Rexford S. Ahima’s research while affiliated with Johns Hopkins Medicine and other places

Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways in which inositol polyphosphate multikinase (IPMK) functions as a rate-limiting enzyme for inositol polyphosphate metabolism. IPMK has been implicated in cellular metabolism, but its function at the systemic level is still poorly understood. Since skeletal muscle is a major contributor to energy homeostasis, we have developed a mouse model in which skeletal muscle IPMK is specifically deleted and examined how a loss of IPMK affects whole-body metabolism. Here, we report that mice in which IPMK knockout is deleted, specifically in the skeletal muscle, displayed an increased body weight, disrupted glucose tolerance, and reduced exercise tolerance under the normal diet. Moreover, these changes were associated with an increased accumulation of triglyceride in skeletal muscle. Furthermore, we have confirmed that a loss of IPMK led to reduced beta-oxidation, increased triglyceride accumulation, and impaired insulin response in IPMK-deficient muscle cells. Thus, our results suggest that IPMK mediates the whole-body metabolism via regulating muscle metabolism and may be potentially targeted for the treatment of metabolic syndromes.

Inner retinal thinning precedes clinical evidence of retinopathy in prediabetes and diabetes mellitus (DM), and may contribute to retinopathy development and progression. Serum levels of the adipokines leptin and adiponectin are inversely related in the setting of impaired glucose homeostasis, but their potential association with inner retinal thickness is unknown. In this prospective study, both eyes from 24 individuals with prediabetes or type 2 DM (glycated hemoglobin [HbA1c] ≥5.7) and 16 controls (HbA1c<5.7) underwent spectral-domain optical coherence tomography imaging of the macula, and thickness of the nerve fiber layer (NFL) and ganglion cell layer-inner plexiform layer (GCL-IPL) was analyzed in each subfield of the Early Treatment Diabetic Retinopathy Study grid. Serum samples were collected and metabolic factors, including adiponectin and leptin, were measured. Adjusted regression analyses revealed inverse associations of these adipokines with NFL thickness that did not differ between prediabetes/DM and controls, but differential positive associations of adiponectin with GCL-IPL thickness only in the prediabetes/DM group. The results of our pilot study suggest opposing roles for adiponectin and leptin in the retina, similar to their relationship in systemic disease, and suggest that serum adiponectin may represent a potential clinical biomarker for inner retinal thickness in patients with elevated HbA1c.

Objective To examine the associations of renin–angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology. Methods Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate‐1 (IRS‐1) and RAC‐alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses. Results Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin‐converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pT³⁰⁸AKT1/total AKT1, but not with pS³⁰⁷IRS‐1/total IRS‐1 or the density of cells stained positive for pS⁶¹⁶ IRS‐1. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau‐neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts. Interpretation Late‐life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles.

OBJECTIVE Little is known about the extent to which microvascular disease is associated with cardiorespiratory fitness (CRF) among individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 4,766 participants with type 2 diabetes underwent maximal exercise testing in the Look AHEAD (Action for Health in Diabetes) study at baseline. Low CRF was defined based on the Aerobics Center Longitudinal Study reference standards. Microvascular disease was defined as having one or more of diabetes-related kidney disease (DKD), retinopathy, and neuropathy. The burden of microvascular disease was defined as the number of microvascular beds affected. RESULTS Of the 4,766 participants (mean age 58.9 ± 6.7 years, 58.5% women, 66.1% White individuals), 1,761 (37%) had microvascular disease. Participants with microvascular complications in three vascular territories had a lower CFR than those without any microvascular disease (mean adjusted metabolic equivalent of task [MET] 6.58 vs. 7.26, P = 0.001). Participants with any microvascular disease had higher odds of low CRF than those without microvascular disease (adjusted odds ratio [OR] 1.45, 95% CI 1.24–1.71). An increasing burden of microvascular disease was associated with higher odds of low CRF (for microvascular disease in three vascular territories, adjusted OR 2.82, 95% CI 1.36–5.85). Adjusted ORs for low CRF were 1.24 (95% CI 0.99–1.55), 1.34 (95% CI 1.02–1.76), and 1.44 (95% CI 1.20–1.73) for neuropathy, retinopathy, and DKD associations, respectively. CONCLUSIONS In a large cohort of adults with type 2 diabetes, the presence of microvascular disease and its burden were independently associated with lower CRF.

Objective To examine associations of serum insulin and related measures with neuropathology and cognition in older persons. Methods We studied 192 older persons (96 with diabetes and 96 without, matched by sex and balanced by age-at-death, education, and postmortem interval) from a community-based, clinical-pathologic study of aging, with annual evaluations including neuropsychological testing (summarized into global cognition and 5 cognitive domains) and postmortem autopsy. We assessed serum insulin, glucose, leptin, adiponectin, hemoglobin A1C, advanced glycation-end products (AGEs), and receptors for advanced glycation-end products, and calculated the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and adiponectin-to-leptin ratio. Using adjusted regression analyses, we examined the associations of serum measures with neuropathology of cerebrovascular disease and Alzheimer's disease, and with the level of cognition proximate-to-death. Results Higher HOMA-IR was associated with the presence of brain infarcts and specifically microinfarcts, and higher HOMA-IR and leptin were each associated with subcortical infarcts. Further, higher leptin levels and lower adiponectin-to-leptin ratios were associated with the presence of moderate-to-severe atherosclerosis. Serum insulin and related measures were not associated with the level of Alzheimer's disease pathology, as assessed by global, as well as amyloid burden or tau tangle density scores. Regarding cognitive outcomes, higher insulin and leptin levels, and lower adiponectin and receptors for advanced glycation-end products levels, respectively, were each associated with lower levels of global cognition. Interpretation Peripheral insulin resistance indicated by HOMA-IR and related serum measures was associated with a greater burden of cerebrovascular neuropathology and lower cognition.