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The Journal of Endocrinology Sep 2023The year 2023 marks 100 years since publication of the first report of a hyperglycemic factor in pancreatic extracts which C P Kimball and John R Murlin named glucagon...
The year 2023 marks 100 years since publication of the first report of a hyperglycemic factor in pancreatic extracts which C P Kimball and John R Murlin named glucagon (from GLUCose AGONist). Glucagon has a range of profound effects on metabolism including, but not limited to, stimulation of hepatic glucose production. Dysregulation of glucagon secretion is a key feature of both major forms of diabetes, leading to the concept that diabetes is a bihormonal disorder. Still, the work to fully understand the production and biological effects of glucagon has proceeded at a slower pace compared to that of insulin. A recent resurgence of interest in the islet alpha (α) cell, the predominant site of glucagon production, has been facilitated in part by technological innovations. This work has led to significant developments in the field, from defining how alpha cells develop and how glucagon secretion from pancreatic alpha cells is regulated to determining the role of glucagon in metabolic homeostasis and the progression of both major forms of diabetes. In addition, glucagon is considered to be a promising target for diabetes therapy, with many new potential applications arising from research in this field. This collection of reviews, led by Guest Editors James Cantley, Vincent Poitout and Rebecca Hull-Meichle, is intended to capture the field's current understanding of glucagon and alpha cell biology, as well stimulate additional interest and research on this important hormone.
Topics: Glucagon; Anniversaries and Special Events; Insulin; Glucose; Glucagon-Secreting Cells
PubMed: 37194667
DOI: 10.1530/JOE-23-0138 -
Annals of Surgery Nov 2023The objective of this study was to describe the pattern of recurrence, treatments received, as well the oncological outcomes, of pancreatic neuroendocrine tumors...
OBJECTIVE
The objective of this study was to describe the pattern of recurrence, treatments received, as well the oncological outcomes, of pancreatic neuroendocrine tumors (PanNETs) following curative surgery.
BACKGROUND
PanNETs recur in 10% to 15% of cases following surgery. Information on the natural history and management of recurring disease is lacking.
MATERIALS AND METHODS
Patients with PanNET that underwent curative surgery at 4 institutions between 2000 and 2019 were identified. Patients with poorly differentiated tumors, unknown tumor grade and differentiation, hereditary syndromes, unknown margin or R2 status, metastatic, and those that had neoadjuvant treatment or perioperative mortality were excluded. Clinical variables were assessed including first site of recurrence, treatment received, and survival outcomes.
RESULTS
A total of 1402 patients were included: 957 (74%) had grade 1, 322 (25%) had grade 2, and 13 (1%) had grade 3 tumors. Median follow-up was 4.8 years (interquartile range: 2-8.2 years). Cumulative incidence of recurrence at 5 years was 13% (95% CI: 11%-15.2%) for distant disease, 1.4% (95% CI: 0.8%-2.3%) for locoregional recurrence, and 0.8% (95% CI: 0.4%-1.5%) for abdominal nodal recurrence. Patients who recurred had 2.89 increased risk of death (95% CI: 2-4.1) as compared with patients who did not recur. Therapy postrecurrence included: somatostatin analogs in 111 (61.0%), targeted therapies in 48 (26.4%), liver-directed therapies in 61 (33.5%), peptide receptor radionuclide therapy in 30 (16.5%), and surgery in 46 (25.3%) patients. Multiple treatments were used in 103 (57%) cases. After the first recurrence, 5-year overall survival was 74.6% (95% CI: 67.4%-82.5%).
CONCLUSIONS
Recurrence following surgery is infrequent but reduces survival. Most recurrences are distant and managed with multiple therapies. Prospective studies are needed to establish strategies for surveillance and the sequence of treatment to control the disease and prolong survival.
Topics: Humans; Neuroendocrine Tumors; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Somatostatin; Neoadjuvant Therapy; Retrospective Studies
PubMed: 37796750
DOI: 10.1097/SLA.0000000000005809 -
Science Advances Sep 2023Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is...
Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and forming cross-β fibers. Fibrillation complicates insulin storage and therapeutic application. Molecular details of insulin fibrillation remain unclear, hindering efforts to prevent fibrillation process. Here, we characterized insulin fibrils using cryo-electron microscopy (cryo-EM), showing multiple forms that contain one or more of the protofilaments containing both the A and B chains of insulin linked by disulfide bonds. We solved the cryo-EM structure of one of the fibril forms composed of two protofilaments at 3.2-Å resolution, which reveals both the β sheet conformation of the protofilament and the packing interaction between them that underlie the fibrillation. On the basis of this structure, we designed several insulin mutants that display reduced fibrillation while maintaining native IR signaling activity. These designed insulin analogs may be developed into more effective therapeutics for type 1 diabetes.
Topics: Humans; Cryoelectron Microscopy; Diabetes Mellitus, Type 1; Insulin; Protein Aggregates
PubMed: 37713485
DOI: 10.1126/sciadv.adi1057 -
Revue de L'infirmiere Jan 2024
Topics: Humans; Insulins
PubMed: 38242627
DOI: 10.1016/j.revinf.2023.11.019 -
JAMA Network Open Oct 2023Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends....
IMPORTANCE
Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends. Cessation of metformin therapy in people with diabetes typically occurs due to signs of kidney dysfunction but sometimes is due to less serious adverse effects associated with metformin.
OBJECTIVE
To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study was conducted at Kaiser Permanente Northern California, a large integrated health care delivery system, among a cohort of metformin users born prior to 1955 without history of diagnosed kidney disease at metformin initiation. Dementia follow-up began with the implementation of electronic health records in 1996 and continued to 2020. Data were analyzed from November 2021 through September 2023.
EXPOSURES
A total of 12 220 early terminators, individuals who stopped metformin with normal estimated glomerular filtration rate (eGFR), were compared with routine metformin users, who had not yet terminated metformin treatment or had terminated (with or without restarting) after their first abnormal eGFR measurement. Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration.
MAIN OUTCOMES AND MEASURES
The outcome of interest was all-cause incident dementia. Follow-up for early terminators and their matched routine users was started at age of termination for the early terminator. Survival models adjusted for sociodemographic characteristics and comorbidities at the time of metformin termination (or matched age). Mediation models with HbA1c level and insulin usage 1 and 5 years after termination tested whether changes in blood glucose or insulin usage explained associations between early termination of metformin and dementia incidence.
RESULTS
The final analytic sample consisted of 12 220 early terminators (5640 women [46.2%]; mean [SD] age at start of first metformin prescription, 59.4 [9.0] years) and 29 126 routine users (13 582 women [46.6%]; mean [SD] age at start of first metformin prescription, 61.1 [8.9] years). Early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users (hazard ratio, 1.21; 95% CI, 1.12 to 1.30). In mediation analysis, contributions to this association by changes in HbA1c level or insulin use ranged from no contribution (0.00 years; 95% CI, -0.02 to 0.02 years) for insulin use at 5 years after termination to 0.07 years (95% CI, 0.02 to 0.13 years) for HbA1c level at 1 year after termination, suggesting that the association was largely independent of changes in HbA1c level and insulin usage.
CONCLUSIONS AND RELEVANCE
In this study, terminating metformin treatment was associated with increased dementia incidence. This finding may have important implications for clinical treatment of adults with diabetes and provides additional evidence that metformin is associated with reduced dementia risk.
Topics: Adult; Humans; Female; Child; Cohort Studies; Glycated Hemoglobin; Incidence; Insulin; Insulin, Regular, Human; Death; Diabetes Mellitus; Dementia
PubMed: 37878309
DOI: 10.1001/jamanetworkopen.2023.39723 -
Frontiers in Endocrinology 2023Fatty acids and glucose are key biomolecules that share several commonalities including serving as energy substrates and as signaling molecules. Fatty acids can be... (Review)
Review
Fatty acids and glucose are key biomolecules that share several commonalities including serving as energy substrates and as signaling molecules. Fatty acids can be synthesized endogenously from intermediates of glucose catabolism via de-novo lipogenesis. Bile acids are synthesized endogenously in the liver from the biologically important lipid molecule, cholesterol. Evidence abounds that fatty acids and bile acids play direct and indirect roles in systemic glucose homeostasis. The tight control of plasma glucose levels during postprandial and fasted states is principally mediated by two pancreatic hormones, insulin and glucagon. Here, we summarize experimental studies on the endocrine effects of fatty acids and bile acids, with emphasis on their ability to regulate the release of key hormones that regulate glucose metabolism. We categorize the heterogenous family of fatty acids into short chain fatty acids (SCFAs), unsaturated, and saturated fatty acids, and highlight that along with bile acids, these biomolecules regulate glucose homeostasis by serving as endogenous ligands for specific G-protein coupled receptors (GPCRs). Activation of these GPCRs affects the release of incretin hormones by enteroendocrine cells and/or the secretion of insulin, glucagon, and somatostatin by pancreatic islets, all of which regulate systemic glucose homeostasis. We deduce that signaling induced by fatty acids and bile acids is necessary to maintain euglycemia to prevent metabolic diseases such as type-2 diabetes and related metabolic disorders.
Topics: Fatty Acids; Glucagon; Bile Acids and Salts; Receptors, G-Protein-Coupled; Insulin; Glucose; Homeostasis
PubMed: 37484954
DOI: 10.3389/fendo.2023.1206063 -
Metabolism: Clinical and Experimental Sep 2023Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between...
BACKGROUND AND AIMS
Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between hyperinsulinemia/insulin resistance (IR) and low-grade inflammation is well documented in the development of diabetes. However, the cross-talk of hyperglucagonemia with low-grade inflammation during diabetes progression is poorly understood. In this study, we investigated the regulatory role of proinflammatory cytokine interleukin-6 (IL-6) on glucagon secretion.
METHODS
The correlations between inflammatory cytokines and glucagon or insulin were analyzed in rhesus monkeys and humans. IL-6 signaling was blocked by IL-6 receptor-neutralizing antibody tocilizumab in obese or T2D rhesus monkeys, glucose tolerance was evaluated by intravenous glucose tolerance test (IVGTT). Glucagon and insulin secretion were measured in isolated islets from wild-type mouse, primary pancreatic α-cells and non-α-cells sorted from GluCre-ROSA26EYFP (GYY) mice, in which the enhanced yellow fluorescent protein (EYFP) was expressed under the proglucagon promoter, by fluorescence-activated cell sorting (FACS). Particularly, glucagon secretion in α-TC1 cells treated with IL-6 was measured, and RNA sequencing was used to screen the mediator underlying IL-6-induced glucagon secretion. SLC39A5 was knocking-down or overexpressed in α-TC1 cells to determine its impact in glucagon secretion and cytosolic zinc density. Dual luciferase and chromatin Immunoprecipitation were applied to analyze the signal transducer and activator of transcription 3 (STAT3) in the regulation of SLC39A5 transcription.
RESULTS
Plasma IL-6 correlate positively with plasma glucagon levels, but not insulin, in rhesus monkeys and humans. Tocilizumab treatment reduced plasma glucagon, blood glucose and HbA1c in spontaneously obese or T2D rhesus monkeys. Tocilizumab treatment also decreased glucagon levels during IVGTT, and improved glucose tolerance. Moreover, IL-6 significantly increased glucagon secretion in isolated islets, primary pancreatic α-cells and α-TC1 cells. Mechanistically, we found that IL-6-activated STAT3 downregulated the zinc transporter SLC39A5, which in turn reduced cytosolic zinc concentration and ATP-sensitive potassium channel activity and augmented glucagon secretion.
CONCLUSIONS
This study demonstrates that IL-6 increases glucagon secretion via the downregulation of zinc transporter SLC39A5. This result revealed the molecular mechanism underlying the pathogenesis of hyperglucagonemia and a previously unidentified function of IL-6 in the pathophysiology of T2D, providing a potential new therapeutic strategy of targeting IL-6/glucagon to preventing or treating T2D.
Topics: Humans; Mice; Animals; Glucagon; Interleukin-6; Diabetes Mellitus, Type 2; Macaca mulatta; Insulin; Blood Glucose; Insulin Resistance; Glucagon-Secreting Cells; Obesity; Inflammation; Glucose; Cation Transport Proteins
PubMed: 37380017
DOI: 10.1016/j.metabol.2023.155641 -
Reviews in Endocrine & Metabolic... Dec 2023Knowledge of ectopic insulinomas comes from single cases. We performed a systematic review through PubMed, Web of Science, Embase, eLibrary and ScienceDirect of all...
Knowledge of ectopic insulinomas comes from single cases. We performed a systematic review through PubMed, Web of Science, Embase, eLibrary and ScienceDirect of all cases reported in the last four decades. We also describe one unreported patient. From 28 patients with ectopic insulinoma, 78.6% were female and mean age was 55.7 ± 19.2 years. Hypoglycaemia was the first symptom in 85.7% while 14.3% complained of abdominal pain or genital symptoms. Median tumour diameter was 27.5 [15-52.5] mm and it was localised by CT (73.1%), MRI (88.9%), [Ga]Ga-DOTA-exedin-4 PET/CT (100%), Ga-labelled-DOTA-conjugated somatostatin analogue PET/TC (100%), somatostatin receptor scintigraphy (40%) and endoscopic ultrasound (50%). Ectopic insulinomas were located at duodenum (n = 3), jejunum (n = 2), and one respectively at stomach, liver, appendix, rectum, mesentery, ligament of Treitz, gastrosplenic ligament, hepatoduodenal ligament and splenic hilum. Seven insulinomas were affecting the female reproductive organs: ovary (n = 5), cervix (n = 2) and remaining tumours were at retroperitoneum (n = 3), kidney (n = 2), spleen (n = 1) and pelvis (n = 1). 89.3% underwent surgery (66.7% surgery vs. 33.3% laparoscopy) and 16% underwent an ineffective pancreatectomy. 85.7% had localized disease at diagnosis and 14.3% developed distant metastasis. Median follow-up time was 14.5 [4.5-35.5] months and mortality was reported in 28.6% with median time until death of 60 [5-144] months. In conclusion, ectopic insulinomas are presented as hypoglycaemia with female preponderance. Functional imaging [Ga]Ga-DOTA-exedin-4 PET/CT and Ga-labelled-DOTA-conjugated somatostatin analogue PET/TC have very high sensitivity. Clinicians should be alert to the possibility of extra-pancreatic insulinomas when classic diagnostic tests and intraoperative pancreas exploration failed to locate the tumour.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Gallium Radioisotopes; Hypoglycemia; Insulinoma; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography; Somatostatin
PubMed: 37434098
DOI: 10.1007/s11154-023-09824-2 -
Radiologie (Heidelberg, Germany) Dec 2023Neuroendocrine tumors (NET) of the pancreas fall into the group of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). The assignment of imaging morphological... (Review)
Review
CLINICAL/METHODOLOGICAL ISSUE
Neuroendocrine tumors (NET) of the pancreas fall into the group of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). The assignment of imaging morphological criteria to this heterogeneous group of complex tumors is often difficult.
STANDARD RADIOLOGICAL METHODS
Diagnostic ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography-CT (PET/CT) are available for the detection of pancreatic NET (also referred to as NEN) and for the diagnosis of spread and the search for metastases.
METHODOLOGICAL INNOVATIONS
In particular, nuclear medicine examination methods with somatostatin analogues are of high value, since they make tumors visible with high sensitivity via radioactively labeled receptor ligands.
PERFORMANCE
CT and MRI have high detection rates of pancreatic NET. Further developments, such as diffusion imaging, have further improved these traditional cross-sectional imaging diagnostics. However, nuclear medicine methods are an important component in detection and are superior to CT and MRI.
ACHIEVEMENTS
It is important for the radiologist to be familiar with NET of the pancreas, as it is an important differential diagnosis-also with regard to prognosis-of other pancreatic lesions.
PRACTICAL RECOMMENDATIONS
Because NET are often hypervascularized, a biphasic examination technique after contrast administration is mandatory for cross-sectional imaging. PET/CT with somatostatin analogues should be performed for further diagnosis.
Topics: Humans; Positron Emission Tomography Computed Tomography; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreas; Tomography, X-Ray Computed; Somatostatin
PubMed: 37947864
DOI: 10.1007/s00117-023-01231-7 -
Diabetologia Jan 2024We hypothesised that islet beta cell antigen presentation in the gut along with a tolerising cytokine would lead to antigen-specific tolerance in type 1 diabetes. We... (Randomized Controlled Trial)
Randomized Controlled Trial
A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab.
AIMS/HYPOTHESIS
We hypothesised that islet beta cell antigen presentation in the gut along with a tolerising cytokine would lead to antigen-specific tolerance in type 1 diabetes. We evaluated this in a parallel open-label Phase 1b study using oral AG019, food-grade Lactococcus lactis bacteria genetically modified to express human proinsulin and human IL-10, as a monotherapy and in a parallel, randomised, double-blind Phase 2a study using AG019 in combination with teplizumab.
METHODS
Adults (18-42 years) and adolescents (12-17 years) with type 1 diabetes diagnosed within 150 days were enrolled, with documented evidence of at least one autoantibody and a stimulated peak C-peptide level >0.2 nmol/l. Participants were allocated to interventions using interactive response technology. We treated 42 people aged 12-42 years with recent-onset type 1 diabetes, 24 with Phase 1b monotherapy (open-label) and 18 with Phase 2a combination therapy. In the Phase 2a study, after treatment of the first two open-label participants, all people involved were blinded to group assignment, except for the Data Safety Monitoring Board members and the unblinded statistician. The primary endpoint was safety and tolerability based on the incidence of treatment-emergent adverse events, collected up to 6 months post treatment initiation. The secondary endpoints were pharmacokinetics, based on AG019 detection in blood and faeces, and pharmacodynamic activity. Metabolic and immune endpoints included stimulated C-peptide levels during a mixed meal tolerance test, HbA levels, insulin use, and antigen-specific CD4 and CD8 T cell responses using an activation-induced marker assay and pooled tetramers, respectively.
RESULTS
Data from 24 Phase 1b participants and 18 Phase 2a participants were analysed. No serious adverse events were reported and none of the participants discontinued AG019 due to treatment-emergent adverse events. No systemic exposure to AG019 bacteria, proinsulin or human IL-10 was demonstrated. In AG019 monotherapy-treated adults, metabolic variables were stabilised up to 6 months (C-peptide, insulin use) or 12 months (HbA) post treatment initiation. In participants treated with AG019/teplizumab combination therapy, all measured metabolic variables stabilised or improved up to 12 months and CD8 T cells with a partially exhausted phenotype were significantly increased at 6 months. Circulating preproinsulin-specific CD4 and CD8 T cells were detected before and after treatment, with a reduction in the frequency of preproinsulin-specific CD8 T cells after treatment with monotherapy or combination therapy.
CONCLUSIONS/INTERPRETATION
Oral delivery of AG019 was well tolerated and safe as monotherapy and in combination with teplizumab. AG019 was not shown to interfere with the safety profile of teplizumab and may have additional biological effects, including changes in preproinsulin-specific T cells. These preliminary data support continuing studies with this agent alone and in combination with teplizumab or other systemic immunotherapies in type 1 diabetes.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03751007, EudraCT 2017-002871-24 FUNDING: This study was funded by Precigen ActoBio.
Topics: Adult; Adolescent; Humans; Diabetes Mellitus, Type 1; Interleukin-10; C-Peptide; CD8-Positive T-Lymphocytes; Proinsulin; Double-Blind Method
PubMed: 37782353
DOI: 10.1007/s00125-023-06014-2