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