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Lipotoxicity in a vicious cycle of pancreatic beta cell exhaustion
Vladimir Grubelnik, Jan Zmazek, Matej Završnik, Marko Marhl, 2022, izvirni znanstveni članek

Opis: Hyperlipidemia is a common metabolic disorder in modern society and may precede hyperglycemia and diabetes by several years. Exactly how disorders of lipid and glucose metabolism are related is still a mystery in many respects. We analyze the effects of hyperlipidemia, particularly free fatty acids, on pancreatic beta cells and insulin secretion. We have developed a computational model to quantitatively estimate the effects of specific metabolic pathways on insulin secretion and to assess the effects of short- and long-term exposure of beta cells to elevated concentrations of free fatty acids. We show that the major trigger for insulin secretion is the anaplerotic pathway via the phosphoenolpyruvate cycle, which is affected by free fatty acids via uncoupling protein 2 and proton leak and is particularly destructive in long-term chronic exposure to free fatty acids, leading to increased insulin secretion at low blood glucose and inadequate insulin secretion at high blood glucose. This results in beta cells remaining highly active in the “resting” state at low glucose and being unable to respond to anaplerotic signals at high pyruvate levels, as is the case with high blood glucose. The observed fatty-acid-induced disruption of anaplerotic pathways makes sense in the context of the physiological role of insulin as one of the major anabolic hormones.
Ključne besede: diabetes, insulin secretion, lipids, PEP cycle, uncoupling proteins, mitochondrial dysfunction
Objavljeno v DKUM: 20.05.2024; Ogledov: 70; Prenosov: 2
.pdf Celotno besedilo (2,47 MB)
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Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart
Mahmoud Abdellatif, Frank Madeo, Guido Kroemer, Simon Sedej, 2022, drugi znanstveni članki

Opis: Although attenuated IGF1R (insulin-like growth factor 1 receptor) signaling has long been viewed to promote longevity in model organisms, adverse effects on the heart have been the subject of major concern. We observed that IGF1R is overexpressed in cardiac tissues from patients with end-stage non-ischemic heart failure, coupled to the activation of the IGF1R downstream effector AKT/protein kinase B and inhibition of ULK1 (unc-51 like autophagy activating kinase 1). Transgenic overexpression of human IGF1R in cardiomyocytes from mice initially induces physiological cardiac hypertrophy and superior function, but later in life confers a negative impact on cardiac health, causing macroautophagy/autophagy inhibition as well as impaired oxidative phosphorylation, thus reducing life expectancy. Treatment with the autophagy inducer and caloric restriction mimetic spermidine ameliorates most of these IGF1R-induced cardiotoxic effects in vivo. Moreover, inhibition of IGF1R signaling by means of a dominant-negative phosphoinositide 3-kinase (PI3K) mutant induces cardioprotective autophagy, restores myocardial bioenergetics and improves late-life survival. Hence, our results demonstrate that IGF1R exerts a dual biphasic impact on cardiac health, and that autophagy mediates the late-life geroprotective effects of IGF1R inhibition in the heart.
Ključne besede: heart failure, IGF1R, PI3K, human, insulin signaling, longevity, mitochondrial dysfunction, mouse
Objavljeno v DKUM: 08.08.2023; Ogledov: 272; Prenosov: 20
.pdf Celotno besedilo (619,72 KB)
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