An insulin-regulated arrestin domain protein controls hepatic glucagon action.

Glucagon signaling is essential for maintaining normoglycemia in mammals. The arrestin fold superfamily of proteins controls the trafficking, turnover, and signaling of transmembrane receptors as well as other intracellular signaling functions. Further investigation is needed to understand the in vivo functions of the arrestin domain-containing 4 (ARRDC4) protein family member and whether it is involved in mammalian glucose metabolism. Here, we show that mice with a global deletion of the ARRDC4 protein have impaired glucagon responses and gluconeogenesis at a systemic and molecular level. Mice lacking ARRDC4 exhibited lower glucose levels after fasting and could not suppress gluconeogenesis at the refed state. We also show that ARRDC4 coimmunoprecipitates with the glucagon receptor, and ARRDC4 expression is suppressed by insulin. These results define ARRDC4 as a critical regulator of glucagon signaling and glucose homeostasis and reveal a novel intersection of insulin and glucagon pathways in the liver.

Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver.

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show that Arrdc3 is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction in Arrdc3 messenger RNA, while, conversely, mice with liver-specific KO of Arrdc3 (L-Arrdc3 KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus, Arrdc3 is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

Continuous glucose monitor use in type 2 diabetes mellitus in pregnancy and perinatal outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess whether continuous glucose monitor use in type 2 diabetes mellitus in pregnancy is associated with improved perinatal outcomes. DATA SOURCES: We searched Ovid MEDLINE, Scopus, ClinicalTrials.gov, and Cochrane library from inception through May 9, 2022. STUDY ELIGIBILITY CRITERIA: We included all studies that compared continuous glucose monitor use with fingerstick glucose monitoring in women with type 2 diabetes mellitus. METHODS: The initial search yielded 2463 unique citations that were screened in Covidence by 2 independent reviewers. Study types included randomized controlled trials, cohort studies, and cross-sectional studies. Our outcomes of interest were macrosomia or large-for-gestational-age infants, hemoglobin A1c, cesarean delivery, hypertensive disorders of pregnancy including preeclampsia, gestational age at delivery, and neonatal hypoglycemia. RESULTS: Three randomized controlled trials met the inclusion criteria. We performed random-effects meta-analyses of estimates from 2 studies without risk of significant bias and reported summary adjusted odds ratios and 95% confidence intervals. Meta-analysis of 56 women with continuous glucose monitor use and 53 control women without continuous glucose monitor use showed that there was no difference in the incidence of large-for-gestational-age infants between continuous glucose monitor users and standard-of-care controls (odds ratio, 0.78; 95% confidence interval, 0.34-1.78) with an I2 of 0%. In addition, there was no difference in the development of preeclampsia between continuous glucose monitor users and standard-of-care controls (odds ratio, 1.63; 95% confidence interval, 0.34-7.22) with an I2 of 0%. CONCLUSION: Continuous glucose monitor use was not associated with improved perinatal outcomes as assessed by large-for-gestational-age infants and preeclampsia. This review is limited by the small amount of data available for this population, and further research is needed.

Loss of mouse Stmn2 function causes motor neuropathy.

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration accompanied by aberrant accumulation and loss of function of the RNA-binding protein TDP43. Thus far, it remains unresolved to what extent TDP43 loss of function directly contributes to motor system dysfunction. Here, we employed gene editing to find whether the mouse ortholog of the TDP43-regulated gene STMN2 has an important function in maintaining the motor system. Both mosaic founders and homozygous loss-of-function Stmn2 mice exhibited neuromuscular junction denervation and fragmentation, resulting in muscle atrophy and impaired motor behavior, accompanied by an imbalance in neuronal microtubule dynamics in the spinal cord. The introduction of human STMN2 through BAC transgenesis was sufficient to rescue the motor phenotypes observed in Stmn2 mutant mice. Collectively, our results demonstrate that disrupting the ortholog of a single TDP43-regulated RNA is sufficient to cause substantial motor dysfunction, indicating that disruption of TDP43 function is likely a contributor to ALS.