Transendothelial Insulin Transport is Impaired in Skeletal Muscle Capillaries of Obese Male Mice.

Objective: The continuous endothelium of skeletal muscle (SkM) capillaries regulates insulin's access to skeletal myocytes. Whether impaired transendothelial insulin transport (EIT) contributes to SkM insulin resistance (IR), however, is unknown.

Methods: Male and female C57/Bl6 mice were fed either chow or a high-fat diet for 16 weeks.

A Patient-Driven Approach to Manage Mealtime Insulin Titration: Tools From the AUTONOMY Study.

Purpose: Patient-centric methods to support diabetes management are important to overcome barriers associated with initiating mealtime insulin. This article describes the subject-driven titration tools implemented in the AUTONOMY trial to initiate and adjust mealtime insulin dose and the methods used to apply these tools in clinical practice.

Conclusions: The methods used to initiate and escalate mealtime insulin in the AUTONOMY trial proved to be safe and effective, and the patient-friendly guide to self-adjusting mealtime insulin dose may mitigate the complexities associated with treatment intensification while empowering patients to reach their glycemic goals.

Evaluation of a patient self-directed mealtime insulin titration algorithm: a US payer perspective.

Objective To model the potential economic impact of implementing the AUTONOMY once daily (Q1D) patient self-titration mealtime insulin dosing algorithm vs standard of care (SOC) among a population of patients with Type 2 diabetes living in the US. Methods Three validated models were used in this analysis: The Treatment Transitions Model (TTM) was used to generate the primary results, while both the Archimedes (AM) and IMS Core Diabetes Models (IMS) were used to test the veracity of the primary results produced by TTM. Models used data from a 'real world' representative sample of patients (2012 US National Health and Nutrition Examination Survey) that matched the characteristics of US patients enrolled in the randomized controlled trial 'AUTONOMY' cohort.

Enhanced mitochondrial superoxide scavenging does not improve muscle insulin action in the high fat-fed mouse.

Improving mitochondrial oxidant scavenging may be a viable strategy for the treatment of insulin resistance and diabetes. Mice overexpressing the mitochondrial matrix isoform of superoxide dismutase (sod2(tg) mice) and/or transgenically expressing catalase within the mitochondrial matrix (mcat(tg) mice) have increased scavenging of O2(˙-) and H2O2, respectively. Furthermore, muscle insulin action is partially preserved in high fat (HF)-fed mcat(tg) mice.

Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice.

Elevated reactive oxygen species (ROS) are linked to insulin resistance and islet dysfunction. Manganese superoxide dismutase (SOD2) is a primary defense against mitochondrial oxidative stress. To test the hypothesis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2(+/+)) and heterozygous knockout mice (sod2(+/-)) were fed a chow or high-fat (HF) diet, which accelerates ROS production.

Relaxin treatment reverses insulin resistance in mice fed a high-fat diet.

The endogenous hormone relaxin increases vascular reactivity and angiogenesis. We demonstrate that acute relaxin infusion in lean C57BL/6J mice enhances skeletal muscle perfusion and augments muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. However, an acute effect was absent in mice fed a high-fat (HF) diet for 13 weeks.

Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance.

Increased deposition of specific extracellular matrix (ECM) components is a characteristic of insulin-resistant skeletal muscle. Hyaluronan (HA) is a major constituent of the ECM. The hypotheses that 1) HA content is increased in the ECM of insulin-resistant skeletal muscle and 2) reduction of HA in the muscle ECM by long-acting pegylated human recombinant PH20 hyaluronidase (PEGPH20) reverses high-fat (HF) diet-induced muscle insulin resistance were tested.

Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance.

Muscle insulin resistance is associated with a reduction in vascular endothelial growth factor (VEGF) action and muscle capillary density. We tested the hypothesis that muscle capillary rarefaction critically contributes to the etiology of muscle insulin resistance in chow-fed mice with skeletal and cardiac muscle VEGF deletion (mVEGF(-/-)) and wild-type littermates (mVEGF(+/+)) on a C57BL/6 background. The mVEGF(-/-) mice had an ~60% and ~50% decrease in capillaries in skeletal and cardiac muscle, respectively.