Efficient skin regeneration remains a clinical challenge due to the complex biological processes involved and the limitations of existing wound dressings, including biological inertness and inadequate biodegradability. Herein, we developed an injectable composite gel consisting of PLCL/CaHA composite microspheres followed by integration into a CMC/mannitol hydrogel carrier, which enables uniform dispersion of CaHA nanoparticles within the PLCL matrix-analogous to a "nuts-in-chocolate" structure. Structural characterization confirmed that CaHA nanoparticles were homogeneously embedded within the porous PLCL microspheres, forming an integrated composite architecture. In vitro, the PLCL/CaHA composite significantly enhanced L929 fibroblast migration, upregulated ECM-related gene expression, and promoted fibronectin deposition and Ki67-positive proliferation compared to controls. In a murine full-thickness wound model, treatment with PLCL/CaHA accelerated wound closure, enhanced angiogenesis with improved vessel maturation, and induced M2 macrophage polarization, leading to superior tissue regeneration. These findings demonstrate that this structurally engineered composite creates a favorable regenerative microenvironment and represents a promising platform for soft tissue repair.

Limited vascularization remains a major barrier for bone regeneration. However, current pro-angiogenic approaches mostly rely on exogenous growth factors, which could result in uncontrolled release, rapid decline in bioactivity, and persistently pro-inflammatory microenvironment in defect area. Here, an injectable carboxymethyl cellulose sodium (CMC) and mannitol hydrogel embedded with poly(L-lactide-co-epsilon-caprolactone)/ carbonated hydroxyapatite (PLCL/CaHA) composite microspheres was developed. The microsphere-in-hydrogel system with homogeneous dispersion of CaHA enables sustained release of Ca2+ and PO43- ions. The system can markedly enhance endothelial activity in vitro, and promote vascular regeneration through sphingosine-1phosphate (S1P)-activated metabolism in bone defect area in vivo. The PLCL/CaHA composite increases the S1P level in defect area, activates S1P receptor 1 (S1PR1), and enhances Ras-related C3 botulinum toxin substrate 1 (RAC1) level, which downstreamly facilitates cytoskeletal remodeling, endothelial activation and the coupling of angiogenic osteogenesis. Our study obtained a PLCL/CaHA microsphere-in-hydrogel system for vascularization in bone defect area, and revealed metabolic reprogramming mechanism, advancing their role from passive structural support to active regulation of the bone regenerative microenvironment.

BACKGROUND:Sodium-glucose cotransporter 2 inhibitor (SGLT2i) improves beta-cell function in animals and humans with diabetes. Herein, we aimed to investigate the effects of SGLT2i on beta-cell regeneration, trace the origin of regenerated beta cells, and reveal the potential mechanism. METHODS:Type 2 and type 1 diabetic mice were treated with canagliflozin (10 mg/kg), dapagliflozin (1 mg/kg), or vehicle. Islet morphology was evaluated to investigate beta-cell regeneration. Inducible pancreatic neurogenin 3 (Ngn3) + progenitor lineage-tracing mice and alpha-cell lineage-tracing mice were used to trace the origin of regenerated cells. Mouse and human islets, alpha cells, and beta cells were incubated with dapagliflozin (12.5 μmol/L) or vehicle. Insulin and glucagon-like peptide-1 (GLP-1) release, gene expression, and RNA sequencing analysis were performed to clarify the direct actions of SGLT2i and to screen potential targets. Alpha cells were transfected with peroxisome proliferator-activated receptor-γ coactivator 1α ( Ppargc1α ) plasmid or with Ppargc1α siRNA, followed by incubation with or without dapagliflozin to confirm the effects of Ppargc1α in alpha-cell phenotype conversion. RESULTS:SGLT2i increased islet and beta-cell areas in type 2 diabetic mice and showed a similar trend in type 1 diabetic mice. SGLT2i induced alpha-cell dedifferentiation into Ngn3 + progenitors and promoted progenitor differentiation toward beta cells. In cultured diabetic mouse and human islets and in stressed alpha cells, SGLT2i increased supernatant insulin and active GLP-1 levels, downregulated alpha-cell-specific marker expression, and upregulated the expression of endocrine progenitor- and beta-cell-specific markers, including prohormone convertase 1/3. Although dapagliflozin did not affect beta cells directly, it affected alpha cells (457 upregulated and 235 downregulated genes). Ppargc1α, a coactivator participating in oxidative phosphorylation, was identified as a potential target. By using overexpression and knockdown, we confirmed that Ppargc1α participated in SGLT2i-induced regulation of alpha-cell phenotype conversion. CONCLUSION:Alpha-cell regression to progenitors and progenitor differentiation toward beta cells represent a novel pathway for beta-cell neogenesis induced by SGLT2i in diabetes, with Ppargc1α playing a role in this process.

Chiral nanostructures exhibit unique immunomodulatory properties by engaging stereospecific recognition mechanisms within biological systems, enabling precision immune engineering. Yet the underlying mechanisms of chiral-dependent effects on immune cells-specifically, how distinct chiral configurations activate intracellular cascades to elicit anti-tumor effects-remain poorly understood. Here, we engineered chiral silver-shelled gold nanoparticles (Au@Ag-L/D NPs) with specifically tailored morphologies and plasmon-enhanced photoresponsivity, demonstrating that chiral particles with weak optical dissymmetric factors can sufficiently elicit enantiomer-dependent immune reprogramming. Notably, D-enantiomers preferentially bind to scavenger receptors to disrupt lysosomal autophagy, effectively repolarizing tumor-associated macrophages from pro-tumorigenic M2 to antitumor M1 phenotypes. Combined with near-infrared light-triggered hyperthermia and ROS generation, chirality-guided M1 polarization amplifies anti-tumor immunity while enabling localized tumor ablation. In vivo, D NPs with photoirradiation enhanced tumor suppression in colorectal cancer models through concerted immunological microenvironment remodeling and multi-modal tumor eradication. This study thus established precise chirality-immunomodulation coordination, by combining phototherapy with immunotherapy to synergistically enhance tumor ablation and reverse immunosuppression.

The overuse of antibiotics has led to the emergence of drug-resistant bacteria, posing a serious threat to human health and increasing the medical burden. Metal–organic frameworks (MOFs) have shown great potential as enzyme mimics for antibacterial applications; however, their performance is often limited by the low density and poor accessibility of active sites. Herein, we report an innovative surface-active agent intercalation–assisted confinement growth strategy for constructing two-dimensional (2D) NH₂-BDC-Cu, Fe nanosheets (NSs) with highly exposed active site to enhance reactive oxygen species (ROS) generation, thereby improving the antibacterial efficiency against drug-resistant bacteria. We demonstrate that the synthesized 2D NH₂-BDC-Cu, Fe NSs exhibit 6.6-fold higher ROS production compared to NH₂-BDC-Cu, Fe nanopowders (NPs). Consequently, NH₂-BDC-Cu, Fe NSs achieve 100 % antibacterial activity against both Staphylococcus aureus and Escherichia coli within 1 h, markedly outperforming NH₂-BDC-Cu, Fe NPs and previously reported biomaterials. Moreover, in vivo experiments confirm that NH₂-BDC-Cu, Fe NSs accelerate wound healing, achieving a 100 % healing rate within 10 days, which is substantially higher than that of NH₂-BDC-Cu, Fe NPs. Overall, this work introduces a novel and efficient strategy for fabricating 2D MOF nanoenzymes with high active-site exposure, offering great promise for the development of advanced biomaterial-based antibacterial therapies.

BACKGROUND:Pancreatic β-cell regeneration represents a promising therapeutic strategy for diabetes, yet safe and effective treatments remain elusive. PURPOSE:We aimed to investigate whether and how mulberry twig (Sangzhi) alkaloids (SZ-A), a newly approved anti-diabetic Chinese medicine, promoted β-cell regeneration. METHODS:Diabetic db/db mice and pancreatic α-cell lineage-tracing mice were treated with SZ-A, acarbose, or vehicle daily via intragastric gavage. Blood glucose and plasma insulin levels were measured. The areas of islets, α-cells and β-cells were quantified. Cell transdifferentiation was assessed by double-immunostaining of glucagon or α-cell lineage-tracing marker with β-cell-specific markers. Mouse α-cells were incubated with SZ-A or its three main components, and the mRNA levels of cell transdifferentiation-related genes were detected. RNA-sequencing was performed to screen potential targets. The activities of five mitochondrial complexes were detected following treatment, and specific inhibitor was utilized to validate the involvement. RESULTS:Both SZ-A and acarbose improved glycemic control, but only SZ-A enlarged islet and β-cell areas in the diabetic mice. SZ-A induced α-to-β-cell conversion, as indicated by glucagon and insulin double-immunostaining and confirmed by α-cell lineage-tracing. In cultured α-cells, SZ-A and its main component 1-deoxynojirimycin (DNJ) downregulated the expressions of α-cell-specific markers, while upregulated the expressions of β-cell-specific markers. DNJ-induced differentially expressed genes were enriched in the mitochondrial protein complex term. DNJ inhibited mitochondrial complex I activity, and the complex inhibitor induced α-to-β-cell conversion. CONCLUSION:SZ-A, especially its main component DNJ, induces α-to-β-cell transdifferentiation via inhibiting mitochondrial complex I. Our finding provides a potential strategy for β-cell regeneration and diabetes treatment.

Introduction and Objective: This study aimed to explore the mechanism of glucagon receptor (GCGR) antagonism-induced α-cell phenotype conversion. Methods: Streptozotocin-induced diabetic mice were treated with GCGR monoclonal antibody (mAb) or vehicle. ELISA, IF and transcriptomic analysis were evaluated to uncover the mechanism. Foxa2 knockdown α-cell line, GLP-1 receptor (GLP-1R) antagonist in mouse primary islets and global Glp1r knockout mice were used to clarify the pathway. Results: The number of glucagon+ cells, glucagon+ GLP-1+ cellls (indicating pro-α-cells), glucagon+Ngn3+ cells (indicating progenitors), and glucagon+insulin+ cells (indicating α-to-β cell transdifferentiation) were higher in GCGR mAb group, suggesting that GCGR antagonism promoted α-cell regeneration and induced α-cell-pro-α-cell-progenitor-β-cell conversion. Additionally, GLP-1 production and GLP-1R staining in α-cells were enhaced with GCGR mAb treatment in diabetic mice. GCGR mAb upregulated Ngn3 and Pcsk1 expression and GLP-1 production in mouse primary islets, while addition of GLP-1R antagonist reversed these effects. Notably, the glucagon+ cell area were boosted to a similar level in GCGR mAb-treated Flox/cre littermates and Glp1r-/- mice, while the numbers of glucagon+GLP-1+ cells and glucagon+insulin+ cells were both decreased in GCGR mAb-treated Glp1r-/- mice compared to GCGR mAb-treated littermates. By transcriptomic analysis, Foxa2 expression was found to decrease in isolated α-cells of GCGR antagonism group and its knockdown in α-cell line resulted in downregulation of mature α-cell markers, Arx and Pax6, and upregulation of Pcsk1, similarly to GCGR antagonism. Conclusion: GCGR antagonism could promote α-cell converting to GLP-1-producing pro-α-cells and to β-cells sequentially. Enhanced GLP-1/GLP-1R autocrine loop mediates GCGR antagonism induced-α-cell phenotype conversion and FoxA2 potentially participate in this process. T. Wei: None. X. Cui: None. D. Wang: None. X. Liao: None. J. Yang: None. R. Wei: None. T. Hong: None. Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0507000, 2023ZD0506900), National Natural Science Foundation of China (82270843, 82400936)

Abstract This study focused on the biosynthetic gene cluster BGC3 of Streptococcus mutans, a primary pathogen in dental caries, and its effects on the cariogenic virulence of Streptococcus mutans. BGC3 and ∆BGC3 Streptococcus mutans strains were constructed, and their growth curves were evaluated. Further, their acid production capacity was assessed by comparing their pH reduction levels. The survival of bacteria in phosphate citrate buffer solution (pH 3.0) was quantified. The expression levels of virulence genes (atpF, gtfC, gtfD, spaP, vicR, and ftf) were analysed using the reverse transcription-quantitative polymerase chain reaction. Bacterial viability was determined by microscopical examination of live/dead staining. Co-culture experiments were conducted to evaluate bacterial adaptability. The elimination of BGC3 did not significantly impact Streptococcus mutans growth or acid production in biofilms. The ∆BGC3 strain exhibited enhanced acid resistance and higher expression levels of virulence genes. In co-culture, ∆BGC3 exhibited superior bacterial viability. BGC3 reduced the cariogenic virulence of Streptococcus mutans in terms of acid tolerance and the expression of related genes. The knockout strain exhibited a more robust survival capability than the wild-type strain.

Bone tissue renewal can be enhanced through co-transplantation of bone mesenchymal stem cells (BMSCs) and vascular endothelial cells (ECs). However, there are apparent limitations in stem cell-based therapy which hinder its clinic translation. Hence, we investigated the potential of alternative stem cell substitutes for facilitating bone regeneration. In this study, we successfully prepared cell membrane vesicles (CMVs) from BMSCs and ECs. The results showed that BMSC-derived cell membrane vesicles (BMSC-CMVs) possessed membrane receptors involved in juxtacrine signaling and growth factors derived from their parental cells. EC-derived cell membrane vesicles (EC-CMVs) also contained BMP2 and VEGF derived from their parental cells. BMSC-CMVs enhanced tube formation and migration ability of hUVECs, while EC-CMVs promoted the osteogenic differentiation of hBMSCs in vitro. Using a rat skull defect model, we found that co-transplantation of BMSC-CMVs and EC-CMVs could stimulate angiogenesis and bone formation in vivo . Therefore, our research might provide an innovative and feasible approach for cell-free therapy in bone tissue regeneration.

Mesenchymal stem cell (MSC) migration determines the healing capacity of bone and is crucial in promoting bone regeneration. Migration of MSCs is highly dependent on degradation of extracellular matrix by proteolytic enzymes. However, the underlying mechanisms of how enzymolysis paves the way for MSCs to migrate from their niche to the defect area is still not fully understood. Here, this study shows that high-temperature requirement A3 (HtrA3) overcomes the physical barrier and provides anchor points through collagen IV degradation, paving the way for MSC migration. HtrA3 is upregulated in MSCs at the leading edge of bone defect during the early stage of healing. HtrA3 degrades the surrounding collagen IV, which increases the collagen network porosity and increases integrin β1 expression. Subsequently, integrin β1 enhances the mechanotransduction of MSCs, thus remodeling the cytoskeleton, increasing cellular stiffness and nuclear translocation of YAP, eventually promoting the migration and subsequent osteogenic differentiation of MSCs. Local administration of recombinant HtrA3 in rat cranial bone defects significantly increases new bone formation and further validates the enhancement of MSC migration. This study helps to reveal the novel roles of HtrA3, explore potential targets for regenerative medicine, and offer new insights for the development of bioactive materials.

Angiogenesis is a complex, highly-coordinated and multi-step process of new blood vessel formation from pre-existing blood vessels. When initiated, the sprouting process is spearheaded by the specialized endothelial cells (ECs) known as tip cells, which guide the organization of accompanying stalk cells and determine the function and morphology of the finally-formed blood vessels. Recent studies indicate that the orchestration and coordination of angiogenesis involve dynamic tip cell selection, which is the competitive selection of cells to lead the angiogenic sprouts. Therefore, this review attempt to summarize the underlying mechanisms involved in tip cell specification in a dynamic manner to enable readers to gain a systemic and overall understanding of tip cell formation, involving cooperative interaction of cell rearrangement with Notch and YAP/TAZ signaling. Various mechanical and chemical signaling cues are integrated to ensure the right number of cells at the right place during angiogenesis, thereby precisely orchestrating morphogenic functions that ensure correct patterning of blood vessels.

Sodium-glucose co-transporter 2 (SGLT2) inhibitor, an efficacious anti-diabetic agent, which has cardiovascular and renal benefits, can promote pancreatic β-cell regeneration in type 2 diabetic mice. However, the underlying mechanism remains unclear. In this study, we aimed to use multi-omics to identify the mediators involved in β-cell regeneration induced by dapagliflozin. We showed that dapagliflozin lowered blood glucose level, upregulated plasma insulin level, and increased islet area in db/db mice. Dapagliflozin reshaped gut microbiota, and modulated microbiotic and plasmatic metabolites related to tryptophan metabolism, especially L-tryptophan, in the diabetic mice. Notably, L-tryptophan upregulated the mRNA level of GLP-1 production-related genes (Gcg and Pcsk1) expression and promoted GLP-1 secretion in cultured mouse intestinal L-cells, and it increased supernatant insulin level in primary human islets, which was eliminated by GPR142 antagonist. Transplantation of fecal microbiota from dapagliflozin-treated mice, supplementation of L-tryptophan or treatment with dapagliflozin upregulated L-tryptophan, GLP-1, and insulin or C-peptide level, and promoted β-cell regeneration in db/db mice. Addition of exendin 9-39, a GLP-1 receptor (GLP-1R) antagonist, or pancreatic Glp1r knockout diminished these beneficial effects. In summary, treatment with dapagliflozin in type 2 diabetic mice promotes β-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism.

The cover image is based on the Research Article Dapagliflozin improves pancreatic islet function by attenuating microvascular endothelial dysfunction in type 2 diabetes by Yunyi Le et al., https://doi.org/10.1002/dmrr.3607.

Dysfunction of glucagon-secreting α-cells participates in the progression of diabetes, and glucagon receptor (GCGR) antagonism is regarded as a novel strategy for diabetes therapy. GCGR antagonism upregulates glucagon and glucagon-like peptide-1 (GLP-1) secretion, and notably promotes β-cell regeneration in diabetic mice. Here, we aimed to clarify the role of GLP-1 receptor (GLP-1R) activated by glucagon and/or GLP-1 in the GCGR antagonism-induced β-cell regeneration. We showed that in db/db mice and type 1 diabetic wild-type or Flox/cre mice, GCGR monoclonal antibody (mAb) improved glucose control, upregulated plasma insulin level, and increased β-cell area. Notably, blockage of systemic or pancreatic GLP-1R signaling by exendin 9-39 (Ex9) or Glp1r knockout diminished the above effects of GCGR mAb. Furthermore, glucagon neutralizing antibody (nAb), which prevents activation of GLP-1R by glucagon, also attenuated the GCGR mAb-induced insulinotropic effect and β-cell regeneration. In cultured primary mouse islets isolated from normal mice and db/db mice, GCGR mAb action to increase insulin release, and to upregulate β-cell specific marker expression, was reduced by a glucagon nAb, or by the GLP-1R antagonist Ex9, or by a pancreas-specific Glp1r knockout. These findings suggest that activation of GLP-1R by glucagon participates in β-cell regeneration induced by GCGR antagonism in diabetic mice.

The deficiency of pancreatic β-cells is the key pathogenesis of diabetes, while glucagon-secreting α-cells are another player in the development of diabetes. Here, we aimed to investigate the effects of glucagon receptor (GCGR) antagonism on β-cell neogenesis in type 2 diabetic (T2D) mice and explore the origins of the neogenic β-cells. We showed that GCGR monoclonal antibody (mAb) elevated plasma insulin level and increased β-cell mass in T2D mice. By using α-cell lineage-tracing (glucagon -cre -β-gal) mice and inducible Ngn3+ pancreatic endocrine progenitor lineage-tracing (Ngn3-CreERT2-tdTomato) mice, we found that GCGR mAb treatment promoted α-cell regression to progenitors, and induced Ngn3+ progenitor reactivation and differentiation toward β-cells. Besides, GCGR mAb upregulated the expression levels of β-cell regeneration-associated genes and promoted insulin secretion in primary mouse islets, indicative of a direct effect on β-cell identity. Our findings suggest that GCGR antagonism not only increases insulin secretion but also promotes pro-α-cell-derived β-cell neogenesis in T2D mice.

Sodium‐glucose co‐transporter 2 inhibitors, including dapagliflozin, improve ß cell function in type 2 diabetic individuals. Whether dapagliflozin can protect islet microvascular endothelial cells (IMECs) and thus contribute to the improvement of ß cell function remains unknown.

Pancreatic β-cell neogenesis in vivo holds great promise for cell replacement therapy in diabetic patients, and discovering the relevant clinical therapeutic strategies would push it forward to clinical application. Liraglutide, a widely used antidiabetic glucagon-like peptide-1 (GLP-1) analog, has displayed diverse β-cell-protective effects in type 2 diabetic animals. Glucagon receptor (GCGR) monoclonal antibody (mAb), a preclinical agent that blocks glucagon pathway, can promote the recovery of functional β-cell mass in type 1 diabetic mice. Here, we conducted a 4-week treatment of the two drugs alone or in combination in type 1 diabetic mice. Although liraglutide neither lowered the blood glucose level nor increased the plasma insulin level, the immunostaining showed that liraglutide expanded β-cell mass through self-replication, differentiation from precursor cells, and transdifferentiation from pancreatic α cells to β-cells. The pancreatic β-cell mass increased more significantly after GCGR mAb treatment, while the combination group did not further increase the pancreatic β-cell area. However, compared with the GCGR mAb group, the combined treatment reduced the plasma glucagon level and increased the proportion of β-cells/α-cells. Our study evaluated the effects of liraglutide, GCGR mAb monotherapy, and combined strategy in glucose control and islet β-cell regeneration and provided useful clues for the future clinical application in type 1 diabetes.

The present study aimed to investigate the effects of sericin on the p38MAPK signaling pathway and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the kidney of rats with type 2 diabetes mellitus (T2DM). A total of 36 male Sprague-Dawley rats were randomly divided into the normal group, T2DM model group and sericin group (n=12 rats/group). A T2DM model was developed through intraperitoneal injection of streptozotocin (35 mg·kg-1·d-1 for 2 consecutive days), and a high-fat and high-sugar diet. The T2DM rats in the sericin group were administered 2.4 g·kg-1·d-1 sericin for 35 days, and rats in the other groups were administered an equal volume of normal saline for 35 days. Fasting blood glucose was measured using the glucose oxidase method. Kidney tissue morphology was observed by H&E staining. Immunohistochemistry, western blotting, ELISA and reverse transcription-quantitative PCR were used to detect the levels of MKK6, p38MAPK, phosphorylated (p)-p38MAPK, NF-κB, IL-1β, IL-6, NLRP3 and caspase-1 in rat kidney tissues. The results revealed that blood glucose concentration, and the expression levels of MKK6, p-p38MAPK, NF-κB, IL-1β, IL-6, NLRP3 and caspase-1 were significantly increased in the T2DM group compared with those in the normal group (P<0.05). In addition, obvious pathological changes were observed in the T2DM group. Conversely, glucose concentration, and the expression levels of MKK6, p-p38MAPK, NF-κB, IL-1β, IL-6, NLRP3 and caspase-1 were significantly reduced in the sericin group compared with those in the T2DM group (P<0.05). The pathological changes were also obviously reduced. Notably, there was no significant difference in p38MAPK expression among the three groups (P>0.05). Collectively, the present study revealed that sericin may downregulate the expression levels of MKK6, p-p38MAPK, NF-κB, IL-1β, IL-6, NLRP3 and caspase-1, and inhibit activation of renal p38MAPK signaling and NLRP3-associated inflammation, which in turn may protect against kidney damage caused by T2DM.

Background: This study explores the prevalence of subthreshold depression (SubD) and its association with factors in type 2 diabetes mellitus (T2DM) patients. Methods: This cross-sectional study involved 808 outpatients with T2DM from ten hospitals in Beijing between September 2015 and January 2016. All participants completed the Patient Health Questionnaire 9-item (PHQ-9) to evaluate depressive status, with scores between 5 and 14 considered SubD. Conditional logistic regression was conducted to investigate the variables associated with SubD in T2DM patients. Results: T2DM patients with SubD comprised 11.6% (n= 94) of the sample. The odd ratios for the variables having significant positive associations with SubD were: being a women (OR= 1.90; 95% CI: 1.09-3.32), divorced/widowed (OR= 3.27; 95% CI: 1.46-7.30), comorbidity of cerebrovascular disease (OR= 2.00; 95% CI: 1.06-3.76), more diabetic complications (OR= 8.04; 95% CI: 2.77-23.31), and higher HbA1c in men (OR= 2.41; 95% CI: 1.25-4.64). Being older (OR= 0.78; 95% CI: 0.62-0.98), exercising more (OR= 0.44; 95% CI: 0.22-0.91) and poverty (OR= 0.36; 95% CI: 0.19-0.69) were negatively related to SubD. Limitations: The sample was mainly recruited from hospital settings, which limits generalization. The study's cross-sectional design precludes making causal inferences. Conclusions: The proportion of SubD was estimated to be 11.6% among T2DM patients in Beijing. Having more diabetic complications and being divorced/widowed made the odds of having SubD 8-fold and 3-fold higher than not having it, respectively. The relationship between SubD and diabetes necessitates early screening for milder forms of depression, which can alleviate the social burden and individual impairment from major depression or other chronic diseases.