-
Physiological Reports Jun 2024Pancreatic β-cell mass is a critical determinant of insulin secretion. Severe endoplasmic reticulum (ER) stress causes β-cell apoptosis; however, the mechanisms of...
Pancreatic β-cell mass is a critical determinant of insulin secretion. Severe endoplasmic reticulum (ER) stress causes β-cell apoptosis; however, the mechanisms of progression and suppression are not yet fully understood. Here, we report that the autocrine/paracrine function of insulin reduces ER stress-induced β-cell apoptosis. Insulin reduced the ER-stress inducer tunicamycin- and thapsigargin-induced cell viability loss due to apoptosis in INS-1 β-cells. Moreover, the effect of insulin was greater than that of insulin-like growth factor-1 at physiologically relevant concentrations. Insulin did not attenuate the ER stress-induced increase in unfolded protein response genes. ER stress did not induce cytochrome c release from mitochondria. Mitochondrial hyperpolarization was induced by ER stress and prevented by insulin. The protonophore/mitochondrial oxidative phosphorylation uncoupler, but not the antioxidants N-acetylcysteine and α-tocopherol, exhibited potential cytoprotection during ER stress. Both procaspase-12 and cleaved caspase-12 levels increased under ER stress. The caspase-12 inhibitor Z-ATAD-FMK decreased ER stress-induced apoptosis. Caspase-12 overexpression reduced cell viability, which was diminished in the presence of insulin. Insulin decreased caspase-12 levels at the post-translational stages. These results demonstrate that insulin protects against ER stress-induced β-cell apoptosis in this cell line. Furthermore, mitochondrial hyperpolarization and increased caspase-12 levels are involved in ER stress-induced and insulin-suppressed β-cell apoptosis.
Topics: Insulin-Secreting Cells; Apoptosis; Endoplasmic Reticulum Stress; Animals; Insulin; Caspase 12; Rats; Mitochondria; Membrane Potential, Mitochondrial; Cell Survival
PubMed: 38884322
DOI: 10.14814/phy2.16106 -
BioMed Research International 2024PPIs, or proton pump inhibitors, are the most widely prescribed drugs. There is a debate regarding the relationship between long-term PPI use and the risk of type 2...
INTRODUCTION
PPIs, or proton pump inhibitors, are the most widely prescribed drugs. There is a debate regarding the relationship between long-term PPI use and the risk of type 2 diabetes mellitus (T2DM). A potential connection between T2DM and PPIs could be an elevated gastrin concentration. This study is aimed at investigating the long-term effects of PPI omeprazole (OZ) on glucose homeostasis and pancreatic gene expression profile in mice.
METHODS
Healthy adult male BALB/c mice were randomly divided into three equal groups ( = 10 in each one): (1) experimental mice that received OZ 20 mg/kg; (2) control mice that received 30 l saline per os; (3) intact mice without any interventions. Mice were treated for 30 weeks. Glucose homeostasis was investigated by fasting blood glucose level, oral glucose tolerance test (GTT), insulin tolerance test (ITT), and basal insulin resistance (HOMA-IR). Serum gastrin and insulin concentration were determined by ELISA. Expressions of , , , , , , , and were measured by RT-PCR.
RESULT
The ROC analysis revealed an increase in fasting blood glucose levels in OZ-treated mice in comparison with control and intact groups during the 30-week experiment. A slight but statistically significant increase in glucose tolerance and insulin sensitivity was observed in OZ-treated mice within 30 weeks of the experiment. The mice treated with OZ exhibited significant increases in serum insulin and gastrin levels, accompanied by a rise in the HOMA-IR level. These animals had a statistically significant increase in , , and mRNA expression. There were no differences in -cell numbers between groups.
CONCLUSION
Long-term OZ treatment induced hypergastrin- and hyperinsulinemia and increased expression of , , and in mouse pancreatic tissues accompanied by specific changes in glucose metabolism. The mechanism of omeprazole-induced mRNA expression and its association with pancreatic cancer risk should be investigated.
Topics: Animals; Omeprazole; Gastrins; Male; Mice; Homeostasis; Mice, Inbred BALB C; Blood Glucose; Insulin Resistance; Insulin; Gene Expression Regulation; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Proton Pump Inhibitors; Glucose
PubMed: 38884019
DOI: 10.1155/2024/7747599 -
Frontiers in Endocrinology 2024Pancreatic islets are important in nutrient homeostasis and improved cellular models of clonal origin may very useful especially in view of relatively scarce primary...
BACKGROUND
Pancreatic islets are important in nutrient homeostasis and improved cellular models of clonal origin may very useful especially in view of relatively scarce primary material. Close 3D contact and coupling between β-cells are a hallmark of physiological function improving signal/noise ratios. Extracellular electrophysiology using micro-electrode arrays (MEA) is technically far more accessible than single cell patch clamp, enables dynamic monitoring of electrical activity in 3D organoids and recorded multicellular slow potentials (SP) provide unbiased insight in cell-cell coupling.
OBJECTIVE
We have therefore asked whether 3D spheroids enhance clonal β-cell function such as electrical activity and hormone secretion using human EndoC-βH1, EndoC-βH5 and rodent INS-1 832/13 cells.
METHODS
Spheroids were formed either by hanging drop or proprietary devices. Extracellular electrophysiology was conducted using multi-electrode arrays with appropriate signal extraction and hormone secretion measured by ELISA.
RESULTS
EndoC-βH1 spheroids exhibited increased signals in terms of SP frequency and especially amplitude as compared to monolayers and even single cell action potentials (AP) were quantifiable. Enhanced electrical signature in spheroids was accompanied by an increase in the glucose stimulated insulin secretion index. EndoC-βH5 monolayers and spheroids gave electrophysiological profiles similar to EndoC-βH1, except for a higher electrical activity at 3 mM glucose, and exhibited moreover a biphasic profile. Again, physiological concentrations of GLP-1 increased AP frequency. Spheroids also exhibited a higher secretion index. INS-1 cells did not form stable spheroids, but overexpression of connexin 36, required for cell-cell coupling, increased glucose responsiveness, dampened basal activity and consequently augmented the stimulation index.
CONCLUSION
In conclusion, spheroid formation enhances physiological function of the human clonal β-cell lines and these models may provide surrogates for primary islets in extracellular electrophysiology.
Topics: Humans; Insulin-Secreting Cells; Spheroids, Cellular; Electrophysiological Phenomena; Insulin Secretion; Glucose; Insulin; Action Potentials; Animals
PubMed: 38883608
DOI: 10.3389/fendo.2024.1402880 -
PloS One 2024The nerve growth factor (NGF) participates in cell survival and glucose-stimulated insulin secretion (GSIS) processes in rat adult beta cells. GSIS is a complex process...
The nerve growth factor (NGF) participates in cell survival and glucose-stimulated insulin secretion (GSIS) processes in rat adult beta cells. GSIS is a complex process in which metabolic events and ionic channel activity are finely coupled. GLUT2 and glucokinase (GK) play central roles in GSIS by regulating the rate of the glycolytic pathway. The biphasic release of insulin upon glucose stimulation characterizes mature adult beta cells. On the other hand, beta cells obtained from neonatal, suckling, and weaning rats are considered immature because they secrete low levels of insulin and do not increase insulin secretion in response to high glucose. The weaning of rats (at postnatal day 20 in laboratory conditions) involves a dietary transition from maternal milk to standard chow. It is characterized by increased basal plasma glucose levels and insulin levels, which we consider physiological insulin resistance. On the other hand, we have observed that incubating rat beta cells with NGF increases GSIS by increasing calcium currents in neonatal cells. In this work, we studied the effects of NGF on the regulation of cellular distribution and activity of GLUT2 and GK to explore its potential role in the maturation of GSIS in beta cells from P20 rats. Pancreatic islet cells from both adult and P20 rats were isolated and incubated with 5.6 mM or 15.6 mM glucose with and without NGF for 4 hours. Specific immunofluorescence assays were conducted following the incubation period to detect insulin and GLUT2. Additionally, we measured glucose uptake, glucokinase activity, and insulin secretion assays at 5.6 mM or 15.6 mM glucose concentrations. We observed an age-dependent variation in the distribution of GLUT2 in pancreatic beta cells and found that glucose plays a regulatory role in GLUT2 distribution independently of age. Moreover, NGF increases GLUT2 abundance, glucose uptake, and GSIS in P20 beta cells and GK activity in adult beta cells. Our results suggest that besides increasing calcium currents, NGF regulates metabolic components of the GSIS, thereby contributing to the maturation process of pancreatic beta cells.
Topics: Animals; Male; Rats; Cells, Cultured; Glucokinase; Glucose; Glucose Transporter Type 2; Insulin; Insulin Secretion; Insulin-Secreting Cells; Nerve Growth Factor; Rats, Wistar
PubMed: 38875221
DOI: 10.1371/journal.pone.0303934 -
Health and Quality of Life Outcomes Jun 2024Compared with multiple daily insulin injections (MDI), continuous subcutaneous insulin infusion (CSII) is significantly more expensive and has not been widely used in... (Comparative Study)
Comparative Study
BACKGROUND
Compared with multiple daily insulin injections (MDI), continuous subcutaneous insulin infusion (CSII) is significantly more expensive and has not been widely used in Chinese type 1 diabetes mellitus (T1DM) patients. So there are still significant knowledge gaps regarding clinical and patient-reported outcomes in China.
AIMS
This study aims to compare the glycated hemoglobin (HbA), insulin therapy related quality of life (ITR-QOL), fear of hypoglycemia (FOH) of adult T1DM patients treated with MDI and CSII based on propensity score matching in real-world conditions in China.
METHODS
Four hundred twenty adult T1DM patients who were treated with MDI or CSII continuously for more than 12 months in a national metabolic center from June 2021 to June 2023 were selected as the study subjects. Their QOL and FOH were evaluated with Insulin Therapy Related Quality of Life Measure Questionnaire-Chinese version (ITR-QOL-CV) and the Chinese Version Hypoglycemia Fear Survey-Worry Scale (CHFSII-WS), and their HbA were collected at the same time. Potential confounding variables between the two groups were matched using propensity score matching.
RESULTS
Of the 420 patients included in the study, 315 were in MDI group and 105 were in CSII group. 102 pairs were successfully matched. After matching, the total score of ITR-QOL-CV scale in CSII group was significantly higher than that in MDI group (87.08 ± 13.53 vs. 80.66 ± 19.25, P = 0.006). Among them, the dimensions of daily life, social life, and psychological state were all statistically different (P < 0.05). The scores of CHFSII-WS (8.33 ± 3.49 vs. 11.77 ± 5.27, P = 0.003) and HbA (7.19 ± 1.33% vs. 7.71 ± 1.93%, P = 0.045) in CSII group were lower than those in MDI group.
CONCLUSIONS
25.0% of T1DM adults are treated with CSII. Compared with adult T1DM patients treated with MDI, those treated with CSII have higher ITR-QOL, less FoH, and better control of HbA in real-world conditions in China. Therefore, regardless of economic factors, CSII is recommended for adult T1DM patients to optimize the therapeutic effect and outcomes.
Topics: Humans; Diabetes Mellitus, Type 1; Male; Female; Propensity Score; China; Adult; Quality of Life; Insulin; Glycated Hemoglobin; Insulin Infusion Systems; Middle Aged; Hypoglycemic Agents; Hypoglycemia; Surveys and Questionnaires
PubMed: 38872219
DOI: 10.1186/s12955-024-02263-w -
Scientific Reports Jun 2024Transplantation of stem cell-derived β-cells is a promising therapeutic advancement in the treatment of type 1 diabetes mellitus. A current limitation of this approach...
Transplantation of stem cell-derived β-cells is a promising therapeutic advancement in the treatment of type 1 diabetes mellitus. A current limitation of this approach is the long differentiation timeline that generates a heterogeneous population of pancreatic endocrine cells. To address this limitation, an inducible lentiviral overexpression system of mature β-cell markers was introduced into human induced-pluripotent stem cells (hiPSCs). Following the selection of the successfully transduced hiPSCs, the cells were treated with doxycycline in the pancreatic progenitor induction medium to support their transition toward the pancreatic lineage. Cells cultured with doxycycline presented the markers of interest, NGN3, PDX1, and MAFA, after five days of culture, and glucose-stimulated insulin secretion assays demonstrated that the cells were glucose-responsive in a monolayer culture. When cultured as a spheroid, the markers of interest and insulin secretion in a static glucose-stimulated insulin secretion assay were maintained; however, insulin secretion upon consecutive glucose challenges was limited. Comparison to human fetal and adult donor tissues identified that although the hiPSC-derived spheroids present similar markers to adult insulin-producing cells, they are functionally representative of fetal development. Together, these results suggest that with optimization of the temporal expression of these markers, forward programming of hiPSCs towards insulin-producing cells could be a possible alternative for islet transplantation.
Topics: Humans; Insulin-Secreting Cells; Homeodomain Proteins; Trans-Activators; Induced Pluripotent Stem Cells; Basic Helix-Loop-Helix Transcription Factors; Nerve Tissue Proteins; Cell Differentiation; Maf Transcription Factors, Large; Insulin; Glucose; Insulin Secretion; Cells, Cultured; Doxycycline
PubMed: 38871849
DOI: 10.1038/s41598-024-64346-4 -
Cureus May 2024The occurrence of hypoglycemia in patients without diabetes is rare, and non-islet cell tumor hypoglycemia (NICTH) accounts for a small portion of these instances. One...
The occurrence of hypoglycemia in patients without diabetes is rare, and non-islet cell tumor hypoglycemia (NICTH) accounts for a small portion of these instances. One of the infrequent causes is associated with tumor cell production of Insulin-like growth factor (IGF)-2. Here is a case of a 66-year-old man with stage IV colon cancer who presented to the emergency department with breathlessness during chemotherapy (Bevacizumab plus FOLFOX4 regimen). He had undergone partial colectomy and chemotherapy three years prior but was recently diagnosed with metastatic liver disease. A CT scan revealed a 15 cm hepatic mass occupying the entire right hepatic lobe. Despite receiving dextrose infusions, he experienced persistent hypoglycemia after meals and during fasting. Given that he had no history of diabetes and denied using any oral hypoglycemic agents, the Endocrinology service was consulted for further evaluation. Plasma blood glucose (BG) was measured at 74 mg/dL (reference range 74-106) during dextrose administration. An 8 AM cortisol test yielded a result of 8.08 mcg/dL (4.30-22.40), ruling out adrenal insufficiency. A 72-hour fast was initiated but terminated at eight hours due to symptomatic hypoglycemia with a plasma BG of 48 mg/dL. C-peptide and Insulin levels were both low, measuring <0.05 ng/mL (0.48-5.05) and <1.0 mU/L (3.0-25), respectively, while beta-hydroxybutyrate (BHB) levels were normal at 1.1 mg/dL (0.2-2.8). Administration of 1 mg glucagon during the fast increased BG to 112 mg/dL within 2 hours. IGF-1 levels were undetectable (<1.9 nmol/L), while IGF-2 levels were at 23 nmol/L (44-129 nmol/L), resulting in an IGF2:IGF1 ratio of 12 (>10), confirming IGF-2 mediated NICTH. Treatment with dexamethasone 10 mg daily was initiated, maintaining blood glucose levels above 70 mg/dL without dextrose infusion. In approximately 50% of cases of NICTH, the tumor is detected before the onset of hypoglycemia, yet up to half the patients may remain asymptomatic despite having very low BG. Despite having a known hepatic lesion, our patient exhibited minimal symptoms despite severely low BG levels. The mechanisms underlying NICTH may involve tumor secretion of insulin, replacement of hepatic tissue, increased glucose utilization by the tumor, or, most commonly, secretion of IGF-2. In cases of IGF-2-mediated hypoglycemia, insulin, proinsulin, C-peptide, and β-hydroxybutyrate levels are typically low. IGF-2 stimulates the insulin receptors resulting in increased glucose uptake by skeletal muscles and suppression of gluconeogenesis, glycogenolysis, and ketogenesis by the liver. Insulin secretion from pancreatic β-cells is suppressed. IGF-1 levels are usually low, while IGF-2 levels may be high or normal, as many IGF-2omas produce IGF-2 precursors (pro-IGF-2). An elevated IGF-2:IGF-1 ratio (>10) confirms the diagnosis which may be helpful when IGF-2 levels are normal. The primary treatment is through surgical removal or debulking of the tumor. Neoadjuvant therapies such as radiation and chemotherapy may reduce occurrences of hypoglycemia, but only temporarily. Glucocorticoids may be used when the underlying malignancy cannot be treated.
PubMed: 38868260
DOI: 10.7759/cureus.60211 -
Computational and Structural... Dec 2024Investigating the causal relationship between insulin secretion and prostate cancer (PCa) development is challenging due to the multifactorial nature of PCa, which...
Investigating the causal relationship between insulin secretion and prostate cancer (PCa) development is challenging due to the multifactorial nature of PCa, which complicates the isolation of the specific impact of insulin-related factors. We conducted a Mendelian randomization (MR) study to investigate the associations between insulin secretion-related traits and PCa. We used 36, 60, 56, 23, 48, and 49 single nucleotide polymorphisms (SNPs) as instrumental variables for fasting insulin, insulin sensitivity, proinsulin, and proinsulin in nondiabetic individuals, individuals with diabetes, and individuals receiving exogenous insulin, respectively. These SNPs were selected from various genome-wide association studies. To clarify the causal relationship between insulin-related traits and PCa, we utilized a multivariable MR analysis to adjust for obesity and body fat percentage. Additionally, two-step Mendelian randomization was conducted to assess the role of insulin-like growth factor 1 (IGF-1) in the relationship between proinsulin and PCa. Two-sample MR analysis revealed strong associations between genetically predicted fasting insulin, insulin sensitivity, proinsulin, and proinsulin in nondiabetic individuals and the development of PCa. After adjustment for obesity and body fat percentage using multivariable MR analysis, proinsulin remained significantly associated with PCa, whereas other factors were not. Furthermore, two-step MR analysis demonstrated that proinsulin acts as a negative factor in prostate carcinogenesis, largely independent of IGF-1. This study provides evidence suggesting that proinsulin may act as a negative factor contributing to the development of PCa. Novel therapies targeting proinsulin may have potential benefits for PCa patients, potentially reducing the need for unnecessary surgical treatments.
PubMed: 38867724
DOI: 10.1016/j.csbj.2024.05.034 -
Journal of the ASEAN Federation of... 2024Insulinoma is one of the causes of recurrent hypoglycemia, one of the chief complaints for emergency department admission. The gold standard in diagnosing insulinoma is... (Review)
Review
BACKGROUND
Insulinoma is one of the causes of recurrent hypoglycemia, one of the chief complaints for emergency department admission. The gold standard in diagnosing insulinoma is a 72-hour fasting test which is inconvenient and inefficient as it requires hospitalization. Research has found that measurement of insulin and C-peptide during OGTT may help diagnose insulinoma. We aimed to assess the diagnostic value of OGTT in diagnosing insulinoma.
METHODOLOGY
The literature search was conducted on 19 August 2022 using several databases (MEDLINE, Scopus, Embase, and ScienceDirect). All studies that measured OGTT as diagnostic tools in diagnosing insulinoma and 72-hour fasting test as reference standard were included. The quality assessment of the selected studies was based on the Centre of Evidence-Based Medicine University of Oxford and the Quality Assessment of Diagnostic Accuracy-2 tool (QUADAS-2). Analysis of the included studies was performed qualitatively. This study was registered on PROSPERO (CRD42022360205).
RESULTS
A total of two case-control studies (106 patients) were included, which were at risk of bias and low concern of applicability. Both studies demonstrated that the combination of insulin and C-peptide levels measured during OGTT had high specificity, sensitivity, positive predictive value, and negative predictive value in diagnosing insulinoma compared to the reference standard. A logistic regression model of 8.305 - (0.441 × insulin 2-h/0-h) - (1.679 × C-peptide 1-h/0-h) >0.351 has the highest diagnostic value in one study (AUC 0.97, Sensitivity 86.5%, Specificity 95.2%, PPV 94.1, NPV 88.9).
CONCLUSION
The measurement of 0-h and 2-h insulin and C-peptide levels during 2-h OGTT was found in two small case-control studies with a total of 106 patients to have good sensitivity and specificity. However, due to these limitations, future research is still needed to validate the potential use of OGTT for the diagnosis of insulinoma.
Topics: Humans; C-Peptide; Insulinoma; Glucose Tolerance Test; Pancreatic Neoplasms; Insulin; Sensitivity and Specificity; Insulin Secretion
PubMed: 38863915
DOI: 10.15605/jafes.039.01.16 -
Journal of the ASEAN Federation of... 2024Hypoglycemic disorders are rare in persons without diabetes, and clinical evaluation to identify its etiology can be challenging. We present a case of insulin autoimmune...
Hypoglycemic disorders are rare in persons without diabetes, and clinical evaluation to identify its etiology can be challenging. We present a case of insulin autoimmune syndrome induced by carbimazole in a middle-aged Chinese man with underlying Graves' disease, which was managed conservatively with a combination of dietary modification and alpha-glucosidase inhibitor.
Topics: Humans; Male; Autoimmune Diseases; Graves Disease; Carbimazole; Antithyroid Agents; Middle Aged; Insulin; Insulin Antibodies; Syndrome; Glycoside Hydrolase Inhibitors
PubMed: 38863913
DOI: 10.15605/jafes.039.01.07