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1. The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

   https://doi.org/10.1038/s41467-022-35176-7  

   Dall’Agnese, Alessandra; Platt, Jesse M.; Zheng, Ming M.; Friesen, Max; Dall’Agnese, Giuseppe; Blaise, Alyssa M.; Spinelli, Jessica B.; Henninger, Jonathan E.; Tevonian, Erin N.; Hannett, Nancy M.; et al (December 2022, Nature Communications)

   Abstract Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches. 

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2. Trafficking of nonesterified fatty acids in insulin resistance and relationship to dysglycemia

   https://doi.org/10.1152/ajpendo.00331.2019  

   Walker, Rachel E.; Ford, Jennifer L.; Boston, Raymond C.; Savinova, Olga V.; Harris, William S.; Green, Michael H.; Shearer, Gregory C. (March 2020, American Journal of Physiology-Endocrinology and Metabolism)

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   In adipose, insulin functions to suppress intracellular lipolysis and secretion of nonesterified fatty acid (NEFA) into plasma. We applied glucose and NEFA minimal models (MM) following a frequently sampled intravenous glucose tolerance test (FSIVGTT) to assess glucose-specific and NEFA-specific insulin resistance. We used total NEFA and individual fatty acids in the NEFA MM, comparing the model parameters in metabolic syndrome (MetSyn) subjects ( n = 52) with optimally healthy controls (OptHC; n = 14). Results are reported as mean difference (95% confidence interval). Using the glucose MM, MetSyn subjects had lower [−73% (−82, −57)] sensitivity to insulin (S i ) and higher [138% (44, 293)] acute insulin response to glucose (AIR g ). Using the NEFA MM, MetSyn subjects had lower [−24% (−35, −13)] percent suppression, higher [32% (15, 52)] threshold glucose (g s ), and a higher [81% (12, 192)] affinity constant altering NEFA secretion (ϕ). Comparing fatty acids, percent suppression was lower in myristic acid (MA) than in all other fatty acids, and the stearic acid (SA) response was so unique that it did not fit the NEFA MM. MA and SA percent of total were increased at 50 min after glucose injection, whereas oleic acid (OA) and palmitic acid (PA) were decreased ( P < 0.05). We conclude that the NEFA MM, as well as the response of individual NEFA fatty acids after a FSIVGTT, differ between OptHC and MetSyn subjects and that the NEFA MM parameters differ between individual fatty acids. 

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3. Hippocampal-specific insulin resistance elicits behavioral despair and hippocampal dendritic atrophy

   https://doi.org/10.1016/j.ynstr.2021.100354  

   Reagan, L.P.; Cowan, H.B.; Woodruff, J.L.; Piroli, G.G.; Erichsen, J.M.; Evans, A.N.; Burzynski, H.E.; Maxwell, N.D.; Loyo-Rosado, F.Z.; Macht, V.A.; et al (November 2021, Neurobiology of Stress)
4. Insulin Resistance as a Therapeutic Target in the Treatment of Alzheimer's Disease: A State-of-the-Art Review

   https://doi.org/10.3389/fnins.2018.00215  

   Benedict, Christian; Grillo, Claudia A. (April 2018, Frontiers in Neuroscience)
5. Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice

   https://doi.org/10.1038/s41467-020-16298-2  

   Alexopoulos, Stephanie J.; Chen, Sing-Young; Brandon, Amanda E.; Salamoun, Joseph M.; Byrne, Frances L.; Garcia, Christopher J.; Beretta, Martina; Olzomer, Ellen M.; Shah, Divya P.; Philp, Ashleigh M.; et al (December 2020, Nature Communications)

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