Kumar, Arathi Prabha

Abstract Insulin resistance (IR) is a modifiable risk factor for dementia, yet its effects on brain metabolism and function remain unclear. In older adults, greater IR was associated with reduced cerebral glucose uptake (indicating impaired mitochondrial metabolism), atrophy, and weakened connectivity between brain regions critical for cognition. In neuron-specific insulin receptor knockout mice, brain IR produced deficits in hippocampal- and prefrontal-dependent tasks accompanied by reduced brain mitochondrial ATP and elevated reactive oxygen species. To evaluate reversibility of IR-induced brain deficits, forty older adults with IR were randomized to 40-weeks of metformin or placebo. Metformin improved insulin sensitivity, increased brain glucose uptake, strengthened cognitive network connectivity, and preserved whole-brain and regional volumes implicated in decision-making and learning. Metformin also improved processing speed and working memory. Collectively, these findings highlight IR as a driver of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.

We investigated the link between enhancement of SI (by hyperinsulinemic–euglycemic clamp) and muscle metabolites after 12 weeks of aerobic (high-intensity interval training [HIIT]), resistance training (RT), or combined training (CT) exercise in 52 lean healthy individuals. Muscle RNA sequencing revealed a significant association between SI after both HIIT and RT and the branched-chain amino acid (BCAA) metabolic pathway. Concurrently with increased expression and activity of branched-chain ketoacid dehydrogenase enzyme, many muscle amino metabolites, including BCAAs, glutamate, phenylalanine, aspartate, asparagine, methionine, and γ-aminobutyric acid, increased with HIIT, supporting the substantial impact of HIIT on amino acid metabolism. Short-chain C3 and C5 acylcarnitines were reduced in muscle with all three training modes, but unlike RT, both HIIT and CT increased tricarboxylic acid metabolites and cardiolipins, supporting greater mitochondrial activity with aerobic training. Conversely, RT and CT increased more plasma membrane phospholipids than HIIT, suggesting a resistance exercise effect on cellular membrane protection against environmental damage. Sex and age contributed modestly to the exercise-induced changes in metabolites and their association with cardiometabolic parameters. Integrated transcriptomic and metabolomic analyses suggest various clusters of genes and metabolites are involved in distinct effects of HIIT, RT, and CT. These distinct metabolic signatures of different exercise modes independently link each type of exercise training to improved SI and cardiometabolic risk. Article Highlights We aimed to understand the link between skeletal muscle metabolites and cardiometabolic health after exercise training. Although aerobic, resistance, and combined exercise training each enhance muscle insulin sensitivity as well as other cardiometabolic parameters, they disparately alter amino and citric acid metabolites as well as the lipidome, linking these metabolomic changes independently to the improvement of cardiometabolic risks with each exercise training mode. These findings reveal an important layer of the unique exercise mode–dependent changes in muscle metabolism, which may eventually lead to more informed exercise prescription for improving SI.

Thoracic outlet syndrome (TOS) refers to a constellation of symptoms resulting from neurovascular compression at the thoracic outlet, causing some combination of pain in the neck and upper extremity, weakness, sensory loss, paresthesia, swelling, and discoloration. Classification of TOS would depend on the anatomical structure that is compressed: venous TOS (VTOS)—compression of Subclavian vein; arterial TOS (ATOS)—compression of subclavian artery; and neurogenic TOS (NTOS)—compression of brachial plexus. Postural Orthostatic Tachycardia Syndrome (POTS) is characterized by orthostatic tachycardia that develops in the absence of orthostatic hypotension, with a symptom duration of >6 months. POTS is now known to be commonly associated with Ehlers-Danlos Syndrome (EDS), thereby raising speculation about the extent of prevalence of TOS symptoms in EDS patients. The aim of the study was to quantify the influx of patients with POTS, reporting symptoms of arm fatigue with or without numbness and tingling. The symptoms were quantified initially by conducting postural maneuvers that would reproduce the symptoms, to rule-in the possibility of TOS and further confirmed by using ultrasonography in upper limbs as the imaging modality of choice to evaluate arterial and/or venous compression. This study also looks at the presence of a concurrent diagnosis of EDS among the symptomatic patients who test positive for TOS.