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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 -
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 -
Diabetes, Obesity & Metabolism Jan 2024The development of pancreatic islet endocrine cells is a tightly regulated process leading to the generation of distinct cell types harbouring different hormones in... (Review)
Review
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. Importantly, the glucose-lowering effects of approved and experimental antidiabetic agents, including glucagon-like peptide-1 mimetics, novel peptides and small molecules, have been associated with preventing or reversing β-cell dedifferentiation or promoting the transdifferentiation of non-β-cells towards an insulin-positive β-cell-like phenotype. Therefore, we review the manifestations of islet cell plasticity in various experimental settings and discuss the physiological and therapeutic sides of this phenomenon, focusing on strategies for preventing β-cell loss or generating new β-cells in diabetes. A better understanding of the molecular mechanisms underpinning islet cell plasticity is a prerequisite for more targeted therapies to help prevent β-cell decline in diabetes.
Topics: Humans; Cell Plasticity; Islets of Langerhans; Insulin; Insulin-Secreting Cells; Diabetes Mellitus; Cell Transdifferentiation
PubMed: 37845573
DOI: 10.1111/dom.15300 -
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 -
Translational Research : the Journal of... Dec 2022Almost 50 years ago, scientists developed the bi-hormonal abnormality hypothesis, stating that diabetes is not caused merely by the impaired insulin signaling. Instead,... (Review)
Review
Almost 50 years ago, scientists developed the bi-hormonal abnormality hypothesis, stating that diabetes is not caused merely by the impaired insulin signaling. Instead, the presence of inappropriate level of glucagon is a prerequisite for the development of type 1 diabetes (T1D). It is widely understood that the hormones insulin and glucagon, secreted by healthy β and α cells respectively, operate in a negative feedback loop to maintain the body's blood sugar levels. Despite this fact, traditional T1D treatments rely solely on exogenous insulin injections. Furthermore, research on cell-based therapies and stem-cell derived tissues tends to focus on the replacement of β cells alone. In vivo, the pancreas is made up of 4 major endocrine cell types, that is, insulin-producing β cells, glucagon-producing α cells, somatostatin-producing δ cells, and pancreatic polypeptide-producing γ cells. These distinct cell types are involved synergistically in regulating islet functions. Therefore, it is necessary to produce a pancreatic islet organoid in vitro consisting of all these cell types that adequately replaces the function of the native islets. In this review, we describe the unique function of each pancreatic endocrine cell type and their interactions contributing to the maintenance of normoglycemia. Furthermore, we detail current sources of whole islets and techniques for their long-term expansion and culture. In addition, we highlight a vast potential of the pancreatic islet organoids for transplantation and diabetes research along with updated new approaches for successful transplantation using stem cell-derived islet organoids.
Topics: Humans; Organoids; Diabetes Mellitus, Type 1; Glucagon; Islets of Langerhans; Insulin; Insulin-Secreting Cells
PubMed: 35772687
DOI: 10.1016/j.trsl.2022.06.014 -
Pancreatology : Official Journal of the... Feb 2024Factors that influence the pancreas microbiome are not well understood. Regular proton pump inhibitor (PPI) use induces significant alterations in the gut microbiome,...
Factors that influence the pancreas microbiome are not well understood. Regular proton pump inhibitor (PPI) use induces significant alterations in the gut microbiome, including an increase in the abundance of Streptococcus, and may be associated with pancreatic cancer risk. The aim of this study was to examine whether PPI use is associated with pancreatic and duodenal tissue microbiomes. We compared 16S rRNA microbiome profiles of normal pancreatic and duodenal tissue from 103 patients undergoing pancreatic surgery for non-malignant indications, including 34 patients on PPIs, accounting for factors including age, smoking, body mass index and the presence of main pancreatic duct dilation. Histologically normal tissue from the pancreatic head had higher alpha diversity and enrichment of Firmicutes by phylum-level analysis and Streptococcus species compared to normal pancreas body/tail tissues (16.8 % vs 8.8 %, P = .02, and 5.9 % vs 1.4 %, P = .03, respectively). Measures of beta diversity differed significantly between the pancreas and the duodenum, but in subjects with main pancreatic duct dilation, beta diversity of pancreatic head tissue was more similar to normal duodenal tissue than those without pancreatic duct dilation. Duodenal tissue of PPI users had significant enrichment of Firmicute phyla (34.7 % vs. 14.1 %, P = .01) and Streptococcus genera (19.5 % vs. 5.2 %, P = .01) compared to non-users; these differences were not evident in pancreas tissues. By multivariate analysis, PPI use was associated with alpha diversity in the duodenum, but not in the pancreas. However, some differences in pancreas tissue beta diversity were observed between PPI users and non-users. In summary, we find differences in the microbiome profiles of the pancreas head versus the pancreatic body/tail and we find PPI use is associated with alterations in duodenal and pancreatic tissue microbiome profiles.
Topics: Humans; Proton Pump Inhibitors; RNA, Ribosomal, 16S; Duodenum; Pancreas; Microbiota; Pancreatic Hormones
PubMed: 38161092
DOI: 10.1016/j.pan.2023.12.010 -
The Journal of Endocrinology Jan 2024Long lagging behind insulin, glucagon research has caught up in large part, thanks to technological breakthroughs. Here we review how the field was propelled by the... (Review)
Review
Long lagging behind insulin, glucagon research has caught up in large part, thanks to technological breakthroughs. Here we review how the field was propelled by the development of novel techniques and approaches. The glucagon radioimmunoassay and islet isolation are methods that now seem trivial, but for decades they were crucial in defining the biology of the pancreatic alpha cell and the role of glucagon in glucose homeostasis. More recently, mouse models have become the main workhorse of this research effort, if not of biomedical research in general. The mouse model allowed detailed mechanistic studies that are revealing alpha cell functions beyond its canonical glucoregulatory role. A recent profusion of gene expression and transcription regulation studies is providing new vistas into what constitutes alpha cell identity. In particular, the combination of transcriptomic techniques with functional recordings promises to move molecular guesswork into real-time physiology. The challenge right now is not to get enamored with these powerful techniques and to make sure that the research continues to be transformative and paradigm shifting. We should imagine a future in which the biology of the alpha cell will be studied at single-cell resolution, non-invasively, and in real time in the human body.
Topics: Mice; Animals; Humans; Glucagon; Glucagon-Secreting Cells; Glucose; Insulin; Insulin-Secreting Cells; Disease Models, Animal; Islets of Langerhans
PubMed: 37888975
DOI: 10.1530/JOE-22-0315 -
Diabetes Dec 2023In type 1 diabetes, the reduced glucagon response to insulin-induced hypoglycemia has been used to argue that β-cell secretion of insulin is required for the full... (Review)
Review
In type 1 diabetes, the reduced glucagon response to insulin-induced hypoglycemia has been used to argue that β-cell secretion of insulin is required for the full glucagon counterregulatory response. For years, the concept has been that insulin from the β-cell core flows downstream to suppress glucagon secretion from the α-cells in the islet mantle. This core-mantle relationship has been supported by perfused pancreas studies that show marked increases in glucagon secretion when insulin was neutralized with antisera. Additional support comes from a growing number of studies focused on vascular anatomy and blood flow. However, in recent years this core-mantle view has generated less interest than the argument that optimal insulin secretion is due to paracrine release of glucagon from α-cells stimulating adjacent β-cells. This mechanism has been evaluated by knockout of β-cell receptors and impairment of α-cell function by inhibition of Gi designer receptors exclusively activated by designer drugs. Other studies that support this mechanism have been obtained by pharmacological blocking of glucagon-like peptide 1 receptor in humans. While glucagon has potent effects on β-cells, there are concerns with the suggested paracrine mechanism, since some of the supporting data are from isolated islets. The study of islets in static incubation or perifusion systems can be informative, but the normal paracrine relationships are disrupted by the isolation process. While this complicates interpretation of data, arguments supporting paracrine interactions between α-cells and β-cells have growing appeal. We discuss these conflicting views of the relationship between pancreatic α-cells and β-cells and seek to understand how communication depends on blood flow and/or paracrine mechanisms.
Topics: Humans; Glucagon; Glucagon-Secreting Cells; Insulin; Insulin-Secreting Cells; Insulin Secretion; Hypoglycemia; Islets of Langerhans; Glucose
PubMed: 37983524
DOI: 10.2337/db23-0292