Treatment Of Type 2 Diabetes Mellitus Research Articles

Evidence of Insulin-Sensitizing and Mimetic Activity of the Sesquiterpene Quinone Avarone, a Protein Tyrosine Phosphatase 1B and Aldose Reductase Dual Targeting Agent from the Marine Sponge Dysidea avara.

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by impaired glucose homeostasis and serious long-term complications. First-line therapeutic options for T2DM treatment are monodrug therapies, often replaced by multidrug therapies to ensure that non-responding patients maintain target glycemia levels. The use of multitarget drugs instead of mono- or multidrug therapies has been emerging as a main strategy to treat multifactorial diseases, including T2DM. Therefore, modern drug discovery in its early stages aims to identify potential modulators for multiple targets; for this purpose, exploration of the chemical space of natural products represents a powerful tool. Our study demonstrates that avarone, a sesquiterpene quinone obtained from the sponge Dysidea avara, is capable of inhibiting in vitro PTP1B, the main negative regulator of the insulin receptor, while it improves insulin sensitivity, and mitochondria activity in C2C12 cells. We observe that when avarone is administered alone, it acts as an insulin-mimetic agent. In addition, we show that avarone acts as a tight binding inhibitor of aldose reductase (AKR1B1), the enzyme involved in the development of diabetic complications. Overall, avarone could be proposed as a novel natural hit to be developed as a multitarget drug for diabetes and its pathological complications.

Hepatic Glucose Metabolism Disorder Induced by Adipose Tissue-Derived miR-548ag via DPP4 Upregulation.

The present study aimed to explore the molecular mechanism underlying the regulation of glucose metabolism by miR-548ag. For the first time, we found that miR-548ag expression was elevated in the abdominal adipose tissue and serum of subjects with obesity and type 2 diabetes mellitus (T2DM). The conditional knockout of adipose tissue Dicer notably reduced the expression and content of miR-548ag in mouse adipose tissue, serum, and liver tissue. The combined use of RNAseq, an miRNA target gene prediction software, and the dual luciferase reporter assay confirmed that miR-548ag exerts a targeted regulatory effect on DNMT3B and DPP4. miR-548ag and DPP4 expression was increased in the adipose tissue, serum, and liver tissue of diet-induced obese mice, while DNMT3B expression was decreased. It was subsequently confirmed both in vitro and in vivo that adipose tissue-derived miR-548ag impaired glucose tolerance and insulin sensitivity by inhibiting DNMT3B and upregulating DPP4. Moreover, miR-548ag inhibitors significantly improved the adverse metabolic phenotype in both obese mice and db/db mice. These results revealed that the expression of the adipose tissue-derived miR-548ag increased in obese subjects, and that this could upregulate the expression of DPP4 by targeting DNMT3B, ultimately leading to glucose metabolism disorder. Therefore, miR-548ag could be utilized as a potential target in the treatment of T2DM.

Benefit-risk assessment of incretin and other anti-diabetic agents in type 2 diabetes using a stochastic multicriteria acceptability analysis model.

Benefit-risk assessment of incretin and other anti-diabetic agents in type 2 diabetes using a stochastic multicriteria acceptability analysis model.

Modeling of Ultrasound Stimulation of Adolescent Pancreas for Insulin Release Therapy.

Our previous published studies have focused on safety and effectiveness of using therapeutic ultrasound (TUS) for treatment of type 2 diabetes mellitus (T2DM) in preclinical models. Here we present a set of simulation studies to explore potential ultrasound application schemes that would be feasible in a clinical setting. Using the multiphysics modeling tool OnScale, we created two-dimensional (2D) models of the human abdomen from CT images captured from one normal weight adolescent patient, and one obese adolescent patient. Based on our previous studies, the frequency of our TUS was 1MHz delivered from a planar unfocused transducer. We tested five different insonation angles, as well as four ultrasound intensities combined with four different duty factors and five durations of application to explore how these variables effect the peak pressure and temperature delivered to the pancreas as well as surrounding tissue in the model. We determined that ultrasound applied directly from the anterior of the patient abdomen at 5W/cm2 delivered consistent acoustic pressures to the pancreas at the levels which we have previously found to be effective at inducing an insulin release from preclinical models. Our modeling work indicates that it may be feasible to non-invasively apply TUS in clinical treatment of T2DM.

Profiling of Targeted miRNAs (8-nt) for the Genes Involved in Type 2 Diabetes Mellitus and Cardiac Hypertrophy

Type 2 Diabetes Mellitus (T2DM) and cardiac hypertrophy (CH) are among the top ten leading cause of deaths, worldwide. T2DM and cardiac hypertrophy are the chronic diseases, have close association and direct life-threatening complications like stroke, myocardial infarction, retinopathy, nephropathy, and limb amputation. In addition to other medical approaches, miRNAs-based strategy is considered most efficient for early detection of chronic diseases and also has potential for the treatment of T2DM and cardiac hypertrophy like it is being used for cancer in clinical trials. MicroRNAs (miRNAs) are single stranded (non-coding) of 20 to 22 nucleotides sequences which bind to their target mRNA upon the complimentary basis, to silence the protein expression at post transcriptional level. Bioinformatic databases are used like online mendelian inheritance in man (OMIM), gene testing registry (GTR), TargetScan and ShinyGO for validation of disease linked genes and sorting the common miRNAs in both diseases, such as miR-30-5p/101-3p.2/190-5p/506-3p/9-5p/128-3p/137/96-5p/7-5p/107/101-3p.1/98-5p/124-3p.2/124-3p.116-5p/15-5p/497-5p/ 424-5p/195-5p/1271-5p, let-7-5p. Aforementioned databases were also used for the miRNAs which have more than one disease linked genes target in each pathological condition. Such miRNAs for cardiac hypertrophy are: miR-19-3p/183-5p.2/153-3p/372-3p/302-3p/520-3p/373-3p/129-5p/144-3p/139-5p and for T2DM are: miR-27-3p/206/1-3p/181-5p. This finding would be helpful for the appropriate selection of miRNAs and to design applicable research project in future. It will require more validation by using the miRNAs expression analysis, mimic, and anti-miRNA approach to check their potential against cardiac hypertrophy and T2DM.

Pattern of macronutrients intake among type-2 diabetes mellitus (T2DM) patients in Malaysia

BackgroundThe incidence of type 2 diabetes mellitus (T2DM) is rising rapidly in Malaysia. Modifying dietary intake is key to both the prevention and treatment of T2DM. This study aims to investigate the pattern of macronutrient intake among T2DM patients in Malaysia.MethodsThis study was carried out on adults aged between 35 and 70 years, residing in urban and rural Malaysian communities. A series of standardised questionnaires was used to assess the sociodemographic information, dietary intake and physical activity level of 15,353 respondents who provided informed consent to participate in this study. Blood sampling (finger prick test) and physical examination were performed to obtain blood glucose and anthropometric data, respectively. The Chi-square test was used to assess differences in the trends of macronutrient intake among T2DM patients.ResultsThe total number of participants diagnosed with T2DM in this study was 2254. Of these, 453 (20.1%) were newly diagnosed, 1156 (51.3%) were diagnosed for ≤5 years and 645 (28.6%) were diagnosed for > 5 years. Male patients show that there were significant differences among the three groups of T2DM according to the following variables: age, BMI, residency, participant comorbidity of hypertension, family history of T2DM and hypertension, and active smoker. Meanwhile, female patients show significant differences among the three groups of T2DM according to the following variables: age, BMI, marital status, education level, residency, participant comorbidity of hypertension and family history of T2DM. Most of the male patients consumed appropriate proportions of carbohydrate (458, 60.7%) and protein (618, 81.9%). However, female patients did not show any significant differences of the macronutrients intake among the three groups of T2DM patients.ConclusionsThe pattern of dietary intake among T2DM patients in this study showed consumption of carbohydrate and protein within the range of Malaysian RNI, coupled with high fat intake. Compliance with the Recommended Nutrient Intake (RNI) was satisfactory for both carbohydrate and protein but not for fat. The pattern indicated a preference for fat rather than protein when carbohydrate intake was restricted.

Evolution of sodium-glucose co-transporter 2 inhibitors from a glucose-lowering drug to a pivotal therapeutic agent for cardio-renal-metabolic syndrome.

Cardio-renal-metabolic (CRM) syndrome, which involves type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and heart failure (HF), is a serious healthcare issue globally, with high morbidity and mortality. The disorders that comprise CRM syndrome are independent can mutually affect and accelerate the exacerbation of each other, thereby substantially increasing the risk of mortality and impairing quality of life. To manage CRM syndrome by preventing vicious interactions among individual disorders, a holistic treatment approach that can simultaneously address multiple disorders underpinning CRM syndrome is of great importance. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) lower blood glucose levels by inhibiting glucose reabsorption in the renal proximal tubule and were first indicated for the treatment of T2DM. Several cardiovascular outcome trials have demonstrated that SGLT2i not only lower blood glucose but also reduce the risk of hospitalization for HF and worsening renal function in patients with T2DM. Results have also suggested that the observed cardiorenal benefits of SGLT2i may be independent of their blood glucose-lowering effects. Several randomized controlled trials subsequently assessed the efficacy and safety of SGLT2i in patients without T2DM, and revealed considerable benefits of SGLT2i treatment against HF and CKD, regardless of the presence of T2DM. Thus, SGLT2i have become an essential therapeutic option to prevent the onset, slow the progression, and improve the prognosis of CRM syndrome. This review assesses the evolution of SGLT2i from a glucose-lowering drug to a therapeutic agent for CRM syndrome by evaluating epoch-making clinical studies, including randomized control trials and real-world studies.

Assessment of type 2 diabetes mellitus patients' behavioral characteristics associated with integrated treatment and prevention services in community health centers in China.

The purpose of this study was to describe behavioral characteristics of type 2 diabetes mellitus (T2DM) patients, identify homogeneous clusters, and explore factors affecting behaviors associated with integrated treatment and prevention (ITP) services for T2DM in community health centers in China. A convenient sampling method was employed at a community health center between January and July 2022 in Nanjing. A total of 354 patients completed the self-reported questionnaires. After performing a Cluster Analysis to create a profile of participants' behaviors, a multiple linear regression analysis was conducted to explore the correlations between T2DM patients' characteristics and their behaviors associated with ITP services. 316 T2DM patients with a mean age of 72.09 years (SD = 5.96) were included. The behavior profiles of patients associated with ITP services were clustered into "Lower" (n = 198) and "Higher" (n = 118) groups, with average scores of 54.41 and 71.46, respectively. Of all the behaviors, complication examination and public health utilization scored the lowest. Health insurance, duration of disease, and treatment modality were independent predictors on the patients' behaviors associated with ITP services for T2DM. Patients' behaviors associated with ITP services for T2DM were moderately good (the score rate was 63.98%). Of all the behaviors, complication examination and public health service utilization scored the lowest and, as such, may warrant further research. The clustering of patients' behaviors tends to be polarization, distributed at the upper and lower ends of the behavior spectrum. It is necessary to develop and implement targeted interventions for different groups to improve T2DM patients' behaviors associated with ITP services.

Egg Microneedle for Transdermal Delivery of Active Liraglutide.

Liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, is promising for safely treating type 2 diabetes mellitus (T2DM), compared to insulin, by significantly reducing the risk of glucose-dependent hypoglycemia. Concerns related to injection prevent T2DM patients from taking liraglutide regularly, even though once-a-day subcutaneous (SC) injections. Dissolving microneedles (DMNs) are promising substitutes for SC injection and for improving patient convenience. However, there are two fundamental limitations: the low drug delivery due to incomplete insertion and loss of drug activity during DMN fabrication. Here, it is shown that an egg microneedle (EMN) designed with three functional layered structures can maintain the maximum activity of the loaded compound during DMN fabrication and deliver it completely into the skin, with the base layer allowing the complete delivery of liraglutide, and the shell layer maintaining the drug activity by mimicking the role of albumin in eggs. In a diabetic mouse model, liraglutide administration via EMN exhibited similar effect when compared to that of injection. Therefore, EMN-mediated liraglutide administration is a good potential option for replacing liraglutide injections in T2DM treatment.

Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay.

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

TXNIP inhibition in the treatment of type 2 diabetes mellitus: design, synthesis, and biological evaluation of quinazoline derivatives

Thioredoxin interacting protein (TXNIP) is a potential drug target for type 2 diabetes mellitus (T2DM) treatment. A series of quinazoline derivatives were designed, synthesised, and evaluated to inhibit TXNIP expression and protect from palmitate (PA)-induced β cell injury. In vitro cell viability assay showed that compounds D-2 and C-1 could effectively protect β cell from PA-induced apoptosis, and subsequent results showed that these two compounds decreased TXNIP expression by accelerating its protein degradation. Mechanistically, compounds D-2 and C-1 reduced intracellular reactive oxygen species (ROS) production and modulated TXNIP-NLRP3 inflammasome signalling, and thus alleviating oxidative stress injury and inflammatory response under PA insult. Besides, these two compounds were predicted to possess better drug-likeness properties using SwissADME. The present study showed that compounds D-2 and C-1, especially compound D-2, were potent pancreatic β cell protective agents to inhibit TXNIP expression and might serve as promising lead candidates for the treatment of T2DM.

Neuromodulatory effect of the combination of metformin and vitamin D3 triggered by purinergic signaling in type 1 diabetes induced-rats

Several studies have indicated the vitamin D deficiency in the development of macro- and microvascular complications of diabetes mellitus (DM) including DM-related cognitive dysfunction. The purinergic system plays an important role in the modulation of a variety of mechanisms, including neuroinflammation, plasticity, and cell-cell communication. In addition, purines, their receptors, and enzymes can regulate the purinergic axis at different levels in type 1 DM (T1DM). This study evaluated the effects of vitamin D3 alone or in combination with metformin in the behavioral performance of streptozotocin-induced T1DM rats. The effects of this combination on the metabolism of ATP and ADP were also studied by NTPDase (CD39), AMP by 5′-nucleotidase (CD73), and adenosine by adenosine deaminase (E-ADA) in the brain and peripheral lymphocytes of type 1 diabetic STZ-induced rats. The results showed that anxiety and memory loss from the DM condition reverted after 30 days of vitamin D3 treatment. Furthermore, the DM state affected systemic enzymes, with no effect on the central enzymes hydrolyzing extracellular nucleotides and nucleosides. Vitamin D3 treatment positively regulated ectonucleotidase (NTPDase and 5′-nucleotidase) activity, E-ADA, and the purinergic receptors as a mechanism to prevent oxidative damage in the cerebral cortex of T1DM rats. A neuroprotector effect of vitamin D3 through adenosine signaling was also observed, by regulating A1 and A2A receptors proteins levels. The present findings suggest that purinergic signaling through vitamin D3 modulation may be a novel alternative strategy for T1DM treatment, and may compensate for the negative changes in the central nervous system.

GLP-1R Signaling and Functional Molecules in Incretin Therapy.

Glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). The GLP-1R cellular signaling mechanism relevant to insulin secretion and blood glucose regulation has been extensively studied. Numerous drugs targeting GLP-1R have entered clinical treatment. However, novel functional molecules with reduced side effects and enhanced therapeutic efficacy are still in high demand. In this review, we summarize the basis of GLP-1R cellular signaling, and how it is involved in the treatment of T2DM. We review the functional molecules of incretin therapy in various stages of clinical trials. We also outline the current strategies and emerging techniques that are furthering the development of novel therapeutic drugs for T2DM and other metabolic diseases.

Impact of Insulin, Biguanide and Sulfonylurea Treatment on hba1c in Diabetic Patients: An Interventional Study in Rajshahi, Bangladesh

Proper management and selection of a single drug or multiple drugs for the treatment of diabetes is very important. The choice of treatment depends on a number of factors. With the proper treatment, the state of diabetes can be managed very smoothly. The main objective of this study was to compare the efficacy of insulin, biguanides and sulfonylurea on HbA1C in diabetic patients. This interventional type of study was carried out among 102 diabetic patients attending at different hospitals in Rajshahi of Bangladesh. In this case purposive sampling technique was followed and data revealed that mean age of the patients was 45.98±11.23 years and most of them (35.30) were housewife. Among the insulin receiving group, 41.18% were male and 58.82% were female. In case of the biguanide receiving taking group 44.12% were male and 55.88% were female while for the sulfonylurea receiving group 35.29% were male and 64.71% were female. Regarding body mass index (BMI) among the respondents, it was found that 0.98% had BMI <18.50 kg/m2, led sedentary lifestyle (65.7%), most of them were from urban area (67.6%) and non-smoker (86.0%) with family history of type 2 diabetes mellitus (T2DM) (17.0%). In the insulin receiving group, 82.35% had desired glycemic control; in the biguanide receiving group, 73.53% had desired glycemic control; and in the sulfonylurea receiving group, 64.71% had desired glycemic control. Data shows that the insulin receiving patients had relatively better glycemic control as compared to the other two mendicant receiving groups at 6th month. This finding suggests that the selection of the best drug is the most key part of the treatment of T2DM. Therefore, this study would help to select the best choice of drug for the treatment of diabetes in Bangladesh. J Bio-Sci. 30(1): 123-130, 2022 (June)

Dual Regulation of Sulfonated Lignin to Prevent and Treat Type 2 Diabetes Mellitus.

With the rapid increase of diabetes cases in the world, there is an increasing demand for slowing down and managing diabetes and its effects. It is considered that a viable prophylactic treatment for type 2 diabetes mellitus (T2DM) is to reduce carbohydrate digestibility by controlling the activities of α-amylase and α-glucosidase to control postprandial hyperglycemia and promote the growth of intestinal beneficial bacteria. In this work, the effects of sulfonated lignin with different sulfonation degrees (0.8 mmol/g, SL1; 2.9 mmol/g, SL2) on the inhibition of α-amylase and α-glucosidase and the proliferation of intestinal beneficial bacteria in vitro were investigated. The results showed that both SL1 and SL2 can inhibit the activity of α-amylase and α-glucosidase. The inhibition capacity (IC50, 32.35 μg/mL) of SL2 with a low concentration (0-0.5 mg/mL) to α-amylase was close to that of acarbose to α-amylase (IC50, 27.33 μg/mL). Compared with the control groups, the bacterial cell concentrations of Bifidobacteria adolescentis and Lactobacillus acidophilus cultured with SL1 and SL2 increased in varying degrees (8-36%), and the produced short-chain fatty acids were about 1.2 times higher. This work demonstrates the prospect of sulfonated lignin as a prebiotic for the prevention and treatment of T2DM, which provides new insights for opening up a brand new field of lignin.

Methanol extract of Inonotus obliquus improves type 2 diabetes mellitus through modifying intestinal flora.

Type 2 diabetes mellitus (T2DM) poses a significant risk to human health. Previous research demonstrated that Inonotus obliquus possesses good hypolipidemic, anti-inflammatory, and anti-tumor properties. In this research, we aim to investigate the potential treatment outcomes of Inonotus obliquus for T2DM and discuss its favourable influences on the intestinal flora. The chemical composition of Inonotus obliquus methanol extracts (IO) was analyzed by ultra-high-performance liquid chromatography-Q extractive-mass spectrometry. IO significantly improved the blood glucose level, blood lipid level, and inflammatory factor level in T2DM mice, and effectively alleviated the morphological changes of colon, liver and renal. Acetic acid, propionic acid, and butyric acid levels in the feces of the IO group were restored. 16S rRNA gene sequencing revealed that the intestinal flora composition of mice in the IO group was significantly modulated. Inonotus obliquus showed significant hypoglycemic and hypolipidemic effects with evident anti-inflammatory activity and improved the morphological structure of various organs and cells. Inonotus obliquus increased the levels of short-chain fatty acids in the environment by increasing the population of certain bacteria that produce acid, such as Alistipes and Akkermansia, which are beneficial to improve intestinal flora disorders and maintain intestinal flora homeostasis. Meanwhile, Inonotus obliquus further alleviated T2DM symptoms in db/db mice by down-regulating the high number of microorganisms that are dangerous, such as Proteobacteria and Rikenellaceae_RC9_gut_group and up-regulating the abundance of beneficial bacteria such as Odoribacter and Rikenella. Therefore, this study provides a new perspective for the treatment of T2DM by demonstrating that drug and food homologous active substances could relieve inflammation via regulating intestinal flora.

Type 1 Diabetes Mellitus: A Review on Advances and Challenges in Creating Insulin Producing Devices.

Type 1 diabetes mellitus (T1DM) is the most common autoimmune chronic disease in young patients. It is caused by the destruction of pancreatic endocrine β-cells that produce insulin in specific areas of the pancreas, known as islets of Langerhans. As a result, the body becomes insulin deficient and hyperglycemic. Complications associated with diabetes are life-threatening and the current standard of care for T1DM consists still of insulin injections. Lifesaving, exogenous insulin replacement is a chronic and costly burden of care for diabetic patients. Alternative therapeutic options have been the focus in these fields. Advances in molecular biology technologies and in microfabrication have enabled promising new therapeutic options. For example, islet transplantation has emerged as an effective treatment to restore the normal regulation of blood glucose in patients with T1DM. However, this technique has been hampered by obstacles, such as limited islet availability, extensive islet apoptosis, and poor islet vascular engraftment. Many of these unsolved issues need to be addressed before a potential cure for T1DM can be a possibility. New technologies like organ-on-a-chip platforms (OoC), multiplexed assessment tools and emergent stem cell approaches promise to enhance therapeutic outcomes. This review will introduce the disorder of type 1 diabetes mellitus, an overview of advances and challenges in the areas of microfluidic devices, monitoring tools, and prominent use of stem cells, and how they can be linked together to create a viable model for the T1DM treatment. Microfluidic devices like OoC platforms can establish a crucial platform for pathophysiological and pharmacological studies as they recreate the pancreatic environment. Stem cell use opens the possibility to hypothetically generate a limitless number of functional pancreatic cells. Additionally, the integration of stem cells into OoC models may allow personalized or patient-specific therapies.

Metformin Mitigates Memory Impairment of Diabetic Mice through Modulation of Plasma Pro-inflammatory Cytokines and Aβ1-42 Levels

Abstract Experimental and clinical studies reported that type 2 diabetes mellitus (T2DM) is associated with cognitive dysfunction and promotes the onset of dementia. Metformin is an antihyperglycemic drug used for the treatment of T2DM. A growing number of evidence revealed neuroprotective, antioxidant, and anti-inflammation effects exerted by metformin. The present study aimed to investigate the effect of metformin on cognitive function, systemic proinflammatory cytokines and amyloid-beta 1-42 (Aβ1-42) which is a pathological hallmark of Alzheimer’s disease (AD) in diabetic mice. C57BL/6N mice were divided into the following experimental groups: normal control group (NC); diabetes mellitus group (DM) induced by a high-fat diet combined with streptozotocin (STZ) injection; diabetes mellitus treated with metformin 100 mg/kg (DM+Met). Cognitive performance was evaluated by the novel object recognition test (NORT). Systemic proinflammatory cytokines and Aβ1-42 were assessed by the enzyme-linked immunosorbant assay (ELISA) test. We found that diabetic mice exhibited cognitive impairment in NORT whereas the treatment with metformin restored the cognitive function of diabetic mice. Moreover, diabetic mice presented an increase in plasma IL-6 and TNF-α levels while Aβ1-42 was decreased when compared to NC mice. Nevertheless, the administration of metformin allowed the levels of plasma IL-6, TNF-α, and Aβ1-42 to normalize in diabetic mice. Taken together, our findings suggest that metformin improves the cognitive function of diabetic mice possibly via the modulation of plasma pro-inflammatory cytokines and Aβ1-42 levels. Metformin may potentially be used as a therapeutic agent for patients with T2DM who show cognitive deficits. Keywords: Diabetes mellitus, Cognitive impairments, Pro-inflammatory cytokines, Amyloid-beta, Metformin

Combination therapy with human amniotic epithelial cells and hyaluronic acid promotes immune balance recovery in type 1 diabetic rats through local engraftment.

Stem cell engraftment is currently a promising approach for type 1 diabetes mellitus (T1DM) treatment. In our previous study, engraftment of a combination of human amniotic epithelial cells (hAECs) and hyaluronic acid (HA) showed potent anti-diabetic effect in streptozotocin (STZ)-induced T1DM mice via tail vein injection. Here, we adopted a different route of stem cell delivery, that is via pancreatic subcapsular transplantation. This combined local engraftment of hAECs and HA in STZ-induced T1DM rats showed potent anti-diabetic activity, leading to stronger hypoglycaemia, more intact islet structure and increased number of insulin-positive cells compared with those with hAECs or insulin treatments. Engraftment of hAECs alone increased the proportion of Th1 and T-reg cells and decreased the proportion of Th2 and Th17 cells to protect islet β cells in STZ-induced T1DM rats, whereas the combined engraftment of hAECs and HA showed more potent regulatory capacity, considerably decreased the level of TNF-α and IL-17 and increased the level of TGF-β1 compared with those by other treatments. The potent synergistic effect of HA contributed to the recovery of immune balance in the diabetic rat model, thereby suggesting a new strategy for effective treatment of T1DM.

Cysteine-Derived Chiral Carbon Quantum Dots: A Fibrinolytic Activity Regulator for Plasmin to Target the Human Islet Amyloid Polypeptide for Type 2 Diabetes Mellitus.

The fibrillization and deposition of the human islet amyloid polypeptide (hIAPP) are the pathological hallmark of type 2 diabetes mellitus (T2DM), and these insoluble fibrotic depositions of hIAPP are considered to strongly affect insulin secretion by inducing toxicity toward pancreatic islet β-cells. The current strategy of preventing amyloid aggregation by nanoparticle-assisted inhibitors can only disassemble fibrotic amyloids into more toxic oligomers and/or protofibrils. Herein, for the first time, we propose a type of cysteine-derived chiral carbon quantum dot (CQD) that targets plasmin, a core natural fibrinolytic protease in humans. These CQDs can serve as fibrinolytic activity regulators for plasmin to cleave hIAPP into nontoxic polypeptides or into even smaller amino acid fragments, thus alleviating hIAPP's fibrotic amyloid-induced cytotoxicity. Our experiments indicate that chiral CQDs have opposing effects on plasmin activity. The l-CQDs promote the cleavage of hIAPP by enhancing plasmin activity at a promotion ratio of 23.2%, thus protecting β-cells from amyloid-induced toxicity. In contrast, the resultant d-CQDs significantly inhibit proteolysis, decreasing plasmin activity by 31.5% under the same reaction conditions. Second harmonic generation (SHG) microscopic imaging is initially used to dynamically characterize hIAPP before and after proteolysis. The l-CQD promotion of plasmin activity thus provides a promising avenue for the hIAPP-targeted treatment of T2DM to treat low fibrinolytic activity, while the d-CQDs, as inhibitors of plasmin activity, may improve patient survival for hyperfibrinolytic conditions, such as those existing during surgeries and traumas.