Diabetes Therapy Research Articles

Near-infrared light-activatable, analgesic nanocomposite delivery system for comprehensive therapy of diabetic wounds in rats

Impaired angiogenesis, bacterial infection, persistent severe pain, exacerbated inflammation, and oxidative stress injury are intractable problems in the treatment of chronic diabetic ulcer wounds. A strategy that effectively targets all these issues has proven challenging. Herein, an in-situ sprayable nanoparticle-gel composite comprising platinum clusters (Pt) loaded-mesoporous polydopamine (MPDA) nanoparticle and QX-314-loaded fibrin gel (Pt@MPDA/QX314@Fibrin) was developed for diabetic wound analgesia and therapy. The composite shows good local analgesic effect of QX-314 mediated by near-infrared light (NIR) activation of transient receptor potential vanilloid 1 (TRPV1) channel, as well as multifunctional therapeutic effects of rapid hemostasis, anti-inflammation, antioxidation, and antibacterial properties that benefit the fast-healing of diabetic wounds. Furthermore, it demonstrates that the composite, with good biodegradability and biosafety, significantly relieved wound pain by inhibiting the expression of c-Fos in the dorsal root ganglion and the activation of glial cells in the spinal cord dorsal horn. Consequently, our designed sprayable Pt@MPDA/QX314@Fibrin composite with good biocompatibility, NIR activation of TRPV1 channel-mediated QX-314 local wound analgesia and comprehensive treatments, is promising for chronic diabetic wound therapy.

Generation of a human induced pluripotent stem cell line overexpressing CCL22 with islet cells differentiation potential

CCL22 is a macrophage-derived immunosuppressive chemokine that recruits regulatory T cells through the CCL22:CCR4 axis, playing an important role in homeostatic and inflammatory responses. A CCL22-overexpressing human induced pluripotent stem cell line (CNNDi001-A-2) was generated by lentiviral transduction to further study the function of CCL22. The cell line was confirmed to have normal proliferation and pluripotency and could be further differentiated into islet cells for cell replacement therapy in diabetes.

Regulation of multiple signaling pathways promotes the consistent expansion of human pancreatic progenitors in defined conditions

The unlimited expansion of human progenitor cells in vitro could unlock many prospects for regenerative medicine. However, it remains an important challenge as it requires the decoupling of the mechanisms supporting progenitor self-renewal and expansion from those mechanisms promoting their differentiation. This study focuses on the expansion of human pluripotent stem (hPS) cell-derived pancreatic progenitors (PP) to advance novel therapies for diabetes. We obtained mechanistic insights into PP expansion requirements and identified conditions for the robust and unlimited expansion of hPS cell-derived PP cells under GMP-compliant conditions through a hypothesis-driven iterative approach. We show that the combined stimulation of specific mitogenic pathways, suppression of retinoic acid signaling, and inhibition of selected branches of the TGFβ and Wnt signaling pathways are necessary for the effective decoupling of PP proliferation from differentiation. This enabled the reproducible, 2000-fold, over 10 passages and 40–45 d, expansion of PDX1+/SOX9+/NKX6-1+ PP cells. Transcriptome analyses confirmed the stabilization of PP identity and the effective suppression of differentiation. Using these conditions, PDX1+/SOX9+/NKX6-1+ PP cells, derived from different, both XY and XX, hPS cell lines, were enriched to nearly 90% homogeneity and expanded with very similar kinetics and efficiency. Furthermore, non-expanded and expanded PP cells, from different hPS cell lines, were differentiated in microwells into homogeneous islet-like clusters (SC-islets) with very similar efficiency. These clusters contained abundant β-cells of comparable functionality as assessed by glucose-stimulated insulin secretion assays. These findings established the signaling requirements to decouple PP proliferation from differentiation and allowed the consistent expansion of hPS cell-derived PP cells. They will enable the establishment of large banks of GMP-produced PP cells derived from diverse hPS cell lines. This approach will streamline SC-islet production for further development of the differentiation process, diabetes research, personalized medicine, and cell therapies.

Regulation of multiple signaling pathways promotes the consistent expansion of human pancreatic progenitors in defined conditions.

The unlimited expansion of human progenitor cells in vitro could unlock many prospects for regenerative medicine. However, it remains an important challenge as it requires the decoupling of the mechanisms supporting progenitor self-renewal and expansion from those mechanisms promoting their differentiation. This study focuses on the expansion of human pluripotent stem (hPS) cell-derived pancreatic progenitors (PP) to advance novel therapies for diabetes. We obtained mechanistic insights into PP expansion requirements and identified conditions for the robust and unlimited expansion of hPS cell-derived PP cells under GMP-compliant conditions through a hypothesis-driven iterative approach. We show that the combined stimulation of specific mitogenic pathways, suppression of retinoic acid signaling, and inhibition of selected branches of the TGFβ and Wnt signaling pathways are necessary for the effective decoupling of PP proliferation from differentiation. This enabled the reproducible, 2000-fold, over 10 passages and 40-45 d, expansion of PDX1+/SOX9+/NKX6-1+ PP cells. Transcriptome analyses confirmed the stabilization of PP identity and the effective suppression of differentiation. Using these conditions, PDX1+/SOX9+/NKX6-1+ PP cells, derived from different, both XY and XX, hPS cell lines, were enriched to nearly 90% homogeneity and expanded with very similar kinetics and efficiency. Furthermore, non-expanded and expanded PP cells, from different hPS cell lines, were differentiated in microwells into homogeneous islet-like clusters (SC-islets) with very similar efficiency. These clusters contained abundant β-cells of comparable functionality as assessed by glucose-stimulated insulin secretion assays. These findings established the signaling requirements to decouple PP proliferation from differentiation and allowed the consistent expansion of hPS cell-derived PP cells. They will enable the establishment of large banks of GMP-produced PP cells derived from diverse hPS cell lines. This approach will streamline SC-islet production for further development of the differentiation process, diabetes research, personalized medicine, and cell therapies.

Fluorometric and colorimetric dual-mode sensing of α-glucosidase based on aggregation-induced emission enhancement of AuNCs.

Herein, a fluorometric and colorimetric dual-mode assay platform used for α-glucosidase (α-Glu) activity sensing based on aggregation-induced emission enhancement (AIEE) of AuNCs was developed for the first time. The quantum yield (QY) and fluorescence lifetime of AuNCs were successfully ameliorated by Ce3+-triggered AIEE (Ce@AuNCs). Subsequently, on the basis of the inner filter effect (IFE) and dynamic quenching effect (DQE) between 2,6-dichlorophenolindophenol (DCIP) and Ce@AuNCs as well as the reduction of DCIP by ascorbic acid (AA) generated from α-Glu-catalyzed hydrolysis of L-ascorbic acid-2-O-α-D-glucopyranosyl (AA2G), the marriage of fluorometric and colorimetric modes applied for α-Glu activity monitoring was achieved. Besides, the feasibility of this dual-mode sensing system was confirmed by the assays versus potential interfering substances and in real samples. In particular, this system was further applied to evaluate natural α-Glu inhibitors (AGIs) including luteolin, apigenin, and hesperidin. Overall, the multi-mode optical sensor newly designed here has the potential for the accurate discovery of natural anti-diabetes drugs and the therapy of diabetes.

Mechanistic analysis of viscosity-sensitive fluorescent probes for applications in diabetes detection.

Diabetes is one of the most detrimental diseases affecting the human life because it can initiate several other afflictions such as liver damage, kidney malfunctioning, and cardiac inflammation. The primary method for diabetes diagnosis involves the analysis of blood samples to quantify the level of glucose, while secondary diagnostic methods involve the qualitative analysis of obesity, fatigue, etc. However, all these symptoms start showing up only when the patient has been suffering from diabetes for a certain period of time. In order to avoid such delay in diagnosis, the development of specific fluorescent probes has attracted considerable attention. Prominent biomarkers for diabetes include abundance of certain analytes in blood serum, e.g., glucose, methylglyoxal, albumin, and reactive oxygen species; high intracellular viscosity; alteration of enzyme functionality, etc. Among these, high viscosity can greatly affect the fluorescence properties of various chromophores owing to the environment sensitivity of fluorescence spectra. In this review article, we have illustrated the application of some prominent fluorophores such as coumarin, BODIPY, xanthene, and rhodamine in the development of viscosity-dependent fluorescent probes. Detailed mechanistic aspects determining the influence of viscosity on the fluorescent properties of the probes have also been elaborated. Fluorescence mechanisms that are directly affected by the high-viscosity heterogeneous microenvironment are based on intramolecular rotations like twisted intramolecular charge transfer (TICT), aggregation-induced emission (AIE), and through-bond energy transfer (TBET). In this regard, this review article will be highly useful for researchers working in the field of diabetes treatment and fluorescent probes. It also provides a platform for the planning of futuristic clinical translation of fluorescent probes for the early-stage diagnosis and therapy of diabetes.

Cognition and depression in older people with diabetes

Cognitive dysfunction, dementia and depression are typical comorbidities of diabetes and are more common in older people with diabetes than in the general population. Both comorbid diseases have asubstantial impact on the therapy of diabetes and lead to areduction of the functional level in everyday life, the quality of life and are associated with increased mortality. This article summarizes the most important results on the etiology of cognitive dysfunction and depression and their consequences for clinical practice.

Hydrogel-Encapsulated Pancreatic Islet Cells as a Promising Strategy for Diabetic Cell Therapy.

Islet transplantation has now become a promising treatment for insulin-deficient diabetes mellitus. Compared to traditional diabetes treatments, cell therapy can restore endogenous insulin supplementation, but its large-scale clinical application is impeded by donor shortages, immune rejection, and unsuitable transplantation sites. To overcome these challenges, an increasing number of studies have attempted to transplant hydrogel-encapsulated islet cells to treat diabetes. This review mainly focuses on the strategy of hydrogel-encapsulated pancreatic islet cells for diabetic cell therapy, including different cell sources encapsulated in hydrogels, encapsulation methods, hydrogel types, and a series of accessorial manners to improve transplantation outcomes. In addition, the formation and application challenges as well as prospects are also presented.

Could the answer to NAFLD be hidden in diabetic therapy? The impact of T2DM treatment on NAFLD.

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Pig Xenotransplantation in Beta Cell Replacement: Addressing Challenges and Harnessing Potential for Type 1 Diabetes Therapy.

This opinion paper evaluates the potential of porcine islets as a promising alternative in beta cell replacement therapy for Type 1 Diabetes (T1D), juxtaposed with the current limitations of human donor islets. It analyzes the compatibility of pig islets with human glucose metabolism, their prospects as a limitless and high-quality source of beta cells, and the unique immunogenic challenges they present in xenotransplantation. Additionally, the paper discusses the regulatory and ethical considerations pertinent to the use of porcine islets. By synthesizing current research and expert perspectives, the paper highlights both the opportunities and significant barriers that need addressing to advance pig islets as a viable therapeutic option. The findings advocate for a balanced and forward-looking approach to the integration of pig islets in T1D treatment, underscoring the need for continued research and dialogue in this evolving field.

Identification, rapid screening, docking mechanism and in vitro digestion stability of novel DPP-4 inhibitory peptides from wheat gluten with ginger protease.

To better understand the hypoglycemic potential of wheat gluten (WG), we screened dipeptidyl peptidase IV (DPP-4) inhibitory active peptides from WG hydrolysates. WG hydrolysates prepared by ginger protease were found to have the highest DPP-4 inhibitory activity among the five enzymatic hydrolysates, from which a 1-3 kDa fraction was isolated by ultrafiltration. Further characterization of the fraction with nano-HPLC-MS/MS revealed 1133 peptides. Among them, peptides with P'2 (the second position of the N-terminal) and P2 (the second position of the C-terminal) as proline residues (Pro) accounted for 12.44% and 43.69%, respectively. The peptides including Pro-Pro-Phe-Ser (PPFS), Ala-Pro-Phe-Gly-Leu (APFGL), and Pro-Pro-Phe-Trp (PPFW) exhibited the most potent DPP-4 inhibitory activity with IC50 values of 56.63, 79.45, and 199.82 μM, respectively. The high inhibitory activity of PPFS, APFGL, and PPFW could be mainly attributed to their interaction with the S2 pocket (Glu205 and Glu206) and the catalytic triad (Ser630 and His740) of DPP-4, which adopted competitive, mixed, and mixed inhibitory modes, respectively. After comparative analysis of PPFS, PPFW, and PPF, Ser was found to be more conducive to enhancing the DPP-4 inhibitory activity. Interestingly, peptides with P2 as Pro also exhibited good DPP-4 inhibitory activity. Meanwhile, DPP-4 inhibitory peptides from WG showed excellent stability, suggesting a potential application in type 2 diabetes (T2DM) therapy or in the food industry as functional components.

Errors in diabetic insulin therapy and the vitality of proper precautions in Bangladesh: Real-life insights from the developing world.

Insulin therapy errors can have life-threatening consequences in patients with diabetes. Given the increasing prevalence of diabetes and insulin therapy in Bangladesh, it is crucial to identify and prevent these errors. This study uses case-based clinical experiences to thematically analyze insulin therapy errors and propose preventive measures. The study aims to provide valuable insights into the challenges faced in managing insulin therapy in a developing country setting and the importance of involving various stakeholders. This is a qualitative research that used a case study approach to identify and analyze errors in insulin therapy in diabetic patients who had experienced adverse clinical consequences. The cases were thematically analyzed to generate insights into current global health problems resulting from erroneous insulin therapy. The two case studies highlight potential risks of errors in insulin therapy, including poor glycemic control, complications, and death. The analysis also highlights the importance of careful monitoring, checks, and communication among health-care providers, patients, and pharmacists to prevent such errors. In addition, it emphasizes the need for education and awareness among patients and health-care providers to ensure safe and effective insulin therapy. Accurate insulin therapy is crucial for diabetes management and preventing adverse outcomes. Identified themes emphasize improved communication, education, and monitoring to minimize therapy errors. Insights from this study can inform policies and practices for better patient outcomes. Further research can identify the root causes and develop interventions to prevent errors, leading to improved quality of life for diabetics.

A Comparative Study of Regular Dressing versus Negative Dressing in Management of Patients with Diabetic Foot

Introduction: Diabetes is prevalent in 10% of the population worldwide. 2.5% of diabetic patients develop diabetic foot ulcers every year. Negative dressing therapy, foam dressing and conventional dressing are common modalities for managing diabetic foot. The purpose of this study was to compare the outcomes of regular dressing vs. negative dressing in diabetic foot patients. Materials and Methods: This study was conducted with 100 patients between the age of 10 and 85 years as per the inclusion and exclusion criteria. Fifty patients underwent regular dressing, and 50 patients underwent negative dressings. Results: In 82% of patients, complete coverage of the wound occurs by negative dressing, and 52% of patients reported that complete coverage of the wound occurs by regular dressing after 4 weeks. Major post-operative complications were significantly less in patients treated with negative dressing. Conclusion: Negative dressing outperforms conventional dressing regarding wound covering, post-operative complications and cost-effectiveness in diabetic diet therapy.

The State of Diabetes: Understanding India's Epidemic

Globally, the prevalence of diabetes is increasing as a result of ageing populations, urbanisation, obesity rates, and decreased physical activity. Diabetes affects young to middle-aged adults disproportionately in Asian countries, in contrast to the West where the disease primarily affects older people. This could have detrimental long-term implications on the economy and health of a country, particularly for emerging nations. According to projections from the International Diabetes Federation (IDF), there were around 50.8 million diabetics in India in 2010; by 2030, that number is expected to rise to 87.0 million. Reaching a near-normal glycaemic level is the main objective in the treatment of diabetes mellitus. In India, vascular problems and inadequate glycaemic management affect almost half of the patients. Consequently, the development of innovative treatment drugs for diabetes that do not compromise safety or cause complications to worsen is desperately needed. Despite extensive research on diabetes, a cure remains elusive for patients. As a result, this overview discusses current developments in diabetes research, treatment, and therapy.

Wharton's Jelly Mesenchymal Stem Cell Conditioned Medium Ameliorates Diabetes-Induced Testicular Damage and Sperm Abnormalities by Mitigating Oxidative Stress, Apoptosis, and Inflammation.

Diabetes leads to testicular damage and infertility. Mesenchymal stem cells and their secretory trophic factors have shown potential as regenerative therapies for diabetes and its associated complications. This study examined the effects of conditioned medium derived from Wharton's jelly mesenchymal stem cells (WJMSCs-CM) on sperm parameters, reproductive hormones, biochemical parameters, and histological changes in the testes of diabetic rats. Fifty-six male Sprague-Dawley rats (250-300 g) were assigned to eight groups: control, diabetes, and six diabetic groups receiving early or late treatments with WJMSCs-CM (D-CME, D-CML), insulin (D-INSE, D-INSL), or DMEM (D-DME, D-DML). In the early treatment groups, insulin (3 U/day, subcutaneously) and WJMSCs-CM (10 mg/week, intraperitoneally) were administered immediately after diabetes induction; in the late treatment groups, these interventions began 30 days postinduction. Blood glucose and insulin levels, along with sperm parameters, were assessed. Sex hormones, testicular antioxidant enzyme activity, malondialdehyde (MDA), and glutathione (GSH) concentrations were measured using colorimetric methods. Real-time PCR detected Bax, Bcl-2, and tumor necrosis factor-alpha (TNF-α) gene expression. Our results showed that diabetes increased blood glucose levels, decreased insulin and sex hormone levels, induced testicular oxidative stress and apoptosis, and reduced sperm parameters compared to the control. WJMSCs-CM significantly ameliorated hyperglycemia, increased insulin and sex hormone levels, and improved sperm quality. In WJMSCs-CM-treated diabetic rats, MDA levels were reduced, while GSH and antioxidant enzyme activity increased. Furthermore, WJMSCs-CM decreased the testicular Bax/Bcl-2 ratio and TNF-α expression, as well as enhanced spermatogenic, Sertoli, and Leydig cells. In conclusion, WJMSC-CM administration effectively mitigated diabetes-induced testicular damage by reducing oxidative stress, inflammation, and apoptosis. Early treatment with WJMSCs-CM was more effective than late treatment for diabetes-induced reproductive dysfunction.

Reduction of Activin A gives rise to comparable expression of key definitive endoderm and mature beta cell markers.

Aim: Cell therapies for diabetes rely on differentiation of stem cells into insulin-producing cells, which is complex and expensive. Our goal was to evaluate production costs and test ways to reduce it. Methods: Cost of Goods (COGs) analysis for differentiation was completed and the effects of replacement or reduction of the most expensive item was tested using qRT-PCR, immunohistochemistry, flow cytometry along with glucose-stimulated insulin release. Results: Activin A (AA) was responsible for significant cost. Replacement with small molecules failed to form definitive endoderm (DE). Reducing AA by 50% did not negatively affect expression of beta cell markers. Conclusion: Reduction of AA concentration is feasible without adversely affecting DE and islet-like cell differentiation, leading to significant cost savings in manufacturing.

Emerging glucagon-based therapies in diabetes mellitus: Toward a better future in diabetes care

Abstract Diabesity and the related complications are challenging problems in the current era. Conventionally, glucagon was known for its benefit in the management of hypoglycemia due to its involvement in the counter-regulatory mechanism. The studies in the last decade have brought a tremendous change in the therapeutic benefits of glucagon, due to the identification of multiple pleiotropic effects of it. This has resulted in the development of newer therapies for diabetes and obesity by the incorporation of glucagon agonism into incretin-based therapies. These novel dual/triple agonists containing glucagon and incretins give promising and synergistic advantages in the management of metabolic complications of diabesity. The metabolic effects of glucagon receptor antagonists have been disappointing. In addition, novel stable formulations have been developed for the management of hypoglycemia. Dual-hormone automated delivery systems containing insulin and glucagon are another attractive advancement on the process of development to minimize hypoglycemia in long-standing diabetes parallelly with improvement in glycemic control. We summarize the novel mechanisms of glucagon identified and the glucagon-based advancements in the management of diabetes mellitus.

Endoplasmic reticulum stress in pancreatic β-cell dysfunctionality and diabetes mellitus: a promising target for generation of functional hPSC-derived β-cells in vitro.

Diabetes mellitus (DM), is a chronic disorder characterized by impaired glucose homeostasis that results from the loss or dysfunction of pancreatic β-cells leading to type 1 diabetes (T1DM) and type 2 diabetes (T2DM), respectively. Pancreatic β-cells rely to a great degree on their endoplasmic reticulum (ER) to overcome the increased secretary need for insulin biosynthesis and secretion in response to nutrient demand to maintain glucose homeostasis in the body. As a result, β-cells are potentially under ER stress following nutrient levels rise in the circulation for a proper pro-insulin folding mediated by the unfolded protein response (UPR), underscoring the importance of this process to maintain ER homeostasis for normal β-cell function. However, excessive or prolonged increased influx of nascent proinsulin into the ER lumen can exceed the ER capacity leading to pancreatic β-cells ER stress and subsequently to β-cell dysfunction. In mammalian cells, such as β-cells, the ER stress response is primarily regulated by three canonical ER-resident transmembrane proteins: ATF6, IRE1, and PERK/PEK. Each of these proteins generates a transcription factor (ATF4, XBP1s, and ATF6, respectively), which in turn activates the transcription of ER stress-inducible genes. An increasing number of evidence suggests that unresolved or dysregulated ER stress signaling pathways play a pivotal role in β-cell failure leading to insulin secretion defect and diabetes. In this article we first highlight and summarize recent insights on the role of ER stress and its associated signaling mechanisms on β-cell function and diabetes and second how the ER stress pathways could be targeted in vitro during direct differentiation protocols for generation of hPSC-derived pancreatic β-cells to faithfully phenocopy all features of bona fide human β-cells for diabetes therapy or drug screening.

Synthesis and evaluation of 2-phenylamino-1,4-naphthoquinones derivatives as potential hypoglycaemic agents.

Due to the severe side effects revealed by most of the currently used antidiabetic medicines, search for finding new and safe drugs to manage diabetes is continued. Naphthoquinones possessing strong antioxidant properties have been employed as candidates for diabetes therapy. Present study is aimed at finding the antioxidant and hypoglycaemic potential of some novel derivatives of 2-phenylamino-1,4-naphthoquinones (PAN) including chloro, nitro, methyl and bromo (5a-d) derivatives synthesized by single pot experiment. Product crystals were purified by TLC and characterized by FT-IR. The antioxidant potential of the compounds was assayed through DPPH radical scavenging and reducing power activities noted as UV-vis. absorbance. The DPPH assay has showed the powerful antioxidant activity of nitro and bromo derivatives, while the nitro derivative showed the significant reduction potential towards FRAP assay. Hypoglycaemic potential of the compounds was studied in rat animal model. All synthesized compounds revealed better hypoglycaemic activity; however, the chloro-derivative exhibited the more potent hypoglycaemic activity showing about 43% reduction in the mean blood glucose levels of the treated animals. As the bioreduction of naphthoquinones may be influenced by changing its redox properties, it has been noticed that the e-donating resonance effect (+R) of 'chloro' group has shown the significant effects on biological activity through stabalization of its imine form which limits the potential of generation of free radicals during bioreduction of quinones and thus has been proposed as the reason of its hypoglycaemic activity. Future studies employing the properties of e-donating groups of PAN may optimize the drug-receptor interaction for better drug designing and drug development strategies against diabetes and also for the clinical trials.

Ameliorative Effect of Enhydra fluctuans on Liver Damage in Diabetic Rats

Diabetes mellitus and insulin resistance cause harm to the liver. In this study, ameliorative effect of Enhydra fluctuans on liver damage in alloxan-induced diabetic rats were examined.
 Thirty acclimatized male albino rats divided into six groups (n = 5). Normal rats were fed a standard diet (Group 1); diabetic rats were provided standard feed (Group 2); diabetic rats were fed standard feed and glibenclamide (Group 3); and diabetic rats were fed standard food and fractions of n-hexane E. fluctuans 57.03, 114.06, and 171.09 mg/kg, respectively (Group 4, 5 and 6). For 21 days, rats were fed the n-hexane fraction orally. On day 1 and day 21 of treatments, blood sugar levels were measured. The histophatology of the liver, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) level were estimated.
 At a dosage of 57.03 mg/kg was substantially (p < 0.05) beneficial in decreasing blood sugar and SGOT. The n-hexane fraction of E. fluctuans ameliorated liver damage in diabetic rats and avoided diabetes complications, according to our findings. As a result, E. fluctuans has a considerable amount of potential as a novel diabetic therapy.
 
 Keywords: Diabetes, Enhydra fluctuans, Insulin resistance, Liver cells regeneration.