Stable analogues of the dual agonist dogfish glucagon show better therapeutic potential than exendin-4 in diet induced obese diabetic mice

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.

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Antihyperglycemic Activity of Hydroalcoholic Extracts of Selective Medicinal Plants Curcuma longa, Lavandula stoechas, Aegle marmelos, and Glycyrrhiza glabra and Their Polyherbal Preparation in Alloxan-Induced Diabetic Mice

Dose-Response ◽

10.1177/1559325819852503 ◽

2019 ◽

Vol 17 (2) ◽

pp. 155932581985250 ◽

Cited By ~ 4

Author(s):

Sodah Bint Mustafa ◽

Muhammad Akram ◽

Hafiz Muhammad Asif ◽

Imran Qayyum ◽

Asif Mehmood Hashmi ◽

...

Keyword(s):

Body Weight ◽

Blood Glucose ◽

Medicinal Plants ◽

Plant Extracts ◽

Therapeutic Potential ◽

Curcuma Longa ◽

Diabetic Mice ◽

Aegle Marmelos ◽

Antihyperglycemic Activity ◽

Lavandula Stoechas

Background: Diabetes mellitus is a metabolic disorder associated with relative or absolute insulin deficiency or resistance, characterized by hyperglycemia. Modern prescriptions such as pioglitazone have better therapeutic potential, but its side effects and financial burden for developing countries have motivated the researchers to find alternative natural drugs to compete hyperglycemia in patients with diabetes. The present study was conducted to explore the therapeutic potential of selected medicinal plants for the treatment of diabetes as an alternative to allopathic medicines. Method: In present study, hydroalcoholic extracts of Curcuma longa, Lavandula stoechas, Aegle marmelos, and Glycyrrhiza glabra and their polyherbal preparation (PHP) as compound drug were investigated for their antihyperglycemic potential in alloxan-induced diabetic mice. The study subjects (mice) were divided into different groups as normal control, diabetic control, pioglitazone treated (standard drug), test groups (plant extract treated 50, 100, and 150 mg/kg body weight), and PHP-treated group. Blood glucose concentration of all the study animals was determined by Glucose strip test. Qualitative phytochemical analysis of all the plant extracts was also performed following standard methods. Result: It was investigated that treatment of alloxan-induced diabetic mice with hydroalcoholic extracts of studied medicinal plants showed significant ( P < .05) effects on fasting blood glucose levels (from baseline to normal range) in a manner comparable to that of the reference drug, pioglitazone (1 mg/kg body weight intraperitoneal). The tested plant extracts significantly ( P < .05) reduced the glucose concentration in blood of diabetes-induced mice in a dose-dependent manner. Conclusion: It could be concluded that studied medicinal plants have antihyperglycemic activity. The study findings favor the use of traditional herbal medicinal practices for the management of diabetes that might due to the presence of bioactive phytoconstituents in plants. However, larger studies are required to identify, isolate, and characterize the bioactive phytoconstituents responsible for antihyperglycemic activity of studied medicinal plants.

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UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00253.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. E72-E86

Author(s):

Petr Zouhar ◽

Günaj Rakipovski ◽

Muhammad Hamza Bokhari ◽

Oliver Busby ◽

Johan F. Paulsson ◽

...

Keyword(s):

Type 1 Diabetes ◽

Therapeutic Potential ◽

Uncoupling Protein ◽

Leptin Resistance ◽

Diabetic Mice ◽

High Fat ◽

Glucose Lowering ◽

Lowering Effect ◽

Glucose Lowering Effect

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity — and thus also leptin levels — in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

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Transgenic Expression of Decoy Receptor 3 Protects Islets from Spontaneous and Chemical-induced Autoimmune Destruction in Nonobese Diabetic Mice

Journal of Experimental Medicine ◽

10.1084/jem.20031939 ◽

2004 ◽

Vol 199 (8) ◽

pp. 1143-1151 ◽

Cited By ~ 55

Author(s):

Hsiang-Hsuan Sung ◽

Jyuhn-Huarng Juang ◽

Yu-Chun Lin ◽

Chien-Hung Kuo ◽

Jung-Tung Hung ◽

...

Keyword(s):

Fas Ligand ◽

Therapeutic Potential ◽

Autoimmune Diabetes ◽

Dependent Manner ◽

Diabetic Mice ◽

Decoy Receptor ◽

Nonobese Diabetic ◽

Decoy Receptor 3 ◽

Nonobese Diabetic Mice ◽

Islet Transplants

Decoy receptor 3 (DCR3) halts both Fas ligand– and LIGHT-induced cell deaths, which are required for pancreatic β cell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 in β cells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and significantly reduced the severity of insulitis. Local expression of the transgene did not alter the diabetogenic properties of systemic lymphocytes or the development of T helper 1 or T regulatory cells. The transgenic islets had a higher transplantation success rate and survived for longer than wild-type islets. We have demonstrated for the first time that the immune-evasion function of DCR3 inhibits autoimmunity and that genetic manipulation of grafts may improve the success and survival of islet transplants.

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NAD+ Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

10.1101/2020.07.03.183111 ◽

2020 ◽

Author(s):

Ying Ann Chiao ◽

Akash Deep Chakraborty ◽

Christine M. Light ◽

Rong Tian ◽

Junichi Sadoshima ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Troponin I ◽

Therapeutic Potential ◽

Redox Balance ◽

Diabetic Mice ◽

Nicotinamide Phosphoribosyltransferase ◽

Redox Imbalance ◽

Nadh Ratio ◽

Regulate Protein

AbstractBackgroundDiabetes is a risk factor of heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with NAD+ redox imbalance; however, the hypothesis that NAD+ redox imbalance leads to dysfunction of diabetic hearts has not been tested. In this study, we employed mouse models with altered NAD+ redox balance to test the hypothesis.Methods and ResultsDiabetes was induced in C57BL/6 mice by streptozotocin injections, and diabetic cardiomyopathy (DCM) was allowed to develop for 16 weeks. Diabetic stress led to cardiac dysfunction and lowered NAD+/NADH ratio. This diabetogenic regimen was administered to cardiac-specific knockout mice of complex I subunit Ndufs4 (cKO), a model with lowered cardiac NAD+/NADH ratio without baseline dysfunction. Cardiac NAD+ redox imbalance in cKO hearts exacerbated systolic and diastolic dysfunction of diabetic mice in both sexes. Collagen levels and transcript analyses of fibrosis and extracellular matrix-dependent pathways did not show change in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was likely due to cardiomyocyte dysfunction. We found that cardiac NAD+ redox imbalance promoted superoxide dismutase 2 (SOD2) acetylation, protein oxidation, induced troponin I S150 phosphorylation and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by nicotinamide phosphoribosyltransferase (NAMPT) normalized NAD+ redox balance, over-expression alleviated cardiac dysfunction and reversed pathogenic mechanisms in diabetic mice.ConclusionOur results show that NAD+ redox imbalance to regulate protein acetylation and phosphorylation is a critical mediator of the progression of DCM, and suggest the therapeutic potential of harnessing NAD+ metabolism in DCM.

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Attenuating Diabetic Vascular and Neuronal Defects by Targeting P2rx7

International Journal of Molecular Sciences ◽

10.3390/ijms20092101 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2101 ◽

Cited By ~ 4

Author(s):

Sofia Pavlou ◽

Josy Augustine ◽

Rónán Cunning ◽

Kevin Harkin ◽

Alan W. Stitt ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Therapeutic Potential ◽

Neuronal Degeneration ◽

Amacrine Cells ◽

Oscillatory Potentials ◽

Transcriptase Inhibitor ◽

Vascular Pathology ◽

Vascular Lesions ◽

Diabetic Mice ◽

New Treatments

Retinal vascular and neuronal degeneration are established pathological features of diabetic retinopathy. Data suggest that defects in the neuroglial network precede the clinically recognisable vascular lesions in the retina. Therefore, new treatments that target early-onset neurodegeneration would be expected to have great value in preventing the early stages of diabetic retinopathy. Here, we show that the nucleoside reverse transcriptase inhibitor lamivudine (3TC), a newly discovered P2rx7 inhibitor, can attenuate progression of both neuronal and vascular pathology in diabetic retinopathy. We found that the expression of P2rx7 was increased in the murine retina as early as one month following diabetes induction. Compared to non-diabetic controls, diabetic mice treated with 3TC were protected against the formation of acellular capillaries in the retina. This occurred concomitantly with a maintenance in neuroglial function, as shown by improved a- and b-wave amplitude, as well as oscillatory potentials. An improvement in the number of GABAergic amacrine cells and the synaptophysin-positive area was also observed in the inner retina of 3TC-treated diabetic mice. Our data suggest that 3TC has therapeutic potential since it can target both neuronal and vascular defects caused by diabetes.

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Does rosuvastatin offer therapeutic potential in autoimmune thyroiditis in nonobese diabetic mice?

Clinical Immunology ◽

10.1016/j.clim.2008.10.002 ◽

2009 ◽

Vol 130 (3) ◽

pp. 375-377 ◽

Cited By ~ 3

Author(s):

Kouki Mori ◽

Katsumi Yoshida ◽

Yoshinori Nakagawa ◽

Saeko Hoshikawa ◽

Hiroshi Ozaki ◽

...

Keyword(s):

Autoimmune Thyroiditis ◽

Therapeutic Potential ◽

Diabetic Mice ◽

Nonobese Diabetic ◽

Nonobese Diabetic Mice

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Mesenchymal Stem Cell-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Ameliorate Diabetic Polyneuropathy in Mice

BioMed Research International ◽

10.1155/2013/259187 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 22

Author(s):

Tatsuhito Himeno ◽

Hideki Kamiya ◽

Keiko Naruse ◽

Zhao Cheng ◽

Sachiko Ito ◽

...

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Cell Transplantation ◽

Pluripotent Stem Cells ◽

Neurotrophic Factors ◽

Therapeutic Potential ◽

Diabetic Polyneuropathy ◽

Therapeutic Effects ◽

Diabetic Mice ◽

Induced Pluripotent

Background. Although pathological involvements of diabetic polyneuropathy (DPN) have been reported, no dependable treatment of DPN has been achieved. Recent studies have shown that mesenchymal stem cells (MSCs) ameliorate DPN. Here we demonstrate a differentiation of induced pluripotent stem cells (iPSCs) into MSC-like cells and investigate the therapeutic potential of the MSC-like cell transplantation on DPN.Research Design and Methods. For induction into MSC-like cells, GFP-expressing iPSCs were cultured with retinoic acid, followed by adherent culture for 4 months. The MSC-like cells, characterized with flow cytometry and RT-PCR analyses, were transplanted into muscles of streptozotocin-diabetic mice. Three weeks after the transplantation, neurophysiological functions were evaluated.Results. The MSC-like cells expressed MSC markers and angiogenic/neurotrophic factors. The transplanted cells resided in hindlimb muscles and peripheral nerves, and some transplanted cells expressed S100βin the nerves. Impairments of current perception thresholds, nerve conduction velocities, and plantar skin blood flow in the diabetic mice were ameliorated in limbs with the transplanted cells. The capillary number-to-muscle fiber ratios were increased in transplanted hindlimbs of diabetic mice.Conclusions. These results suggest that MSC-like cell transplantation might have therapeutic effects on DPN through secreting angiogenic/neurotrophic factors and differentiation to Schwann cell-like cells.

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