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1.
Human beta cell functional adaptation and dysfunction in insulin resistance and its reversibility
Maša Skelin, Jan Kopecky, Jurij Dolenšek, Andraž Stožer, 2023, drugi znanstveni članki

Opis: Background: Beta cells play a key role in the pathophysiology of diabetes since their functional adaptation is able to maintain euglycemia in the face of insulin resistance, and beta cell decompensation or dysfunction is a necessary condition for full-blown type 2 diabetes (T2D). The mechanisms behind compensation and decompensation are incompletely understood, especially for human beta cells, and even less is known about influences of chronic kidney disease (CKD) or immunosupressive therapy after transplantation on these processes and the development of posttransplant diabetes. Summary: During compensation, beta cell sensitivity to glucose becomes left-shifted, i.e., their sensitivity to stimulation increases, and this is accompanied by enhanced signals along the stimulus-secretion coupling cascade from membrane depolarization to intracellular calcium and the most distal insulin secretion dynamics. There is currently no clear evidence regarding changes in intercellular coupling during this stage of disease progression. During decompensation, intracellular stimulus-secretion coupling remains enhanced to some extent at low or basal glucose concentrations but seems to become unable to generate effective signals to stimulate insulin secretion at high or otherwise stimulatory glucose concentrations. Additionally, intercellular coupling becomes disrupted, lowering the number of cells that contribute to secretion. During progression of CKD, beta cells also seem to drift from a compensatory left-shift to failure, and immunosupressants can further impair beta cell function following kidney transplantation. Key Messages: Beta cell stimulus-secretion coupling is enhanced in compensated insulin resistance. With worsening insulin resistance, both intra- and intercellular coupling become disrupted. CKD can progressively disrupt beta cell function, but further studies are needed, especially regarding changes in intercellular coupling.
Ključne besede: human beta cell, functional adaptation, dysfunction, insulin resistance
Objavljeno v DKUM: 15.04.2024; Ogledov: 85; Prenosov: 8
.pdf Celotno besedilo (387,53 KB)
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2.
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: 250; Prenosov: 19
.pdf Celotno besedilo (619,72 KB)
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3.
Diabetic cardiomyopathy : an under-recognized cause of heart failure in diabetic patients
David Šuran, Vojko Kanič, Andreja Sinkovič, 2020, pregledni znanstveni članek

Ključne besede: left ventricular diastolic dysfunction
Objavljeno v DKUM: 23.01.2023; Ogledov: 440; Prenosov: 49
.pdf Celotno besedilo (93,94 KB)
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