Exosome-Mediated Insulin Delivery for the Potential Treatment of Diabetes Mellitus

Exosomes are extracellular nanovesicles between 30 and 150 nm that serve as essential messengers for different biological signaling and pathological processes. After their discovery, a wide range of applications have been developed, especially in therapeutic drug delivery. In this context, the aim of this work was to test the efficiency of exosome-mediated human insulin delivery using exosomes extracted from three different cell lines: hepatocellular carcinoma (HepG2); primary dermal fibroblasts (HDFa) and pancreatic β cells (RIN-m); all are related to the production and/or the ability to sense insulin and to consequently regulate glucose levels in the extracellular medium. The obtained results revealed that the optimal insulin loading efficiency was achieved by a 200 V electroporation, in comparison with incubation at room temperature. Moreover, the maximum in vitro exosome uptake was reached after incubation for 6 h, which slightly decreased 24 h after adding the exosomes. Glucose quantification assays revealed that exosome-mediated incorporation of insulin presented significant differences in HDFa and HepG2 cells, enhancing the transport in HDFa, in comparison with free human insulin effects in the regulation of extracellular glucose levels. No significant differences were found between the treatments in RIN-m cells. Hence, the results suggest that exosomes could potentially become a valuable tool for stable and biocompatible insulin delivery in diabetes mellitus treatment alternatives.

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Juxtamedullary microvascular dysfunction during the hyperfiltration stage of diabetes mellitus

AJP Renal Physiology ◽

10.1152/ajprenal.1994.267.1.f99 ◽

1994 ◽

Vol 267 (1) ◽

pp. F99-F105 ◽

Cited By ~ 11

Author(s):

K. Ohishi ◽

M. I. Okwueze ◽

R. C. Vari ◽

P. K. Carmines

Keyword(s):

Diabetes Mellitus ◽

Microvascular Dysfunction ◽

Sprague Dawley ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Sprague Dawley Rats ◽

Vasoconstrictor Response ◽

Wide Range ◽

Single Nephron

This study was designed to identify and localize defects in renal microvascular function during the hyperfiltration stage of diabetes mellitus. Male Sprague-Dawley rats were injected intravenously with 65 mg/kg streptozotocin (IDDM rats) or vehicle (sham rats). IDDM rats received insulin (3 U.kg-1.day-1) via an osmotic minipump; sham rats received diluent. During the ensuing 2-wk period, blood glucose levels averaged 89 +/- 2 mg/dl in 33 sham rats and 290 +/- 13 mg/dl in 37 IDDM rats. At the end of this period, inulin clearance was elevated in eight IDDM rats (1.43 +/- 0.17 ml.min-1.g kidney wt-1) compared with six sham rats (0.78 +/- 0.05 ml.min-1.g kidney wt-1). The remaining animals served as tissue donors for study of the renal microvasculature using the in vitro blood-perfused juxtamedullary nephron technique. Kidneys from sham and IDDM rats were perfused with homologous blood at a renal arterial pressure of 110 mmHg. Juxtamedullary single-nephron glomerular filtration rate was higher in IDDM rats (41.5 +/- 5.4 nl/min) than in sham rats (25.4 +/- 2.4 nl/min). Afferent arteriolar inside diameter was greater in IDDM rats (34 +/- 2 microns) than in sham rats (22 +/- 1 microns); however, efferent arteriolar diameter did not differ between groups. The afferent arteriolar vasoconstrictor response to norepinephrine (NE) was attenuated in IDDM rats, relative to sham rats, over a wide range of NE concentrations. In contrast, NE evoked similar degrees of efferent vasoconstriction in IDDM and sham rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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Discovery of Galangin as a Potential DPP-4 Inhibitor That Improves Insulin-Stimulated Skeletal Muscle Glucose Uptake: A Combinational Therapy for Diabetes

International Journal of Molecular Sciences ◽

10.3390/ijms20051228 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1228 ◽

Cited By ~ 4

Author(s):

Poonam Kalhotra ◽

Veera Chittepu ◽

Guillermo Osorio-Revilla ◽

Tzayhri Gallardo-Velázquez

Keyword(s):

Diabetes Mellitus ◽

Skeletal Muscle ◽

Side Effects ◽

Therapeutic Drug ◽

Diabetic Patients ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Glucose Levels ◽

Muscle Health

Dipeptidyl peptidase-4 (DPP-4) is a well-known therapeutic drug target proven to reduce blood glucose levels in diabetes mellitus, and clinically, DPP-4 inhibitors are used in combination with other anti-diabetic agents. However, side effects and skeletal muscle health are not considered in the treatment for diabetic patients. Recently, natural compounds have been proven to inhibit DPP-4 with fewer side effects. In this work, initially, molecular docking simulations revealed that a natural compound, Galangin, possess a binding energy of −24 KJ/mol and interaction residues SER 630 and TYR 547, that are responsible for potent DPP-4 inhibition. In vitro studies showed that galangin not only inhibits DPP-4 in a concentration-dependent manner but also regulates glucose levels, enabling the proliferation of rat L6 skeletal muscle cells. The combination of galangin with insulin benefits regulation of glucose levels significantly in comparison to galangin alone (p < 0.05). These findings suggest the beneficial effect of the use of galangin, both alone or in combination with insulin, to reduce glucose levels and improve skeletal muscle health in diabetes mellitus.

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Teucrium polium: Potential Drug Source for Type 2 Diabetes Mellitus

Biology ◽

10.3390/biology11010128 ◽

2022 ◽

Vol 11 (1) ◽

pp. 128

Author(s):

Yaser Albadr ◽

Andrew Crowe ◽

Rima Caccetta

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Secretion ◽

Β Cells ◽

Pancreatic Β Cells ◽

Glucose Levels ◽

Teucrium Polium

The prevalence of type 2 diabetes mellitus is rising globally and this disease is proposed to be the next pandemic after COVID-19. Although the cause of type 2 diabetes mellitus is unknown, it is believed to involve a complex array of genetic defects that affect metabolic pathways which eventually lead to hyperglycaemia. This hyperglycaemia arises from an inability of the insulin-sensitive cells to sufficiently respond to the secreted insulin, which eventually results in the inadequate secretion of insulin from pancreatic β-cells. Several treatments, utilising a variety of mechanisms, are available for type 2 diabetes mellitus. However, more medications are needed to assist with the optimal management of the different stages of the disease in patients of varying ages with the diverse combinations of other medications co-administered. Throughout modern history, some lead constituents from ancient medicinal plants have been investigated extensively and helped in developing synthetic antidiabetic drugs, such as metformin. Teucrium polium L. (Tp) is a herb that has a folk reputation for its antidiabetic potential. Previous studies indicate that Tp extracts significantly decrease blood glucose levels r and induce insulin secretion from pancreatic β-cells in vitro. Nonetheless, the constituent/s responsible for this action have not yet been elucidated. The effects appear to be, at least in part, attributable to the presence of selected flavonoids (apigenin, quercetin, and rutin). This review aims to examine the reported glucose-lowering effect of the herb, with a keen focus on insulin secretion, specifically related to type 2 diabetes mellitus. An analysis of the contribution of the key constituent flavonoids of Tp extracts will also be discussed.

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Oral DhHP-6 for the Treatment of Type 2 Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms20061517 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1517 ◽

Cited By ~ 1

Author(s):

Kai Wang ◽

Yu Su ◽

Yuting Liang ◽

Yanhui Song ◽

Liping Wang

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Blood Glucose ◽

Enzymatic Activity ◽

Glucose Levels ◽

Blood Glucose Levels

Type 2 diabetes mellitus (T2DM) is associated with pancreatic β-cell dysfunction which can be induced by oxidative stress. Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6) is a microperoxidase mimetic that can scavenge reactive oxygen species (ROS) in vivo. In our previous studies, we demonstrated an increased stability of linear peptides upon their covalent attachment to porphyrins. In this study, we assessed the utility of DhHP-6 as an oral anti-diabetic drug in vitro and in vivo. DhHP-6 showed high resistance to proteolytic degradation in vitro and in vivo. The degraded DhHP-6 product in gastrointestinal (GI) fluid retained the enzymatic activity of DhHP-6, but displayed a higher permeability coefficient. DhHP-6 protected against the cell damage induced by H2O2 and promoted insulin secretion in INS-1 cells. In the T2DM model, DhHP-6 reduced blood glucose levels and facilitated the recovery of blood lipid disorders. DhHP-6 also mitigated both insulin resistance and glucose tolerance. Most importantly, DhHP-6 promoted the recovery of damaged pancreas islets. These findings suggest that DhHP-6 in physiological environments has high stability against enzymatic degradation and maintains enzymatic activity. As DhHP-6 lowered the fasting blood glucose levels of T2DM mice, it thus represents a promising candidate for oral administration and clinical therapy.

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Drug Delivery Systems for Diabetes Treatment

Current Pharmaceutical Design ◽

10.2174/1381612825666190306153838 ◽

2019 ◽

Vol 25 (2) ◽

pp. 166-173 ◽

Cited By ~ 4

Author(s):

Bozidarka L. Zaric ◽

Milan Obradovic ◽

Emina Sudar-Milovanovic ◽

Jovan Nedeljkovic ◽

Vesna Lazic ◽

...

Keyword(s):

Diabetes Mellitus ◽

Drug Delivery ◽

Drug Release ◽

Vascular Complications ◽

Insulin Delivery ◽

Delivery Systems ◽

Diabetes Treatment ◽

Glucose Levels ◽

Normal Glucose ◽

Nanoparticles Stability

Background:Insulin is essential for the treatment of Type 1 diabetes mellitus (T1DM) and is necessary in numerous cases of Type 2 diabetes mellitus (T2DM). Prolonged administration of anti-diabetic therapy is necessary for the maintenance of the normal glucose levels and thereby preventing vascular complications. A better understanding of the disease per se and the technological progress contribute to the development of new approaches with the aim to achieve better glycemic control.Objective:Current therapies for DM are faced with some challenges. The purpose of this review is to analyze in detail the current trends for insulin delivery systems for diabetes treatment.Results:Contemporary ways have been proposed for the management of both types of diabetes by adequate application of drug via subcutaneous, buccal, oral, ocular, nasal, rectal and pulmonary ways. Development of improved oral administration of insulin is beneficial regarding mimicking physiological pathway of insulin and minimizing the discomfort of the patient. Various nanoparticle carriers for oral and other ways of insulin delivery are currently being developed. Engineered specific properties of nanoparticles (NP): controlling toxicity of NP, stability and drug release, can allow delivery of higher concentration of the drug to the desired location.Conclusions:The successful development of any drug delivery system relies on solving three important issues: toxicity of nanoparticles, stability of nanoparticles, and desired drug release rate at targeted sites. The main goals of future investigations are to improve the existing therapies by pharmacokinetic modifications, development of a fully automatized system to mimic insulin delivery by the pancreas and reduce invasiveness during admission.

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“Oil-soluble” Reversed Lipid Nanoparticles for Oral Insulin Delivery

10.21203/rs.3.rs-25661/v1 ◽

2020 ◽

Author(s):

Tao Wang ◽

Dongqin Quan

Keyword(s):

Oral Absorption ◽

Insulin Delivery ◽

Lipid Nanoparticles ◽

Oral Insulin ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Transmission Electron ◽

Insulin Solution

Abstract Background In this study, we aimed to design a novel oral insulin delivery system, named “oil-soluble” reversed lipid nanoparticles (ORLN), in which a hydrophilic insulin molecule is encapsulated by a phospholipid (PC) shell and dissolved in oil to prevent the enzymatic degradation of insulin. ORLN was characterized by transmission electron microscopy and dynamic light scattering. Results In vitro enzymatic stability studies showed higher concentrations of insulin in cells incubated with ORLN-encapsulated insulin than in those incubated with free insulin solution in artificial intestinal fluid (pH 6.5). The protective effect of ORLN was attributed to its special release behavior and the formulation of the PC shell and oil barrier. Furthermore, an in vivo oral efficacy study confirmed that blood glucose levels were markedly decreased after ORLN administration in both healthy and diabetic mice. In vivo pharmacokinetic results showed that the bioavailability of ORLN-conjugated insulin was approximately 28.7% relative to that of the group subcutaneously administered with an aqueous solution of insulin, indicating enhanced oral absorption. Conclusions In summary, the ORLN system developed here shows promise as a nanocarrier for improving the oral absorption of insulin.

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Dermal fibroblasts cultured from donors with type 2 diabetes mellitus retain an epigenetic memory associated with poor wound healing responses

Scientific Reports ◽

10.1038/s41598-020-80072-z ◽

2021 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Aaiad H. A. Al-Rikabi ◽

Desmond J. Tobin ◽

Kirsten Riches-Suman ◽

M. Julie Thornton

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Wound Healing ◽

Type 2 Diabetes Mellitus ◽

Chronic Wounds ◽

Dermal Fibroblasts ◽

Necrosis Factor Alpha ◽

Tnf Α

AbstractThe prevalence of Type 2 diabetes mellitus (T2DM) is escalating globally. Patients suffer from multiple complications including the development of chronic wounds that can lead to amputation. These wounds are characterised by an inflammatory environment including elevated tumour necrosis factor alpha (TNF-α). Dermal fibroblasts (DF) are critical for effective wound healing, so we sought to establish whether there were any differences in DF cultured from T2DM donors or those without diabetes (ND-DF). ND- and T2DM-DF when cultured similarly in vitro secreted comparable concentrations of TNF-α. Functionally, pre-treatment with TNF-α reduced the proliferation of ND-DF and transiently altered ND-DF morphology; however, T2DM-DF were resistant to these TNF-α induced changes. In contrast, TNF-α inhibited ND- and T2DM-DF migration and matrix metalloprotease expression to the same degree, although T2DM-DF expressed significantly higher levels of tissue inhibitor of metalloproteases (TIMP)-2. Finally, TNF-α significantly increased the secretion of pro-inflammatory cytokines (including CCL2, CXCL1 and SERPINE1) in ND-DF, whilst this effect in T2DM-DF was blunted, presumably due to the tendency to higher baseline pro-inflammatory cytokine expression observed in this cell type. Collectively, these data demonstrate that T2DM-DF exhibit a selective loss of responsiveness to TNF-α, particularly regarding proliferative and secretory functions. This highlights important phenotypic changes in T2DM-DF that may explain the susceptibility to chronic wounds in these patients.

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Effects on thrombocytic hemostasis of a new derivate indolinone

Bangladesh Journal of Medical Science ◽

10.3329/bjms.v18i3.41628 ◽

2019 ◽

Vol 18 (3) ◽

pp. 574-576

Author(s):

VV Bykov ◽

V Yu Serebrov ◽

VV Udut ◽

EV Udut ◽

VP Fisenko

Keyword(s):

Diabetes Mellitus ◽

Platelet Aggregation ◽

Acetylsalicylic Acid ◽

Medical Science ◽

Antiplatelet Drug ◽

Control Group ◽

Antiplatelet Activity ◽

Wide Range

Objective. Specific activity of an antiplatelet drug of indolinone series (codenamed DI) was studied in vitro in a model of ADP-induced platelet aggregation in vitro and in vivo in a model of streptozotocininduced diabetes mellitus in rats. Material and Methods. Acetylsalicylic acid and dipyridamole were used as reference drugs. In vitro tests have demonstrated that DI exhibits antiplatelet activity in a wide range of concentrations (0,75×10-6 – 1.5×10-5 М, р<0,05), being comparable to acetylsalicylic acid and dipyridamole. In vivo tests have demonstrated dose-dependent antiplatelet activity of DI in doses of 2,5 – 20 mg/kg (21-14 %). Results and Discussion.Increasing the dose of DI above 10 mg/kg doesn’t increase its antiplatelet activity. After multiple oral administration to rats with streptozotocin-induced diabetes mellitus in 10 mg/kg dose, DI has exhibited antiplatelet activity, reducing the platelet aggregation rate to that of the control group (р<0,05). Conclusion. Thus, DI isapromisingcompound for furtherdevelopmentof an antiplatelet drug with new mechanism of action Bangladesh Journal of Medical Science Vol.18(3) 2019 p.574-576

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Hypoglycemic Effects of Plant Flavonoids: A Review

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/2057333 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Foo Sok Yen ◽

Chan Shu Qin ◽

Sharryl Tan Shi Xuan ◽

Puah Jia Ying ◽

Hong Yi Le ◽

...

Keyword(s):

Diabetes Mellitus ◽

Blood Glucose ◽

Antioxidant Activities ◽

Diabetic Rats ◽

The Body ◽

High Blood Glucose ◽

Glucose Levels ◽

Multiple Organs

Diabetes mellitus is a metabolic disorder with chronic high blood glucose levels, and it is associated with defects in insulin secretion, insulin resistance, or both. It is also a major public issue, affecting the world's population. This disease contributes to long-term health complications such as dysfunction and failure of multiple organs, including nerves, heart, blood vessels, kidneys, and eyes. Flavonoids are phenolic compounds found in nature and usually present as secondary metabolites in plants, vegetables, and fungi. Flavonoids possess many health benefits such as anti-inflammatory and antioxidant activities, and naturally occurring flavonoids contribute to antidiabetic effects.Many studies conducted in vivo and in vitro have proven the hypoglycemic effect of plant flavonoids. A large number of studies showed that flavonoids hold positive results in controlling the blood glucose level in streptozotocin (STZ)-induced diabetic rats and further prevent the complications of diabetes. The future development of flavonoid-based drugs is believed to provide significant effects on diabetes mellitus and diabetes complication diseases. This review aims at summarizing the various types of flavonoids that function as hyperglycemia regulators such as inhibitors of α-glucosidase and glucose cotransporters in the body. This review article discusses the hypoglycemic effects of selected plant flavonoids namely quercetin, kaempferol, rutin, naringenin, fisetin, and morin. Four search engines, PubMed, Google Scholar, Scopus, and SciFinder, are used to collect the data.

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Novel long non-coding RNA lnc-URIDS delays diabetic wound healing by targeting Plod1

10.2337/figshare.12735455.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Mengdie Hu ◽

Yuxi Wu ◽

Chuan Yang ◽

Xiaoyi Wang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Wound Healing ◽

Diabetic Foot ◽

Dermal Fibroblasts ◽

Diabetic Wound ◽

Delayed Wound Healing ◽

Impaired Wound Healing ◽

Diabetic Wound Healing

Impaired wound healing is one of the main reasons that leads to diabetic foot ulcerations. However, the exact mechanism of delayed wound healing in diabetes mellitus is not fully understood. Long non-coding RNAs (lncRNAs) are widely involved in a variety of biological processes and diseases, including diabetes and its associated complications. Here, w<a>e identified a novel lncRNA MRAK052872, named lnc-URIDS (lncRNA UpRegulated in Diabetic Skin), which regulates wound healing in diabetes mellitus. </a>Lnc-URIDS was highly expressed in diabetic skin and dermal fibroblasts treated with advanced glycation end products (AGEs). Lnc-URIDS knockdown promoted migration of dermal fibroblasts under AGEs treatment in vitro and accelerated diabetic wound healing in vivo. Mechanistically, <a>lnc-URIDS interacts with procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (Plod1), a critical enzyme responsible for collagen cross-linking. </a><a>The binding of lnc-URIDS to Plod1 results in a decreased protein stability of Plod1, which ultimately leads to the dysregulation of collagen production and deposition and delays wound healing. Collectively, this study identifies a novel lncRNA that regulates diabetic wound healing by targeting Plod1. </a><a>The findings of the present study offer some insight into the potential mechanism for the delayed wound healing in diabetes and provide a potential therapeutic target for diabetic foot.</a>

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