In Vitro and In Vivo Studies of a Naturally Occurring Variant of the Human p85  Regulatory Subunit of the Phosphoinositide 3-Kinase: Inhibition of Protein Kinase B and Relationships With Type 2 Diabetes, Insulin Secretion, Glucose Disappearance Constant, and Insulin Sensitivity

The phenomenon of lipid-induced pancreatic β-cell dysfunction (“lipotoxicity”) has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.

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The Role of Oestrogen Receptor Beta (ERβ) in the Aetiology and Treatment of Type 2 Diabetes Mellitus

Current Diabetes Reviews ◽

10.2174/1573399814666180119141836 ◽

2019 ◽

Vol 15 (2) ◽

pp. 100-104 ◽

Cited By ~ 1

Author(s):

Wendy Amy Ofosu ◽

Dahir Mohamed ◽

Olivia Corcoran ◽

Opeolu Oyejide Ojo

Keyword(s):

Type 2 Diabetes ◽

Therapeutic Potential ◽

In Vivo Studies ◽

Oestrogen Receptors ◽

Alternative Pathways ◽

Therapeutic Outcomes

Introduction: Challenges facing the treatment of type 2 diabetes necessitate the search for agents which act via alternative pathways to provide better therapeutic outcomes. Recently, an increasing body of evidence implicates the activation of oestrogen receptors (ERα and ERβ) in the development and treatment of underlying conditions in type 2 diabetes. This article summarizes available evidence for the involvement of oestrogen receptors in insulin secretion, insulin resistance as well as glucose uptake and highlights the potential of ERβ as a therapeutic target. Background: Recent studies indicate an association between the activation of each of the isoforms of ER and recent findings indicate that ERβ shows promise as a potential target for antidiabetic drugs. In vitro and in vivo studies in receptor knockout mice indicate beneficial actions of selective agonists of ERβ receptor and underscore its therapeutic potential. Conclusion: Studies are needed to further elucidate the exact mechanism underlying the role of ERβ activation as a therapeutic approach in the management of type 2 diabetes.

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Trans-11 Vaccenic Acid Improves Glucose Turnover In Vivo and Insulin Secretion In Vitro in Models of Type 2 Diabetes

Canadian Journal of Diabetes ◽

10.1016/j.jcjd.2014.07.045 ◽

2014 ◽

Vol 38 (5) ◽

pp. S17

Author(s):

Xiaofeng Wang ◽

Catherine Chan

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Vaccenic Acid ◽

Glucose Turnover ◽

Insulin Secretion In Vitro

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Taspoglutide, an Analog of Human Glucagon-Like Peptide-1 with Enhanced Stability and in Vivo Potency

Endocrinology ◽

10.1210/en.2009-1459 ◽

2010 ◽

Vol 151 (6) ◽

pp. 2474-2482 ◽

Cited By ~ 36

Author(s):

Elena Sebokova ◽

Andreas D. Christ ◽

Haiyan Wang ◽

Sabine Sewing ◽

Jesse Z. Dong ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Affinity Constant ◽

Camp Production ◽

Dipeptidyl Peptidase 4 ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Taspoglutide is a novel analog of human glucagon-like peptide-1 [hGLP-1(7-36)NH2] in clinical development for the treatment of type 2 diabetes. Taspoglutide contains α-aminoisobutyric acid substitutions replacing Ala8 and Gly35 of hGLP-1(7-36)NH2. The binding affinity [radioligand binding assay using [125I]hGLP-1(7-36)NH2], potency (cAMP production in CHO cells stably overexpressing hGLP-1 receptor), and in vitro plasma stability of taspoglutide compared with hGLP-1(7-36)NH2 have been evaluated. Effects on basal and glucose-stimulated insulin secretion were determined in vitro in INS-1E cells and in vivo in normal rats. Taspoglutide has comparable affinity (affinity constant 1.1 ± 0.2 nm) to the natural ligand (affinity constant 1.5 ± 0.3 nm) for the hGLP-1 receptor and exhibits comparable potency in stimulating cAMP production (EC50 Taspo 0.06 nm and EC50 hGLP-1(7-36)NH2 0.08 nm). Taspoglutide exerts insulinotropic action in vitro and in vivo and retains the glucoincretin property of hGLP-1(7-36)NH2. Stimulation of insulin secretion is concentration dependent and evident in the presence of high-glucose concentrations (16.7 mm) with a taspoglutide concentration as low as 0.001 nm. Taspoglutide is fully resistant to dipeptidyl peptidase-4 cleavage (during 1 h incubation at room temperature with purified enzyme) and has an extended in vitro plasma half-life relative to hGLP-1(7-36)NH2 (9.8 h vs. 50 min). In vitro, taspoglutide does not inhibit dipeptidyl peptidase-4 activity. This study provides the biochemical and pharmacological basis for the sustained plasma drug levels and prolonged therapeutic activity seen in early clinical trials of taspoglutide. Excellent stability and potency with substantial glucoincretin effects position taspoglutide as a promising new agent for treatment of type 2 diabetes.

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Dietary Flavonoids and Insulin Signaling in Diabetes and Obesity

Cells ◽

10.3390/cells10061474 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1474

Author(s):

María Ángeles Martín ◽

Sonia Ramos

Keyword(s):

Phenolic Compounds ◽

Insulin Signaling ◽

In Vivo Studies ◽

Chemopreventive Agents ◽

Naturally Occurring ◽

Diabetes And Obesity ◽

Dietary Flavonoids

Type 2 diabetes (T2D) and obesity are relevant worldwide chronic diseases. A common complication in both pathologies is the dysregulation of the insulin-signaling pathway that is crucial to maintain an accurate glucose homeostasis. Flavonoids are naturally occurring phenolic compounds abundant in fruits, vegetables and seeds. Rising evidence supports a role for the flavonoids against T2D and obesity, and at present, these compounds are considered as important potential chemopreventive agents. This review summarizes in vitro and in vivo studies providing data related to the effects of flavonoids and flavonoid-rich foods on the modulation of the insulin route during T2D and obesity. Notably, few human studies have evaluated the regulatory effect of these phenolic compounds at molecular level on the insulin pathway. In this context, it is also important to note that the mechanism of action for the flavonoids is not fully characterized and that a proper dosage to obtain a beneficial effect on health has not been defined yet. Further investigations will contribute to solve all these critical challenges and will enable the use of flavonoids to prevent, delay or support the treatment of T2D and obesity.

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Experimental Type 2 Diabetes Differently Impacts on the Select Functions of Bone Marrow-Derived Multipotent Stromal Cells

Cells ◽

10.3390/cells10020268 ◽

2021 ◽

Vol 10 (2) ◽

pp. 268

Author(s):

Jonathan Ribot ◽

Cyprien Denoeud ◽

Guilhem Frescaline ◽

Rebecca Landon ◽

Hervé Petite ◽

...

Keyword(s):

Type 2 Diabetes ◽

Bone Marrow ◽

Stromal Cells ◽

Adipogenic Differentiation ◽

Therapeutic Modality ◽

Multipotent Stromal Cells ◽

Cell Therapies

Bone marrow-derived multipotent stromal cells (BMMSCs) represent an attractive therapeutic modality for cell therapy in type 2 diabetes mellitus (T2DM)-associated complications. T2DM changes the bone marrow environment; however, its effects on BMMSC properties remain unclear. The present study aimed at investigating select functions and differentiation of BMMSCs harvested from the T2DM microenvironment as potential candidates for regenerative medicine. BMMSCs were obtained from Zucker diabetic fatty (ZDF; an obese-T2DM model) rats and their lean littermates (ZL; controls), and cultured under normoglycemic conditions. The BMMSCs derived from ZDF animals were fewer in number, with limited clonogenicity (by 2-fold), adhesion (by 2.9-fold), proliferation (by 50%), migration capability (by 25%), and increased apoptosis rate (by 2.5-fold) compared to their ZL counterparts. Compared to the cultured ZL-BMMSCs, the ZDF-BMMSCs exhibited (i) enhanced adipogenic differentiation (increased number of lipid droplets by 2-fold; upregulation of the Pparg, AdipoQ, and Fabp genes), possibly due to having been primed to undergo such differentiation in vivo prior to cell isolation, and (ii) different angiogenesis-related gene expression in vitro and decreased proangiogenic potential after transplantation in nude mice. These results provided evidence that the T2DM environment impairs BMMSC expansion and select functions pertinent to their efficacy when used in autologous cell therapies.

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PAR-4/Ca2+-calpain pathway activation stimulates platelet-derived microparticles in hyperglycemic type 2 diabetes

Cardiovascular Diabetology ◽

10.1186/s12933-021-01267-w ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Alessandra Giannella ◽

Giulio Ceolotto ◽

Claudia Maria Radu ◽

Arianna Cattelan ◽

Elisabetta Iori ◽

...

Keyword(s):

Type 2 Diabetes ◽

Normal Glucose Tolerance ◽

Calpain Inhibitor ◽

Pathway Activation ◽

Normal Glucose ◽

Circulating Levels ◽

Dependent Mechanism

Abstract Background Patients with type 2 diabetes (T2DM) have a prothrombotic state that needs to be fully clarified; microparticles (MPs) have emerged as mediators and markers of this condition. Thus, we investigate, in vivo, in T2DM either with good (HbA1c ≤ 7.0%; GGC) or poor (HbA1c > 7.0%; PGC) glycemic control, the circulating levels of MPs, and in vitro, the molecular pathways involved in the release of MPs from platelets (PMP) and tested their pro-inflammatory effects on THP-1 transformed macrophages. Methods In 59 T2DM, and 23 control subjects with normal glucose tolerance (NGT), circulating levels of CD62E+, CD62P+, CD142+, CD45+ MPs were determined by flow cytometry, while plasma levels of ICAM-1, VCAM-1, IL-6 by ELISA. In vitro, PMP release and activation of isolated platelets from GGC and PGC were investigated, along with their effect on IL-6 secretion in THP-1 transformed macrophages. Results We found that MPs CD62P+ (PMP) and CD142+ (tissue factor-bearing MP) were significantly higher in PGC T2DM than GGC T2DM and NGT. Among MPs, PMP were also correlated with HbA1c and IL-6. In vitro, we showed that acute thrombin exposure stimulated a significantly higher PMP release in PGC T2DM than GGC T2DM through a more robust activation of PAR-4 receptor than PAR-1 receptor. Treatment with PAR-4 agonist induced an increased release of PMP in PGC with a Ca2+-calpain dependent mechanism since this effect was blunted by calpain inhibitor. Finally, the uptake of PMP derived from PAR-4 treated PGC platelets into THP-1 transformed macrophages promoted a marked increase of IL-6 release compared to PMP derived from GGC through the activation of the NF-kB pathway. Conclusions These results identify PAR-4 as a mediator of platelet activation, microparticle release, and inflammation, in poorly controlled T2DM.

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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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Abstract 424: An IFNg-regulated Macrophage Protein Network Links Type 2 Diabetes to Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.424 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Catherine A Reardon ◽

Amulya Lingaraju ◽

Kelly Q Schoenfelt ◽

Guolin Zhou ◽

Ning-Chun Liu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Increased Risk ◽

Macrophage Dysfunction ◽

Macrophage Protein

Type 2 diabetics have a higher risk for atherosclerosis, but the mechanisms underlying the increased risk are poorly understood. Macrophages, which are activated in type 2 diabetes (T2D) and have a role in all stages of atherogenesis, are an attractive link. Our hypothesis is that T2D promotes macrophage dysfunction to promote atherosclerosis. To investigate the relationship between T2D and macrophage dysfunction, we used a proteomics approach to identify dysregulated proteins secreted from peritoneal macrophages in a diet induced mouse model of obesity and insulin resistance in the absence of hypercholesterolemia. Twenty-seven T2D responsive proteins were identified that predict defects in many of the critical functions of macrophages in atherosclerosis (e.g. decreased apoE- cholesterol efflux; decreased MFGE8 – efferocytosis, increased MMP12- matrix degradation). The macrophages from lean and obese mice were not lipid loaded, but the obese macrophages accumulated significantly more cholesterol when exposed to high levels of atherogenic lipoproteins in vitro suggesting that dysregulation of the T2D responsive proteins in diabetic mice render macrophages more susceptible to cholesterol loading. Importantly, many of these same protein changes, which were present in atherosclerotic Ldlr-/- mice with T2D, were normalized when these mice were fed non-diabetogenic hypercholesterolemic diets. Thus, foam cell formation in the presence and absence of T2D produces distinct effects on macrophage protein levels, and hence function. Further, we identify IFNγ as a mediator of the T2D responsive protein dysfunction. IFNγ, but not other cytokines, insulin or glucose, promote the T2D responsive protein dysregulation and increased susceptibility to cholesterol accumulation in vitro and the dysregulation is not observed in macrophage foam cells obtained from obese, diabetic IFNγ receptor 1 knockout animals. We also demonstrate that IFNγ can target these proteins in arterial wall macrophages in vivo . These studies suggest that IFNγ is an important mediator of macrophage dysfunction in T2D that may contribute to the enhanced cardiovascular risk in these patients.

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