(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells

Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15 μM/EC50 = 26 nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.

THE INSULINOTROPIC EFFECT OF THIAZOLIDINEDIONE DERIVATIVES IN TYPE II DIABETIC MODEL, RIN-5F CELLS, AND ITS ACTION ON CULTURED HUMAN LUNG FIBROBLAST SHOWS OXYGEN FREE-RADICAL SCAVENGING ACTIVITY

Objective: Diabetes mellitus is a persistent disorder caused by deficiency in insulin production. Oxidative stress plays an important role in physiopathology of diabetes. The present research determined the antidiabetic and antioxidant effects of 5-naphthalidin thiazolidinediones derivatives. Methods: Both in vitro and in vivo experiments were carried out on diabetes induced male Swiss albino rats by single intramuscular injection of alloxan (0.15 mg/kg i.m) and IDDM-rats received 4b, 4c, or 4d (36 mg/kg, p.o). The derivatives were further subjected to insulin secretion by RIN-5F cells confirmed insulinotropic effect. In vitro antioxidant activity was evaluated using enzymatic activities on cell lines In addition, all the synthesized derivatives showed non-toxic effects against a diseased human lung fibroblast (COPD), HCC7231 (TACC CCL-96). Results: The results revealed that 4b, 4c, and 4d showed promising results by substantially lowering the blood glucose levels on 21st day of post-administration. Serum insulin levels substantially rose, suggesting that derivatives exert insulinotropic effects through different pathways. 4c showed oxygen free-radical scavenging activity. Conclusion: Our study proves that oral administration of 5-naphthalidin-TZD twice a day is a valuable treatment for type II diabetes. It seems to be a good drug moiety endowed significant oxygen free-radical scavenging activity.

Telmisartan Potentiates Insulin Secretion Via Ion Channels, Independent of The AT1 Receptor and PPARγ.

Background and aim: Angiotensin II type 1 (AT1) receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the direct effects of ARBs on insulin secretion remain unclear. In this study, we aimed to investigate the insulinotropic effect of ARBs and the underlying electrophysiological mechanism. Methods: Islets isolated from Wistar rats or db/db mice were incubated with drugs under different glucose conditions for 30 minutes, then supernatant liquid was collected for insulin secretion. Intracellular Ca2+ ([Ca2+]i) levels of β-cells were measured by calcium imaging technology. Patch-clamp technology was applied to detect effects on action potential duration (APD), Voltage-dependent potassium (Kv) channels, and voltage-gated calcium channels (VGCC). In our in vivo experiment, the 8-week-old and 11-week-old db/db mice were separately administered acute oral acute oral telmisartan treatment (15 mg/kg), then the oral glucose tolerance test (OGTT) was performed to observe the insulinotropic effect of telmisartan at 2 hours following drug intake.Results: Only telmisartan among the three ARBs（telmisartan, valsartan, and irbesartan）exhibited an insulin secretagogue role in rat islets. Independent of AT1 receptor and peroxisome proliferator-activated receptor γ (PPARγ), telmisartan exerted effects on ion channels including Kv channels and L-type VGCCs to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. Furthermore, we identified that telmisartan directly inhibited Kv2.1 channel on a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of db/db mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in OGTT. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets isolated from db/db mice. Conclusions: Our results establish an important insulinotropic function of telmisartan distinct from other ARBs in the treatment of diabetes.

Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs

IntroductionThe insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals.Research design and methodsGLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a 68Ga-labeled GLP-1r agonist. The effect of hyperinsulinemia on GLP-1r was assessed using sequential positron emission tomography (PET), both in the fasted state and during a clamp. The impact of tissue perfusion, which could account for changes in GLP-1r agonist uptake, was also investigated using 68Ga-DOTA imaging.ResultsGLP-1r binding potential in the obese pancreas was reduced by 75% compared with lean animals. Similar reductions were evident for fat tissue, but not for the duodenum. In the lean group, induced hyperinsulinemia reduced pancreatic GLP-1r density to a level comparable with that of the obese group. The reduction in blood to tissue transfer of the GLP-1r ligand paralleled that of tissue perfusion estimated using 68Ga-DOTA.ConclusionsThese observations establish that a reduction in abdominal tissue perfusion and a lower GLP-1r density account for the diminished insulinotropic effect of GLP-1 agonists in type 2 diabetes.

A SYNERGISTIC INSULINOTROPIC EFFECT OF GREEN TEA EXTRACT AND POMEGRANATE EXTRACT WITH ROSIGLITAZONE: BOTH IN VIVO AND IN VITRO EXPERIMENT

Objective: Scientists have growing interest in traditional medicinal plants as they contain active ingredients for the treatment of various diseases. Tea is one of the most popular beverages worldwide. The variety of tea and tea extracts in the market has different polyphenol profiles, which are the bioactive chemical entities. We performed a direct comparison between Thea sinensis, green tea extracts (GTEs), and Punica granatum peel powder (PGPP), which have been chemically well characterized in a type II diabetic mouse model. Methods: We conducted both in vivo and in vitro experiments in the present paper. In vivo studies were carried out on male Swiss albino rats having type II diabetes, induced by single intravenous injection of streptozotocin (0.7 mg/Kg i.m.) and IDDM rats received either PGPP (200 mg/kg) or GTE (100 mg/kg) as a single oral dose. After the above result, the extracts were further subjected to know the effect of insulin secretion by RIN-5F cells providing confirmation of insulinotropic effect. Results: The results revealed that both PGPP and GTE substantially lowered blood glucose levels and ameliorated glucose intolerance, both were effective in antihyperglycemic activity and in lowering body weight gain. Serum insulin levels significantly increased in GTE group as well as in PGPP group, suggesting that they were exerting hypoglycemic effects through different pathways. Conclusion: Synergistic action of PGPP and GTE is an effective alternative for the treatment of type II diabetes through the regeneration of β cells of pancreas.

Testosterone enhances GLP-1 efficacy at the plasma membrane and endosomes to augment insulin secretion in male pancreatic β cells

Male mice with elimination of the androgen receptor (AR) in islet β cells (βARKO) exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hypoinsulinemia and hyperglycemia when challenged with a Western diet. Testosterone activation of an extranuclear AR in β cells potentiates GSIS by amplifying the insulinotropic action of glucagon-like peptide-1 (GLP-1). Here, using a combination of βARKO and β cell-selective GLP-1 receptor knockout mice and their islets, we show that AR activation in β cells amplifies the insulinotropic effect of islet-derived GLP-1. In β cell models expressing cAMP sensors, testosterone enhances the ability of GLP-1, but not that of glucose-dependent insulinotropic polypeptide or glucagon, to produce cAMP. Accordingly, testosterone selectively enhances the ability of GLP-1 to potentiate GSIS. Notably, testosterone enhances GLP-1 production of cAMP at the plasma membrane and endosomes. In male mouse and human islets, the insulinotropic effect of testosterone is abolished following inhibition of the membrane and endosomal cAMP-dependent protein kinase A and exchange protein activated by cAMP islet 2 pathways. Thus, membrane localization of AR enhances the ability of the GLP-1 receptor to produce cAMP, thus increasing glucose-stimulated insulin exocytosis.Significance StatementThis study reveals that testosterone, acting on the androgen receptor (AR) in insulin-producing β cells amplifies the insulinotropic action of glucagon-like peptide-1 (GLP-1) by increasing GLP-1-mediated production of cAMP at the plasma membrane and endosomal compartments, to promote insulin vesicles exocytosis in human β cells. This study establishes a novel biological paradigm in which membrane location of a steroid nuclear receptor enhances the ability of a G protein-coupled receptor to produce cAMP. It has exceptional clinical significance for targeted delivery of testosterone to β cells in the large population of aging and androgen-deficient men who are at increased risk of diabetes.

Correction: Sartorius et al. “Postprandial Effects of a Proprietary Milk Protein Hydrolysate Containing Bioactive Peptides in Prediabetic Subjects” Nutrients 2019, 11, 1700

Milk proteins have been hypothesized to protect against type 2 diabetes (T2DM) by beneficially modulating glycemic response, predominantly in the postprandial status. This potential is, amongst others, attributed to the high content of whey proteins, which are commonly a product of cheese production. However, native whey has received substantial attention due to its higher leucine content, and its postprandial glycemic effect has not been assessed thus far in prediabetes. In the present study, the impact of a milk protein hydrolysate of native whey origin with alpha-glucosidase inhibiting properties was determined in prediabetics in a randomized, cross-over trial. Subjects received a single dose of placebo or low- or high-dosed milk protein hydrolysate prior to a challenge meal high in carbohydrates. Concentration–time curves of glucose and insulin were assessed. Incremental areas under the curve (iAUC) of glucose as the primary outcome were significantly reduced by low-dosed milk peptides compared to placebo (p = 0.0472), and a minor insulinotropic effect was seen. A longer intervention period with the low-dosed product did not strengthen glucose response but significantly reduced HbA1c values (p = 0.0244). In conclusion, the current milk protein hydrolysate of native whey origin has the potential to modulate postprandial hyperglycemia and hence may contribute in reducing the future risk of developing T2DM.

Rapid hepatic metabolism blunts the endocrine action of portally infused GLP-1 in male rats

Glucagon-like peptide-1 (GLP-1) is an enteral peptide that contributes to the incretin effect. GLP-1 action is typically described as endocrine, but this mechanism has been questioned because rapid inactivation in the circulation by dipeptidylpeptidase 4 (DPP4) results in a short half-life, limiting the amount of the hormone that can reach the pancreatic islet. An alternative mechanism for GLP-1 to regulate insulin secretion through neuroendocrine signaling originating from sensors in the portal vein has been proposed. We hypothesized that portal infusion of GLP-1 would cause greater glucose-stimulated insulin secretion than equimolar administration into the jugular vein. To test this, hyperglycemic clamps with superimposed graded infusions of GLP-1 into the jugular or portal veins of male rats were performed. These experiments were repeated with pharmacologic DPP4 inhibition to determine the effect of GLP-1 metabolism in the jugular and portal venous beds. Contrary to our hypothesis, we found a higher insulinotropic effect with jugular compared with portal GLP-1, which was associated with higher plasma concentrations of intact GLP-1. The greater insulinotropic effect of jugular venous GLP-1 persisted even with pharmacological DPP4 inhibition. These findings do not support an important role of portal vein GLP-1 signaling for the incretin effect but highlight the hepatoportal bed as a major site of GLP-1 degradation that persists even with pharmacological inhibition. Together, these results support rapid inactivation of enterally released GLP-1 in the liver as limiting endocrine actions on the β-cell and raise questions about the conventional endocrine model of pharmacologic effects of DPP4 inhibitors.

Postprandial Effects of a Proprietary Milk Protein Hydrolysate Containing Bioactive Peptides in Prediabetic Subjects

Milk proteins have been hypothesized to protect against type 2 diabetes (T2DM) by beneficially modulating glycemic response, predominantly in the postprandial status. This potential is, amongst others, attributed to the high content of whey proteins, which are commonly a product of cheese production. However, native whey has received substantial attention due to its higher leucine content, and its postprandial glycemic effect has not been assessed thus far in prediabetes. In the present study, the impact of a milk protein hydrolysate of native whey origin with alpha-glucosidase inhibiting properties was determined in prediabetics in a randomized, cross-over trial. Subjects received a single dose of placebo or low- or high-dosed milk protein hydrolysate prior to a challenge meal high in carbohydrates. Concentration–time curves of glucose and insulin were assessed. Incremental areas under the curve (iAUC) of glucose as the primary outcome were significantly reduced by low-dosed milk peptides compared to placebo (p = 0.0472), and a minor insulinotropic effect was seen. A longer intervention period with the low-dosed product did not strengthen glucose response but significantly reduced HbA1c values (p = 0.0244). In conclusion, the current milk protein hydrolysate of native whey origin has the potential to modulate postprandial hyperglycemia and hence may contribute in reducing the future risk of developing T2DM.