The interplay between sodium/glucose cotransporter type 2 and mitochondrial ionic environment.

Mitochondrial volume is maintained through the permeability of the inner mitochondrial membrane by a specific aquaporin and the osmotic balance between the mitochondrial matrix and cellular cytoplasm. Various electrolytes, such as calcium and hydrogen ions, potassium, and sodium, as well as other osmotic substances, affect the swelling of mitochondria. Intracellular glucose levels may also affect mitochondrial swelling, although the relationship between mitochondrial ion homeostasis and intracellular glucose is poorly understood. This article reviews what is currently known about how the Sodium-Glucose transporter (SGLT) may impact mitochondrial sodium (Na+) homeostasis. SGLTs regulate intracellular glucose and sodium levels and, therefore, interfere with mitochondrial ion homeostasis because mitochondrial Na+ is closely linked to cytoplasmic calcium and sodium dynamics. Recently, a large amount of data has been available on the effects of SGLT2 inhibitors on mitochondria in different cell types, including renal proximal tubule cells, endothelial cells, mesangial cells, podocytes, neuronal cells, and cardiac cells. The current evidence suggests that SGLT inhibitors (SGLTi) may affect mitochondrial dynamics regarding intracellular Sodium and hydrogen ions. Although the regulation of mitochondrial ion channels by SGLTs is still in its infancy, the evidence accumulated thus far of the effect of SGLTi on mitochondrial functions certainly will foster further research in this direction.

Functional and Clinical Importance of SGLT2-inhibitors in Frailty: From the Kidney to the Heart.

SGLT2 (sodium-glucose cotransporter 2) enables glucose and sodium reabsorption in the kidney. SGLT2-inhibitors (also known as gliflozins, which include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) act by increasing glycosuria, thereby reducing glycemia. These drugs are critical to reach and keep glycemic control, a crucial feature, especially in patients with comorbidities, like frail individuals. Several studies evaluated the effects of SGLT2-inhibitors in different settings beyond diabetes, revealing that they are actually pleiotropic drugs. We recently evidenced the favorable effects of SGLT2-inhibition on physical and cognitive impairment in frail older adults with diabetes and hypertension. In the present overview, we summarize the latest clinical and preclinical studies exploring the main effects of SGLT2-inhibitors on kidney and heart, emphasizing their potential beneficial actions in frailty.

Functional role of miR-34a in diabetes and frailty.

Emerging evidence has shown that microRNAs (miRNAs) play critical role in the pathogenesis of several disorders. In the present minireview, we focus our attention on the functional role of a specific miRNA, namely miR-34a, in the pathophysiology of frailty and diabetes mellitus. Based on the current literature, we speculate that this miRNA may serve as a potential biomarker of frailty in diabetic older adults. Additionally, its actions on oxidative stress might represent a druggable target to obtain new potentials treatments.

The Dopamine System: Insights between Kidney and Brain.

BACKGROUND: Chronic kidney disease (CKD) is one of the most common diseases in adult age, and it is typical of older adults. Recent data suggest that almost half of the elders have CKD. It is now clear that CKD is accompanied, in the early stages, by cognitive impairment, together with depression and subtle abnormalities in motor control (such as gait and balance alterations). SUMMARY: Several data suggest a link between brain dopamine and kidney diseases. Metabolic syndrome and diabetes can affect dopamine neuron survival (leading to Parkinson's disease). Several uremic toxins in CKD (uric acid, indoxyl sulfate) and trace elements accumulating in CKD (aluminum, manganese) can also modify the dopaminergic system. Hormones produced by the kidney such as vitamin D are neuroprotective for dopamine neurons. Dopaminergic drugs are useful for the treatment of a common sleep disorder in CKD, the restless legs syndrome. However, experiments on animal models of CKD show conflicting results regarding a modification of dopamine neurons. KEY MESSAGES: Several observations suggest a limited relevance of the dopaminergic system in CKD-related cognitive impairment. However, a common sleep disturbance in CKD, the restless legs syndrome, improves with dopaminergic drugs. Therefore, it remains to be established the role of the dopamine system in subtle motor dysfunction observed in CKD, such as tremors, gait alterations, and central sleep apnea.

Omega-3 fatty acids coordinate glucose and lipid metabolism in diabetic patients.

Omega 3 polyunsaturated fatty acids (n-3 PUFA) are known to have beneficial effects on cardiovascular and metabolic health. However, whether different sources of n-3 PUFA, for instance fatty fish vs vegetable oils, could elicit different effects on glucose and lipid metabolism, remains to be determined. Herein we examine recent findings showing that while a plant-based n-3 PUFA supplementation for six months can reduce fasting blood glucose, marine-based n-3 PUFA can instead reduce serum levels of triglycerides. We also discuss the potential molecular mechanisms that could underlie these different effects on the regulation of glycolipid metabolism.

Physical decline and cognitive impairment in frail hypertensive elders during COVID-19.

BACKGROUND: Hypertension is common in older adults and its incidence increases with age. We investigated the correlation between physical and cognitive impairment in older adults with frailty and hypertension. METHODS: We recruited frail hypertensive older adults during the COVID-19 pandemic, between March 2021 and December 2021. Global cognitive function was assessed through the Montreal Cognitive Assessment (MoCA), physical frailty assessment was performed following the Fried criteria, and all patients underwent physical evaluation through 5-meter gait speed test. RESULTS: We enrolled 203 frail hypertensive older adults and we found a significant correlation between MoCA score and gait speed test (r: 0.495; p<0.001) in our population. To evaluate the impact of comorbidities and other factors on our results, we applied a linear regression analysis with MoCA score as a dependent variable, observing a significant association with age, diabetes, chronic obstructive pulmonary disease (COPD), and gait speed test. CONCLUSIONS: Our study revealed for the first time a significant correlation between physical and cognitive impairment in frail hypertensive elderly subjects.

Brain dysfunction in tubular and tubulointerstitial kidney diseases.

Kidney function has two important elements: glomerular filtration and tubular function (secretion and reabsorption). A persistent decrease in glomerular filtration rate (GFR), with or without proteinuria, is diagnostic of chronic kidney disease (CKD). While glomerular injury or disease is a major cause of CKD and usually associated with proteinuria, predominant tubular injury, with or without tubulointerstitial disease, is typically non-proteinuric. CKD has been linked with cognitive impairment, but it is unclear how much this depends on a decreased GFR, altered tubular function or the presence of proteinuria. Since CKD is often accompanied by tubular and interstitial dysfunction, we explore here for the first time the potential role of the tubular and tubulointerstitial compartments in cognitive dysfunction. To help address this issue we selected a group of primary tubular diseases with preserved GFR in which to review the evidence for any association with brain dysfunction. Cognition, mood, neurosensory and motor disturbances are not well characterized in tubular diseases, possibly because they are subclinical and less prominent than other clinical manifestations. The available literature suggests that brain dysfunction in tubular and tubulointerstitial diseases is usually mild and is more often seen in disorders of water handling. Brain dysfunction may occur when severe electrolyte and water disorders in young children persist over a long period of time before the diagnosis is made. We have chosen Bartter and Gitelman syndromes and nephrogenic diabetes insipidus as examples to highlight this topic. We discuss current published findings, some unanswered questions and propose topics for future research.

Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia.

Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8; p < 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment.

Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control.

Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions. Dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson's disease (PD), schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we will discuss the current insights on the role of DA in motor control and reward learning mechanisms and its involvement in the modulation of synaptic dynamics through different pathways. In particular, we will consider the role of DA as neuromodulator of two forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD) in several cortical and subcortical areas. Finally, we will delineate how the effect of DA on dendritic spines places this molecule at the interface between the motor and the cognitive systems. Specifically, we will be focusing on PD, vascular dementia, and schizophrenia.