MicroRNAs Associated with Metformin Treatment in the Diabetes Prevention Program.

The Diabetes Prevention Program (DPP) randomized controlled trial demonstrated that metformin treatment reduced progression to type 2 diabetes (T2D) by 31% compared to placebo in adults with prediabetes. Circulating micro-ribonucleic acids (miRs) are promising biomarkers of T2D risk, but little is known about their associations with metformin regimens for T2D risk reduction. We compared the change in 24 circulating miRs from baseline to 2 years in a subset from DPP metformin intervention (n = 50) and placebo (n = 50) groups using Wilcoxon signed rank tests. Spearman correlations were used to evaluate associations between miR change and baseline clinical characteristics. Multiple linear regression was used to adjust for covariates. The sample was 73% female, 17% Black, 13% Hispanic, and 50 ± 11 years. Participants were obese, normotensive, prediabetic, and dyslipidemic. Change in 12 miR levels from baseline to 2 years was significantly different in the metformin group compared with placebo after adjusting for multiple comparisons: six (let-7c-5p, miR-151a-3p, miR-17-5p, miR-20b-5p, miR-29b-3p, and miR-93-5p) were significantly upregulated and six (miR-130b-3p, miR-22-3p, miR-222-3p, miR-320a-3p, miR-320c, miR-92a-3p) were significantly downregulated in the metformin group. These miRs help to explain how metformin is linked to T2D risk reduction, which may lead to novel biomarkers, therapeutics, and precision health strategies.

Intranasal delivery of low-dose insulin ameliorates motor dysfunction and dopaminergic cell death in a 6-OHDA rat model of Parkinson's Disease.

Emerging evidence continues to demonstrate that disrupted insulin signaling and altered energy metabolism may play a key role underpinning pathology in neurodegenerative conditions. Intranasally administered insulin has already shown promise as a memory-enhancing therapy in patients with Alzheimer's and animal models of the disease. Intranasal drug delivery allows for direct targeting of insulin to the brain, bypassing the blood brain barrier and minimizing systemic adverse effects. In this study, we sought to expand upon previous results that show intranasal insulin may also have promise as a Parkinson's therapy. We treated 6-OHDA parkinsonian rats with a low dose (3 IU/day) of insulin and assessed apomorphine induced rotational turns, motor deficits via a horizontal ladder test, and dopaminergic cell survival via stereological counting. We found that insulin therapy substantially reduced motor dysfunction and dopaminergic cell death induced by unilateral injection of 6-OHDA. These results confirm insulin's efficacy within this model, and do so over a longer period after model induction which more closely resembles Parkinson's disease. This study also employed a lower dose than previous studies and utilizes a delivery device, which could lead to an easier transition into human clinical trials as a therapeutic for Parkinson's disease.

Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation.

In addition to the hallmark accumulation of amyloid and hyper-phosphorylation of tau, brain changes in Alzheimer's disease are multifactorial including inflammation, oxidative stress, and metal dysregulation. Metal chelators have been explored as a less well known approach to treatment. One chelator currently being developed is deferoxamine (DFO), administered via the intranasal (IN) route. In the current study, APP/PS1 amyloid mice were treated with a chronic, low dose of IN DFO, subjected to a rigorous battery of behavior tests, and the mechanism of action was examined. Mice were treated 3x/week with 0.24 C IN DFO for 18 weeks from 36 to 54 weeks of age, 4 weeks of behavior tests were performed that included both working and reference memory, anxiolytic and motor behaviors, and finally brain tissues were analyzed for amyloid, protein oxidation, and other proteins affected by DFO. We found that IN DFO treatment significantly decreased loss of both reference and working memory in the Morris and radial arm water mazes (p < 0.05), and also decreased soluble Aß40 and Aß42 in cortex and hippocampus (p < 0.05). Further, IN DFO decreased activity of GSK3ß, and led to decreases in oxidative stress (p < 0.05). These data demonstrate that low doses of IN DFO can modify several targets along the multiple pathways implicated in the neuropathology of Alzheimer's, making it an attractive candidate for the treatment of this heterogeneous disease.