L'inibizione del trasporto renale del glucosio determina il ciclo evolutivo cellulare - A. Avogaro Università di Padova
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L’inibizione del trasporto renale del glucosio
determina il ciclo evolutivo cellulare
A. Avogaro
Università di Padova
Conflitti di Interesse di Angelo Avogaro
Il Prof. Angelo Avogaro dichiara di aver ricevuto negli ultimi due anni
compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o
Diagnostiche:
AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly,
Bruno Farmaceutici, Mundipharma, Neopharmed, Amgen, Servier,
Recordati, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Novo
Nordisk, Sanofi, Takeda.
CVD: From when and why?
Finch and Crimmins’s general model of the environmental impact on the atherosclerosis
Why in humans?
Humans cannot synthesize Neu5Gc, due to a specific exon deletion in the gene
encoding the enzyme cytidine monophospho-N-acetylneuraminic acid hydroxylase
(CMAH), responsible for the generation of Neu5Gc from the precursor
sialic acid N-acetylneuraminic acid (Neu5Ac).
Varki et al. 2007
Cellular Programs
The defense program The dormancy program
• Activation of the • Metabolic suppressed, and
immune response insulin is reduced
• Anabolic metabolism. • Catabolism and stem cell
quiescence prevail
PI3K, mTOR, c-Myc,
• Immune system is suppressed
MAPK.
• Activation of fatty acid
• Increased level of white oxidation
blood cells • Increased production of ketone
• Immune activation bodies
• Increase of circulating FGF 21
• Activation of FOXO and AMPKFAVORABLE
ENVIROMENT
GROWTH REPRODUCTION MAINTENANCE
Avogaro, Fadini, Del Prato Diab Care 2020FAVORABLE
ENVIROMENT
GROWTH REPRODUCTION MAINTENANCE
• STRESS
↑ PI3K
HOSTILE ENVIROMENT: ↑ mTOR • ANABOLISM
HYPERGLYCEMIA DEFENSE ↑ c-Myc • GLYCOLISIS
• IMMUNE
PROGRAM ↑ MAPK
ACTIVATION
Avogaro, Fadini, Del Prato Diab Care 2020Model of glucose transporter 1 expression and glucose uptake
during an immune response to HIV-1 infection
Palmer et al. Trends in Immunol 2012Obesity-induced inflammatory changes in adipose tissue J Clin Invest DOI: 10.1172/JCI20514
Inflammation is a crucial component of
atherosclerotic plaque: response-to-injury
Weber et al. Nat Med 2011FAVORABLE
ENVIROMENT
GROWTH REPRODUCTION MAINTENANCE
• STRESS
↑ PI3K
HOSTILE ENVIROMENT: ↑ mTOR • ANABOLISM
HYPERGLYCEMIA DEFENSE ↑ c-Myc • GLYCOLISIS
• IMMUNE
PROGRAM ↑ MAPK
ACTIVATION
↑ FAO
• ENERGY
DORMANCY ↑ p53
CONSERVATION
↑ KB
PROGRAM ↑ FGF21 • RESISTANCE TO
↑ FoXo STRESS
↑ AMPK
↑ Autophagy
Avogaro, Fadini, Del Prato Diab Care 2020Switch from carbohydrate to fatty acids as the
primary source of fuel during hibernation.
Carey et al. Physiol Rev 2003Plasma b-hydroxybutyrate concentration over the
annual hibernation cycle.
Otis et al. PlosOne 2015Opposing Activity Changes in AMP Deaminase and AMP-
Activated Protein Kinase in the Hibernating Ground Squirrel
Lanaspa et al. PlosOne 2015FAVORABLE
ENVIROMENT
GROWTH REPRODUCTION MAINTENANCE
• STRESS
↑ PI3K
HOSTILE ENVIROMENT: ↑ mTOR • ANABOLISM
HYPERGLYCEMIA DEFENSE ↑ c-Myc • GLYCOLISIS
• IMMUNE
PROGRAM ↑ MAPK
ACTIVATION
↑ FAO
↑ p53
• ENERGY
DORMANCY ↑ KB
CONSERVATION
↑ FGF21
PROGRAM ↑ FoXo • RESISTANCE TO
↑ AMPK STRESS
HOSTILE ENVIROMENT: ↑ Autophagy
HYPERGLYCEMIA
DEFENSE
PROGRAM
X • ENERGY
↓ mTOR CONSERVATION
↑ AMPK • RESISTANCE TO
SGLT2i ↑ Shift from STRESS
M1 to M2 Φ • ↓ IMMUNE
↑ KB ACTIVATION
DORMANCY ↑ FGF21 • HIBERNATION-LIKE
PROGRAM MODIFICATIONS
Avogaro, Fadini, Del Prato Diab Care 2020BTBR: BTBR ob/ob mice [BTBR.V(B6)-Lepob/WiscJ]
SGLT2 inhibition reprograms systemic metabolism via
FGF21-dependent and-independent mechanisms
JCI Insight. 2019;4(5):e123130Liver-to-brain hormonal axis regulating energy
homeostasis
Potthoff, M. J. (2016) A new frontier in FGF21 biology
Nat. Rev. Endocrinol. doi:10.1038/nrendo.2016.206Empagliflozin Reduces The Levels Of CD36 And
Cardiotoxic Lipids While Improving Autophagy
AlanaAragón-Herrera et al. Biochem Pharmacol 2019Raised circulating FFAs are taken up by the liver and metabolized
via β-oxidation.
Ele Ferrannini et al. Dia Care 2016;39:1108-1114Onset of hibernation could enhance the capacity for both
lipid catabolism and anabolism in iWAT to prepare for
metabolic challenges during the HIB.
Chayama et al. Front. Physiol. 2019Model of stress induction and tolerance during
torpor-arousal cycles in hibernators
Carey et al. Physiol Rev 2003Cell
Life
History
Hyperglycemia
Defence Program Dormancy Program SGLT2i
↑ PI3K, ↑ mTOR, ↑ c-Myc, ↑ MAPK ↑ FAO, ↑ p53, ↑ KB, ↑ FGF21, ↑ FoXo ↓ mTOR, ↑ AMPK,↑ Shift from M1 to
•STRESS
↑ AMPK, ↑ Autophagy
M2 Φ, ↑ KB, ↑ FGF21
•ANABOLISM •ENERGY CONSERVATION
•RESISTANCE TO STRESS •RESISTANCE TO STRESS
•GLYCOLISIS
•IMMUNE ACTIVATION
•IMMUNE ACTIVATION •HIBERNATION-LIKE MODIFICATIONSYou can also read
