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JCI Insight Aug 2023Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet...
Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell-enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non-β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.
Topics: Adult; Humans; Animals; Mice; MafB Transcription Factor; Diabetes Mellitus, Type 2; Islets of Langerhans; Insulin-Secreting Cells; Insulin
PubMed: 37606041
DOI: 10.1172/jci.insight.166386 -
ELife Sep 2023Pancreatic α-cells secrete glucagon, an insulin counter-regulatory peptide hormone critical for the maintenance of glucose homeostasis. Investigation of the function of...
Pancreatic α-cells secrete glucagon, an insulin counter-regulatory peptide hormone critical for the maintenance of glucose homeostasis. Investigation of the function of human α-cells remains a challenge due to the lack of cost-effective purification methods to isolate high-quality α-cells from islets. Here, we use the reaction-based probe diacetylated Zinpyr1 (DA-ZP1) to introduce a novel and simple method for enriching live α-cells from dissociated human islet cells with ~95% purity. The α-cells, confirmed by sorting and immunostaining for glucagon, were cultured up to 10 days to form α-pseudoislets. The α-pseudoislets could be maintained in culture without significant loss of viability, and responded to glucose challenge by secreting appropriate levels of glucagon. RNA-sequencing analyses (RNA-seq) revealed that expression levels of key α-cell identity genes were sustained in culture while some of the genes such as , , were altered in α-pseudoislets in a time-dependent manner. In conclusion, we report a method to sort human primary α-cells with high purity that can be used for downstream analyses such as functional and transcriptional studies.
Topics: Humans; Glucagon; Transcriptome; Islets of Langerhans; Insulin; Glucagon-Secreting Cells; Glucose; Fluoresceins; Insulin-Secreting Cells
PubMed: 37732504
DOI: 10.7554/eLife.85056 -
JPMA. the Journal of the Pakistan... Mar 2023This communication discusses the physiology and pathology of the insulin glucagon ratio, with respect to obesity. Though high insulin levels are associated with obesity...
This communication discusses the physiology and pathology of the insulin glucagon ratio, with respect to obesity. Though high insulin levels are associated with obesity in this manuscript the authors specifically highlight its role in the causation and clinical management of obesity. It suggests that the term insulin glucagon ratio be used in preference to glucagon insulin ratio, and shares insights which may be helpful in informing future research.
Topics: Humans; Insulin; Glucagon; Obesity; Glucagon-Like Peptide 1
PubMed: 36932791
DOI: 10.47391/JPMA.23-20 -
Endokrynologia Polska 2022Not required for Clinical Vignette.
Not required for Clinical Vignette.
Topics: Gastrinoma; Humans; Pancreatic Neoplasms; Somatostatin
PubMed: 35381105
DOI: 10.5603/EP.a2021.0101 -
Life Science Alliance Aug 2022Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We...
Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon (<i>GCG</i>, 56%), amylin (<i>IAPP</i>, 52%), insulin (<i>INS</i>, 44%), and somatostatin (<i>SST</i>, 24%). Inhibition of two DEGs, <i>UNC5D</i> and <i>SERPINE2</i>, impaired glucose-stimulated insulin secretion and impacted cell survival in a human β-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.
Topics: Diabetes Mellitus, Type 2; Glucagon; Humans; Insulin; Islets of Langerhans; Serpin E2
PubMed: 35948367
DOI: 10.26508/lsa.202201376 -
International Journal of Molecular... Aug 2023Research in the treatment of type 1 diabetes has been addressed into two main areas: the development of "intelligent insulins" capable of auto-regulating their own... (Review)
Review
Research in the treatment of type 1 diabetes has been addressed into two main areas: the development of "intelligent insulins" capable of auto-regulating their own levels according to glucose concentrations, or the exploitation of artificial intelligence (AI) and its learning capacity, to provide decision support systems to improve automated insulin therapy. This review aims to provide a synthetic overview of the current state of these two research areas, providing an outline of the latest development in the search for "intelligent insulins," and the results of new and promising advances in the use of artificial intelligence to regulate automated insulin infusion and glucose control. The future of insulin treatment in type 1 diabetes appears promising with AI, with research nearly reaching the possibility of finally having a "closed-loop" artificial pancreas.
Topics: Humans; Insulin; Diabetes Mellitus, Type 1; Artificial Intelligence; Insulin, Regular, Human; Intelligence
PubMed: 37685946
DOI: 10.3390/ijms241713139 -
Frontiers in Endocrinology 2020Obesity and obesity-related diseases are major public health concerns that have been exponentially growing in the last decades. Bariatric surgery is an effective...
Obesity and obesity-related diseases are major public health concerns that have been exponentially growing in the last decades. Bariatric surgery is an effective long-term treatment to achieve weight loss and obesity comorbidity remission. Post-bariatric hypoglycemia (PBH) is a late complication of bariatric surgery most commonly reported after Roux-en-Y gastric bypass (RYGB). PBH is the end result of postprandial hyperinsulinemia but additional endocrine mechanisms involved are still under debate. Our aim was to characterize entero-pancreatic hormone dynamics associated with postprandial hypoglycemia after RYGB. Individuals previously submitted to RYGB (=23) in a single tertiary hospital presenting PBH symptoms (, =14) and asymptomatic weight-matched controls (, =9) were enrolled. Participants underwent a mixed-meal tolerance test (MMTT) to assess glucose, total amino acids (total AA), insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and neurotensin (NT). We found that hypoglycemia during the MMTT was equally frequent in and groups (=1.000). Re-grouped according to glucose nadir during the MMTT ( =11 vs =12; nadir <3.05 mmol/l vs ≥3.05 mmol/l), subjects presented no differences in anthropometric (BMI: =0.527) or metabolic features (HbA: =0.358), yet distinct meal-elicited hormone dynamics were identified. Postprandial glucose excursion and peak glucose levels were similar (>0.05), despite distinct late glycemic outcomes (t=60 min and t=90 min: <0.01), with overall greater glycemic variability in group (minimum-to-maximum glucose ratio: <0.001). group meal-triggered hormone profile was characterized by lower early glucagon (t=15 min: <0.01) and higher insulin (t=30 min: <0.05, t=45 min: <0.001), C-peptide (t=30 min: <0.01, t=45 min: <0.001, t=60 min: <0.05), and GLP-1 (t=45 min: <0.05) levels. Hyperinsulinemia was an independent risk factor for hypoglycemia (<0.05). After adjusting for hyperinsulinemia, early glucagon correlated with glycemic nadir (<0.01), and prevented postprandial hypoglycemia (<0.05). A higher insulin to glucagon balance in was observed (<0.05). No differences were observed in total AA, GIP or NT excursions (>0.05). In sum, after RYGB, postprandial hyperinsulinemia is key in triggering PBH, but a parallel and earlier rise in endogenous glucagon might sustain the inter-individual variability in glycemic outcome beyond the effect of hyperinsulinism, advocating a potential pivotal role for glucagon in preventing hyperinsulinemic hypoglycemia.
Topics: Adult; Amino Acids; Bariatric Surgery; Blood Glucose; Body Mass Index; Cohort Studies; Female; Glucagon; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Middle Aged; Pancreatic Hormones; Postoperative Complications; Postprandial Period
PubMed: 33424773
DOI: 10.3389/fendo.2020.608248 -
Journal of Diabetes Jun 2023The objective of this study was to provide recommendations regarding effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting... (Review)
Review
The objective of this study was to provide recommendations regarding effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting plasma glucose of five basal insulins (glargine U-300, degludec U-100, glargine U-100, detemir, and insulin protamine Hagedorn) in insulin-naïve adult patients with type 2 diabetes in the Asia-Pacific region. Based on evidence from a systematic review, we developed an Asia-Pacific clinical practice guideline through comprehensive internal review and external review processes. We set up and used clinical thresholds of trivial, small, moderate, and large effects for different critical and important outcomes in the overall certainty of evidence assessment and balancing the magnitude of intervention effects when making recommendations, following GRADE methods (Grading of Recommendations, Assessment, Development, and Evaluation). The AGREE (Appraisal of Guidelines, Research and Evaluation) and RIGHT (Reporting Items for practice Guidelines in HealThcare) guideline reporting checklists were complied with. After the second-round vote by the working group members, all the recommendations and qualifying statements reached over 75% agreement rates. Among 44 contacted external reviewers, we received 33 clinicians' and one patient's comments. The overall response rate was 77%. To solve the four research questions, we made two strong recommendations, six conditional recommendations, and two qualifying statements. Although the intended users of this guideline focused on clinicians in the Asia-Pacific region, the eligible evidence was based on recent English publications. We believe that the recommendations and the clinical thresholds set up in the guideline can be references for clinicians who take care of patients with type 2 diabetes worldwide.
Topics: Humans; Adult; Diabetes Mellitus, Type 2; Insulin Glargine; Insulin; Insulin, Long-Acting; Asia
PubMed: 37088916
DOI: 10.1111/1753-0407.13392 -
Journal of Diabetes Investigation Sep 2023Glucagon is secreted from pancreatic α-cells and plays an important role in amino acid metabolism in liver. Various animal models deficient in glucagon action show...
AIMS/INTRODUCTION
Glucagon is secreted from pancreatic α-cells and plays an important role in amino acid metabolism in liver. Various animal models deficient in glucagon action show hyper-amino acidemia and α-cell hyperplasia, indicating that glucagon contributes to feedback regulation between the liver and the α-cells. In addition, both insulin and various amino acids, including branched-chain amino acids and alanine, participate in protein synthesis in skeletal muscle. However, the effect of hyperaminoacidemia on skeletal muscle has not been investigated. In the present study, we examined the effect of blockade of glucagon action on skeletal muscle using mice deficient in proglucagon-derived peptides (GCGKO mice).
MATERIALS AND METHODS
Muscles isolated from GCGKO and control mice were analyzed for their morphology, gene expression and metabolites.
RESULTS
GCGKO mice showed muscle fiber hypertrophy, and a decreased ratio of type IIA and an increased ratio of type IIB fibers in the tibialis anterior. The expression levels of myosin heavy chain (Myh) 7, 2, 1 and myoglobin messenger ribonucleic acid were significantly lower in GCGKO mice than those in control mice in the tibialis anterior. GCGKO mice showed a significantly higher concentration of arginine, asparagine, serine and threonine in the quadriceps femoris muscles, and also alanine, aspartic acid, cysteine, glutamine, glycine and lysine, as well as four amino acids in gastrocnemius muscles.
CONCLUSIONS
These results show that hyperaminoacidemia induced by blockade of glucagon action in mice increases skeletal muscle weight and stimulates slow-to-fast transition in type II fibers of skeletal muscle, mimicking the phenotype of a high-protein diet.
Topics: Animals; Mice; Amino Acids; Glucagon; Muscle, Skeletal; Proglucagon
PubMed: 37300240
DOI: 10.1111/jdi.14032 -
International Journal of Molecular... Aug 2023The aryl hydrocarbon receptor (AHR) is a transcription factor that is commonly upregulated in pancreatic ductal adenocarcinoma (PDAC). AHR hinders the shuttling of human...
The aryl hydrocarbon receptor (AHR) is a transcription factor that is commonly upregulated in pancreatic ductal adenocarcinoma (PDAC). AHR hinders the shuttling of human antigen R (ELAVL1) from the nucleus to the cytoplasm, where it stabilises its target messenger RNAs (mRNAs) and enhances protein expression. Among these target mRNAs are those induced by gemcitabine. Increased AHR expression leads to the sequestration of ELAVL1 in the nucleus, resulting in chemoresistance. This study aimed to investigate the interaction between AHR and ELAVL1 in the pathogenesis of PDAC in vitro. and genes were silenced by siRNA transfection. The RNA and protein were extracted for quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) analysis. Direct binding between the ELAVL1 protein and mRNA was examined through immunoprecipitation (IP) assay. Cell viability, clonogenicity, and migration assays were performed. Our study revealed that both AHR and ELAVL1 inter-regulate each other, while also having a role in cell proliferation, migration, and chemoresistance in PDAC cell lines. Notably, both proteins function through distinct mechanisms. The silencing of ELAVL1 disrupts the stability of its target mRNAs, resulting in the decreased expression of numerous cytoprotective proteins. In contrast, the silencing of diminishes cell migration and proliferation and enhances cell sensitivity to gemcitabine through the AHR-ELAVL1-deoxycytidine kinase (DCK) molecular pathway. In conclusion, AHR and ELAVL1 interaction can form a negative feedback loop. By inhibiting AHR expression, PDAC cells become more susceptible to gemcitabine through the ELAVL1-DCK pathway.
Topics: Humans; Carcinoma, Pancreatic Ductal; ELAV-Like Protein 1; Gemcitabine; Pancreas; Pancreatic Hormones; Pancreatic Neoplasms; Receptors, Aryl Hydrocarbon; RNA, Messenger; Deoxycytidine Kinase
PubMed: 37685961
DOI: 10.3390/ijms241713155