Tissue interstitial fluid (ISF) surrounds cells and is an underutilized source of biomarkers that complements conventional sources such as blood and urine. However, ISF has received limited attention ...due largely to lack of simple collection methods. Here, we developed a minimally invasive, microneedle-based method to sample ISF from human skin that was well tolerated by participants. Using a microneedle patch to create an array of micropores in skin coupled with mild suction, we sampled ISF from 21 human participants and identified clinically relevant and sometimes distinct biomarkers in ISF when compared to companion plasma samples based on mass spectrometry analysis. Many biomarkers used in research and current clinical practice were common to ISF and plasma. Because ISF does not clot, these biomarkers could be continuously monitored in ISF similar to current continuous glucose monitors but without requiring an indwelling subcutaneous sensor. Biomarkers distinct to ISF included molecules associated with systemic and dermatological physiology, as well as exogenous compounds from environmental exposures. We also determined that pharmacokinetics of caffeine in healthy adults and pharmacodynamics of glucose in children and young adults with diabetes were similar in ISF and plasma. Overall, these studies provide a minimally invasive method to sample dermal ISF using microneedles and demonstrate human ISF as a source of biomarkers that may enable research and translation for future clinical applications.
In this phase 2 trial, children and young adults with newly diagnosed overt type 1 diabetes were randomly assigned to receive golimumab, a human monoclonal antibody to tumor necrosis factor
α
, or ...placebo. Golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo.
The clinical impact of biotechnology has been constrained by the limitations of traditional hypodermic injection of biopharmaceuticals. Microneedle patches have been proposed as a minimally invasive ...alternative. In this study, the translation of a dissolving microneedle patch designed for simple, painless self‐administration of biopharmacetucials that generates no sharp biohazardous waste is assessed. To study the pharmacokinetics and safety of this approach, human growth hormone (hGH) was encapsulated in 600 μm‐long dissolving microneedles composed of carboxymethylcellulose and trehalose using an aqueous, moderate‐temperature process that maintained complete hGH activity after encapsulation and retained most activity after storage for up to 15 months at room temperature and humidity. After manual insertion into the skin of hairless rats, hGH pharmacokinetics were similar to conventional subcutaneous injection. After patch removal, the microneedles had almost completely dissolved, leaving behind only blunt stubs. The dissolving microneedle patch was well tolerated, causing only slight, transient erythema. This study suggests that a dissolving microneedle patch can deliver hGH and other biopharmaceuticals in a manner suitable for self‐administration without sharp biohazardous waste.
Human growth hormone is encapsulated without loss of activity in a dissolving microneedle patch. The patch is designed for painless self‐administration without generating sharp, biohazardous waste. It achieves a systemic pharmacokinetic profile similar to subcutaneous hypodermic injection in rats, and the microneedles almost completely dissolve while the patch is worn.
Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process ...remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin αIIbβ3 on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to αIIbβ3 adhesive function that leads to a distinct prothrombotic phenotype in diabetes.
Abstract
Context
Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by ...hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled.
Objective
The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones.
Methods
In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo.
Results
DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) SE −5.94 0.879 vs −4.27 1.145; P = .198), but did so in participants with severe hyperphagia (LSmean SE −9.67 1.429 vs −4.26 1.896; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement CGI-I; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant).
Conclusion
DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.
Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies ...show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes.
We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18–45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L−1 on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed).
Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI −0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six 13% participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten 22% participants in the imatinib group and two 9% in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events.
A 26-week course of imatinib preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required.
Juvenile Research Diabetes Foundation.
We report a 13-year-old female with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, panhypopituitarism, dyslipidemia, type 2 diabetes ...mellitus, and nonalcoholic fatty liver disease, who developed rhabdomyolysis and acute kidney injury, two weeks after switching from lovastatin to rosuvastatin. She had been on lovastatin for eight years without any adverse effects.
Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative ...and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D.
In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses.
A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01).
In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy.
https://clinicaltrials.gov/ NCT00965458.
NIH and Astellas.
Aims
To compare the stress level in parents of children with new‐onset type 1 diabetes receiving a fixed insulin dose for a fixed range of carbohydrates (CHOs) to parents of children receiving a ...precise insulin dose for a precise number of CHOs using an insulin‐to‐carbohydrate ratio (ICR).
Methods
Twenty‐four participants (8–14 years) were randomized to receive a fixed dose of insulin for a fixed range of CHOs (FD group) or a precise dose of insulin for a precise number of carbohydrates using an ICR (ICR group). The primary endpoint was parental stress measured with the parental stress survey (PSS) 1 to 4 months after diagnosis. Secondary endpoints included glycemic variability, glycated haemoglobin (HbA1C) and safety.
Results
Compared to parents of children in the ICR group, those from the FD group reported less stress during the first 4 months after diagnosis (p = 0.022). Glycemic variability and HbA1C were similar in both groups. None of the patients from either group required an emergency department visit or hospitalization.
Conclusions
In comparison to precise insulin dosing using an ICR, fixed insulin dosing for a fixed range of CHOs may be less stressful for parents to learn and employ when initially taught diabetes management skills for their child with new‐onset type 1 diabetes.
Microneedles have previously been used to deliver insulin to animal models, but not in human subjects. This study tested the hypothesis that hollow microneedles can deliver insulin to modulate blood ...glucose levels in subjects with type 1 diabetes in a minimally invasive manner.
This study was carried out in two adults with type 1 diabetes and evaluated bolus delivery of lispro insulin using a hollow microneedle compared to a catheter infusion set (9 mm). The study first determined the minimum insulin delivery depth by administering insulin from microneedles inserted 1, 3.5, and 5 mm into the skin of fasting subjects and then assessed the efficacy of insulin delivery from microneedles inserted 1 mm into the skin to reduce postprandial glucose levels. Blood samples were periodically assayed for plasma free insulin and plasma glucose levels for up to 3.5 h.
The first phase of the study indicated that microneedles inserted at the shallowest depth of 1 mm within the skin led to rapid insulin absorption and reduction in glucose levels. Bolus insulin delivery followed by consumption of a standardized meal in the second phase revealed that microneedles were effective in reducing postprandial glucose levels. Subjects reported no pain from microneedle treatments, and there were no adverse events.
This study provides the first proof of concept that hollow microneedles can effectively deliver bolus insulin to type 1 diabetes subjects in a minimally invasive manner.
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