Interplay of adenosine monophosphate‐activated protein kinase/sirtuin‐1 activation and sodium influx inhibition mediates the renal benefits of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes: A novel conceptual framework

2020 ◽  
Vol 22 (5) ◽  
pp. 734-742 ◽  
Author(s):  
Milton Packer
Keyword(s):  
Type 2 Diabetes ◽  
Protein Kinase ◽  
Conceptual Framework ◽  
Adenosine Monophosphate ◽  
Sirtuin 1 ◽  
Sodium Influx

scholarly journals Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors

2020 ◽  
Vol 51 (4) ◽  
pp. 289-293 ◽  
Author(s):  
Milton Packer
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Renin Angiotensin System ◽  
Tissue Expansion ◽  
Adenosine Monophosphate ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Glomerular Hyperfiltration ◽  
Sodium Glucose Cotransporter

The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

scholarly journals Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

2021 ◽  
Vol 14 (9) ◽  
pp. 890
Author(s):  
Saghar Rabiei Poor ◽  
Miren Ettcheto ◽  
Amanda Cano ◽  
Elena Sanchez-Lopez ◽  
Patricia Regina Manzine ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Adenosine Monophosphate ◽  
Sirtuin 1 ◽  
Health Concern ◽  
Therapeutic Effects ◽  
Age Related

Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to “type 3 diabetes” and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models.

scholarly journals Metformin: A Potential Therapeutic Tool for Rheumatologists

2020 ◽  
Vol 13 (9) ◽  
pp. 234 ◽  
Author(s):  
Teresa Salvatore ◽  
Pia Clara Pafundi ◽  
Raffaele Galiero ◽  
Klodian Gjeloshi ◽  
Francesco Masini ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Type 2 Diabetes ◽  
Adenosine Monophosphate ◽  
Nuclear Factor Κb ◽  
Janus Kinase ◽  
Experimental Investigations ◽  
Beneficial Effects ◽  
Rheumatologic Diseases ◽  
Inflammatory Conditions

Metformin is an oral antihyperglycemic drug widely used to treat type 2 diabetes, acting via indirect activation of 5′ Adenosine Monophosphate-activated Protein Kinase (AMPK). Actually, evidence has accumulated of an intriguing anti-inflammatory activity, mainly mediated by AMPK through a variety of mechanisms such as the inhibition of cytokine-stimulated Nuclear Factor-κB (NF-κB) and the downregulation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathways. Moreover, AMPK plays an important role in the modulation of T lymphocytes and other pivotal cells of the innate immune system. The current understanding of these AMPK effects provides a strong rationale for metformin repurposing in the management of autoimmune and inflammatory conditions. Several studies demonstrated metformin’s beneficial effects on both animal and human rheumatologic diseases, especially on rheumatoid arthritis. Unfortunately, even though data are large and remarkable, they almost exclusively come from experimental investigations with only a few from clinical trials. The lack of support from prospective placebo-controlled trials does not allow metformin to enter the therapeutic repertoire of rheumatologists. However, a large proportion of rheumatologic patients can currently benefit from metformin, such as those with concomitant obesity and type 2 diabetes, two conditions strongly associated with rheumatoid arthritis, osteoarthritis, and gout, as well as those with diabetes secondary to steroid therapy.

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