Alpha-to-beta cell trans-differentiation for treatment of diabetes

Diabetes mellitus is a significant cause of morbidity and mortality in the United States and worldwide. According to the CDC, in 2017, ∼34.2 million of the American population had diabetes. Also, in 2017, diabetes was the seventh leading cause of death and has become the number one biomedical financial burden in the United States. Insulin replacement therapy and medications that increase insulin secretion and improve insulin sensitivity are the main therapies used to treat diabetes. Unfortunately, there is currently no radical cure for the different types of diabetes. Loss of β cell mass is the end result that leads to both type 1 and type 2 diabetes. In the past decade, there has been an increased effort to develop therapeutic strategies to replace the lost β cell mass and restore insulin secretion. α cells have recently become an attractive target for replacing the lost β cell mass, which could eventually be a potential strategy to cure diabetes. This review highlights the advantages of using α cells as a source for generating new β cells, the various investigative approaches to convert α cells into insulin-producing cells, and the future prospects and problems of this promising diabetes therapeutic strategy.

An Update of Anthraquinone Derivatives Emodin, Diacerein, and Catenarin in Diabetes

Diabetes is part of metabolic diseases and is characterized by high blood sugar levels over a prolonged period as result of an insulin-deficient production or an inappropriate response to insulin by our cells. This chronic disease was the direct cause of 1.6 million deaths in 2016 as reported by the World Health Organization. Emodin is a natural product and active ingredient of various Chinese herbs with the chemical formula 1,3,8-trihydroxy-6-methylanthraquinone. Diacerein is another naturally occurring anthraquinone (1,8-diacetoxy-3-carboxyanthraquinone) commonly used as commercial drug to treat osteoarthritis. These two anthraquinone derivatives have been shown to exert antidiabetic activities. Emodin seems to enhance the glucose tolerance and insulin sensibility via activation of PPARγ and modulation of metabolic-related genes. Diacerein seems to decrease inflammatory cytokines and increase insulin secretion enhancing insulin sensibility and therefore improving glucose control. Other naturally occurring anthraquinone derivatives, such as catenarin (1,4,6,8-tetrahydroxy-3-methylanthraquinone), have been shown to have antidiabetic activities although few studies have been performed. The synthesis of new emodin derivatives is increasing, but these new molecules have not been tested for diabetes treatment. In the current work, available literature on anthraquinone derivatives' effects in diabetes disease is reviewed. Moreover, we discuss the chemistry, food sources, bioavailability, and toxicity of the naturally occurring anthraquinone with antidiabetic effects.

Broadening the role of osteocalcin in hypothalamic-pituitary-gonadal axis

Bone is emerging as a versatile endocrine organ and its interactions with apparently unrelated organs are being more widely recognized. Osteocalcin (OCN), a polypeptide hormone secreted by osteoblasts, has been found to exert multiple endocrine functions through its metabolically active form, uncarboxylated OCN (uOCN). Mounting evidence has shown that following its binding to G-protein coupled receptor 6a (Gprc6a) in the peripheral tissues, uOCN acts on pancreatic β cells to increase insulin secretion, and on muscle and white adipose tissue to promote glucose and lipid metabolism. More strikingly, researchers have found a surprising role of uOCN in testicular function to facilitating testosterone biosynthesis and regulating male fertility via a pancreas-bone-gonadal axis. However, the detailed functional mechanisms of uOCN on the hypothalamic-pituitary-gonadal axis or the pancreas-bone-gonadal axis are not fully understood. Besides highlighting the regulatory mechanisms of uOCN in the central nervous system, hypothalamus and pituitary, we also discuss its role in male as well as female fertility and its potential clinical implications in some reproductive endocrine diseases and pubertal developmental disorders.

Molecules Isolated from Mexican Hypoglycemic Plants: A Review

Like in many developing countries, in Mexico, the use of medicinal plants is a common practice. Based on our own field experience, there are at least 800 plants used for treating diabetes nowadays. Thus, their investigation is essential. In this context, this work aims to provide a comprehensive and critical review of the molecules isolated from Mexican hypoglycemic plants, including their source and target tested. In the last few years, some researchers have focused on the study of Mexican hypoglycemic plants. Most works describe the hypoglycemic effect or the mechanism of action of the whole extract, as well as the phytochemical profile of the tested extract. Herein, we analyzed 85 studies encompassing 40 hypoglycemic plants and 86 active compounds belonging to different classes of natural products: 28 flavonoids, 25 aromatic compounds, other than flavonoids, four steroids, 23 terpenoids, 4 oligosaccharides, and 1 polyalcohol. These compounds have shown to inhibit α-glucosidases, increase insulin secretion levels, increase insulin sensitivity, and block hepatic glucose output. Almost half of these molecules are not common metabolites, with a narrow taxonomic distribution, which makes them more interesting as lead molecules. Altogether, this analysis provides a necessary inventory useful for future testing of these active molecules against different hypoglycemic targets, to get a better insight into the already described mechanisms, and overall, to contribute to the knowledge of Mexican medicinal plants.

The Potential of Hibiscus sabdariffa Linn in Inducing Glucagon-Like Peptide-1 via SGLT-1 and GLPR in DM Rats

Background. Glucagon-like peptide 1 (GLP-1) hormone is an incretin hormone that is secreted in the ileum and plays a role in the pancreas to increase insulin secretion, stimulate proliferation, and prevent pancreatic β-cell apoptosis. Currently, diabetes mellitus (DM) treatment based on GLP-1 work is being developed, for instance, from herbal plants such as Hibiscus sabdariffa Linn (H. sabdariffa). Therefore, this study aims to determine the potential of H. sabdariffa in GLP-1 secretion in the ileum and its action in pancreatic β-cells. In addition, this study also aims to determine the active ingredients of H. sabdariffa (Hib) that interact with sodium-glucose cotransporter-1 (SGLT-1) so that it can increase GLP-1 secretion in the ileum and interact with GLP-1 receptors (GLP-1R) in the pancreas. Method. This experimental study used 24 experimental animals of Sprague–Dawley type (aged 8–10 weeks, weight 200–250 g) that were divided into 6 groups, namely, (i) normal (C), (ii) normal-Hib 200 (C-Hib200), (iii) normal-Hib 500 (C-Hib500), (iv) DM (C-DM), (v) DM-Hib200, and (vi) DM-Hib500. H. sabdariffa extract was given orally once a day for 5 weeks. Testing of GLP-1 levels in the ileum and pancreatic tissue was performed by enzyme-linked immunosorbent assay. The prediction of the interaction mechanism of the active substance H. sabdariffa against GLP-1 was done using molecular docking. Results. There was a decrease in GLP-1 levels in the ileum of DM rats (p<0.05). However, DM rats administered H. sabdariffa 500 mg/kg BW had GLP-1 levels that were the same as in normal rats (p>0.05). This is due to active ingredients such as leucosin, which binds to SGLT-1. Administration of 500 mg/kg BW H. sabdariffa in DM rats resulted in GLP-1 levels in the pancreas that were the same as in normal rats (p>0.05). In addition, the active ingredient of H. sabdariffa, delphinidin, binds to GLPR in the pancreas. Conclusion. The active ingredient of H. sabdariffa can increase GLP-1 secretion in the ileum and can interact with G protein-linked receptors in the pancreas.

Insulin secretory effect of sitagliptin: assessment with a hyperglycemic clamp combined with a meal challenge

Sitagliptin, a dipeptidyl peptidase-IV inhibitor (DPP-4), sustains activity of the incretin hormones GLP-1 and GIP and improves hyperglycemia in Type 2 diabetes mellitus (T2DM). It has however proven challenging to quantify the effect of sitagliptin on rates of insulin secretion (ISR) during a prandial challenge. The tight feedback governance of ISR by plasma glucose means that in the face of treatment-related lowering of postprandial glycemia, corresponding stimulation of ISR is lessened. We postulated that sustaining a stable level of moderate hyperglycemia before and during a meal challenge (MC) would be a platform that enables greater clarity to assess the effect of sitagliptin on ISR and an approach that could be valuable to evaluate novel targets that increase insulin secretion directly and by augmenting incretins. A hyperglycemic clamp (HGC) at 160 mg/dl was conducted in 12 healthy volunteers (without diabetes) for 6 h; 3 h into the HGC, MC was administered while maintaining stable hyperglycemia of the HGC for an additional 3 h. Modeling of C-peptide response was used to calculate ISR. In crossover design of three periods (sitagliptin twice and placebo once), the effect of sitagliptin vs. placebo on ISR and the reproducibility of the response to sitagliptin were assessed. Sitagliptin increased ISR compared with placebo by 50% and 20% during the HGC alone and the HGC-MC phases, respectively ( P < 0.001 for both). There was an associated significant treatment-based increase in circulating insulin, as well as active levels of GLP-1. Robust reproducibility of the sitagliptin-mediated ISR response was observed; the intraclass correlation value was 0.94. The findings delineate the effect of sitagliptin to stimulate insulin secretion, and these benchmark data also demonstrate that an HGC-MC can be a useful platform for interrogating therapeutic targets that could potentially modulate ISR via direct action on beta-cells as well as by augmenting release or action of incretins.