Papel del péptido insulinotrópico dependiente de glucosa en la programación nutricional del síndrome metabólico / Role of glucose-dependent insulinotropic peptide in the nutritional programming of metabolic syndrome

La restricción nutricional precoz ha sido asociada con una mayor incidencia de patologías relacionadas con el síndrome metabólico durante la edad adulta. Sin embargo, los mecanismos subyacentes que determinan el desarrollo de dichas patologías aún no se conocen en su totalidad. En el presente trabajo, se analizó el papel del péptido insulinotrópico dependiente de glucosa (GIP) en el desarrollo dichas patologías en un modelo de rata Wistar. Las ratas gestantes fueron alimentadas ad libitum (C) o sometidas a restricción nutricional (S) durante el embarazo y la lactancia, al final de la cual las crías fueron realimentadas con dieta grasa (CR, SR) durante 22 semanas. Tanto los machos como las hembras SR mostraron un fenotipo obesogénico caracterizado por hiperfagia, acumulación de grasa visceral e hipertrofia adipocitaria, de manera más pronunciada que la población CR. Los test de tolerancia oral a la glucosa mostraron que las hembras SR experimentaron intolerancia a la glucosa e hipersecreción de insulina y GIP. La administración del antagonista del receptor de GIP, (Pro3)GIP, a las hembras SR dio lugar a una significativa reducción del tejido adiposo y del tamaño adipocitario, junto a una mejora de la tolerancia a la glucosa y de la sensibilidad a la insulina. En conclusión, la exacerbada secreción de GIP parece representar el estímulo para la hipersecreción de insulina y el desarrollo de resistencia a la misma en las hembras SR, lo que sugiere que GIP jugaría un papel esencial en el desarrollo de alteraciones metabólicas asociadas a la rehabilitación nutricional

Early nutritional restriction has been associated with increased incidence of metabolic syndrome-associated pathologies in adulthood. However, the underlying mechanisms that determine the development of these diseases are not yet fully known. In the present work, we explored the relevance of glucose-dependent insulinotropic polypeptide (GIP) in the development of these pathologies in a model of Wistar rats. Two groups of dams were fed ad libitum (C) or food-restricted (U) during pregnancy and suckling. At that time, rats were refed a high-fat diet (HFD; CHF and UHF) for 22 weeks. Both male and female UHF rats showed an obese phenotype characterized by hyperphagia, visceral fat accumulation and adipocyte hypertrophy, which was more pronounced than in CHF rats. Oral glucose tolerance tests showed that female UHF rats experienced glucose intolerance, insulin hypersecretion and an exacerbated GIP secretion. Administration of the GIP receptor antagonist, (Pro3)GIP, to UHF female rats markedly reduced visceral fat mass and adipocyte hypertrophy, and these changes were accompanied by improvement of glucose tolerance and insulin sensitivity. In conclusion, the exacerbated production and secretion of GIP seems to represent the stimulus for insulin hypersecretion and insulin resistance shown by UHF female rats, suggesting that GIP may play a critical role in the development of metabolic disturbances related to nutritional rehabilitation

Early and Long-term Undernutrition in Female Rats Exacerbates the Metabolic Risk Associated with Nutritional Rehabilitation.

Human studies have suggested that early undernutrition increases the risk of obesity, thereby explaining the increase in overweight among individuals from developing countries who have been undernourished as children. However, this conclusion is controversial, given that other studies do not concur. This study sought to determine whether rehabilitation after undernutrition increases the risk of obesity and metabolic disorders. We employed a published experimental food-restriction model. Wistar female rats subjected to severe food restriction since fetal stage and controls were transferred to a moderately high-fat diet (cafeteria) provided at 70 days of life to 6.5 months. Another group of undernourished rats were rehabilitated with chow. The energy intake of undernourished animals transferred to cafeteria formula exceeded that of the controls under this regime and was probably driven by hypothalamic disorders in insulin and leptin signal transduction. The cafeteria diet resulted in greater relative increases in both fat and lean body mass in the undernourished rats when compared with controls, enabling the former group to completely catch up in length and body mass index. White adipose tissues of undernourished rats transferred to the high-lipid regime developed a browning which, probably, contributed to avoid the obesigenic effect observed in controls. Nevertheless, the restricted group rehabilitated with cafeteria formula had greater accretion of visceral than subcutaneous fat, showed increased signs of macrophage infiltration and inflammation in visceral pad, dyslipidemia, and ectopic fat accumulation. The data indicate that early long-term undernutrition is associated with increased susceptibility to the harmful effects of nutritional rehabilitation, without causing obesity.

Resveratrol treatment restores peripheral insulin sensitivity in diabetic mice in a sirt1-independent manner.

SCOPE: Mice with deletion of insulin receptor substrate (IRS) 2 develop hyperglycaemia, impaired hepatic insulin signaling and elevated gluconeogenesis. Protein tyrosine phosphatase 1B (PTP1B) inhibition by resveratrol improves peripheral insulin sensitivity of these mice. Although resveratrol activates Sirtuin1 (Sirt1), the mechanisms underlying its beneficial effects are not totally elucidated. In this study, we have investigated whether Sirt1 mediates the effects of resveratrol in controlling insulin resistance in diabetic mice. METHODS AND RESULTS: We attempted to ameliorate peripheral insulin resistance in two diabetic models, Irs2-deficient (Irs2(-/-)) mice and streptozotocin (STZ)-injected mice by resveratrol treatment or Sirt1 overexpression. Resveratrol improved systemic insulin sensitivity of Irs2-deficient mice. Irs2-deficient mice are characterized by high levels of PTP1B expression in liver and muscle. Interestingly, resveratrol decreased PTP1B in both tissues, thereby restoring IRS1-mediated insulin signaling. Moreover, resveratrol also restored insulin sensitivity and hepatic insulin signaling in STZ-diabetic mice. In contrast, moderate overexpression of Sirt1 neither normalized PTP1B levels nor restored insulin signaling in Irs2-deficient mice or STZ-diabetic mice. CONCLUSION: Resveratrol improves peripheral insulin signaling independently of Sirt1 in diabetic mice in association with the inhibition of PTP1B and, therefore, this polyphenol could be an effective adjuvant for the treatment of diabetes.

Cocoa-rich diet attenuates beta cell mass loss and function in young Zucker diabetic fatty rats by preventing oxidative stress and beta cell apoptosis.

We have recently shown that cocoa flavanols may have anti-diabetic potential by promoting survival and function of pancreatic beta-cells in vitro. In this work, we investigated if a cocoa-rich diet is able to preserve beta-cell mass and function in an animal model of type 2 diabetes and the mechanisms involved. Our results showed that cocoa feeding during the prediabetic state attenuates hyperglycaemia, reduces insulin resistant, and increases beta cell mass and function in obese Zucker diabetic rats. At the molecular level, cocoa-rich diet prevented beta-cell apoptosis by increasing the levels of Bcl-xL and decreasing Bax levels and caspase-3 activity. Cocoa diet enhanced the activity of endogenous antioxidant defenses, mainly glutathione peroxidase, preventing thus oxidative injury induced by the pre-diabetic condition and leading to apoptosis prevention. These findings provide the first in vivo evidence that a cocoa-rich diet may delay the loss of functional beta-cell mass and delay the progression of diabetes by preventing oxidative stress and beta-cell apoptosis.