glucagon-like-peptide-1 and Hyperplasia

We reported that native incretins, liraglutide and dipeptidyl peptidase-4 inhibitors (DPP-4i) all confer an anti-atherosclerotic effect in apolipoprotein E-null (Apoe (-/-)) mice. We confirmed the anti-atherogenic property of incretin-related agents in the mouse wire injury model, in which the neointimal formation in the femoral artery is remarkably suppressed. Furthermore, we showed that DPP-4i substantially suppresses plaque formation in coronary arteries with a marked reduction in the accumulation of macrophages in cholesterol-fed rabbits. DPP-4i showed an anti-atherosclerotic effect in Apoe (-/-) mice mainly through the actions of glucagon-like peptide-1 and glucose-dependent insulinotropic polypepide. However, the dual incretin receptor antagonists partially attenuated the suppressive effect of DPP-4i on atherosclerosis in diabetic Apoe (-/-) mice, suggesting an incretin-independent mechanism. Exendin-4 and glucose-dependent insulinotropic polypepide elicited cyclic adenosine monophosphate generation, and suppressed the lipopolysaccharide-induced gene expression of inflammatory molecules, such as interleukin-1β, interleukin-6 and tumor necrosis factor-α, in U937 human monocytes. This suppressive effect, however, was attenuated by an inhibitor of adenylate cyclase and mimicked by 8-bromo-cyclic adenosine monophosphate or forskolin. DPP-4i substantially suppressed the lipopolysaccharide-induced expression of inflammatory cytokines without affecting cyclic adenosine monophosphate generation or cell proliferation. DPP-4i more strongly suppressed the lipopolysaccharide-induced gene expression of inflammatory molecules than incretins, most likely through inactivation of CD26. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypepide suppressed oxidized low-density lipoprotein-induced macrophage foam cell formation in a receptor-dependent manner, which was associated with the downregulation of acyl-coenzyme A cholesterol acyltransferase-1 and CD36, as well as the up-regulation of adenosine triphosphate-binding cassette transporter A1. Our studies strongly suggest that incretin-related agents have favorable effects on macrophage-driven atherosclerosis in experimental animals.

Topics: Animals; Anti-Inflammatory Agents; Apolipoproteins E; Atherosclerosis; Coronary Restenosis; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Foam Cells; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperplasia; Incretins; Inflammation; Inflammation Mediators; Liraglutide; Macrophages; Mice; Mice, Knockout; Monocytes

The alpha cells that coinhabit the islets with the insulin-producing beta cells have recently captured the attention of diabetes researchers because of new breakthrough findings highlighting the importance of these cells in the maintenance of beta cell health and functions. In normal physiological conditions alpha cells produce glucagon but in conditions of beta cell injury they also produce glucagon-like peptide-1 (GLP-1), a growth and survival factor for beta cells. In this review we consider these new findings on the functions of alpha cells. Alpha cells remain somewhat enigmatic inasmuch as they now appear to be important in the maintenance of the health of beta cells, but their production of glucagon promotes diabetes. This circumstance prompts an examination of approaches to coax alpha cells to produce GLP-1 instead of glucagon.

Topics: Animals; Cell Dedifferentiation; Cell Lineage; Cell Transdifferentiation; Diabetes Mellitus, Experimental; Enteroendocrine Cells; Epithelial-Mesenchymal Transition; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Homeodomain Proteins; Humans; Hyperplasia; Insulin-Secreting Cells; Islets of Langerhans; Mice; Paired Box Transcription Factors; Proprotein Convertase 1; Signal Transduction; Transcription Factors

Foxo1, a member of the Fox0 subfamily of winged-helix forkhead transcription factors, is a target of insulin and insulin-like growth factor-1 (IGF-1) signal transduction pathways that activate protein kinase B (PKB) in pancreatic beta cells. Foxo1 is a substrate for PKB, and its phosphorylation results in nuclear exclusion with concomitant alterations in gene expression that are important to cellular growth and differentiation. Because activation of PKB can require insulin receptor substrate proteins (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase (PI3K), it is of interest to determine whether the activity of Foxo1 is also regulated by heterotrimeric G protein-coupled receptors (GPCRs) with IRS-1 or -2, PI3K, or PKB signaling potential. Indeed, studies of beta cells have demonstrated that activation of a GPCR for the blood glucose-lowering hormone GLP-1 leads to major alterations of IRS-2, PI3K, and PKB activity. By promoting nuclear exclusion of Foxo1 in a PKB-mediated manner, GLP-1 may up-regulate the expression of a homeodomain transcription factor (PDX-1) that serves as a master regulator of beta-cell growth and differentiation. This STKE Perspective summarizes signaling properties of GLP-1 that may explain its ability to increase beta-cell mass, to increase pancreatic insulin secretory capacity, and to lower levels of blood glucose in type 2 diabetic subjects.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeodomain Proteins; Humans; Hyperplasia; Insulin; Insulin Receptor Substrate Proteins; Insulin Secretion; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Mice; Mice, Knockout; Models, Biological; Phosphoproteins; Proto-Oncogene Proteins c-akt; Rats; Receptors, Glucagon; Secretory Rate; Signal Transduction; Trans-Activators

Dipeptidyl peptidase 4 inhibitors are widely used in patients with type 2 diabetes mellitus to accomplish glycemic control through an increase in the blood glucagon-like peptide 1 (GLP-1) concentration. These agents also inhibit vascular inflammation (eg, in atherosclerosis). This study was undertaken to determine whether and how vildagliptin (a potent dipeptidyl peptidase 4 inhibitor) might reduce intimal hyperplasia in vein grafts.. Twelve rabbits were randomly divided into two groups; one group received vildagliptin orally (10 mg/kg/d; n = 6), whereas the control group (n = 6) did not. Vildagliptin administration was started 7 days before rabbits underwent interposition reversed autologous jugular vein grafting and ended at graft harvesting (28 days after the operation). Histochemical changes in the vascular wall were examined, as were changes in the acetylcholine-induced effects on the endothelial Ca(2+) concentration ([Ca(2+)]i) and endothelium-dependent relaxation.. Under fasting conditions, vildagliptin increased the plasma GLP-1 concentration, without affecting plasma glucose or insulin. Acetylcholine induced endothelium-dependent relaxation only in the vildagliptin group, and this was blocked by the nitric oxide synthase inhibitor N(ω)-nitro-l-arginine. Acetylcholine did not modify the endothelial [Ca(2+)]i in either the control or vildagliptin group. Intimal hyperplasia was significantly less in the vildagliptin group (0.11 ± 0.02 mm, n = 5) than in the controls (0.31 ± 0.06 mm, n = 4; P < .01).. Vildagliptin increased the plasma GLP-1 concentration. It also enhanced acetylcholine-induced [Ca(2+)]i-independent endothelial nitric oxide release and reduced vein graft intimal hyperplasia, independently of any glycemic control action.

Topics: Adamantane; Administration, Oral; Animals; Autografts; Calcium; Calcium Signaling; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Hyperplasia; Jugular Veins; Male; Neointima; Nitric Oxide; Nitric Oxide Synthase; Nitriles; Pyrrolidines; Time Factors; Vasodilation; Vasodilator Agents; Vildagliptin

Bariatric procedures, such as Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG), are the most effective approaches to resolve type 2 diabetes in obese individuals. Alimentary glucose absorption and intestinal disposal of blood glucose have not been directly compared between individuals or animals that underwent RYGB vs VSG. We evaluated in rats and humans how the gut epithelium adapts after surgery and the consequences on alimentary glucose absorption and intestinal disposal of blood glucose.. Obese male rats underwent RYGB, VSG, or sham (control) operations. We collected intestine segments from all rats; we performed histologic analyses and measured levels of messenger RNAs encoding the sugar transporters SGLT1, GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5. Glucose transport and consumption were assayed using ex vivo jejunal loops. Histologic analyses were also performed on Roux limb sections from patients who underwent RYGB 1-5 years after surgery. Roux limb glucose consumption was assayed after surgery by positron emission and computed tomography imaging.. In rats and humans that underwent RYGB, the Roux limb became hyperplasic, with an increased number of incretin-producing cells compared with the corresponding jejunal segment of controls. Furthermore, expression of sugar transporters and hypoxia-related genes increased and the nonintestinal glucose transporter GLUT1 appeared at the basolateral membrane of enterocytes. Ingested and circulating glucose was trapped within the intestinal epithelial cells of rats and humans that underwent RYGB. By contrast, there was no hyperplasia of the intestine after VSG, but the intestinal absorption of alimentary glucose was reduced and density of endocrine cells secreting glucagon-like peptide-1 increased.. The intestine adapts differently to RYGB vs VSG. RYGB increases intestinal glucose disposal and VSG delays glucose absorption; both contribute to observed improvements in glycemia.

Topics: Adaptation, Physiological; Adult; Animals; Blood Glucose; Disease Models, Animal; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Transport Proteins, Facilitative; Humans; Hyperplasia; Intestinal Absorption; Intestinal Mucosa; Jejunum; Male; Middle Aged; Obesity; Positron-Emission Tomography; Rats; Retrospective Studies; RNA, Messenger; Time Factors; Tomography, X-Ray Computed

Bariatric operations in obese patients with type 2 diabetes often improve diabetes before weight loss is observed. In patients mainly Roux-en-Y-gastric bypass with partial stomach resection is performed. Duodenojejunal bypass (DJB) and ileal interposition (IIP) are employed in animal experiments. Due to increased glucose exposition of L-cells located in distal ileum, all bariatric surgery procedures lead to higher secretion of antidiabetic glucagon like peptide-1 (GLP-1) after glucose gavage. After DJB also downregulation of Na(+)-d-glucose cotransporter SGLT1 was observed. This suggested a direct contribution of decreased glucose absorption to the antidiabetic effect of bariatric surgery. To investigate whether glucose absorption is also decreased after IIP, we induced diabetes with decreased glucose tolerance and insulin sensitivity in male rats and investigated effects of IIP on diabetes and SGLT1. After IIP, we observed weight-independent improvement of glucose tolerance, increased insulin sensitivity, and increased plasma GLP-1 after glucose gavage. The interposed ileum was increased in diameter and showed increased length of villi, hyperplasia of the epithelial layer, and increased number of L-cells. The amount of SGLT1-mediated glucose uptake in interposed ileum was increased 2-fold reaching the same level as in jejunum. Thus, improvement of glycemic control by bariatric surgery does not require decreased glucose absorption.

Topics: Animals; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose; Hyperglycemia; Hyperplasia; Hypoglycemia; Ileum; Insulin Resistance; Intestinal Absorption; Male; Microvilli; Obesity; Rats, Inbred Lew; Sodium-Glucose Transporter 1; Specific Pathogen-Free Organisms

Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell-to-α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from duct cells and transdifferentiation of α-cells are potential contributors to the β-cell compensatory response to insulin resistance in the absence of overt diabetes.

Topics: Adult; Aged; Female; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Hyperplasia; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Middle Aged; Pancreatectomy

Glucagon-like peptide-1 is an incretin hormone from the gastrointestinal tract, which enhances insulin secretion, slows gastric emptying, and reduces food intake. GLP-1 receptor agonists are being developed for Type 2 diabetes mellitus. GLP-1 is rapidly degraded by serum dipeptidyl peptidase IV, so analogues with a prolonged serum half-life are used clinically. Exenatide was the first GLP-1 agonist approved and is a synthetic version of exendin-4 derived from the Gila monster. Liraglutide was approved for clinical use in 2010. GLP-1 receptor agonists have been shown to increase calcitonin secretion and stimulate C-cell hyperplasia and neoplasia in rats and mice of both sexes. Rat C-cells are more sensitive to the effects of GLP-1 agonists than mice. The effects of GLP-1 agonists on C-cell proliferation or neoplasia have not been documented in nonhuman primates or humans. The proliferative C-cell effects may be rodent-specific. GLP-1 receptors have been demonstrated on normal rodent C-cells, but are either not present or occur in low numbers on C-cells of nonhuman primates and humans. Hyperplasia and neoplasia of C-cells in rodents treated with GLP-1 agonists represent a unique example of an on-target species-specific effect that may not have relevance to humans.

Topics: Animals; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperplasia; Hypoglycemic Agents; Immunohistochemistry; Liraglutide; Mice; Peptides; Rats; Receptors, Glucagon; Thyroid Gland; Thyroid Neoplasms; Venoms

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hyperplasia; Incretins; Metaplasia; Pancreas; Pancreatic Neoplasms; Pancreatitis

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates the insulin secretion depending on blood glucose level. Recent studies show that the unsaturated fatty acids can promote GLP-1 secretion from intestinal L-cells. We have shown previously that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) administered into a mouse closed intestinal loop, especially into the colonic segment, stimulate GLP-1 and insulin secretion and have a hypoglycemic effect, suggesting that DHA and EPA have potential as antidiabetic agents. The present study examined the antidiabetic effect of DHA following long-term in vivo delivery to the colon using normal ddY and diabetic KK-A(y) mice. The plasma GLP-1 concentration of KK-A(y) mice increased after long-term DHA administration, and this had a significant hypoglycemic effect. In contrast, although GLP-1 secretion in ddY mice tended to increase after DHA administration, blood glucose concentration did not differ between vehicle- and DHA-treated ddY mice. Immunostaining of the pancreas after long-term DHA administration showed that continuous DHA treatment stimulated β-cell apoptosis and accordingly suppressed islet cell growth in KK-A(y) mice. Colon targeting of DHA may provide a new strategy for improving impaired glucose tolerance in type 2 diabetes mellitus by stimulating GLP-1 secretion, which may subsequently suppress the compensatory hyperplasia of pancreatic islets.

Topics: Animals; Blood Glucose; Colon; Diabetes Mellitus, Type 2; Docosahexaenoic Acids; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperplasia; Hypoglycemic Agents; Islets of Langerhans; Male; Mice; Mice, Transgenic

Glucagon like peptide-1 (GLP-1) mimetic therapy induces medullary thyroid neoplasia in rodents. We sought to establish whether C cells in human medullary thyroid carcinoma, C cell hyperplasia, and normal human thyroid express the GLP-1 receptor.. Thyroid tissue samples with medullary thyroid carcinoma (n = 12), C cell hyperplasia (n = 9), papillary thyroid carcinoma (n = 17), and normal human thyroid (n = 15) were evaluated by immunofluorescence for expression of calcitonin and GLP-1 receptors.. Coincident immunoreactivity for calcitonin and GLP-1 receptor was consistently observed in both medullary thyroid carcinoma and C cell hyperplasia. GLP-1 receptor immunoreactivity was also detected in 18% of papillary thyroid carcinoma (three of 17 cases). Within normal human thyroid tissue, GLP-1 receptor immunoreactivity was found in five of 15 of the examined cases in about 35% of the total C cells assessed.. In humans, neoplastic and hyperplastic lesions of thyroid C cells express the GLP-1 receptor. GLP-1 receptor expression is detected in 18% papillary thyroid carcinomas and in C cells in 33% of control thyroid lobes. The consequence of long-term pharmacologically increased GLP-1 signaling on these GLP-1 receptor-expressing cells in the thyroid gland in humans remains unknown, but appropriately powered prospective studies to exclude an increase in medullary or papillary carcinomas of the thyroid are warranted.

Topics: Adult; Aged; Animals; Carcinoma; Carcinoma, Neuroendocrine; Carcinoma, Papillary; Chlorocebus aethiops; CHO Cells; COS Cells; Cricetinae; Cricetulus; Female; Gene Expression; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperplasia; Male; Middle Aged; Receptors, Glucagon; Thyroid Cancer, Papillary; Thyroid Gland; Thyroid Neoplasms; Tissue Distribution; Validation Studies as Topic; Young Adult

Topics: Animals; Disease Models, Animal; Glucagon-Like Peptide 1; Humans; Hyperplasia; Pancreas, Exocrine; Pancreatic Ducts; Pancreatitis; Pancreatitis, Chronic; Rats; United States; United States Food and Drug Administration

Incretins are hormones released by enteroendocrine cells in response to meals, depending upon absorption of nutrients. The present study aimed to elucidate the mechanisms through which a high-fat diet (HFD) induces insulin resistance and insulin hypersecretion by focusing on the effects on enteroendocrine cells, especially those secreting glucose-dependent insulinotropic polypeptide (GIP).. Forty male Wistar rats, 4 months old, were randomised into two groups; one group received a chow diet and the other one received a purified tripalmitin-based HFD ad libitum. An OGTT was performed every 10 days and histological and immunofluorescence evaluations of the duodenum were obtained at 60 days from the beginning of the diets. Plasma glucose, insulin, GIP and glucagon-like peptide-1 (GLP-1) levels were measured. Immunofluorescence analysis of duodenal sections for pancreatic duodenal homeobox-1 (PDX-1), KI67, GLP-1, GIP and insulin were performed.. Compared with chow diet, HFD induced a progressive significant increase of the glucose, insulin and GIP responses to OGTT, whereas GLP-1 circulating levels were reduced over time. After 60 days of HFD, cellular agglomerates of KI67 and PDX-1 positive cells, negative for insulin and GLP-1 but positive for GIP staining, were found inside the duodenal mucosa, and apoptosis was significantly increased.. With the limitation that we could not establish a causal relationship between events, our study shows that HFD stimulates duodenal proliferation of endocrine cells differentiating towards K cells and oversecreting GIP. The progressive increment of GIP levels might represent the stimulus for insulin hypersecretion and insulin resistance.

Topics: Analysis of Variance; Animals; Area Under Curve; Blood Glucose; Body Weight; Dietary Fats; Duodenum; Enteroendocrine Cells; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hyperplasia; In Situ Nick-End Labeling; Insulin; Intestinal Mucosa; Male; Random Allocation; Rats; Rats, Wistar

Topics: Animals; Cell Proliferation; Comorbidity; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hyperinsulinism; Hyperplasia; Hypertrophy; Hypoglycemia; Incidence; Insulin; Insulin Secretion; Insulin-Secreting Cells; Nesidioblastosis; Obesity, Morbid; Postoperative Complications; Rats

Topics: Adenosine Deaminase Inhibitors; Dipeptidyl Peptidase 4; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glycoproteins; Humans; Hyperinsulinism; Hyperplasia; Hypoglycemia; Islets of Langerhans; Nesidioblastosis; Obesity; Peptide Fragments; Postoperative Complications; Protein Precursors; Signal Transduction

After jejunectomy, a rapid and sustained increase in the abundance of proglucagon mRNA occurs in residual ileum and is accompanied by increases in plasma intestinal proglucagon-derived peptides. This response may be a component of adaptive growth, or proglucagon-derived peptides may regulate adaptive growth. To distinguish these possibilities, rats were treated with difluoromethylornithine, blocking ornithine decarboxylase activity and thereby adaptive bowel growth. Three groups fed ad libitum were compared: (1) resect: rats with 80% proximal small bowel resection; (2) resect + difluoromethylornithine: resected rats given difluoromethylornithine in drinking water; and (3) transect: transected controls. Six days after surgery, the resect + difluoromethylornithine group demonstrated inhibition of adaptive bowel growth. Abundance of ileal proglucagon mRNA in resect and resect + difluoromethylornithine groups was double that in the transect group (P < 0.02), whereas ornithine decarboxylase mRNA levels did not differ. Plasma enteroglucagon and glucagon-like peptide-I levels were greater in resect than transect groups (P < 0.002) and did not differ between resect and resect + difluoromethylornithine groups. The rise in ileal proglucagon mRNA after proximal small bowel resection is not inhibited by difluoromethylornithine despite blocking bowel growth and, therefore, is not merely a component of adaptive growth. Proglucagon-derived peptides are possible modulators of adaptive bowel but cannot stimulate growth when ornithine decarboxylase activity is inhibited.

Topics: Adaptation, Physiological; Animals; Blotting, Northern; Eflornithine; Enzyme Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hyperplasia; Ileum; Intestinal Mucosa; Jejunum; Male; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Peptide Fragments; Proglucagon; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger