Cafeteria diet compromises natural adaptations of islet cell transdifferentiation and turnover in pregnancy.

Background: Pancreatic islet β-cell mass expands during pregnancy, but underlying mechanisms are not fully understood. This study examines the impact of pregnancy and cafeteria diet on islet morphology, associated cellular proliferation/apoptosis rates as well as β-cell lineage.

Methods: Non-pregnant and pregnant Ins1;Rosa26-eYFP transgenic mice were maintained on either normal or high-fat cafeteria diet, with pancreatic tissue obtained at 18 days gestation.

Dopamine signalling in pancreatic islet cells and role in adaptations to metabolic stress.

Objectives: Dopamine and related receptors are evidenced in pancreatic endocrine tissue, but the impact on islet β-cell stimulus-secretion as well as (patho)physiological role are unclear.

Methods: The present study has evaluated islet cell signalling pathways and biological effects of dopamine, as well as alterations of islet dopamine in rodent models of diabetes of different aetiology.

Key Findings: The dopamine precursor l-DOPA partially impaired glucose tolerance in mice and attenuated glucose-, exendin-4, and alanine-induced insulin secretion.

Strategy for the Identification of Host-Defense Peptides in Frog Skin Secretions with Therapeutic Potential as Antidiabetic Agents.

Several amphibian peptides that were first identified on the basis of their antimicrobial or cytotoxic properties have subsequently shown potential for development into agents for the treatment of patients with Type 2 diabetes. A strategy is presented for the isolation and characterization of such peptides that are present in norepinephrine-stimulated skin secretions from a range of frog species. The methodology involves (1) fractionation of the secretions by reversed-phase HPLC, (2) identification of fractions containing components that stimulate the rate of release of insulin from BRIN-BD11 clonal β-cells without simultaneously stimulating the release of lactate dehydrogenase, (3) identification of active peptides in the fractions in the mass range 1-6 kDa by MALDI-ToF mass spectrometry, (4) purification of the peptides to near homogeneity by further reversed-phase HPLC on various column matrices, and (5) structural characterization by automated Edman degradation.

Molecular determinants and intracellular targets of taurine signalling in pancreatic islet β-cells.

Aim: Despite its abundance in pancreatic islets of Langerhans and proven antihyperglycemic effects, the impact of the essential amino acid, taurine, on islet β-cell biology has not yet received due consideration, which prompted the current studies exploring the molecular selectivity of taurine import into β-cells and its acute and chronic intracellular interactions.

Methods: The molecular aspects of taurine transport were probed by exposing the clonal pancreatic BRIN BD11 β-cells and primary mouse and human islets to a range of the homologs of the amino acid (assayed at 2-20 mM), using the hormone release and imaging of intracellular signals as surrogate read-outs. Known secretagogues were employed to profile the interaction of taurine with acute and chronic intracellular signals.

Pancreatic islet cell plasticity: Pathogenic or therapeutically exploitable?

The development of pancreatic islet endocrine cells is a tightly regulated process leading to the generation of distinct cell types harbouring different hormones in response to small changes in environmental stimuli. Cell differentiation is driven by transcription factors that are also critical for the maintenance of the mature islet cell phenotype. Alteration of the insulin-secreting β-cell transcription factor set by prolonged metabolic stress, associated with the pathogenesis of diabetes, obesity or pregnancy, results in the loss of β-cell identity through de- or transdifferentiation.

The impact of diabetes and obesity on fertility and the potential role of gut hormones as treatment.

Aims: Alongside its metabolic implications, obesity and associated diabetes impair female reproductive function, causing infertility and polycystic ovarian syndrome (PCOS). Recently, gut hormones and their receptors have been identified in various reproductive organs indicating their potential regulatory effects on reproductive function. This review aims to give an overview of their potential effects.

Sex-based impact of pancreatic islet stressors in GluCreERT2/Rosa26-eYFP mice.

The present study examines differences in metabolic and pancreatic islet adaptative responses following streptozotocin (STZ) and hydrocortisone (HC) administration in male and female transgenic GluCreERT2/Rosa26-eYFP mice. Mice received five daily doses of STZ (50 mg/kg, i.p.

Disturbed ovarian morphology, oestrous cycling and fertility of high fat fed rats are linked to alterations of incretin receptor expression.

Obesity is a major cause of infertility in females with a direct correlation between energy intake and reproductive dysfunction. To explore underlying mechanisms, disturbances in reproductive health and incretin/reproductive hormone receptor expression were studied in female Wistar rats fed a high-fat-diet for 20-weeks. Metabolic parameters and ovarian/adrenal gene expression were monitored along with estrous cycling and fertility upon mating.

Orally-delivered insulin-peptide nanocomplexes enhance transcytosis from cellular depots and improve diabetic blood glucose control.

Insulin regulates blood glucose levels, and is the mainstay for the treatment of type-1 diabetes and type-2 when other drugs provide inadequate control. Therefore, effective oral Insulin delivery would be a significant advance in drug delivery. Herein, we report the use of the modified cell penetrating peptide (CPP) platform, Glycosaminoglycan-(GAG)-binding-enhanced-transduction (GET), as an efficacious transepithelial delivery vector in vitro and to mediate oral Insulin activity in diabetic animals.

PYY (3-36) protects against high fat feeding induced changes of pancreatic islet and intestinal hormone content and morphometry.

Background: Prolonged high fat feeding negatively impacts pancreatic and intestinal morphology. In this regard, direct effects of PYY(3-36) on intestinal cell and pancreatic islet morphometry are yet to be fully explored in the setting of obesity.

Methods: We examined the influence of 21-days twice daily treatment with PYY(3-36) on these parameters in mice fed a high fat diet (HFD).

Synthalin: a lost lesson for glucagon suppression in diabetes therapeutics.

Objectives: Within mammalian pancreatic islets, there are two major endocrine cell types, beta-cells which secrete insulin and alpha-cells which secrete glucagon. Whereas, insulin acts to lower circulating glucose, glucagon counters this by increasing circulating glucose via the mobilisation of glycogen. Synthalin A (Syn A) was the subject of much research in the 1920s and 1930s as a potential pancreatic alpha-cell toxin to block glucagon secretion.

Towards an affinity-free, centrifugal microfluidic system for rapid, automated forensic differential extraction.

Biological evidence originating from victims of sexual assault is often comprised of unbalanced cellular mixtures with significantly higher contributions from the victim's genetic material. Enrichment of the forensically-critical sperm fraction (SF) with single-source male DNA relies on differential extraction (DE), a manually-intensive process that is prone to contamination. Due to DNA losses from sequential washing steps, some existing DE methods often fail to generate sufficient sperm cell DNA recovery for perpetrator(s) identification.

Taurine rescues pancreatic β-cell stress by stimulating α-cell transdifferentiation.

The semi-essential ubiquitous amino acid taurine has been shown to alleviate obesity and hyperglycemia in humans; however, the pathways underlying the antidiabetic actions have not been characterized. We explored the effect of chronic taurine exposure on cell biology of pancreatic islets, in degenerative type 1-like diabetes. The latter was modeled by small dose of streptozotocin (STZ) injection for 5 days in mice, followed by a 10-day administration of taurine (2% w/v, orally) in the drinking water.

NKCC transport mediates the insulinotropic effects of taurine and other small neutral amino acids.

Aims: Despite its high concentration in pancreatic islets of Langerhans and broad range of antihyperglycemic effects, the route facilitating the import of dietary taurine into pancreatic β-cell and mechanisms underlying its insulinotropic activity are unclear. We therefore studied the impact of taurine on beta-cell function, alongside that of other small neutral amino acids, L-alanine and L-proline.

Main Methods: Pharmacological profiling of insulin secretion was conducted using clonal BRIN BD11 β-cells, the impact of taurine on the metabolic fate of glucose carbons was assessed using NMR and the findings were verified by real-time imaging of Ca dynamics in the cytosol of primary mouse and human islet beta-cells.

Evidence for Involvement of GIP and GLP-1 Receptors and the Gut-Gonadal Axis in Regulating Female Reproductive Function in Mice.

Substantial evidence suggests crosstalk between reproductive and gut-axis but mechanisms linking metabolism and reproduction are still unclear. The present study evaluated the possible role of glucose-dependent-insulinotropic-polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) in reproductive function by examining receptor distribution and the effects of global GIPR and GLP-1R deletion on estrous cycling and reproductive outcomes in mice. GIPR and GLP-1R gene expression were readily detected by PCR in female reproductive tissues including pituitary, ovaries and uterine horn.

Ac3IV, a V1a and V1b receptor selective vasopressin analogue, protects against hydrocortisone-induced changes in pancreatic islet cell lineage.

The Avpr1a (V1a) and Avpr1b (V1b) receptor selective, vasopressin (AVP) analogue, Ac3IV has been shown to improve metabolism and pancreatic islet structure in diabetes and insulin resistance. The present study further investigates these actions by assessing the ability of Ac3IV to protect against pancreatic islet architectural disturbances induced by hydrocortisone (HC) treatment in transgenic Ins1;Rosa26-eYFP mice, that possess beta-cell lineage tracing capabilities. HC intervention increased (p < 0.

Classical and non-classical islet peptides in the control of β-cell function.

The dual role of the pancreas as both an endocrine and exocrine gland is vital for food digestion and control of nutrient metabolism. The exocrine pancreas secretes enzymes into the small intestine aiding digestion of sugars and fats, whereas the endocrine pancreas secretes a cocktail of hormones into the blood, which is responsible for blood glucose control and regulation of carbohydrate, protein and fat metabolism. Classical islet hormones, insulin, glucagon, pancreatic polypeptide and somatostatin, interact in an autocrine and paracrine manner, to fine-tube the islet function and insulin secretion to the needs of the body.

Beneficial impact of Ac3IV, an AVP analogue acting specifically at V1a and V1b receptors, on diabetes islet morphology and transdifferentiation of alpha- and beta-cells.

Ac3IV (Ac-CYIQNCPRG-NH2) is an enzymatically stable vasopressin analogue that selectively activates Avpr1a (V1a) and Avpr1b (V1b) receptors. In the current study we have employed streptozotocin (STZ) diabetic transgenic Ins1Cre/+;Rosa26-eYFP and GluCreERT2;Rosa26-eYFP mice, to evaluate the impact of sustained Ac3IV treatment on pancreatic islet cell morphology and transdifferentiation. Twice-daily administration of Ac3IV (25 nmol/kg bw) to STZ-diabetic Ins1Cre/+;Rosa26-eYFP mice for 12 days increased pancreatic insulin (p<0.

Effects of first-line diabetes therapy with biguanides, sulphonylurea and thiazolidinediones on the differentiation, proliferation and apoptosis of islet cell populations.

Aims: Metformin, rosiglitazone and sulfonylureas enhance either insulin action or secretion and thus have been used extensively as early stage anti-diabetic medication, independently of the aetiology of the disease. When administered to newly diagnosed diabetes patients, these drugs produce variable results. Here, we examined the effects of the three early stage oral hypoglycaemic agents in mice with diabetes induced by multiple low doses of streptozotocin, focusing specifically on the developmental biology of pancreatic islets.

Weight-reducing, lipid-lowering and antidiabetic activities of a novel arginine vasopressin analogue acting at the V1a and V1b receptors in high-fat-fed mice.

Aim: To assess the beneficial metabolic effects of the nonapeptide hormone, arginine vasopressin (AVP), on metabolism.

Materials And Methods: We exchanged amino acids at position 3 and 8 of AVP, namely phenylalanine and arginine, with those of oxytocin, to generate novel analogues with altered receptor selectivity. Secondary modification by N-terminal acetylation was used to impart stability to circulating endopeptidases.

Effects of long-acting analogues of lamprey GLP-1 and paddlefish glucagon on alpha- to beta-cell transdifferentiation in an insulin-deficient transgenic mouse model.

The abilities of the long-acting, dual-agonist anti-diabetic peptides [D-Ala ]palmitoyl-lamprey GLP-1 and [D-Ser ]palmitoyl-paddlefish glucagon to induce α-cell to β-cell transdifferentiation were investigated in Glu ;ROSA26-eYFP mice. These animals have been genetically engineered so that yellow fluorescent protein is specifically expressed in glucagon-producing α-cells, thereby allowing cell lineage tracing. Insulin deficiency was produced by treatment of the mice with multiple low doses of streptozotocin.

Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice.

Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic ; and ; mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in ; mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status.

Beneficial actions of the [A14K] analog of the frog skin peptide PGLa-AM1 in mice with obesity and degenerative diabetes: A mechanistic study.

The antidiabetic actions of [A14K]PGLa-AM1, an analog of peptide glycine-leucine-amide-AM1 isolated from skin secretions of the octoploid frog Xenopus amieti, were investigated in genetically diabetic-obese db/db mice. Twice daily administration of [A14K]PGLa-AM1 (75 nmol/kg body weight) for 28 days significantly (P < 0.05) decreased circulating blood glucose and HbA1c and increased plasma insulin concentrations leading to improvements in glucose tolerance.

Development and characterisation of novel, enzymatically stable oxytocin analogues with beneficial antidiabetic effects in high fat fed mice.

Background: There is growing evidence to support beneficial effects of the hypothalamic synthesised hormone, oxytocin, on metabolism. However, the biological half-life of oxytocin is short and receptor activation profile unspecific.

Methods: We have characterised peptide-based oxytocin analogues with structural modifications aimed at improving half-life and receptor specificity.

Mechanisms of action of the antidiabetic peptide [S4K]CPF-AM1 in db/db mice.

The antidiabetic effects and mechanisms of action of an analogue of a frog skin host-defence peptide belonging to the caerulein-precursor fragment family, [S4K]CPF-AM1 were investigated in db/db mice with a genetically inherited form of degenerative diabetes-obesity. Twice-daily treatment with the peptide (75 nmol/kg body weight) for 28 days significantly decreased blood glucose (P < 0.01) and HbA1c (P < 0.