The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been ...proposed to contribute to the pathology of type 2 diabetes. However, few treatment options exist that directly target ectopic lipid accumulation. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Here we show that decreased VEGF-B signalling in rodent models of type 2 diabetes restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic lipid deposition, increased muscle glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved β-cell function and ameliorated dyslipidaemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGF-B neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipid-transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
42.
Endocrine aspects of obesity Proietto, Joseph
Molecular and cellular endocrinology,
03/2010, Letnik:
316, Številka:
2
Journal Article
Scalable knee osteoarthritis programs are needed to deliver recommended education, exercise, and weight loss interventions.
To evaluate two 6-month, telehealth-delivered exercise programs, 1 with and ...1 without dietary intervention.
3-group, parallel randomized (5:5:2) trial. (Australian New Zealand Clinical Trials Registry: ACTRN12618000930280).
Australian private health insurance members.
415 persons with symptomatic knee osteoarthritis and a body mass index between 28 and 40 kg/m
who were aged 45 to 80 years.
All groups received access to electronic osteoarthritis information (control). The exercise program comprised 6 physiotherapist consultations via videoconference for exercise, self-management advice, and behavioral counseling, plus exercise equipment and resources. The diet and exercise program included an additional 6 dietitian consultations for a ketogenic very-low-calorie diet (2 formulated meal replacements and a low-carbohydrate meal daily) followed by a transition to healthy eating, as well as nutrition and behavioral resources.
Primary outcomes were changes in knee pain (numerical rating scale NRS of 0 to 10, higher indicating worse) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index WOMAC; scale, 0 to 68, higher indicating worse) at 6 months (primary time point) and 12 months. Secondary outcomes were weight, physical activity, quality of life, mental health, global change, satisfaction, willingness to have surgery, orthopedic appointments, and knee surgery.
A total of 379 participants (91%) provided 6-month primary outcomes, and 372 (90%) provided 12-month primary outcomes. At 6 months, both programs were superior to control for pain (between-group mean difference in change on NRS: diet and exercise, -1.5 95% CI, -2.1 to -0.8; exercise, -0.8 CI, -1.5 to -0.2) and function (between-group mean difference in change on WOMAC: diet and exercise, -9.8 CI, -12.5 to -7.0; exercise, -7.0 CI, -9.7 to -4.2). The diet and exercise program was superior to exercise (pain, -0.6 CI, -1.1 to -0.2; function, -2.8 CI, -4.7 to -0.8). Findings were similar at 12 months.
Participants and clinicians were unblinded.
Telehealth-delivered exercise and diet programs improved pain and function in people with knee osteoarthritis and overweight or obesity. A dietary intervention conferred modest additional pain and function benefits over exercise.
Medibank, the Medibank Better Health Foundation Research Fund, and a National Health and Medical Research Council Centre of Research Excellence.
Objective
The aim of this study was to determine whether the hormone changes following weight loss are proportional to the degree of weight loss and to starting BMI.
Methods
A very low‐energy diet ...was used to achieve 15% weight loss. Fasting and postprandial gut hormones and leptin were measured during a meal test at baseline and at 5% (1%), 10% (2%), and 15% (2.5%) weight loss. Linear mixed‐effects models were used to analyze hormone changes.
Results
From baseline to 5% weight loss, decreases were seen in fasting concentrations of leptin (−8.25 ng/mL; p < 0.001), amylin (−21.3 pg/mL; p < 0.001), and glucagon‐like peptide 1 (−59.55 pg/mL; p < 0.001). There was a small further reduction in leptin between 5% and 15% weight loss (−1.88 ng/mL; p = 0.019) but not in glucagon‐like peptide 1 and amylin. Fasting ghrelin showed a significant increase at 10% weight loss (41.64 pg/mL; p = 0.002), with a nonsignificant increase from 10% to 15% loss (26.03 pg/mL; p = 0.065). Postprandial changes in hormone levels were variable. There was no correlation between baseline weight and the degree of hormone changes.
Conclusions
The majority of changes in fasting gut hormones and leptin occurred in early weight loss, with minor further changes up to 15% weight loss. Starting weight did not affect the degree of hormone change.
Suppressor of cytokine signaling 1 (SOCS1) is an intracellular inhibitor of cytokine, growth factor, and hormone signaling. Socs1–/– mice die before weaning from a multiorgan inflammatory disease. ...Neonatal Socs1–/– mice display severe hypoglycemia and hypoinsulinemia. Concurrent interferonγ gene deletion (Ifng–/–) prevented inflammation and corrected the hypoglycemia. In hyperinsulinemic clamp studies, however, Socs1–/–Ifng–/– mice had enhanced hepatic insulin sensitivity demonstrated by greater suppression of endogenous glucose production compared with controls with no difference in glucose disposal. Socs1–/–Ifng–/– mice had elevated liver insulin receptor substrate 2 expression (IRS-2) and IRS-2 tyrosine phosphorylation. This was associated with lower phosphoenolpyruvate carboxykinase mRNA expression. These effects were not associated with elevated hepatic AMP-activated protein kinase activity. Hepatic insulin sensitivity and IRS-2 levels play central roles in the pathogenesis of type 2 diabetes. Socs1 deficiency increases IRS-2 expression and enhances hepatic insulin sensitivity in vivo indicating that inhibition of SOCS1 may be a logical strategy in type 2 diabetes.
Abstract
Background
Obesity contributes to disability in older adults, and this is offset by weight loss and exercise. Very Low Calorie Diets (VLCDs) achieve rapid weight loss; however, these have ...not been rigorously evaluated in older people.
Methods
A randomized trial was conducted from August 2012 through December 2015. The intervention was 12 weeks of thrice weekly exercise combined with either healthy eating advice (Ex/HE), hypocaloric diet (Ex/Diet), or VLCD (Ex/VLCD). Outcomes were physical function, measured by 6-minute walk test (6MWT) and De Morton Mobility Index (DEMMI). Other measures were body composition measured by Dual Energy X-Ray Absorptiometry, and nutritional parameters (albumin, vitamins B12 and D, ferritin and folate).
Results
36, 40, and 41 participants were randomized to Ex/HE, Ex/Diet, and Ex/VLCD, respectively. At 12 weeks, weight was reduced by 3.7, 5.1, and 11.1% (p < .01), respectively. Ex/VLCD had significant reduction in fat (16.8%), lean mass (4.8%), and bone mineral density (1.2%), but increased relative lean mass (3.8%). DEMMI improved by 14.25, 14.25, and 13.75 points in Ex/HE, Ex/Diet, and Ex/VLCD, respectively; however, there was no between-group difference (p = .30). 6MWT improved by 53.1, 64.7, and 84.4 meters in Ex/HE, Ex/Diet, and Ex/VLCD (p = .18). Post hoc stratification for gender and adjustment for initial physical function and type 2 diabetes only revealed significant between-group differences for men in the 6MWT, with improvement by 57.8, 77.8, and 140.3 meters in Ex/HE, Ex/Diet, and Ex/VLCD, respectively (p = .01). Improvements in nutritional parameters were seen in Ex/VLCD, but not in Ex/HE and Ex/Diet. The VLCD was well tolerated.
Conclusions
VLCDs have potential in the treatment of obesity in older persons; of particular benefit is improvement in nutritional status. The gait speed improvement observed in men warrants further investigation.
Time for a new obesity narrative Ralston, Johanna; Brinsden, Hannah; Buse, Kent ...
The Lancet (British edition),
10/2018, Letnik:
392, Številka:
10156
Journal Article
Recenzirano
Obesity is not only a risk factor for non-communicable diseases (NCDs) but it is also a complex chronic disease.2 Yet efforts to address obesity have been stymied, not by inadequate knowledge but by ...a faulty framing of the issue that has led to stigmatisation, siloed approaches, political inaction, and an absence of coherent strategies within food and health systems.3 The need to rewrite the narrative is important as follow-up to the third UN High-Level Meeting on NCDs, at which language on obesity was included in the Political Declaration4 and it was acknowledged that countries are behind in meeting WHO targets to halt rising obesity prevalence.5 To date, obesity has not had a coherent framing narrative to connect its range of drivers and solutions. ...change the words and images used to portray obesity to shift blame away from individuals and towards upstream drivers. ...prioritise childhood obesity and the growing burden of obesity in low-income settings.12 Rights-based policy approaches that address inequalities and social and physical determinants of obesity are particularly relevant.13 Finally, appreciate that obesity is a chronic disease within the health system, with both its prevention and management embedded within calls for effective and comprehensive universal health coverage globally.
Obesity is associated with chronic inflammation and contributes to the development of insulin resistance and nonalcoholic fatty liver disease. The suppressor of cytokine signaling‐3 (SOCS3) protein ...is increased in inflammation and is thought to contribute to the pathogenesis of insulin resistance by inhibiting insulin and leptin signaling. Therefore, we studied the metabolic effects of liver‐specific SOCS3 deletion in vivo. We fed wild‐type (WT) and liver‐specific SOCS3 knockout (SOCS3 LKO) mice either a control diet or a high‐fat diet (HFD) for 6 weeks and examined their metabolic phenotype. We isolated hepatocytes from WT and SOCS3 LKO mice and examined the effects of tumor necrosis factor α and insulin on Akt phosphorylation and fatty acid metabolism and lipogenic gene expression. Hepatocytes from control‐fed SOCS3 LKO mice were protected from developing tumor necrosis factor α–induced insulin resistance but also had increased lipogenesis and expression of sterol response element–binding protein‐1c target genes. Lean SOCS3 LKO mice fed a control diet had enhanced hepatic insulin sensitivity; however, when fed an HFD, SOCS3 LKO mice had increased liver fat, inflammation, and whole‐body insulin resistance. SOCS3 LKO mice fed an HFD also had elevated hypothalamic SOCS3 and fatty acid synthase expression and developed greater obesity due to increased food intake and reduced energy expenditure. Conclusion: Deletion of SOCS3 in the liver increases liver insulin sensitivity in mice fed a control diet but paradoxically promotes lipogenesis, leading to the development of nonalcoholic fatty liver disease, inflammation, and obesity. (HEPATOLOGY 2010.)
To examine the impact of a prepregnancy very-low-energy diet (VLED) program on time to pregnancy in women with obesity.
Substudy of a two-arm parallel group randomized controlled trial.
Multiple ...tertiary care centers.
Women 18–38 years old with obesity (body mass index 30–55 kg/m2) and planning conception.
One hundred sixty-four normoglycemic women with body mass index 30–55 kg/m2, aged 18–38 years, and planning pregnancy were recruited through a social media platform for a two-arm randomized controlled trial. Women were allocated to a 12-week standard dietary intervention (SDI) or modified VLED. Completers of the intervention were observed for up to 48 weeks, and time to pregnancy was recorded.
The prespecified exploratory outcome for this substudy was time to pregnancy between the completion of the 12-week intervention and the date of conception.
Maternal weight loss at the end of the 12-week intervention was 3.1% in the SDI group and 11.9% in the VLED group. In completers of the 12-week intervention, time to pregnancy was significantly shorter in the women allocated to the VLED group than in the SDI group. Post hoc analysis showed that this difference in time to conception was particularly overt within 90 days of the intervention.
A VLED program that achieves substantial weight loss before conception reduces time to pregnancy compared with an SDI in women with obesity.
ACTRN12614001160628.
El tiempo en conseguir el embarazo después de un programa pregestacional, con una dieta muy baja en calorías en mujeres con obesidad: sub estudio de un ensayo controlado aleatorio.
Examinar el impacto de un programa de una dieta muy baja en calorías (VLED) en el tiempo para conseguir el embarazo en mujeres con obesidad.
Sub estudio de un ensayo controlado aleatorio de dos grupos en paralelo.
Múltiples centros de atención terciaria.
Mujeres de 18-38 años con obesidad (índice de masa corporal 30 a 55 kg / m2) y que han planificado concebir.
Se reclutaron ciento sesenta y cuatro mujeres normo glucémicas con índice de masa corporal de 30 a 55 kg / m2, de 18 a 38 años y que planeaban un embarazo, a través de una plataforma de redes sociales para un ensayo controlado aleatorio de dos grupos. Las mujeres fueron asignadas a una intervención dietética estándar (SDI) de 12 semanas o VLED modificado. Se observó a quienes completaron la intervención hasta 48 semanas y se registró el tiempo hasta conseguir el embarazo.
El resultado exploratorio preespecifico para este sub estudio fue el tiempo transcurrido hasta el embarazo, entre la finalización de la intervención a las 12 semanas y la fecha de la concepción.
La pérdida de peso materno al final de la intervención a las 12 semanas fue del 3,1% en el grupo de SDI y del 11,9% en el grupo de VLED. En aquellos casos que completaron la intervención de 12 semanas, el tiempo hasta el embarazo fue significativamente más corto en las mujeres asignadas al grupo VLED que en el grupo SDI. El análisis post hoc mostró que esta diferencia en el tiempo hasta la concepción fue particularmente evidente dentro de los 90 días posteriores a la intervención.
Un programa VLED en el que se logra una pérdida de peso sustancial antes de la concepción, reduce el tiempo en que se consigue el embarazo, en comparación con un SDI, en mujeres con obesidad.
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