[Investigation on the mechanism of acupuncture in treatment of diabetes mellitus type 2 based on the network of islet macrophages-pancreatic adipose cells-islet ß cells].

To explore the possible new mechanism of acupuncture in the treatment of diabetes mellitus type 2 (T2DM) based on the islet inflammatory response. Islet macrophages, pancreatic adipose cells and islet ß cells all participate in the pathogenesis of T2DM, and the three could form a network interaction. Acupuncture could regulate the functional phenotype of islet macrophages, improve the ectopic deposition of pancreatic adipose and repair the function of islet ß cells, and play a unique advantage of overall regulation. It is suggested that acupuncture can be a potential treatment strategy for T2DM.

Investigation on the mechanism of acupuncture in treatment of diabetes mellitus type 2 based on the network of islet macrophages-pancreatic adipose cells-islet β cells / 中国针灸

To explore the possible new mechanism of acupuncture in the treatment of diabetes mellitus type 2 (T2DM) based on the islet inflammatory response. Islet macrophages, pancreatic adipose cells and islet β cells all participate in the pathogenesis of T2DM, and the three could form a network interaction. Acupuncture could regulate the functional phenotype of islet macrophages, improve the ectopic deposition of pancreatic adipose and repair the function of islet β cells, and play a unique advantage of overall regulation. It is suggested that acupuncture can be a potential treatment strategy for T2DM.

Aloperine protects beta-cells against streptozocin-induced injury to attenuate diabetes by targeting NOS1.

Type 1 diabetes (T1D) is a metabolic dysfunction characterized by the selective destruction of islet ß-cells, with oxidative stress playing an essential role in the manifestation of this disease state. Aloperine (ALO) represents the main active alkaloid extracted from the traditional Chinese herbal Sophora alopecuroides L. and features outstanding antioxidative properties. In this study, T1D was induced by a single high dose streptozotocin (STZ, 150 mg/kg, intraperitoneal) in mice. Diabetic animals were intragastrically administered ALO at a dose of 50 mg/kg/day. Notably, treatment of ALO (50 mg/kg/day) for seven consecutive days could observably reverse the onset of diabetes induced by STZ accompanied by weight gain, lower blood glucose levels, and relief of ß-cells damage. Our in vitro study further demonstrated that ALO protected ß-cells from STZ/hydrogen peroxide-induced oxidative damage as manifested by increased expression of MnSOD and CAT. Furthermore, a network pharmacology study revealed that NOS1 represented the main target of ALO. Mechanistic studies subsequently showed that treatment of ALO increased the expression of NOS1, whereas NOS2 was decreased. Moreover, a docking study carried out suggested that ALO could fit into the binding pocket of human NOS1 and molecular dynamics simulation further validated this docking event. Collectively, the administration of ALO prior to diabetes could be a viable approach to the prevention of ß-cell injury. This study may offer a novel potential herbal medicine against T1D and may further help improve the understanding of the underlying molecular mechanisms of ALO-mediated protection against oxidative stress.

The HDAC Inhibitor Butyrate Impairs ß Cell Function and Activates the Disallowed Gene Hexokinase I.

Histone deacetylase (HDAC) inhibitors such as butyrate have been reported to reduce diabetes risk and protect insulin-secreting pancreatic ß cells in animal models. However, studies on insulin-secreting cells in vitro have found that butyrate treatment resulted in impaired or inappropriate insulin secretion. Our study explores the effects of butyrate on insulin secretion by BRIN BD-11 rat pancreatic ß cells and examined effects on the expression of genes implicated in ß cell function. Robust HDAC inhibition with 5 mM butyrate or trichostatin A for 24 h in ß cells decreased basal insulin secretion and content, as well as insulin secretion in response to acute stimulation. Treatment with butyrate also increased expression of the disallowed gene hexokinase I, possibly explaining the impairment to insulin secretion, and of TXNIP, which may increase oxidative stress and ß cell apoptosis. In contrast to robust HDAC inhibition (>70% after 24 h), low-dose and acute high-dose treatment with butyrate enhanced nutrient-stimulated insulin secretion. In conclusion, although protective effects of HDAC inhibition have been observed in vivo, potent HDAC inhibition impairs ß cell function in vitro. The chronic low dose and acute high dose butyrate treatments may be more reflective of in vivo effects.

The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror.

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans' islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (ß) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to ß cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.

Superiority of Purple Okra (Abelmoschus esculentus) to Green Okra in Insulin Resistance and Pancreatic ß Cell Improvement in Diabetic Rats.

INTRODUCTION: Antidiabetic medicinal plants are increasingly used in the treatment of diabetes as they are generally assumed to pro-duce minimal side effects. Okra is a quercetin-containing plant which can induce pancreas regeneration and has antidiabetic effect. There has been a lot of research that demonstrate that purple okra contains more quercetin than green okra. AIM: To demonstrate the advantages of purple okra over green okra on the diabetic markers improvement in diabetic rats. MATERIALS AND METHODS: Fifteen male 2-month-old Wistar rats were injected intraperitoneally with 65 mg streptozotocin and 110 mg niacinamide. Their blood glucose levels were measured three days after the injection. The induction of diabetes was deemed  successful if the glucose level of the rats got higher than 250 mg/dL, and then such rats were considered diabetic. The diabetic rats were divided into three groups: an acarbose group, a purple okra powder group, and a green okra powder group. The latter two were given, respectively, purple and green okra powder for 28 days. Blood serum was taken to examine the fasting blood glucose, insulin, HOMA-B and GLUT-4 levels. Pancreas was examined histologically for damage using hematoxylin eosin staining. RESULTS: Fasting blood glucose, insulin, HOMA-B, and GLUT-4 levels of diabetic rats that received purple okra powder (p<0.05) were better than those of the rats that received green okra powder. The least damage (p<0.05) to pancreatic beta cells was found in the purple okra powder group. CONCLUSIONS: Purple okra is superior to green okra in terms of improving the diabetic markers of rats.

Alleviation of diabetes mellitus through the restoration of ß-cell function and lipid metabolism by Aloe vera (L.) Burm. f. extract in obesogenic WNIN/GR-Ob rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloe vera (L.) Burm. f. extract has been medicinally used for over 5000 years in different cultures for its curative and therapeutic properties ranging from dermatitis to diabetes. It has been demonstrated to alleviate diabetes through its protective effects on pancreatic islets and by improving insulin secretion. AIM OF THE STUDY: To investigate the simultaneous effect of ethanolic A. vera gel extract on diabetes and obesogenic milieu in Streptozotocin-induced WNIN/GR-Ob mutant obese rats. MATERIALS AND METHODS: A total of 30 rats were grouped equally into WNIN/GR-Ob control (received water as a vehicle), WNIN/GR-Ob Diabetic rats (Streptozotocin-35 mg/kg bw), WNIN/GR-Ob Diabetic rats + Sitagliptin (10 mg/kg bw), WNIN/GR-Ob Diabetic rats + A. vera (300 mg/kg bw) and GR-Ob control + A. vera (300 mg/kg bw). After 4 weeks of treatment, fasting blood glucose, serum insulin, Homeostatic Model Assessment - Insulin Resistance and ß-cell function, glucose-stimulated insulin secretion, Dipeptidyl peptidase-IV activity, and lipid profiles were studied. In addition, ultrastructural analysis of isolated islets and dual-energy X-ray absorptiometry analysis for body composition were also carried out. RESULTS: The A. vera treated group showed a significant reduction (p < 0.05) in triglyceride, Very low-density lipoprotein levels, Triglyceride to High-density lipoprotein ratio as well as fasting blood glucose levels and DPP-IV activity with a concomitant increase in the serum insulin levels. The increase in IR was observed in both WNIN/GR-Ob control and diabetic rats with a significant decrease in ß-cell function in the diabetic rats as per Homeostatic Model Assessment values. Oral administration of A. vera was effective in both reducing Homeostatic Model Assessment-Insulin Resistance and increasing Homeostatic Model Assessment-ß values. Also, the treated group demonstrated preservation of islets and a significant increase (p < 0.05) in the diameter of ß-cell as evident through Scanning electron microscope analysis. The increase in lean body mass was manifested in the treated group with a reduction in Fat percent in comparison with other groups. CONCLUSION: The beneficial effects of A. vera in WNIN/GR-Ob strain may be attributed to its ability to lower lipid profile thus improve insulin sensitivity and/or modulating ß-cell function. Thus, it has great therapeutic potential as an herbal remedy for the treatment of diabetes and associated adverse effects such as obesity. The exact mechanism underlying the observation needs to be investigated further to explore the anti-obesity and anti-diabetic properties of A. vera and advocate its potential application as alternative medicine.

Vitamin D Rescues Pancreatic ß Cell Dysfunction due to Iron Overload via Elevation of the Vitamin D Receptor and Maintenance of Ca2+ Homeostasis.

SCOPE: Accumulating evidence indicates that micronutrients are related to metabolic diseases. However, comparatively less attention has been devoted to their influence on each other during the development of metabolic diseases. To investigate the underlying mechanisms, the effects of iron and vitamin D on pancreatic ß cell functions are examined. METHODS AND RESULTS: Iron overload is induced in INS-1 rat insulinoma pancreatic ß cells and it is found that iron overload dramatically reduce expression of the vitamin D receptor (VDR). Iron overload-induced ß cell dysfunction is rescued by 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ) cotreatment via restoration of VDR level and the consequent maintenance of Ca2+ homeostasis. Iron accumulation is also observed in the islets of 22-month-old C57BL/6 mice fed with a chow diet (1000 IU vitamin D3 per kg). In contrast, islet iron accumulation and hyperinsulinemia are ameliorated in mice fed with a vitamin D3 -supplemented diet (20 000 IU kg-1 ). CONCLUSION: The authors show that functional failure of ß cells due to iron accumulation is rescued by 1,25(OH)2 D3 , and iron overload significantly reduces VDR levels in ß cells. These results suggest that iron and vitamin D inversely influence pancreatic ß cell function.

A novel low-molecular-mass pumpkin polysaccharide: Structural characterization, antioxidant activity, and hypoglycemic potential.

The novel natural low-molecular-mass polysaccharide (SLWPP-3) from pumpkin (Cucurbia moschata) was separated from the waste supernatant after macromolecular polysaccharide production and purified using a DEAE cellulose-52 column and gel-filtration chromatography. Chemical and instrumental studies revealed that SLWPP-3 with a molecular mass of 3.5 kDa was composed of rhamnose, glucose, arabinose, galactose and uronic acid with a weight ratio of 1: 1: 4: 6: 15, and primarily contained →3,6)-ß-d-Galp-(1→, →4)-α-GalpA-(1→(OMe), →4)-α-GalpA-(1→, →2,4)-α-d-Rhap-(1→, →3)-ß-d-Galp-(1→, →4)-α-d-Glcp, and →4)-ß-d-Galp residues in the backbone. The branch chain passes were connected to the main chain through the O-4 atom of glucose and O-3 atom of arabinose. Physiologically, the ability of SLWPP-3 to inhibit carbohydrate-digesting enzymes and DPPH and ABTS radicals, as well as protect pancreatic ß cells from oxidative damage by decreasing MDA levels and increasing SOD activities, was confirmed. The findings elucidated the structural types of pumpkin polysaccharides and revealed a potential adjuvant natural product with hypoglycemic effects.

Natural Product Luteolin Rescues THAP-Induced Pancreatic ß-Cell Dysfunction through HNF4α Pathway.

Endoplasmic reticulum stress (ER stress) plays a main role in pancreatic [Formula: see text]-cell dysfunction and death because of intracellular Ca[Formula: see text] turbulence and inflammation activation. Although several drugs are targeting pancreatic [Formula: see text]-cell to improve [Formula: see text]-cell function, there still lacks agents to alleviate [Formula: see text]-cell ER stress conditions. Therefore we used thapsigargin (THAP) or high glucose (HG) to induce ER stress in [Formula: see text]-cell and aimed to screen natural molecules against ER stress-induced [Formula: see text]-cell dysfunction. Through screening the Traditional Chinese drug library ([Formula: see text] molecules), luteolin was finally discovered to improve [Formula: see text]-cell function. Cellular viability results indicated luteolin reduced the THAP or HG-induced [Formula: see text]-cell death and apoptosis through MTT and flow cytometry assay. Moreover, luteolin improved [Formula: see text]-cell insulin secretion ability under ER stress conditions. Also ER stress-induced intracellular Ca[Formula: see text] turbulence and inflammation activation were inhibited by luteolin treatment. Mechanically, luteolin inhibited HNF4[Formula: see text] signaling, which was induced by ER stress. Moreover, luteolin reduced the transcriptional level of HNF4[Formula: see text] downstream gene, such as Asnk4b and HNF1[Formula: see text]. Conversely HNF4[Formula: see text] knockdown abolished the effect of luteolin on [Formula: see text]-cell using siRNA. These results suggested the protective effect of luteolin on [Formula: see text]-cell was through HNF4[Formula: see text]/Asnk4b pathway. In conclusion, our study discovered that luteolin improved [Formula: see text]-cell function and disclosed the underlying mechanism of luteolin on [Formula: see text]-cell, suggesting luteolin is a promising agent against pancreatic dysfunction.

Low methyl-esterified pectin protects pancreatic ß-cells against diabetes-induced oxidative and inflammatory stress via galectin-3.

Insufficient intake of dietary fibers in Western societies is considered a major contributing factor in the high incidence rates of diabetes. The dietary fiber pectin has been suggested to be beneficial for management of both Diabetes Type 1 and Type 2, but mechanisms and effects of pectin on insulin producing pancreatic ß-cells are unknown. Our study aimed to determine the effects of lemon pectins with different degree of methyl-esterification (DM) on ß-cells under oxidative (streptozotocin) and inflammatory (cytokine) stress and to elucidate the underlying rescuing mechanisms, including effects on galectin-3. We found that specific pectins had rescuing effects on toxin and cytokine induced stress on ß-cells but effects depended on the pectin concentration and DM-value. Protection was more pronounced with low DM5 pectin and was enhanced with higher pectin-concentrations. Our findings show that specific pectins might prevent diabetes by making insulin producing ß-cells less susceptible for stress.

In vitro model using cytokine cocktail to evaluate apoptosis in Min6 pancreatic beta cells.

INTRODUCTION: Development of therapy options for treatment of type 1 diabetes mellitus is hampered by non-availability of appropriate experimental models that can exactly mimic the in vivo situation. Apoptosis of beta cells by T cells and cytokine action leads to loss of beta cells. We propose a simple and elegant model using cytokine cocktail of TNF-α, IFN-γ and IL-1ß, the major cytokines responsible for apoptosis in Min6 beta cell line. METHODS: A cocktail of TNF-α, IFN-γ and IL-1ß was used to induce apoptosis in Min6 beta cell line. Apoptosis was assessed by flow cytometry using CytoFLEX (Beckman Coulter). The destruction of beta cells is through production of nitric oxide (NO), oxidative stress and change in mitochondrial membrane permeability. NO was measured using Griess reagent. Oxidative stress was assessed using 2',7'-dichlorofluorescein diacetate, a cell-permeable fluorogenic dye and mitochondrial membrane potential was determined on the basis of retention of rhodamine 123 using flow cytometer. RESULTS AND DISCUSSION: Very low concentration of the cocktail viz. TNF-α 25 ng/ml, IFN-γ 25 ng/ml and IL-1ß 50 ng/ml has demonstrated effective early and late apoptosis in as short a time period as 6 h. The experimental model used demonstrated 1.5 fold higher production of NO, 1.2 fold increased oxidative stress and lower mitochondrial membrane potential as compared to the positive control used. Hence the above model can be easily used for assessment and screening of drugs that can prevent apoptosis of beta cells and stop progression of type 1 diabetes.

Antidiabetic Potency, Antioxidant Effects, and Mode of Actions of Citrus reticulata Fruit Peel Hydroethanolic Extract, Hesperidin, and Quercetin in Nicotinamide/Streptozotocin-Induced Wistar Diabetic Rats.

This study is aimed at assessing the antihyperglycemic, antihyperlipidemic, and antioxidant effects of Citrus reticulata (C. reticulata) fruit peel hydroethanolic extract and two flavonoids, hesperidin and quercetin, in nicotinamide (NA)/streptozotocin- (STZ-) induced type 2 diabetic rats. In addition, GC-MS and HPLC-MS analyses of the extract were performed and the results indicated the presence of multiple flavonoids including hesperidin, quercetin, naringin, and polymethoxylated flavones (nobiletin and tangeretin). To achieve the aim of the study, diabetic rats with NA/STZ-induced T2DM were orally treated with C. reticulata fruit peel hydroethanolic extract, hesperidin, and quercetin at a dose of 100 mg/kg b.w./day for four weeks. The treatments with C. reticulata fruit peel extract, hesperidin, and quercetin significantly ameliorated the impaired oral glucose tolerance; the elevated serum fructosamine level; the diminished serum insulin and C-peptide levels; the altered HOMA-IR, HOMA-IS, and HOMA-ß cell function; the decreased liver glycogen content; the increased liver glucose-6-phosphatase and glycogen phosphorylase activities; the deleteriously affected serum lipid profile; the elevated serum AST and ALT activities; and the raised serum creatinine and urea levels in the diabetic rats. The treatments also produced remarkable improvement in the antioxidant defense system manifested by a decrease in the elevated liver lipid peroxidation and an increase in the lowered glutathione content and GPx, GST, and SOD activities. Furthermore, the three treatments enhanced the mRNA expression of GLUT-4 and the insulin receptor ß-subunit, but only quercetin produced a significant increase in the expression of adiponectin in adipose tissue of diabetic rats. In conclusion, C. reticulata fruit peel hydroethanolic extract, hesperidin, and quercetin have potent antidiabetic effects which may be mediated through their insulinotropic effects and insulin-sensitizing actions. In addition, the alleviation of the antioxidant defense system by the extract, hesperidin, and naringin may have an important action to enhance the antidiabetic actions and to improve liver and kidney functions in NA/STZ-induced diabetic rats.

A polysaccharide extract from the medicinal plant Maidong inhibits the IKK-NF-κB pathway and IL-1ß-induced islet inflammation and increases insulin secretion.

The herb dwarf lilyturf tuber (Maidong, Ophiopogonis Radix) is widely used in Chinese traditional medicine to manage diabetes and its complications. However, the role of Maidong polysaccharide extract (MPE) in pancreatic ß-cell function is unclear. Here, we investigated whether MPE protects ß-cell function and studied the underlying mechanisms. We treated db/db and high-fat diet (HFD)-induced obese mice with 800 or 400 mg/kg MPE or water for 4 weeks, followed by an oral glucose tolerance test. Pancreas and blood were collected for molecular analyses, and clonal MIN6 ß-cells and primary islets from HFD-induced obese mice and normal chow diet-fed mice were used in additional analyses. In vivo, MPE both increased insulin secretion and reduced blood glucose in the db/db mice but increased only insulin secretion in the HFD-induced obese mice. MPE substantially increased the ß-cell area in both models (3-fold and 2-fold, p < 0.01, for db/db and HFD mice, respectively). We observed reduced nuclear translocation of the p65 subunit of NF-κB in islets of MPE-treated db/db mice, coinciding with enhanced glucose-stimulated insulin secretion (GSIS). In vitro, MPE potentiated GSIS and decreased interleukin 1ß (IL-1ß) secretion in MIN6 ß-cells. Incubation of MIN6 cells with tumor necrosis factor α (TNFα), interferon-γ, and IL-1ß amplified IL-1ß secretion and inhibited GSIS. These effects were partially reversed with MPE or the IκB kinase ß inhibitor PS1145, coinciding with reduced activation of p65 and p-IκB in the NF-κB pathway. We conclude that MPE may have potential for therapeutic development for ß-cell protection.

The modulatory role of prime identified compounds in the bioactive fraction of Homalium zeylanicum in high-fat diet fed-streptozotocin-induced type 2 diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Homalium zeylanicum (Gardner) Benth. is a medicinal plant traditionally used in controlling diabetes which thus far has been assessed by the authors only to a very limited extent. PURPOSE: To fill the research gap in the literature review, we investigated the antihyperglycemic effects of hydro alcohol fraction of bark of H. zeylanicum (HAHZB) by modulating oxidative stress and inflammation in high-fat diet fed-streptozotocin (HFD/STZ)-induced type-2 diabetic rats. MATERIALS AND METHODS: To understand the antioxidant capacity of HAHZB, oxygen radical absorbance capacity (ORAC) and cell-based antioxidant protection in erythrocytes (CAP-e) were performed. GC-MS/MS analysis was performed to assess the bioactive components in HAHZB. HFD/STZ-induced diabetic rats were treated orally with HAHZB (300 and 400 mg/kg) for 28 days. After the end of the experiment, marker profiling and histopathological observation of blood and pancreas were examined. The study also highlights interaction between diabetes, oxidative stress and inflammation by examining the increased pro-inflammatory cytokines e.g. TNF-α and C-reactive protein (CRP) promotes DNA damage e.g. oxidation of 8-hydroxy-2-deoxyguanosine (8-OHdG) in chronic hyperglycaemia. RESULTS: In ex vivo cellular antioxidant capacity of -CAP-e and ORAC assays, HAHZB showed remarkable free radical scavenging ability in a dose dependent manner. GC-MS/MS analysis identified 28 no. of compounds and out of which, oleic acid (1.03%), ethyl tridecanoate (11.77%), phytol (1.29), 9,12-octadecadienoic acid, methyl ester, (E,E)-(5.97%), stigmasterol (1.30%) and ß-sitosterol (2.86%) have antioxidant, anti-inflammatory and anti-diabetic activities. HAHZB 400 mg/kg significantly (p < 0.001) improved the lipid profile (TC: 74.66 ± 0.59, HDL-C: 22.08 ± 0.46, LDL-C: 38.06 ± 0.69, and TG: 171.92 ± 1.01 mg/dL) as well as restoring antidiabetic markers (SG: 209.62 ± 1.05 mg/dL, SI: 15.07 ± 0.11 µIU/mL, HOMA-IR: 7.79 ± 0.04 %, and HbA1C: 8.93 ± 0.03 %) and renal functional markers (Tg: 291.26 ± 0.57 pg/mL, BUN: 23.79 ± 0.14 mg/dL, and Cr: 1.34 ± 0.04 mg/dL) in diabetic rats. Oxidative stress markers of pancreas (MDA: 3.65 ± 0.17 nM TBARS /mg protein, SOD: 3.14 ± 0.28 U/mg protein, CAT: 7.88 ± 0.23 U/mg protein, GSH: 12.63 ± 0.28 µM/g of tissue) were restored to normal as evidenced by histological architecture of pancreatic islet cells. The increased level of pro-inflammatory cytokines and oxidative DNA damage were significantly restored (TNF-α: 54.48 ± 3.19 pg/mL, CRP: 440.22 ± 7.86 ng/mL, and 8-OHdG: 63.65 ± 1.84 ng/mL) by HAHZB in diabetic rats. CONCLUSION: The present findings confirm that the presence of bioactive compounds in HAHZB exert therapeutic protective effect by decreasing oxidative, inflammation and pancreatic ß-cell damage in oxidative stress induced diabetic rats.

Costus pictus D. Don leaf extract stimulates GLP-1 secretion from GLUTag L-cells and has cytoprotective effects in BRIN-BD11 ß-cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Costus pictus D. Don, commonly known as insulin plant, is a traditional Indian antidiabetic herbal medicine with glucose-lowering and insulin secretory effects having been reported in animal models and humans with Type 2 diabetes. However, its effects on GLP-1 secretion from intestinal endocrine L-cells and potential metabolic and protective effects in insulin secreting pancreatic ß-cells are not yet fully understood. AIM OF THE STUDY: This study is aimed to elucidate the effects of Costus pictus D. Don leaf extract (CPE) on L-cell function and GLP-1 secretion using the established murine GLUTag L-cell model and to investigate its potential cytoprotective effects against detrimental effects of palmitate and cytokines in pancreatic ß-cells using BRIN-BD11 cells. METHODS: Costus pictus D. Don dried leaf powder was extracted by soxhlet method. Cell viability was determined by MTT assay. Changes in gene and protein expression were quantified by qPCR and western blotting, respectively. GLP-1 and insulin secretion were measured by ELISA. RESULTS: CPE significantly enhanced the percentage of viable BRIN-BD11 and GLUTag cells and protected BRIN-BD11 cells against palmitate- and proinflammatory cytokine-induced toxicity. CPE enhanced acute GLP-1 secretion 6.4-16.3-fold from GLUTag cells at both low (1.1 mM) and high (16.7 mM) glucose (P < 0.01) concentrations. Antioxidant (Nrf2, Cat & Gpx1) and pro-proliferative (Erk1 and Jnk1) gene expression were upregulated by 24 h culture with CPE, while proinflammatory transcription factor NF-κB was downregulated. CONCLUSION: Diminished postprandial GLP-1 secretion and loss of insulin secreting ß-cells are known contributors of T2DM. Our data suggests that CPE acutely stimulates GLP-1 secretion from L-cells. Long term exposure of the BRIN-BD11 cells to CPE enhances cell number and may protect against palmitate and proinflammatory cytokines by activating multiple pathways. Thus, the current study suggests that the possible antidiabetic properties of CPE may be linked to enhanced GLP-1 secretion and ß-cell protection which could be beneficial in the management of T2DM.

Potential Therapeutic Effects of Exogenous Ketone Supplementation for Type 2 Diabetes: A Review.

Type 2 diabetes (T2D) is among the most prevalent non-communicable lifestyle diseases. We propose that overnutrition and low levels of physical activity can contribute to a vicious cycle of hyperglycemia, inflammation and oxidative stress, insulin resistance, and pancreatic ß-cell dysfunction. The pathophysiological manifestations of T2D have a particular impact on the vasculature and individuals with T2D are at high risk of cardiovascular disease. Targeting aspects of the vicious cycle represent therapeutic approaches for improving T2D and protecting against cardiovascular complications. The recent advent of exogenous oral ketone supplements represents a novel, non-pharmacological approach to improving T2D pathophysiology and potentially protecting against cardiovascular disease risk. Herein, we review the emerging literature regarding the effects of exogenous ketone supplementation on metabolic control, inflammation, oxidative stress, and cardiovascular function in humans and highlight the potential application for breaking the vicious cycle of T2D pathophysiology.

Steamed Ginger May Enhance Insulin Secretion through KATP Channel Closure in Pancreatic ß-Cells Potentially by Increasing 1-Dehydro-6-Gingerdione Content.

Ginger (Zingiber officinale Roscoe) and its active compounds (gingerols, shogaols and paradols) have been reported as having beneficial functions for several diseases, including diabetes. In this study, we revealed that the steaming process could enhance the anti-diabetic potential of ginger. To confirm the anti-diabetic effect of steamed ginger extract (GG03), we assessed pancreatic islets impaired by alloxan in zebrafish and demonstrated anti-hyperglycemic efficacy in a mouse model. The EC50 values of ginger extract (GE) and GG03 showed that the efficacy of GG03 was greater than that of GE. In addition, LC50 values demonstrated that GG03 had lower toxicity than GE, and the comparison of the Therapeutic Index (TI) proved that GG03 is a safer functional food. Furthermore, our data showed that GG03 significantly lowered hyperglycemia in a diabetic mouse model. HPLC was performed to confirm the change in the composition of steamed ginger. Interestingly, GG03 showed a 375% increase in 1-dehydro-6-gingerdione (GD) compared with GE. GD has not yet been studied much pharmacologically. Thus, we identified the protective effects of GD in the damaged pancreatic islets of diabetic zebrafish. We further assessed whether the anti-diabetic mechanism of action of GG03 and GD involves insulin secretion. Our results suggest that GG03 and GD might stimulate insulin secretion by the closure of KATP channels in pancreatic ß-cells.

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 ß-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 ß-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.

The Protective Role of Calbindin-D9k on Endoplasmic Reticulum Stress-Induced Beta Cell Death.

Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. In this study, we aimed to investigate the effect of CaBP-9k on cell survival in pancreatic beta cells. Six-month-old wildtype CaBP-9k, CaBP-28k, and CaBP-9k/28k knockout (KO) mice were used to compare the pathological phenotypes of calcium-binding protein-deleted mice. Subsequently, the endoplasmic reticulum (ER) stress reducer tauroursodeoxycholic acid (TUDCA) was administered to wildtype and CaBP-9k KO mice. In vitro assessment of the role of CaBP-9k was performed following CaBP-9k overexpression and treatment with the ER stress inducer thapsigargin. Six-month-old CaBP-9k KO mice showed reduced islet volume and up-regulation of cell death markers resulting from ER stress, which led to pancreatic beta cell death. TUDCA treatment recovered islet volume, serum insulin level, and abdominal fat storage by CaBP-9k ablation. CaBP-9k overexpression elevated insulin secretion and recovered thapsigargin-induced ER stress in the INS-1E cell line. The results of this study show that CaBP-9k can protect pancreatic beta cell survival from ER stress and contribute to glucose homeostasis, which can reduce the risk of type 1 diabetes and provide the molecular basis for calcium supplementation to diabetic patients.