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Skeletal muscle is the main metabolic tissue responsible for glucose homeostasis in the body. It is surrounded by the extracellular matrix (ECM) consisting of three layers: epimysium, perimysium, and endomysium. ECM plays an important role in the muscle, as it provides integrity and scaffolding cells. The observed disturbances in this structure are related to the abnormal remodeling of the ECM (through an increase in the concentration of its components). ECM rearrangement may impair insulin action by increasing the physical barrier to insulin transport and reducing insulin transport into muscle cells as well as by directly inhibiting insulin action through integrin signaling. Thus, improper ECM remodeling may contribute to the development of insulin resistance (IR) and related comorbidities. In turn, IR-associated conditions may further aggravate disturbances of ECM in skeletal muscle. This review describes the major components of the ECM that are necessary for its proper function. Particular attention was also paid to receptors (integrins) involved in the signaling of metabolic pathways. Finally, changes in ECM components in the context of clinical and animal studies are discussed. This article will help the reader to systematize knowledge related to the ECM and to better understand the relationship between ECM remodeling and IR, and its role in the pathogenesis of T2DM. The information in this article presents the concept of the role of ECM and its remodeling in the pathogenesis of IR, which may contribute to developing new therapeutic solutions.

Investigating sex chromosome trisomies (SCTs) may help in understanding neurodevelopmental pathways underlying the risk for neurobehavioral problems and psychopathology. Knowledge about the neurobehavioral phenotype is needed to improve clinical care and early intervention for children with SCT. This is especially relevant considering the increasing number of early diagnosed children with the recent introduction of noninvasive prenatal screening. The TRIXY Early Childhood Study is a longitudinal study designed to identify early neurodevelopmental risks in children with SCT, aged 1–7 years. This review summarizes the results from the TRIXY Early Childhood Study, focusing on early behavioral symptoms in areas of autism spectrum disorder, attention-deficit hyperactivity disorder, and communication disorders, and underlying neurocognitive mechanisms in domains of language, emotion regulation, executive functioning, and social cognition. Behavioral symptoms were assessed through structured behavior observation and parental questionnaires. Neurocognition was measured using performance tests, eyetracking, and psychophysiological measures of arousal. In total, 209 children aged 1–7 years were included: 107 children with SCT (33 XXX, 50 XXY, and 24 XYY) and 102 age-matched population controls. Study outcomes showed early behavioral symptoms in young children with SCT, and neurocognitive vulnerabilities, already from an early age onward. Neurobehavioral and neurocognitive difficulties tended to become more pronounced with increasing age and were rather robust, independent of specific karyotype, pre/postnatal diagnosis, or ascertainment strategy. A more longitudinal perspective on neurodevelopmental ‘at-risk’ pathways is warranted, also including studies assessing the effectiveness of targeted early interventions. Neurocognitive markers that signal differences in neurodevelopment may prove to be helpful in this. Focusing on early development of language, social cognition, emotion regulation, and executive functioning may help in uncovering early essential mechanisms of (later) neurobehavioral outcome, allowing for more targeted support and early intervention.

Conditions related to cardiometabolic disease, including metabolic syndrome and type 2 diabetes, are common among men with Klinefelter syndrome (KS). The molecular mechanisms underlying this aberrant metabolism in KS are largely unknown, although there is an assumption that chronic testosterone deficiency plays a role. This cross-sectional study compared plasma metabolites in 31 pubertal adolescent males with KS to 32 controls of similar age (14 ± 2 years), pubertal stage, and body mass index z-score of 0.1 ± 1.2 and then between testosterone-treated (n = 16) and untreated males with KS. The plasma metabolome in males with KS was distinctly different from that in controls, with 22% of measured metabolites having a differential abundance and seven metabolites nearly completely separating KS from controls (area under the curve > 0.9, P < 0.0001). Multiple saturated free fatty acids were higher in KS, while mono- and polyunsaturated fatty acids were lower, and the top significantly enriched pathway was mitochondrial β-oxidation of long-chain saturated fatty acids (enrichment ratio 16, P < 0.0001). In contrast, there were no observed differences in metabolite concentrations between testosterone-treated and untreated individuals with KS. In conclusion, the plasma metabolome profile in adolescent males with KS is distinctly different from that in males without KS independent of age, obesity, pubertal development, or testosterone treatment status and is suggestive of differences in mitochondrial β-oxidation.

This study aimed to characterize how the dysregulation of counter-regulatory hormones can contribute to insulin resistance and potentially to diabetes. Therefore, we investigated the association between insulin sensitivity and the glucose- and insulin-dependent secretion of glucagon, adrenocorticotropic hormone (ACTH), and cortisol in non-diabetic individuals using a population model analysis. Data, from hyperinsulinemic–hypoglycemic clamps, were pooled for analysis, including 52 individuals with a wide range of insulin resistance (reflected by glucose infusion rate 20–60 min; GIR_20–60min). Glucagon secretion was suppressed by glucose and, to a lesser extent, insulin. The GIR_20–60min and BMI were identified as predictors of the insulin effect on glucagon. At normoglycemia (5 mmol/L), a 90% suppression of glucagon was achieved at insulin concentrations of 16.3 and 43.4 µU/mL in individuals belonging to the highest and lowest quantiles of insulin sensitivity, respectively. Insulin resistance of glucagon secretion explained the elevated fasting glucagon for individuals with a low GIR_20–60min. ACTH secretion was suppressed by glucose and not affected by insulin. The GIR_20–60min was superior to other measures as a predictor of glucose-dependent ACTH secretion, with 90% suppression of ACTH secretion by glucose at 3.1 and 3.5 mmol/L for insulin-sensitive and insulin-resistant individuals, respectively. This difference may appear small but shifts the suppression range into normoglycemia for individuals with insulin resistance, thus, leading to earlier and greater ACTH/cortisol response when the glucose falls. Based on modeling of pooled glucose-clamp data, insulin resistance was associated with generally elevated glucagon and a potentiated cortisol-axis response to hypoglycemia, and over time both hormonal pathways may therefore contribute to dysglycemia and possibly type 2 diabetes.