Worldwide approximately 232 million or 50% of people with type 2 diabetes mellitus (T2D) are undiagnosed. Furthermore, 81% with prediabetes (PreD), more than 77 million in the United States, are undiagnosed. This disproportionately affects the underserved, underrepresented, and lower socioeconomic communities, which account for 79% with T2D. Earlier identification could halt or delay disease progression, decreasing irreversible complications, and helping reduce the associated $966 billion global expenditure. Our prior publications demonstrated that increased deltoid muscle echo intensity (MEI) on ultrasound (US) was accurate for the incidental detection of T2D and PreD, independent of the patient’s age and duration of disease (including those recently diagnosed with T2D/PreD). This increased skeletal MEI was also more pronounced when compared to subjects with obesity but without T2D/PreD. Furthermore, it was observed in undiagnosed/incident T2D and PreD by ADA criteria, and in some patients it appeared to predate abnormal HbA1c elevations. Additionally, our exciting preliminary findings demonstrated that this increased skeletal MEI corresponded with varying degrees of skeletal muscle insulin resistance and muscle dysfunction—including fibrosis, myosteatosis, and reduced contractile force. The potential to noninvasively detect developing skeletal muscle insulin resistance and muscle dysfunction, before the onset of glucose dysregulation, as a harbinger of T2D, is a metabolic circumstance that does not exist. The overall objective of this project is to test the hypothesis that increased MEI can be used to accurately detect developing skeletal muscle insulin resistance and muscle dysfunction. We propose to accomplish this in two specific aims. First, by performing prospective USs of upper and lower extremity skeletal muscles in two cohorts with MEI quantifications and obtaining concurrent labs (Aim 1), we can define the relationship between MEI and clinical markers of diabetes and insulin resistance. Also, for the first time, biopsies will be taken directly from this increased skeletal MEI (Aim 2) to elucidate this novel early T2D-related US muscle abnormality and its association with muscle dysfunction. We hypothesize that by performing prospective US, labs, and muscle biopsies, we will clarify the associations and impact of this muscle finding for structural, functional, and histopathologic alterations (Aims 1 and 2). This proposed project has the potential to clarify the cause and significance of this muscle abnormality which could represent earlier detection of developing muscle insulin resistance and muscle dysfunction, prior to clinically apparent metabolic dysfunction. An easy, noninvasive, inexpensive, and nonionizing imaging method to detect developing skeletal muscle insulin resistance and muscle dysfunction, as a harbinger of T2D, would have tremendous clinical impact by allowing earlier interventions and more aggressive treatments for metabolic and muscle dysfunction, prior to these complications accelerating. Furthermore, expanding our understanding about factors in skeletal muscle that underlie elevated MEI can help optimize treatments to prevent or treat this abnormality.
