Brigitta Ellycia Sitepu

Background: The coexistence of tuberculosis (TB) with other chronic diseases, such as diabetes mellitus (DM) and hypertension, presents a growing challenge for efforts to end TB due to the complex interactions of coordinated care among relevant care providers and increased risk of adverse outcomes. The comorbidities between TB and DM underscore the necessity of integrated care approaches that span screening, diagnosis, and treatment. Although integrated care models have the potential to improve patient outcomes by supporting people to complete treatment, improving retention in care, and streamlining service delivery, the understanding of low integration within existing health systems is also limited. This scoping review aims to map existing models of integrated TB, DM, and hypertension case management, identify potential benefits and examine barriers to integration, and define strategies for effective implementation. Methods: This scoping review examined original research papers on the integrated management of TB, DM, and hypertension, published from January 2005 to January 2025. Studies of various designs were included and sourced from databases such as MEDLINE, Scopus, ScienceDirect, and EMERALD using targeted search terms. Four reviewers independently screened and extracted data using a standardized form. Findings were synthesized qualitatively and discussed with experts for additional insights. Discussion: From 7,983 studies screened, 126 studies met the inclusion criteria. The findings reveal that integrated management of TB, DM, and hypertension can improve access to care, program retention, and early detection of comorbidities. Integration of services—including screening, diagnosis, treatment, counseling, and support for patients’ self-management—was generally well-received, practical to implement, and contributed to improved patient outcomes. Nevertheless, several barriers remain, such as fragmented health systems, lack of standardized protocols, inadequate provider training, limited health information systems, and insufficient financing mechanisms. Addressing these challenges requires systemic interventions, including strengthened policy and regulatory frameworks, capacity-building through structured training, robust and interoperable information systems, inter-program coordination, task-shifting strategies, and patient-centered care approaches. While the evidence highlights the potential of integrated care, gaps remain in demonstrating long-term outcomes and cost-effectiveness, underscoring the need for further research and evaluation to support the scale-up of successful models across diverse health system contexts.

Mitochondrial RNA (mtRNA) modifications have emerged as critical regulators of pancreatic β-cell bioenergetics, influencing glucose-stimulated insulin secretion (GSIS) and the early pathogenesis of diabetes mellitus (DM). This review synthesizes current evidence on the diversity, mechanisms, and functional implications of mtRNA modifications—such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), pseudouridine (Ψ), and 5-formylcytosine (f5C)—within β-cell mitochondria. These chemical marks, installed and recognized by specific writer, eraser, and reader proteins, regulate mitochondrial translation, oxidative phosphorylation (OXPHOS) complex assembly, and redox balance. Defects in mtRNA modification machinery, exemplified by β-cell-specific knockout of TFB1M, MRM2, or PUS1, impair ribosome biogenesis, disrupt ATP production, and precipitate insulin secretory failure, as demonstrated in human islets, rodent models, and monogenic diabetes syndromes. Advances in epitranscriptomic mapping technologies—including nanopore direct RNA sequencing, RNA immunoprecipitation (RIP)-seq, and mass spectrometry—have enabled high-resolution profiling of mtRNA modification landscapes under physiological and diabetic conditions, revealing their dynamic regulation in response to metabolic stress. Furthermore, mtRNA modifications interact with environmental stressors, such as oxidative damage and toxic metals, modulating β-cell vulnerability via pathways like the mitochondrial unfolded protein response (UPRmt). Therapeutically, modulation of RNA-modifying enzymes or restoration of specific chemical marks holds promise for preserving β-cell function, with potential applications in early diagnosis, risk stratification, and precision medicine approaches for DM. Despite substantial progress, critical gaps remain in understanding the interplay between mtRNA modifications, mitochondrial-nuclear crosstalk, and β-cell plasticity. Addressing these gaps will be pivotal for translating mtRNA biology into novel biomarkers and targeted interventions for early-stage diabetes.