: Hypertriacylglycerolaemia is a hallmark of diabetic dyslipidaemia with increased concentrations of triacylglycerol (TG)-rich VLDL1 particles. However, whether VLDL1 secretion or removal is abnormal in type 2 diabetes remains unclear. The aim of this study was to compare basal and insulin-mediated VLDL1- and VLDL2-TG kinetics in men with type 2 diabetes and healthy men using a novel direct VLDL1- and VLDL2-TG labelling method. METHODS: Twelve men with type 2 diabetes and 12 healthy men matched for age and BMI were recruited. VLDL1- and VLDL2-TG turnover were measured during a 4 h basal period and a 3.5 h hyperinsulinaemic clamp period using a primed-constant infusion of ex vivo labelled VLDL1-TG and VLDL2-TG. RESULTS: Basal VLDL1-TG and VLDL2-TG secretion rates were similar in men with diabetes and healthy men. During hyperinsulinaemia, VLDL1-TG secretion rates were suppressed significantly in both groups, whereas no suppression of VLDL2-TG secretion rate was observed. VLDL1-TG to VLDL2-TG transfer rate was not significantly different from zero in both groups, while VLDL1-TG fatty acid oxidation rate was substantial, with a contribution to total energy expenditure of approximately 15% during postabsorptive conditions. VLDL1 and VLDL2 particle size (TG/apolipoprotein B [apoB] ratio) and apoB-100 concentration were unaltered by hyperinsulinaemia in men with type 2 diabetes, but significantly reduced in healthy men. CONCLUSIONS/INTERPRETATION: Insulin inhibits VLDL1-TG secretion rate similarly in age- and BMI-matched men with type 2 diabetes and healthy men, while VLDL2-TG secretion is unaltered by hyperinsulinaemia. However, VLDL1- and VLDL2-apoB levels are not lowered by hyperinsulinaemia in men with type 2 diabetes, which is indicative of a diminished hepatic response to insulin. TRIAL REGISTRATION: ClinicalTrials.gov NCT01564550.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Lipoproteínas VLDL/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Humanos , Insulina , Resistência à Insulina , Cinética , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade
14.
Transpl Int ; 29(4): 483-93, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26749337

RESUMO

Post-transplant lymphoproliferative disorder (PTLD) incidence is difficult to determine, mainly because both early and other lesions may go unrecognized and unregistered. Few studies have included systematic pathology review to maximize case identification and decide more accurately PTLD frequency after long-term post-transplantation follow-up. A retrospective population-based cohort study including all kidney transplant recipients at two Danish centres (1990-2011; population covered 3.1 million; 2175 transplantations in 1906 patients). Pathology reports were reviewed for all patient biopsies to identify possible PTLDs. Candidate PTLDs underwent histopathological review and classification. Seventy PTLD cases were identified in 2175 transplantations (3.2%). The incidence rate (IR) after first transplantation was 5.4 cases per 1000 patient-years (95% CI: 4.0-7.3). Most PTLDs were monomorphic (58.5%), or early lesions (21.5%). Excluding early lesions and patients <18 years, IR was 3.7 (95% CI: 2.9-5.5). Ten patients with PTLD were retransplanted, 2 developing further PTLDs. Post-transplant patient survival was inferior in patients with PTLD, while death-censored graft survival was not. Using registry data together with extensive pathological review and long follow-up, a rather high incidence of PTLD was found.


Assuntos
Transplante de Rim/efeitos adversos , Transtornos Linfoproliferativos/diagnóstico , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Dinamarca , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Incidência , Lactente , Estimativa de Kaplan-Meier , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/epidemiologia , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Reoperação , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
15.
Diabetologia ; 58(2): 355-62, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25385409

RESUMO

AIMS/HYPOTHESIS: In type 1 diabetes, abnormalities of both glucose and lipoprotein metabolism are seen. The relationship between these factors is not understood, but studies indicate that hyperglycaemia may increase hepatic VLDL-triacylglycerol (VLDL-TG) secretion and reduce VLDL-TG fatty acid oxidation, which could lead to the development of dyslipidaemia. The aim of this study was to determine the isolated effect of hyperglycaemia on VLDL-TG and NEFA kinetics in men with type 1 diabetes. METHODS: VLDL-TG and palmitate kinetics were measured in eight men with type 1 diabetes using ex vivo labelled VLDL-TG and palmitate tracers. A 2.5 h basal period (plasma glucose 5 mmol/l) was followed by a 4 h hyperglycaemic period (plasma glucose 16 mmol/l). Steady-state VLDL-TG kinetics (VLDL-TG secretion, clearance and oxidation rates) were assessed by an isotope dilution technique using an intravenous primed-constant infusion of ex vivo labelled [1-(14)C]VLDL-TG in combination with sampling of blood and expired air. Palmitate turnover was measured using [9,10-(3)H]palmitate. RESULTS: The VLDL-TG secretion rate (36.0 ± 9.6 vs 30.8 ± 6.1 µmol/min, NS) and clearance rate (209 ± 30.4 vs 197 ± 41.7 ml/min, NS) were unchanged during the basal and hyperglycaemic periods, resulting in unchanged VLDL-TG concentrations (0.25 ± 0.11 µmol/l vs 0.28 ± 0.10 µmol/l, NS). In addition, VLDL-TG fatty acid oxidation and palmitate flux were not changed during hyperglycaemia. CONCLUSIONS/INTERPRETATION: Four hours of acute hyperglycaemia (16 mmol/l) without a concomitant increase in insulin does not alter VLDL-TG and NEFA kinetics in men with type 1 diabetes. CLINICAL TRIAL REGISTRY NUMBER: NCT01178957.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Dislipidemias/sangue , Hiperglicemia/sangue , Insulina/metabolismo , Lipoproteínas VLDL/sangue , Triglicerídeos/sangue , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Técnica Clamp de Glucose , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Lipoproteínas VLDL/metabolismo , Masculino , Pessoa de Meia-Idade , Palmitatos/metabolismo , Triglicerídeos/metabolismo
16.
Am J Physiol Endocrinol Metab ; 307(2): E199-208, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24895285

RESUMO

Overweight is associated with abnormalities of lipid metabolism, many of which are reversed by exercise. We investigated the impact of experimental antilipolysis and acute exercise on lipid kinetics and oxidation from VLDL-TG, plasma FFA, and "residual lipids" in overweight men (n = 8) using VLDL-TG and palmitate tracers in combination with muscle biopsies in a randomized, placebo-controlled design. Participants received placebo or acipimox on each study day (4 h of rest, 90 min of exercise at 50% V(O(2 max))). Exercise suppressed VLDL-TG secretion significantly during placebo but not acipimox (placebo-rest: 64.2 ± 9.4; placebo-exercise: 48.3 ± 8.0; acipimox-rest: 55.2 ± 13.4; acipimox-exercise: 52.0 ± 10.9). Resting oxidation of VLDL-TG FA and FFA was significantly reduced during acipimox compared with placebo, whereas "residual lipid oxidation" increased significantly [VLDL-TG oxidation (placebo: 18 ± 3 kcal/h; acipimox: 11 ± 2 kcal/h), FFA oxidation (placebo: 14 ± 2 kcal/h; acipimox: 4 ± 0.5 kcal/h), and residual lipid oxidation (placebo: 3 ± 5 kcal/h; acipimox: 14 ± 5 kcal/h)]. Additionally, during exercise on both placebo and acipimox, oxidation of VLDL-TG and FFA increased, but the relative contribution to total lipid oxidation diminished, except for FFA, which remained unchanged during acipimox. Residual lipid oxidation increased significantly during exercise in both absolute and relative terms. Changes in selected cellular enzymes and proteins provided no explanations for kinetic changes. In conclusion, suppressed FFA availability blunts the effect of exercise on VLDL-TG secretion and modifies the contribution of lipid sources for oxidation.


Assuntos
Exercício Físico/fisiologia , Hipolipemiantes/administração & dosagem , Lipólise/fisiologia , Sobrepeso/metabolismo , Pirazinas/administração & dosagem , Adulto , Humanos , Lipólise/efeitos dos fármacos , Lipoproteínas VLDL/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ácido Palmítico/metabolismo , Triglicerídeos/metabolismo , Adulto Jovem
17.
Can J Diabetes ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38969062

RESUMO

OBJECTIVES: Exercise is a recommended component of type 1 diabetes (T1D) treatment because high physical activity levels improve health outcomes. However, many people with T1D do not meet physical activity recommendations. Our aim in this study was to identify factors influencing physical activity levels in people with T1D. METHODS: This questionnaire-based study included adults with T1D from 1 outpatient clinic in the United Kingdom and 2 clinics in Denmark. Exercise characteristics, motivators, and barriers were assessed. Physical activity level was measured using the Saltin-Grimby Physical Activity Level Scale. Respondents were categorized into 3 activity groups: inactive, light active, and moderate-to-vigourous active. RESULTS: Of the 332 respondents, 8.4% rated themselves as inactive, 48% as light active, and 43% as moderate-to-vigourous active. Seventy-eight percent of inactive and light active repondents expressed a desire to become more physically active. Fifty-three percent of respondents had received guidance concerning exercise/physical activity from their diabetes team. Being male and having received guidance were associated with a higher physical activity level. The major motivators for exercising/being physically active were improved mental and physical health and glycemic control, whereas the most frequent barriers were busyness with work/private life and lack of motivation. Worries about glucose excursions, costs, lack of knowledge, and health-related reasons were more prevalent barriers in the least active groups. CONCLUSIONS: This study demonstrated that 78% of inactive and light active respondents reported wishing to become more physically active. Receiving guidance about exercise/physical activity was associated with a higher physical activity level, but only 53% of respondents had received support from their diabetes team.

18.
J Nutr Metab ; 2024: 9301369, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39139216

RESUMO

Background: Beta-hydroxybuturate (ß-OHB) supplements are commonly utilized in sports by both recreational and professional athletes. In a recent study, we observed a drop in testosterone levels following the oral ingestion of racemic sodium-ß-OHB. In this investigation, we aim to determine whether a single oral dose of ketone ester (study I) and prolonged endogenous ketosis (study II) also reduces testosterone levels. Design: This investigation integrated samples from two distinct studies. Study I was a randomized, controlled, crossover trial with ten healthy, young male participants receiving either a weight-adjusted ketone ester or control (water, CTR) and vice versa following an overnight fast. Repeated blood sampling was used to monitor plasma ß-OHB and testosterone levels. Study II, another randomized, controlled, crossover trial, included 11 middle-aged participants (five males). They followed either a ketogenic diet (KD) characterized by low carbohydrates and high fat content or a standard diet (SDD) for three weeks. After each study period, participants underwent examination following an overnight fast, with repeated measures employed to analyze concentrations of plasma ß-OHB and sex hormone levels. Results: Study I: Testosterone decreased from 23.8 ± 2.4 nmol/l to 22.3 ± 2.5 nmol/l 300 minutes after the ketone ester and increased from 20.9 ± 2.1 nmol/l to 22.2 ± 1.9 300 minutes after CTR. This difference was not significant, p = 0.06. Study II. Total testosterone was unaffected after the KD compared to the SDD in men (20.2 ± 1.23 nmol/l vs. 18.2 ± 1.23 nmol/l (p = 0.1)) and was lower after KD in women (0.87 ± 0.06 vs. 1.1 ± 0.06 nmol/l (p < 0.0001)). Sex hormone-binding globulin (SHBG) increased in men after KD compared with SDD (31.2 ± 2.6 nmol/l vs 25.0 ± 2.6 nmol/l, p < 0.0001) and women (26.5 ± 3.05 nmol/l vs 24.2 ± 3.05 nmol/l, p = 0.003). The free androgen index decreased after KD in men (ratio: 0.65 ± 0.05 vs. ratio: 0.74 ± 0.05, p = 0.04) and in women (ratio: 0.036 ± 0.006 vs. SDD 0.05 ± 0.006, p = 0.0001). Free estradiol index was also found lower after KD in men (ratio: 3.1 ± 0.8 vs. ratio: 4.8 ± 0.8, p = 0.0003) and in women (ratio: 1.2 ± 2.2 vs. 9.8 ± 2.2, p = 0.0001). Conclusion: Our findings indicate that the acute ingestion of ketone ester may not reduce testosterone levels in healthy young males. However, a three-week exposure to KB from a KD results in an increase in SHBG in men and women with obesity as well as it lowers free testosterone and estradiol for men and women. We thus present evidence of crosstalk between alterations in a metabolite, ß-OHB, and the regulation of the hypothalamic-pituitary-gonadal axis from a KD. The clinical impact of this reduction remains to be investigated. This trial is registered with NCT04156477 and NCT05012748.

19.
Diabetes ; 73(10): 1631-1640, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39052652

RESUMO

A ketogenic diet (KD) can induce weight loss and improve glycemic regulation, potentially reducing the risk of type 2 diabetes development. To elucidate the underlying mechanisms behind these beneficial effects of a KD, we investigated the impact of a KD on organ-specific insulin sensitivity (IS) in skeletal muscle, liver, and adipose tissue. We hypothesized that a KD would increase IS in skeletal muscle. The study included 11 individuals with obesity who underwent a randomized, crossover trial with two 3-week interventions: 1) a KD and 2) a standard diet. Skeletal muscle IS was quantified as the increase in glucose disposal during a hyperinsulinemic-euglycemic clamp (HEC). Hepatic IS and adipose tissue IS were quantified as the relative suppression of endogenous glucose production (EGP) and the relative suppression of palmitate flux during the HEC. The KD led to a 2.2-kg weight loss and increased insulin-stimulated glucose disposal, whereas the relative suppression of EGP during the HEC was similar. In addition, the KD decreased insulin-mediated suppression of lipolysis. In conclusion, a KD increased skeletal muscle IS in individuals with obesity.


Assuntos
Estudos Cross-Over , Dieta Cetogênica , Técnica Clamp de Glucose , Resistência à Insulina , Músculo Esquelético , Obesidade , Humanos , Obesidade/metabolismo , Obesidade/dietoterapia , Músculo Esquelético/metabolismo , Resistência à Insulina/fisiologia , Masculino , Adulto , Feminino , Tecido Adiposo/metabolismo , Pessoa de Meia-Idade , Fígado/metabolismo , Insulina/metabolismo , Insulina/sangue , Glicemia/metabolismo
20.
Can J Diabetes ; 48(3): 204-210.e1, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38218396

RESUMO

OBJECTIVES: Physical activity is associated with improved health in people with type 1 diabetes. However, physical activity level may be associated with socioeconomic status. The primary aim of this study was to investigate the association between education level and physical activity level among people with type 1 diabetes. METHODS: In this cross-sectional study, data on physical activity level (high or low) was measured using the Saltin-Grimby Physical Activity Level Scale, and education level (low, medium, or high) was self-reported. RESULTS: Respondents were recruited from outpatient clinics (Steno Diabetes Centre Aarhus, Denmark; Nordsjællands Hospital, Denmark; or Sheffield Diabetes and Endocrine Centre, United Kingdom), by health-care personnel from September 2019 to July 2021. A total of 324 people with type 1 diabetes were included (54% male, median age 50 years [interquartile range 30-60 years]). Education level was low in 10%, medium in 33%, and high in 57%. A logistic regression analysis, adjusted for age, sex, cohabitation status and nationality, found that a medium vs. high education level was associated with lower odds of a high physical activity level (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.32-0.94, p=0.029), while no association was found for low vs. high education level with high physical activity level (OR 0.56, 95% CI 0.25-1.29, p=0.173). CONCLUSIONS: Medium education level compared with a high education level was associated with a lower level of physical activity in people with type 1 diabetes. Health-care professionals are advised to be attentive of physical activity levels among people with type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1 , Escolaridade , Exercício Físico , Humanos , Diabetes Mellitus Tipo 1/epidemiologia , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Dinamarca/epidemiologia , Inglaterra/epidemiologia
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