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Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) for which the molecular mediators remain unclear. We therefore conducted an expression analysis of human muscle biopsies from patients with T2D; normoglycemic but insulin-resistant subjects with a parental family history (FH + ) of T2D; and family history-negative control individuals (FH -). Actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator megakaryoblastic leukemia 1 (MKL1) had increased expression in T2D and FH + groups. Furthermore, striated muscle activator of Rho signaling (STARS), an activator of SRF, was upregulated in T2D and FH + and was inversely correlated with insulin sensitivity. Skeletal muscle from insulin-resistant mice recapitulated this gene expression pattern and showed reduced G-actin and increased nuclear localization of MKL1, each of which regulates SRF activity. Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation, whereas reduction of STARS expression increased insulin signaling and glucose uptake. Pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice in vivo. Thus, SRF pathway alterations are linked to insulin resistance, may contribute to T2D pathogenesis, and could represent therapeutic targets.

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Introduction Deaths have increased, and prescription medications are involved in a significant percentage of deaths. Emergency department (ED) changes to managing acute pain and prescription drug monitoring programs (PDMPs) can impact the potential for abuse. Methods We analyzed the impact of a series of quality improvement initiatives on the opioid prescribing habits of emergency department physicians and advanced practice providers. We compared historical prescribing patterns with those after three interventions: 1) the implementation of a PDMP, 2) clinician education on alternatives to opioids (ALTOs), and 3) electronic health record (EHR) process changes. Results There was a 61.8% decrease in the percentage of opioid-eligible ED discharges that received a prescription for an opioid from 19.4% during the baseline period to 7.4% during the final intervention period. Among these discharges, the cumulative effect of the interventions resulted in a 17.3% decrease in the amount of morphine milligram equivalents (MME) prescribed per discharge from a mean of 104.9 MME/discharge during the baseline period to 86.8 MME/discharge. In addition, the average amount of MME prescribed per discharge became aligned with recommended guidelines over the intervention periods. Conclusions Initiating a PDMP and instituting an aggressive ALTO program along with EHR-modified process flows have cumulative benefits in decreasing MME prescribed in an acute ED setting.

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