Post on 18-May-2021
L’inibizione del trasporto renale del glucosio determina il ciclo evolutivo cellulare
A. AvogaroUniversità 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 precursorsialic acid N-acetylneuraminic acid (Neu5Ac).
Varki et al. 2007
Cellular ProgramsThe defense program• Activation of the
immune response• Anabolic metabolism.
PI3K, mTOR, c-Myc, MAPK.
• Increased level of white blood cells
• Immune activation
The dormancy program • Metabolic suppressed, and
insulin is reduced • Catabolism and stem cell
quiescence prevail• Immune system is suppressed• Activation of fatty acid
oxidation • Increased production of ketone
bodies • Increase of circulating FGF 21 • Activation of FOXO and AMPK
FAVORABLE ENVIROMENT
GROWTH REPRODUCTION MAINTENANCE
Avogaro, Fadini, Del Prato Diab Care 2020
FAVORABLE ENVIROMENT
GROWTH REPRODUCTION MAINTENANCE
HOSTILE ENVIROMENT:HYPERGLYCEMIA DEFENSE
PROGRAM
• STRESS• ANABOLISM• GLYCOLISIS• IMMUNE
ACTIVATION
↑ PI3K↑ mTOR ↑ c-Myc ↑ MAPK
Avogaro, Fadini, Del Prato Diab Care 2020
Model of glucose transporter 1 expression and glucose uptakeduring an immune response to HIV-1 infection
Palmer et al. Trends in Immunol 2012
Obesity-induced inflammatory changes in adipose tissue
J Clin Invest DOI: 10.1172/JCI20514
Weber et al. Nat Med 2011
Inflammation is a crucial component of atherosclerotic plaque: response-to-injury
FAVORABLE ENVIROMENT
GROWTH REPRODUCTION MAINTENANCE
HOSTILE ENVIROMENT:HYPERGLYCEMIA DEFENSE
PROGRAM
DORMANCY PROGRAM
• STRESS• ANABOLISM• GLYCOLISIS• IMMUNE
ACTIVATION
↑ PI3K↑ mTOR ↑ c-Myc ↑ MAPK
↑ FAO↑ p53↑ KB
↑ FGF21↑ FoXo↑ AMPK
↑ Autophagy
• ENERGY CONSERVATION
• RESISTANCE TO STRESS
Avogaro, Fadini, Del Prato Diab Care 2020
Switch from carbohydrate to fatty acids as the primary source of fuel during hibernation.
Carey et al. Physiol Rev 2003
Plasma b-hydroxybutyrate concentration over the annual hibernation cycle.
Otis et al. PlosOne 2015
Opposing Activity Changes in AMP Deaminase and AMP-Activated Protein Kinase in the Hibernating Ground Squirrel
Lanaspa et al. PlosOne 2015
FAVORABLE ENVIROMENT
GROWTH REPRODUCTION MAINTENANCE
HOSTILE ENVIROMENT:HYPERGLYCEMIA DEFENSE
PROGRAM
DORMANCY PROGRAM
• STRESS• ANABOLISM• GLYCOLISIS• IMMUNE
ACTIVATION
↑ PI3K↑ mTOR ↑ c-Myc ↑ MAPK
↑ FAO↑ p53↑ KB
↑ FGF21↑ FoXo↑ AMPK
↑ Autophagy
• ENERGY CONSERVATION
• RESISTANCE TO STRESS
HOSTILE ENVIROMENT:HYPERGLYCEMIA DEFENSE
PROGRAM
DORMANCY PROGRAM
↓ mTOR↑ AMPK
↑ Shift from M1 to M2 Φ
↑ KB↑ FGF21
• ENERGY CONSERVATION
• RESISTANCE TO STRESS
• ↓ IMMUNE ACTIVATION
• HIBERNATION-LIKE MODIFICATIONS
SGLT2i
X
Avogaro, Fadini, Del Prato Diab Care 2020
BTBR: BTBR ob/ob mice [BTBR.V(B6)-Lepob/WiscJ]
JCI Insight. 2019;4(5):e123130
SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and-independent mechanisms
Liver-to-brain hormonal axis regulating energy homeostasis
Potthoff, M. J. (2016) A new frontier in FGF21 biologyNat. Rev. Endocrinol. doi:10.1038/nrendo.2016.206
AlanaAragón-Herrera et al. Biochem Pharmacol 2019
Empagliflozin Reduces The Levels Of CD36 And Cardiotoxic Lipids While Improving Autophagy
Raised circulating FFAs are taken up by the liver and metabolized via β-oxidation.
Ele Ferrannini et al. Dia Care 2016;39:1108-1114
Onset 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. 2019
Model of stress induction and tolerance during torpor-arousal cycles in hibernators
Carey et al. Physiol Rev 2003
Defence Program↑ PI3K, ↑ mTOR, ↑ c-Myc, ↑ MAPK
•STRESS•ANABOLISM•GLYCOLISIS
•IMMUNE ACTIVATION
Dormancy Program↑ FAO, ↑ p53, ↑ KB, ↑ FGF21, ↑ FoXo
↑ AMPK, ↑ Autophagy
•ENERGY CONSERVATION•RESISTANCE TO STRESS
SGLT2i↓ mTOR, ↑ AMPK,↑ Shift from M1 to
M2 Φ, ↑ KB, ↑ FGF21
•RESISTANCE TO STRESS•IMMUNE ACTIVATION
•HIBERNATION-LIKE MODIFICATIONS
CellLife
History
Hyperglycemia