Local delivery of parathyroid hormone-related protein-derived peptides coated onto a hydroxyapatite-based implant enhances bone regeneration in old and diabetic rats.

Diabetes mellitus (DM) and aging are associated with bone fragility and increased fracture risk. Both (1-37) N- and (107-111) C-terminal parathyroid hormone-related protein (PTHrP) exhibit osteogenic properties. We here aimed to evaluate and compare the efficacy of either PTHrP (1-37) or PTHrP (107-111) loaded into gelatin-glutaraldehyde-coated hydroxyapatite (HA-Gel) foams to improve bone repair of a transcortical tibial defect in aging rats with or without DM, induced by streptozotocin injection at birth.

Islet amyloid polypeptide exerts a novel autocrine action in β-cell signaling and proliferation.

The toxic effects of human islet amyloid polypeptide (IAPP) on pancreatic islets have been widely studied. However, much less attention has been paid to the physiologic actions of IAPP on pancreatic β cells, which secrete this peptide together with insulin upon glucose stimulation. Here, we aimed to explore the signaling pathways and mitogenic actions of IAPP on β cells.

Differential effect of amylin on endothelial-dependent vasodilation in mesenteric arteries from control and insulin resistant rats.

Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, amylin has long been related to IR. However the role of amylin in the vascular dysfunction associated to IR is not well addressed.

The vertebrae of prematurely aging mice as a skeletal model of involutional osteoporosis.

Oxidative stress in bone increases with age, which leads to bone frailty and a high fracture risk. Animal models show that early changes in trabecular structure occur in age-related osteopenia. These models might be valuable to assess the contribution of oxidative stress in age-related bone loss.

Src kinases mediate VEGFR2 transactivation by the osteostatin domain of PTHrP to modulate osteoblastic function.

Parathyroid hormone-related protein (PTHrP) stimulates osteoblastic function through its N- and C-terminal domains. Since the osteogenic action of the latter domain appears to depend at least in part on its interaction with the vascular endothelial growth factor (VEGF) system, we aimed to explore the putative mechanism underlying this interaction in osteoblasts. Using native conditions for protein extraction and immunoblotting, we found that both PTHrP (107-139) and the shorter PTHrP (107-111) peptide (known as osteostatin), at 100 nM, promoted the appearance of a VEGF receptor (VEGFR) 2 protein band of apparent Mr.

Characterization of skeletal alterations in a model of prematurely aging mice.

An age-related bone loss occurs, apparently associated with the concomitant increase in an oxidative stress situation. However, the underlying mechanisms of age-related osteopenia are ill defined since these studies are time consuming and require the use of many animals (mainly rodents). Here, we aimed to characterize for the first time the bone status of prematurely aging mice (PAM), which exhibit an increased oxidative stress.

Normalizing action of exendin-4 and GLP-1 in the glucose metabolism of extrapancreatic tissues in insulin-resistant and type 2 diabetic states.

Exendin-4 (Ex-4) mimics glucagon-like peptide-1 (GLP-1 or GCG as listed in the HUGO database), being anti-diabetic and anorectic, in stimulating glucose and lipid metabolism in extrapancreatic tissues. We studied the characteristics of Ex-4 and GLP-1 action, during prolonged treatment, on GLUTs expression (mRNA and protein), glycogen content (GC), glucose transport (GT), glycogen synthase a (GSa), and kinase (PI3K and MAPKs) activity, in liver, muscle, and fat of insulin-resistant (IR, by fructose) and type 2 diabetic (T2D, streptozotocin at birth) rats compared with normal rats. In both IR and T2D, the three tissues studied presented alterations in all measured parameters.

Characteristic of GLP-1 effects on glucose metabolism in human skeletal muscle from obese patients.

Direct effects of GLP-1, kinase-mediated, on glucose and lipid metabolism in rat and human extrapancreatic tissues, are amply documented and also changes in type-2 diabetic (T2D) patients. Here, we explored the characteristics of the GLP-1 action and those of its analogs Ex-4 and Ex-9, on muscle glucose transport (GT) and metabolism in human morbid obesity (OB), as compared with normal and T2D subjects. In primary cultured myocytes from OB, GT and glycogen synthase a (GSa) activity values were lower than normal, and comparable to those reported in T2D patients; GT was increased by either GLP-1 or Ex-9 in a more efficient manner than in normal or T2D, up to normal levels; the Ex-4 increasing effect on GSa activity was two times that in normal cells, while Ex-9 failed to modify the enzyme activity.

GLP-1 and exendin-4 can reverse hyperlipidic-related osteopenia.

Increased fat mass contributes to bone deterioration. Glucagon-like peptide 1 (GLP-1) and its related peptide exendin 1-39 amide (Ex-4), two lipid-lowering peptides, exert osteogenic effects in diabetic states. We examined the actions of 3-day administration of GLP-1 or Ex-4 on bone remodeling markers and on bone mass and structure in hyperlipidic (HL) and hypercaloric rats.

Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor.

Glucagon-like peptide 1 (GLP-1) controls glucose metabolism in extrapancreatic tissues through receptors other than the pancreatic cAMP-linked GLP-1 receptor; also, GLP-1 induces an insulin- and PTH-independent bone anabolic action in insulin-resistant and type-2 diabetic rats. Here we searched for the presence and characteristics of GLP-1 receptors in osteoblastic MC3T3-E1 cells. [(125)I]-GLP-1 specific binding to MC3T3-E1 cells was time- and temperature-dependent, reaching maximal value at 30 min at 25 degrees C; in these conditions, [(125)I]-GLP-1 binding was dissociable, and displaced by GLP-1, partially by GLP-2, but not by exendin-4 (Ex-4), exendin-9 (Ex-9), glucagon or insulin; Scatchard analysis of the unlabeled GLP-1 data showed high and low affinity binding sites; cross-linking of GLP-1 binding revealed an estimated 70 kDa band, almost undetectable in the presence of 10(-6) M GLP-1.

Exendin-4 exerts osteogenic actions in insulin-resistant and type 2 diabetic states.

Poor control of glucose homeostasis accounts for diabetes-related bone loss. Incretins - GLP-1 and GIP - have been proposed to affect bone turnover. GLP-1, apart from its anti-diabetic and other actions, has shown to exert a bone anabolic effect in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rats.

Effect of GLP-1 treatment on bone turnover in normal, type 2 diabetic, and insulin-resistant states.

It has been suggested that hormones released after nutrient absorption, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 2 (GLP-2), could be responsible for changes in bone resorption. However, information about the role of GLP-1 in this regard is scanty. Diabetes-related bone loss occurs as a consequence of poor control of glucose homeostasis, but the relationship between osteoporosis and type 2 diabetes remains unclear.

Effect of exendin-4 treatment upon glucose uptake parameters in rat liver and muscle, in normal and type 2 diabetic state.

Exendin-4, like GLP-1, is insulinotropic, antidiabetic and glucoregulatory among other properties, which are thought to be exerted through the pancreatic GLP-1 receptor; exendin-4 is also an agonist of the GLP-1 stimulatory action upon liver and muscle glucose metabolism, where GLP-1 receptor is distinct from that in the pancreas. We investigated the action of prolonged treatment with exendin-4 upon glucose transport parameters in skeletal muscle and liver of normal rats and streptozotocin-induced type 2 diabetic rats (T2D). Muscle of T2D showed lower than normal glucose transport; exendin-4 did not modify the value in normal but normalized that in the T2D; unlike previously detected with GLP-1, no apparent modification was observed in GLUT-4 expression in either group after exendin-4, except for an increased GLUT-4 protein in normal rats.

Characteristics of GLP-1 and exendins action upon glucose transport and metabolism in type 2 diabetic rat skeletal muscle.

Exendin-4, a peptide 53% structurally homologous with glucagon-like peptide 1 (GLP-1), is insulinotropic and has an antidiabetic effect even more prolonged than that of GLP-1. Exendin-9 is an antagonist of GLP-1 receptor and action in several cell systems, but shows GLP-1- and exendin-4-agonistic characteristics in human muscle cells and tissue. The action of GLP-1 upon glucose transport and metabolism in muscle is mediated by specific receptors.

The action of GLP-1 and exendins upon glucose transport in normal human adipocytes, and on kinase activity as compared to morbidly obese patients.

A role of GLP-1 (glucagon-like peptide-1) in the recovery of the metabolic conditions of morbidly obese patients after bariatric surgery has been proposed. Exendin 4 (Ex-4) and exendin 9 (Ex-9) both have GLP-1-like effects upon glucose metabolism in human myocytes. We investigated in normal human adipocytes the effect of GLP-1, Ex-4 and Ex-9, compared with insulin upon the activity of PI3K, PKB, MAPKs and p70s6 kinases, and the participation of these enzymes in their action upon 2-deoxy-D-glucose transport by using potential inhibitors.

Effect of GLP-1 on D-glucose transport, lipolysis and lipogenesis in adipocytes of obese subjects.

GLP-1 has anorectic properties and regulates fuel homeostasis through both its insulinotropic and insulinotrophic actions and effects in extrapancreatic tissue. This study is aimed at characterizing the response to GLP-1 of adipocytes from obese patients, in terms of D-glucose transport and lipid metabolism, in comparison with data from normal subjects. Adipocytes were obtained by enzymatic digestion from the abdominal fat tissue of 25 morbidly obese patients and 8 normal subjects undergoing bariatric or inguinal hernia surgery, respectively.

GLP-1 signalling and effects on glucose metabolism in myocytes from type 2 diabetic patients.

Changes in the activity of glycogen synthase a and related kinases (phosphatidylinositol-3-kinase, protein kinase B, p44/42 MAP kinases and p70s6 kinase) evoked by GLP-1 in human myocytes from normal subjects were recently implied in the effect of this hormone upon D-glucose transport and glycogen synthesis in the same cells. The major aims of the present study were i) to investigate the possible extension of this knowledge to myocytes obtained from type 2 diabetic patients, ii) to compare in these patients the response to GLP-1, insulin or the structurally related GLP-1 peptides, exendin (1-39)amide and exendin(9-39)amide, and iii) to explore possible differences in the responsiveness to these agents between normal and diabetic subjects. Apart from the much higher basal PI3K activity and impaired response to insulin of p44/42 MAP kinases in the diabetic patients, the changes in enzyme activity caused by either hormone or peptide, although not identical, were essentially comparable.

Effects of glucagon-like peptide-1 and exendins on kinase activity, glucose transport and lipid metabolism in adipocytes from normal and type-2 diabetic rats.

Several kinases have been implicated in the metabolic response of human and rat myocytes to glucagon-like peptide-1 (GLP-1), exendin-4 (Ex-4) and exendin-9 (Ex-9). We have investigated, in isolated rat adipocytes, the changes caused by GLP-1, Ex-4 and Ex-9 compared with those provoked by insulin or glucagon, upon the activity of phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB), p42/44 MAP kinases (MAPKs) and p70s6 kinase (p70s6k), and the participation of these kinases and protein kinase C (PKC) in their action upon 2-deoxy-d-glucose uptake, lipolysis and lipogenesis. The study was conducted in normal rats, and extended to a streptozotocin-induced type-2 diabetic model (STZ-rats).

Effects of an olive oil-enriched diet on plasma GLP-1 concentration and intestinal content, plasma insulin concentration, and glucose tolerance in normal rats.

The present study aims mainly at measuring, in normal rats, the GLP-1 response to oral intake of an olive oil-enriched diet (OO), and at assessing the long-term effects of such a diet on the GLP-1 content of the intestinal tract, as well as the plasma D-glucose, insulin, and GLP-1 pattern during an oral glucose tolerance test. In meal-trained rats, the mean increment in plasma GLP-1 concentration at min 10 and 20 was 1.39 +/- 0.

Changes in glucagon-like peptide-1 (GLP-1) secretion after biliopancreatic diversion or vertical banded gastroplasty in obese subjects.

Background: Bariatric operations promote weight loss and improve glucose homeostasis. Glucagon-like peptide-1 (GLP-1) is considered as a possible mediator of the antidiabetic effects of such operations.

Methods: The present study aimed to gain information on the time course for changes in glucose tolerance, as well as insulin, glucagon and GLP-1 secretion, during an oral glucose tolerance test (OGTT), in 31 obese patients examined 1, 3 and 6 months after Larrad's biliopancreatic diversion (BPD) or 6 months after vertical banded gastroplasty (VBG).

Effect of GLP-1 on glucose transport and its cell signalling in human myocytes.

Glucagon-like peptide-1 (GLP-1) controls glucose metabolism in extrapancreatic tissues participating in glucose homeostasis, through receptors not associated to cAMP. In rat hepatocytes, activation of PI3K/PKB, PKC and PP-1 mediates the GLP-1-induced stimulation of glycogen synthase. We have investigated the effect of GLP-1 in normal human myocytes, and that of its structurally related peptides exendin-4 (Ex-4) and its truncated form 9-39 (Ex-9) upon glucose uptake, and the participation of cellular enzymes proposed to mediate insulin actions.

Plasma D-glucose, D-fructose and insulin responses after oral administration of D-glucose, D-fructose and sucrose to normal rats.

Objective: To assess whether oral D-fructose modifies the plasma D-glucose and insulin responses to oral D-glucose administration in normal rats.

Design: Oral D-glucose (1.7, 3.

Bioactive GLP-1 in gut, receptor expression in pancreas, and insulin response to GLP-1 in diabetes-prone rats.

Glucagon-like peptide-1 (GLP-1) is the most insulinogenic of the glucagon-like peptides secreted mainly by L cells in the small and large intestine in response to the ingestion of nutrients. It binds to a specific GLP-1 receptor (GLP-1R) on beta-cells and can increase islet neogenesis and beta-cell mass. It is not clear whether the transmission of information from the gut to islet beta-cells by messengers such as GLP-1 is different in individuals who develop autoimmune diabetes.

Stimulation of proinsulin biosynthesis by K+ in rat pancreatic islets.

Glucose-stimulated proinsulin biosynthesis is regulated mainly at the translational level. This study aims at investigating the possible role of the B-cell K+ content in such a process. In order to increase the islet cells K+ content, rat pancreatic islets exposed to a low D-glucose concentration (e.