-
Peptides Mar 2016Bariatric surgery for obesity has proved to be an extremely effective method of promoting long-term weight reduction with additional beneficial metabolic effects, such... (Review)
Review
Bariatric surgery for obesity has proved to be an extremely effective method of promoting long-term weight reduction with additional beneficial metabolic effects, such as improved glucose tolerance and remission of type 2 diabetes. A range of bariatric procedures are in common use, including gastric banding, sleeve gastrectomy and the Roux-en-Y gastric bypass. Although the mechanisms underlying the efficacy of bariatric surgery are unclear, gastrointestinal and pancreatic peptides are thought to play an important role. The aim of this review is to summarise the effects of different bariatric surgery procedures upon gastrointestinal and pancreatic peptides, including ghrelin, gastrin, cholecystokinin (CCK), glucose-dependent insulinotropic hormone (GIP), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), oxyntomodulin, insulin, glucagon and somatostatin.
Topics: Animals; Appetite; Bariatric Surgery; Gastrointestinal Hormones; Gastrointestinal Tract; Humans; Obesity; Pancreas; Pancreatic Hormones
PubMed: 26344355
DOI: 10.1016/j.peptides.2015.08.013 -
International Journal of Molecular... Feb 2023Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell... (Review)
Review
Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, highlighting the importance of alterations in the mitochondrial melatonergic pathway of pancreatic β-cells in driving mitochondrial dysfunction. The suppression of mitochondrial melatonin makes pancreatic β-cells susceptible to oxidative stress and dysfunctional mitophagy, partly mediated by the loss of melatonin's induction of PTEN-induced kinase 1 (PINK1), thereby suppressing mitophagy and increasing autoimmune associated major histocompatibility complex (MHC)-1. The immediate precursor to melatonin, -acetylserotonin (NAS), is a brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor, TrkB. As both the full-length and truncated TrkB play powerful roles in pancreatic β-cell function and survival, NAS is another important aspect of the melatonergic pathway relevant to pancreatic β-cell destruction in T1DM. The incorporation of the mitochondrial melatonergic pathway in T1DM pathophysiology integrates wide bodies of previously disparate data on pancreatic intercellular processes. The suppression of , , butyrate, and the shikimate pathway-including by bacteriophages-contributes to not only pancreatic β-cell apoptosis, but also to the bystander activation of CD8 T cells, which increases their effector function and prevents their deselection in the thymus. The gut microbiome is therefore a significant determinant of the mitochondrial dysfunction driving pancreatic β-cell loss as well as 'autoimmune' effects derived from cytotoxic CD8 T cells. This has significant future research and treatment implications.
Topics: Humans; Melatonin; Diabetes Mellitus, Type 1; Brain-Derived Neurotrophic Factor; Gastrointestinal Microbiome; CD8-Positive T-Lymphocytes; Pancreatic Hormones; Butyrates
PubMed: 36834709
DOI: 10.3390/ijms24043300 -
Journal of Diabetes Investigation Apr 2016The gut epithelium's large surface area, its direct exposure to ingested nutrients, its vast stem cell population and its immunotolerogenic environment make it an... (Review)
Review
The gut epithelium's large surface area, its direct exposure to ingested nutrients, its vast stem cell population and its immunotolerogenic environment make it an excellent candidate for therapeutic cells to treat diabetes. Thus, several attempts have been made to coax immature gut cells to differentiate into insulin-producing cells by altering the expression patterns of specific transcription factors. Furthermore, because of similarities in enteroendocrine and pancreatic endocrine cell differentiation pathways, other approaches have used genetically engineered enteroendocrine cells to produce insulin in addition to their endogenous secreted hormones. Several studies support the utility of both of these approaches for the treatment of diabetes. Converting a patient's own gut cells into meal-regulated insulin factories in a safe and immunotolerogenic environment is an attractive approach to treat and potentially cure diabetes. Here, we review work on these approaches and indicate where we feel further advancements are required.
Topics: Animals; Cell Differentiation; Cell Engineering; Diabetes Mellitus; Enteroendocrine Cells; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Mice; Rats; Stem Cell Transplantation; Stem Cells
PubMed: 27186362
DOI: 10.1111/jdi.12479 -
Molecular Metabolism Jan 2023Abnormalities that characterize the pathophysiology of type 2 diabetes (T2D) include deficiencies of β-cells and the expansion of α-cells in pancreatic islets,...
Inhibition of stearoyl-CoA desaturase 1 in the mouse impairs pancreatic islet morphogenesis and promotes loss of β-cell identity and α-cell expansion in the mature pancreas.
Abnormalities that characterize the pathophysiology of type 2 diabetes (T2D) include deficiencies of β-cells and the expansion of α-cells in pancreatic islets, manifested by lower insulin release and glucagon oversecretion. The molecular mechanisms that determine intra-islet interactions between pancreatic α- and β-cells are still not fully understood. The present study showed that stearoyl-coenzyme A (CoA) desaturase 1 (SCD1), an enzyme that is implicated in fatty acid metabolism, serves as a checkpoint in the control of endocrine cell equilibrium in pancreatic islets. Our data showed that SCD1 activity is essential for proper α-cell and β-cell lineage determination during morphogenesis of the pancreas and the maintenance of mature β-cell identity. The inhibition of SCD1 expression/activity led to both a decrease in the expression of β-cell signature genes (e.g., Pdx1, Nkx6.1, MafA, and Neurod1, among others) and induction of the expression of the dedifferentiation marker Sox9 in mature pancreatic islets. The transcriptional repression of Pdx1 and MafA in SCD1-deficient β-cells was related to the excessive methylation of promoter regions of these transcription factors. In contrast, SCD1 ablation favored the formation of α-cells over β-cells throughout pancreas organogenesis and did not compromise α-cell identity in adult pancreatic islets. Such molecular changes that were caused by SCD1 downregulation resulted in the mislocalization of α-cells within the core of islets and increased the ratio of pancreatic α- to β-cell mass. This was followed by islet dysfunction, including impairments in glucose-stimulated insulin release, simultaneously with elevations of basal glucagon secretion. Altogether, these findings provide additional mechanistic insights into the role of SCD1 in the pathogenesis of T2D.
Topics: Mice; Animals; Stearoyl-CoA Desaturase; Diabetes Mellitus, Type 2; Glucagon; Islets of Langerhans; Insulin; Glucagon-Secreting Cells; Morphogenesis
PubMed: 36529318
DOI: 10.1016/j.molmet.2022.101659 -
Frontiers in Endocrinology 2022Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and... (Review)
Review
Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and mortality. Prompt diagnosis and appropriate treatment is necessary to prevent hypoglycaemia mediated brain damage. At present, the medical treatment of CHI is limited to diazoxide as first line and synthetic somatostatin receptor ligands (SRLs) as second line options; therefore understanding somatostatin biology and treatment perspectives is important. Under healthy conditions, somatostatin secreted from pancreatic islet δ-cells reduces insulin release through somatostatin receptor induced cAMP-mediated downregulation and paracrine inhibition of β- cells. Several SRLs with extended duration of action are now commercially available and are being used off-label in CHI patients. Efficacy remains variable with the present generation of SRLs, with treatment effect often being compromised by loss of initial response and adverse effects such as bowel ischaemia and hepatobiliary dysfunction. In this review we have addressed the biology of the somatostatin system contexualised to CHI. We have discussed the clinical use, limitations, and complications of somatostatin agonists and new and emerging therapies for CHI.
Topics: Biology; Child; Congenital Hyperinsulinism; Diazoxide; Humans; Insulin; Ligands; Receptors, Somatostatin; Somatostatin
PubMed: 36237195
DOI: 10.3389/fendo.2022.921357 -
Physiology & Behavior Aug 2016Insulin-dependent individuals with diabetes are at risk for a severe hypoglycemic event that may predispose them to several repeat episodes during which the normal... (Review)
Review
Insulin-dependent individuals with diabetes are at risk for a severe hypoglycemic event that may predispose them to several repeat episodes during which the normal counter regulatory mechanisms that protect against hypoglycemia fail to be activated. This state of hypoglycemia unawareness is characterized by a failure of glucagon release, preventing mobilization of endogenous glucose stores from the liver. We describe the discovery of a novel hormone, produced in pancreatic delta cells, which stimulates glucagon production and release, particularly under low glucose conditions. We hypothesize that this hormone, called neuronostatin, may be effective as a co-therapy with insulin to prevent repeated, potentially fatal episodes of recurrent hypoglycemia.
Topics: Animals; Glucagon; Humans; Hypoglycemia; Insulin; Peptide Hormones
PubMed: 27080082
DOI: 10.1016/j.physbeh.2016.04.012 -
Peptides Jun 2024Circulating insulin levels are known to be increased in people with higher body mass index (BMI) due to effects of adiposity on insulin resistance, whilst gut hormones...
Circulating insulin levels are known to be increased in people with higher body mass index (BMI) due to effects of adiposity on insulin resistance, whilst gut hormones have a more complex relationship, with fasting peptideYY (PYY) reported to be inversely related to BMI. This study aimed to further explore fasting and post prandial pancreatic and gut hormone concentrations in plasma samples from obese and non-obese participants. Participants with healthy BMI (n=15), overweight BMI (n=29) and obesity (n=161) had samples taken fasting and 30 min post mixed liquid meal for analysis of glucagon-like peptide-1 (GLP-1), PYY, glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon. Data visualiation used linear discriminant analysis for dimensionality reduction, to visualise the data and assess scaling of each hormone. Fasting levels of insulin, GIP and PYY were shown to be key classifiers between the 3 groups on ANCOVA analysis, with an observation of increased GIP levels in overweight, but not obese participants. In non-obese subjects, fasting GIP, PYY and insulin correlated with BMI, whereas in subjects with obesity only the pancreatic hormones glucagon and insulin correlated with BMI. Concentrations of total GLP-1 in the fasting state correlated strongly with glucagon levels, highlighting potential assay cross-reactivities. The study, which included a relatively large number of subjects with severe obesity, supported previous evidence of BMI correlating negatively with fasting PYY and positively with fasting insulin. The observation of increased fasting GIP levels in overweight but not obese participants deserves further validation and mechanistic investigation.
Topics: Humans; Obesity; Male; Female; Adult; Fasting; Peptide YY; Middle Aged; Glucagon-Like Peptide 1; Gastric Inhibitory Polypeptide; Body Mass Index; Insulin; Postprandial Period; Glucagon; Gastrointestinal Hormones
PubMed: 38490484
DOI: 10.1016/j.peptides.2024.171186 -
Diabetologia Jun 2022Urocortin-3 (UCN3) is a glucoregulatory peptide produced in the gut and pancreatic islets. The aim of this study was to clarify the acute effects of UCN3 on glucose...
AIM/HYPOTHESIS
Urocortin-3 (UCN3) is a glucoregulatory peptide produced in the gut and pancreatic islets. The aim of this study was to clarify the acute effects of UCN3 on glucose regulation following an oral glucose challenge and to investigate the mechanisms involved.
METHODS
We studied the effect of UCN3 on blood glucose, gastric emptying, glucose absorption and secretion of gut and pancreatic hormones in male rats. To supplement these physiological studies, we mapped the expression of UCN3 and the UCN3-sensitive receptor, type 2 corticotropin-releasing factor receptor (CRHR2), by means of fluorescence in situ hybridisation and by gene expression analysis.
RESULTS
In rats, s.c. administration of UCN3 strongly inhibited gastric emptying and glucose absorption after oral administration of glucose. Direct inhibition of gastrointestinal motility may be responsible because UCN3's cognate receptor, CRHR2, was detected in gastric submucosal plexus and in interstitial cells of Cajal. Despite inhibited glucose absorption, post-challenge blood glucose levels matched those of rats given vehicle in the low-dose UCN3 group, because UCN3 concomitantly inhibited insulin secretion. Higher UCN3 doses did not further inhibit gastric emptying, but the insulin inhibition progressed resulting in elevated post-challenge glucose and lipolysis. Incretin hormones and somatostatin (SST) secretion from isolated perfused rat small intestine was unaffected by UCN3 infusion; however, UCN3 infusion stimulated secretion of somatostatin from delta cells in the isolated perfused rat pancreas which, unlike alpha cells and beta cells, expressed Crhr2. Conversely, acute antagonism of CRHR2 signalling increased insulin secretion by reducing SST signalling. Consistent with these observations, acute drug-induced inhibition of CRHR2 signalling improved glucose tolerance in rats to a similar degree as administration of glucagon-like peptide-1. UCN3 also powerfully inhibited glucagon secretion from isolated perfused rat pancreas (perfused with 3.5 mmol/l glucose) in a SST-dependent manner, suggesting that UCN3 may be involved in glucose-induced inhibition of glucagon secretion.
CONCLUSIONS/INTERPRETATION
Our combined data indicate that UCN3 is an important glucoregulatory hormone that acts through regulation of gastrointestinal and pancreatic functions.
Topics: Animals; Blood Glucose; Glucagon; Glucose; Insulin; Islets of Langerhans; Male; Rats; Somatostatin; Urocortins
PubMed: 35325259
DOI: 10.1007/s00125-022-05675-9 -
Frontiers in Endocrinology 2022Although important for digestion and metabolism in repose, the healthy endocrine pancreas also plays a key role in facilitating energy transduction around physical... (Review)
Review
Although important for digestion and metabolism in repose, the healthy endocrine pancreas also plays a key role in facilitating energy transduction around physical exercise. During exercise, decrements in pancreatic β-cell mediated insulin release opposed by increments in α-cell glucagon secretion stand chief among the hierarchy of glucose-counterregulatory responses to decreasing plasma glucose levels. As a control hub for several major glucose regulatory hormones, the endogenous pancreas is therefore essential in ensuring glucose homeostasis. Type 1 diabetes (T1D) is pathophysiological condition characterised by a destruction of pancreatic β-cells resulting in pronounced aberrations in glucose control. Yet perhaps less considered is the impact of T1D on all other pancreatic endocrine cell responses during exercise and whether they differ to those observed in healthy man. For physicians, understanding how the endocrine pancreas responds to exercise in people with and without T1D may serve as a useful model from which to identify whether there are clinically relevant adaptations that need consideration for glycaemic management. From a physiological perspective, delineating differences or indeed similarities in such responses may help inform appropriate exercise test interpretation and subsequent program prescription. With more complex advances in automated insulin delivery (AID) systems and emerging data on exercise algorithms, a timely update is warranted in our understanding of the endogenous endocrine pancreatic responses to physical exercise in people with and without T1D. By placing our focus here, we may be able to offer a nexus of better understanding between the clinical and engineering importance of AIDs requirements during physical exercise.
Topics: Blood Glucose; Diabetes Mellitus, Type 1; Exercise; Glucagon; Glucagon-Secreting Cells; Glucose; Humans; Insulin; Islets of Langerhans; Male
PubMed: 36147573
DOI: 10.3389/fendo.2022.981723 -
Peptides Dec 2022Chromogranin A (CgA) is a 439 amino acid protein secreted by neuroendocrine cells. Proteolytic processing of CgA results in the production of different bioactive... (Review)
Review
Chromogranin A (CgA) is a 439 amino acid protein secreted by neuroendocrine cells. Proteolytic processing of CgA results in the production of different bioactive peptides. These peptides have been associated with inflammatory bowel disease, diabetes, and cancer. One of the chromogranin A-derived peptides is ∼52 amino acid long Pancreastatin (PST: human (h)CgA, murine (m)CgA). PST is a glycogenolytic peptide that inhibits glucose-induced insulin secretion from pancreatic islet β-cells. In addition to this metabolic role, evidence is emerging that PST also has inflammatory properties. This review will discuss the immunomodulatory properties of PST and its possible mechanisms of action and regulation. Moreover, this review will discuss the potential translation to humans and how PST may be an interesting therapeutic target for treating inflammatory diseases.
Topics: Humans; Animals; Mice; Chromogranin A; Pancreatic Hormones; Chromogranins; Peptides; Amino Acids
PubMed: 36244579
DOI: 10.1016/j.peptides.2022.170893