Browsing by Subject "type 2 diabetes"

Background: The global rise in early-onset type 2 diabetes (T2D) is impacting the lives of millions of young individuals around the world. To address the knowledge gap and emotional burden in young adults with T2D, the research team designed a four-week education and goal-based peer support intervention, Kanasina Gulabi (Kannada: My Dream Rose), implemented in Mysore, India between June and July 2023. Methods: The Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework was used to assess feasibility. Peer navigators (n=3, mean age: 33 years) were recruited from the community and trained to deliver the intervention. Twenty-eight adults ≤ 40 years of age with T2D were recruited and quasi-randomly allocated to the intervention group (n=14, mean age: 33 years) or the control group (n=14, mean age: 33 years). Hemoglobin A1c, T2D knowledge, diabetes distress, diabetes-related stigma, depression severity, and optimism were assessed at baseline, immediately after the intervention, and at the 2-month follow-up. Attendance, fidelity, and acceptability were also assessed. Results: Intervention participants expressed high satisfaction with Kanasina Gulabi and gratitude for the guided knowledge and mentorship from their peer navigators. Participants displayed excellent attendance and adherence, with an average of 5 hours of Kanasina Gulabi exposure over 4 weeks. Peer navigators delivered the intervention with 100% fidelity. Results immediately following the intervention showed reductions in diabetes distress (Intervention: 30.9%, Control: 6.5%), diabetes-related stigma (Intervention: 25.3%, Control: 14.5%), and depression severity (Intervention: 58.3%, Control: 38.5%). Both groups presented an increase in T2D knowledge (Intervention: 19.7%, Control: 25.2%). Conclusion: Implementing Kanasina Gulabi in Mysore is feasible and acceptable, with intervention participants showing more positive changes on multiple psychosocial outcomes compared to the control group. Results support a full trial to evaluate its effectiveness and sustainability in young adults with T2D.

Globalization scholars have disagreed about the effects of globalization on the production and reproduction of difference: Do fundamental differences endure, do cultures converge, or is there hybridization? This dissertation analyzes the durability of distinct medical cultures in two technologically advanced healthcare systems that rely on an evidence-based, biomedical approach. Durability refers to the tendency to maintain or develop diverse, even idiosyncratic, practices and beliefs--even as the forces of globalization are perceived to be pressing health practices everywhere toward a single global standard. To do so, this dissertation offers a comparative, empirically based argument using the case of type 2 diabetes in the U.S. and Japan. As an inductive, theory-constructing project, the argument has at its foundation 11 months of ethnographic field work in Japanese hospitals and clinic exam rooms, 115 semi-structured interviews with patients and biomedical health practitioners in Japan, and 25 interviews with American health care providers and patients. I argue that physicians in both research sites, Okayama, Japan and North Carolina, USA, practice empirical biomedicine, but that empirical biomedicine is not all there is to biomedical practice. Practicing physicians in both contexts act not only on increasingly globalized professional standards, but also on local knowledge, on their own explanatory models for type 2 diabetes, and in reaction to local patient populations' explanatory models. Further, local knowledge and patient interactions shape the ways in which practicing physicians interpret global standards and best practices. Occasionally, they may even be reshaped beyond recognition without interfering with physicians' self-evaluation as participants in a universal, standardized scientific project. The interaction of globalizing standards of practice, local knowledge, and local explanatory models of illness can result in dramatically divergent medical practice across different social contexts--in this case, the U.S. and Japan.

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The delivery of therapeutic peptides and proteins is often challenged by a short circulation half-life, necessitating frequent injections that limit efficacy, reduce patient compliance and increase treatment cost. The covalent conjugation of therapeutic peptides and proteins, and more recently oligonucleotide-based drugs, with the “stealth” polymer poly(ethylene glycol) (PEG), termed PEGylation, is one of the most commonly used approaches to increase the in vivo half-life and reduce the immunogenicity of these therapeutic biomolecules. However, after several decades of research and clinical use, the limitations of PEGylation have begun to emerge.

Conventional methods for synthesizing peptide/protein-polymer conjugates have drawbacks including low yield, non-trivial separation of conjugates from reactants, and lack of control over site and stoichiometry of conjugation, which results in heterogeneous products with significantly compromised biological activity. Additionally, anti-PEG antibodies have been induced in patients treated with PEGylated drugs and have been shown to correlate with rapid clearance of these drugs. High levels of pre-existing anti-PEG antibodies have also been found in individuals naïve to PEGylated agents, which are associated with serious first-exposure allergic reactions.

To address the synthetic limitations of PEGylation, a general approach for the high-yield synthesis of site-specific (C-terminal) and stoichiometric (1:1) peptide/protein-polymer conjugates, named sortase-catalyzed polymer conjugation, was developed. Demonstrating proof-of-concept of the approach with green fluorescent protein (GFP) as a model protein, sortase A from Staphylococcus aureus was used to site-specifically attach an initiator solely at the C-terminus of GFP, followed by in situ growth of the PEG-based brush polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) from the protein macroinitiator by atom transfer radical polymerization (ATRP). Sortase-catalyzed initiator attachment proceeded with high specificity and near-complete (~ 95%) product conversion. Subsequent in situ ATRP in aqueous buffer produced 1:1 stoichiometric conjugates with > 90% yield, tunable MW, low dispersity, and no denaturation of the protein. The extraordinarily high yield compares favorably to order of magnitude losses typically seen in conventional PEGylation processes.

Next, the therapeutic potential of POEGMAlation, or the conjugation of POEGMA to a peptide or protein, was demonstrated by implementing the developed sortase-catalyzed polymer conjugation strategy with exendin-4 (exendin), a therapeutic peptide for treating type 2 diabetes, to synthesize exendin-C-POEGMA conjugates with a wide and tunable range of molecular weights (MWs) and low dispersity. A single subcutaneous injection of exendin-C-POEGMA conjugates lowered blood glucose for up to 120 h in a diabetic mouse model. Most intriguingly, we showed that appending PEG as oligomeric side-chains on the conjugated POEGMA and tuning the side-chain length completely eliminated the reactivity of exendin-C-POEGMA conjugates toward patient-derived anti-PEG antibodies without compromising in vivo efficacy. Clinically, the lack of anti-PEG antigenicity of POEGMA conjugates is expected to completely eliminate serious first-exposure allergic reactions and the accelerated blood clearance of POEGMA-drug conjugates due to pre-existing anti-PEG antibodies in patients.

Collectively, these results establish POEGMAlation as a next-generation PEGylation technology that is highly useful for improving the pharmacological performance of therapeutic biomolecules while providing a timely solution to the increasing levels of pre-existing anti-PEG antibodies in patients that are seriously hindering the safety and efficacy of traditional PEGylated drugs.

Abstract

Problem: African Americans face a disparate risk for renal disease development secondary to type 2 diabetes (T2D), and African-American women have shown to be at the highest risk. Despite this, there is minimal research on African American's awareness of renal disease and existing renal disease risk perceptions, and none focused specifically on African-American women with T2D. Although the literature has shown that a portion of this disparate risk is due to modifiable social and cultural factors, there is still a significant amount of unexplained risk. Since past research has shown that risk perceptions can influence preventative behaviors, it is important to gain an in-depth understanding of renal disease beliefs and existing risk perceptions among high-risk African-American women with T2D. Once risk perceptions are better understood in this population, interventions can be developed to correct inaccurate beliefs and risk perceptions and aim to decrease renal disease risk.

Methods: Three different methods of analyses were employed in this dissertation, including: 1) a systematic review of the literature, 2) an exploratory, descriptive, qualitative study, and 3) a quantitative secondary analysis, including descriptive statistics, a cluster analysis and mixed modeling. The Common Sense Model guided all three studies and these three methods of evaluation helped us to gain a more complete understanding of renal disease risk perceptions in African Americans, particularly African-American women with T2D, and provided guidance for future intervention research in this population.

Conclusions: The findings of this dissertation illustrated there is a significant gap in the literature on African American's renal disease awareness and risk perceptions, yet the available research was used to guide the in-depth interviews with African-American women with T2D. Overall, African Americans underestimate their renal disease risk and lack an understanding of the disease, even in the presence of risk factors. African-American women, in particular, related renal disease directly to the end-stages of the disease, perceived a greater risk for other complications of diabetes, and exhibited significant fear related to their perceived consequences of the disease. This fear frequently initiated maladaptive coping mechanisms, which influenced risk perceptions negatively and hindered preventative behaviors. This study also found that health care providers rarely discussed the disease and often exhibited provider control. Therefore, these findings suggest an urgent need for clinical practice suggestions and intervention research aimed at correcting inaccurate risk perceptions. The secondary analysis findings showed that a culturally relevant intervention with coping skills training resulted in significant improvements in renal disease risk factors among high-risk African-American women with T2D; however, we cannot be sure which facets of the intervention or control care for equal attention may have influenced these outcomes, and renal disease beliefs and risk perceptions were not assessed in the parent study. Therefore, the knowledge gained from this dissertation can be used to guide intervention research that evaluates change over time in renal disease risk representations, risk perceptions, coping procedures and outcomes among participants at high-risk for renal disease.