Insulin Beta-cell Research Articles

The Effectiveness of Cognitive-Behavioral Rehabilitation Therapy Based on Stress Immunization Training on Metacognitions and Coping Styles in Women with Type 2 Diabetes

Background: Type 2 diabetes is a chronic medical condition characterized by relative insulin imbalance due to pancreatic beta cell dysfunction and insulin resistance in target organs. Objectives: The aim of this study was to evaluate the effectiveness of cognitive-behavioral rehabilitation treatment based on stress immunization training on metacognitions and coping styles in women with type 2 diabetes. Methods: This quasi-experimental study utilized a pretest-posttest design with a control group. The statistical population consisted of women with type 2 diabetes in Sari. A total of 30 women were purposefully selected from patients referred to the office of Dr. Mashayekh Bakhshi, a specialist in endocrinology and metabolism. These participants were randomly assigned to experimental (n = 15) and control (n = 15) groups. Data were collected using the Metacognition questionnaire and the Coping Styles questionnaire. Results: Demographic findings showed that the mean (and standard deviation) age of participants was 32.933 (7.759) in the experimental group and 36.733 (9.254) in the control group. The results indicated that cognitive-behavioral rehabilitation treatment based on stress immunization training significantly improved metacognitions and coping styles in women with type 2 diabetes (P < 0.05). Conclusions: Cognitive-behavioral rehabilitation based on stress immunization training encourages patients with diabetes to reduce negative spontaneous thoughts related to depression and correct their self-talk. This process reduces negative metacognitions, adjusts emotional strategies, and enhances problem-solving strategies in patients with diabetes, ultimately alleviating their challenges.

A Mechanism-Based Comparative Review on Functional Food with Phytomolecules and Marketed Formulation for Type II Diabetes Mellitus

Abstract: Type II diabetes mellitus is a chronic disorder characterized by pancreatic beta cell dysfunction, insulin resistance, and hyperglycemia. Administration of different classes of anti-diabetic drugs over the long term is essential to maintain normoglycemic levels in affected individuals. This study is focused on natural analogs as substitutes for the most marketed synthetic and semi-synthetic anti-diabetic drugs. This study aimed to review phytoconstituents with their mechanism of action, which are comparatively equivalent to that of the allopathic anti-diabetic marketed drugs, like biguanides, sulphonylurea, and thiazolidinediones. The methodology used for the review involved using the keywords collected from online sites, like PubMed, ScienceDirect, and Google Scholar. At present, different drugs are available for the treatment of diabetes and work with different mechanisms, like metformin induces the AMPK pathway in hepatocytes and muscle fibers with increased glucose uptake in peripheral tissues, whereas the phytoconstituents, like quercetin (flavonoid), mahanimbine, and koenidine (carbazole alkaloids) involve same mechanism as metformin. Sulfonylureas drugs bind to specific receptors in hepatocytes, resulting in glucose-independent insulin release. The phytomolecule amyrins (pentacyclic triterpenoid) and kaempferol (flavonoid) have similar effects as that of sulphonylureas. Thiazoglinediones target adipocytes and cause GLUT-4 translocation and up-regulation of PPAR and adiponectin gene expression. Phytoconstituents, like cyanidin-3-glucoside (anthocyanin) and protocatechuic acid (tannin), exhibit a similar mechanism of action to that of thiazolidinediones. In this review, it can be concluded that the selected compounds have the same antidiabetic activity as the synthetic drugs. In the future, a new polyherbal formulation can be developed with these selected molecules having the same mechanisms of action, with significant therapeutic value without side effects.

Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1

AimsA number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance. MethodsWe enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m2) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, n = 19), impaired glucose tolerant (IGT, n = 20) or newly diagnosed diabetes (DM) (n = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters. ResultsExtractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo. ConclusionsOur data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes.

Clinical utility of novel diabetes subgroups in predicting vascular complications and mortality: up to 25 years of follow-up of the HUNT Study

IntroductionCluster analysis has previously revealed five reproducible subgroups of diabetes, differing in risks of diabetic complications. We aimed to examine the clusters’ predictive ability for vascular complications as compared with...

Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab.

We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate. OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8+ T memory cell and programmed death-1 (PD-1) expression were evaluated in each group. Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearancesignificantlydecreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1+ CD8+ T effector memory cells. OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.

Effects of Saccharomyces cerevisiae on Pancreatic Alpha and Beta Cells and Metabolic Profile in Broilers.

To evaluate the impact of Saccharomyces cerevisiae (SC) supplementation on pancreatic islet areas, alpha and beta cell populations, blood glucose levels, and lipid profiles in broilers, broilers were randomly assigned to two groups: a control group (T1) without SC and a treatment group (T2) supplemented with SC. Islet areas, alpha and beta cell counts, serum glucose and insulin levels, and lipid profiles were assessed. SC supplementation significantly decreased blood glucose levels compared to the control group. Additionally, HDL cholesterol levels were elevated in the SC-supplemented group. Although insulin levels remained unchanged, SC supplementation altered the correlation between pancreatic islet areas and alpha and beta cell populations, suggesting a potential influence on pancreatic islet function. Dietary supplementation with Saccharomyces cerevisiae can improve glycemic control and lipid profile in broilers. These findings highlight the potential benefits of using SC as a dietary additive in broiler production.

Long-term safety of photobiomodulation exposure to beta cell line and rat islets in vitro and in vivo

This study evaluates the safety and potential benefits of PBM on pancreatic beta cells and islets. PBM was applied to insulin-secreting cell lines (MIN6) and rat pancreatic islets using a 670 nm light source, continuous output, with a power density of 2.8 mW/cm², from 5 s to several 24 h. Measure of cell viability, insulin secretion, mitochondrial function, ATP content, and cellular respiration were assessed. Additionally, a diabetic rat model is used for islet transplantation (pre-conditioning with PBM or not) experiments. Short and long-term PBM exposure did not affect beta cell islets viability, insulin secretion nor ATP content. While short-term PBM (2 h) increases superoxide ion content, this was not observed for long exposure (24 h). Mitochondrial respirations were slightly decreased after PBM. In the islet transplantation model, both pre-illuminated and non-illuminated islets improved metabolic control in diabetic rats with a safety profile regarding the post-transplantation period. In summary, for the first time, long-term PBM exhibited safety in terms of cell viability, insulin secretion, energetic profiles in vitro, and post-transplantation period in vivo. Further investigation is warranted to explore PBM’s protective effects under conditions of stress, aiding in the development of innovative approaches for cellular therapy.

Interactions of genes with alcohol consumption affect insulin sensitivity and beta cell function.

Alcohol consumption has complex effects on diabetes and metabolic disease, but there is widespread heterogeneity within populations and the specific reasons are unclear. Genetic factors may play a role and warrant exploration. The aim of this study was to elucidate genetic variants modulating the impact of alcohol consumption on insulin sensitivity and pancreatic beta cell function within populations presenting normal glucose tolerance (NGT). We recruited 4194 volunteers in Nanjing, 854 in Jurong and an additional 5833 in Nanjing for Discovery cohorts 1 and 2 and a Validation cohort, respectively. We performed an OGTT on all participants, establishing a stringent NGT group, and then assessed insulin sensitivity and beta cell function. Alcohol consumption was categorised as abstinent, light-to-moderate (<210 g per week) or heavy (≥210 g per week). After excluding ineligible individuals, an exploratory genome-wide association study identified potential variants interacting with alcohol consumption in 1862 NGT individuals. These findings were validated in an additional cohort of 2169 NGT individuals. Cox proportional hazard regression was further employed to evaluate the effect of the interaction between the potential variants and alcohol consumption on the risk of type 2 diabetes within the UK Biobank cohort. A significant correlation was observed between drinking levels and insulin sensitivity, accompanied by a consequent inverse relationship with insulin resistance and beta cell insulin secretion after adjusting for confounding factors in NGT individuals. However, no significant associations were noted in the disposition indexes. The interaction of variant rs56221195 with alcohol intake exhibited a pronounced effect on the liver insulin resistance index (LIRI) in the discovery set, corroborated in the validation set (combined p=1.32 × 10-11). Alcohol consumption did not significantly affect LIRI in rs56221195 wild-type (TT) carriers, but a strong negative association emerged in heterozygous (TA) and homozygous (AA) individuals. The rs56221195 variant also significantly interacts with alcohol consumption, influencing the total insulin secretion index INSR120 (the ratio of the AUC of insulin to glucose from 0 to 120 min) (p=2.06 × 10-9) but not disposition index. In the UK Biobank, we found a significant interaction between rs56221195 and alcohol consumption, which was linked to the risk of type 2 diabetes (HR 0.897, p=0.008). Our findings reveal the effects of the interaction of alcohol and rs56221195 on hepatic insulin sensitivity in NGT individuals. It is imperative to weigh potential benefits and detriments thoughtfully when considering alcohol consumption across diverse genetic backgrounds.

Development of a Diabetes Dietary Quality Index: Reproducibility and Associations with Measures of Insulin Resistance, Beta Cell Function, and Hyperglycemia.

Various dietary risk factors for type 2 diabetes have been identified. A short assessment of dietary patterns related to the risk for type 2 diabetes mellitus may be relevant in clinical practice given the largely preventable nature of the disease. The aim of this study was to investigate the reproducibility of a short food frequency questionnaire based on available knowledge of diabetes-related healthy diets. In addition, we aimed to investigate whether a Diabetes Dietary Quality Index based on this questionnaire was related to metabolic risk factors, including measures of beta cell function and insulin sensitivity. A short food frequency questionnaire was composed by selecting fourteen questions (representing eight dietary factors) from existing food frequency questionnaires on the basis of their reported relationship with diabetes risk. Healthy participants (N = 176) from a Dutch family study completed the questionnaire and a subgroup (N = 123) completed the questionnaire twice. Reproducible items from the short questionnaire were combined into an index. The association between the Diabetes Dietary Quality index and metabolic risk factors was investigated using multiple linear regression analysis. Measures of beta cell function and insulin sensitivity were derived from a mixed meal test and an euglycemic-hyperinsulinemic and modified hyperglycemic clamp test. Our results show that this new short food frequency questionnaire is reliable (Intraclass Correlations ranged between 0.5 and 0.9). A higher Diabetes Dietary Quality index score was associated with lower 2 h post-meal glucose (β -0.02, SE 0.006, p < 0.05), HbA1c (β -0.07, SE 0.02, p < 0.05), total cholesterol, (β -0.02, SE 0.07, p < 0.05), LDL cholesterol, (β -0.19, SE 0.07, p < 0.05), fasting (β -0.4, SE 0.16, p < 0.05) and post-load insulin, (β -3.9, SE 1.40, p < 0.05) concentrations and the incremental AUC of glucose during MMT (β -1.9, SE 0.97, p < 0.05). The scores obtained for the oral glucose insulin sensitivity-derived mixed meal test were higher in subjects who scored higher on the Diabetes Dietary Quality index (β 0.89, 0.39, p < 0.05). In contrast, we found no significant associations between the Diabetes Dietary Quality index and clamp measures of beta cell function. We identified a questionnaire-derived Diabetes Dietary Quality index that was reproducible and inversely associated with a number of type 2 diabetes mellitus and metabolic risk factors, like 2 h post-meal glucose, Hba1c and LDL, and total cholesterol. Once relative validity has been established, the Diabetes Dietary Quality index could be used by health care professionals to identify individuals with diets adversely related to development of type 2 diabetes.

Cadmium-induced pancreatic toxicity in rats: comparing vitamin C and Nigella sativa as protective agents: a histomorphometric and ultrastructural study

The study aimed to assess the toxic effect of cadmium (Cd) on the exocrine and endocrine functions of pancreas, the changes in pancreatic tissue after Cd withdrawal, and the protective effects of vitamin C (VC) and Nigella sativa (NS) against Cd-induced damage. Rats were assigned to: control, Cd-treated (0.5 mg/kg/d intraperitoneal [IP] injection), VC and Cd-treated (receiving 100 mg/kg/d VC orally and Cd concomitantly), NS and Cd-treated (receiving 20 mg/kg/d NS and Cd, simultaneously), and Cd withdrawal (receiving Cd for 30 d then living free for recovery for other 30 d). Blood samples were collected and post-sacrifice pancreatic specimens were processed for light and electron microscope study. Quantitative analyses of pancreatic collagen area%, pancreatic islet parameters, β cell density, and insulin immunoexpression were done. Fasting blood glucose was significantly increased in Cd-treated and Cd-withdrawal groups, while co-treatment with VC and NS caused significant reductions (p < 0.05). Cd-induced extensive degenerative changes in pancreatic acini and islets at light and ultrastructure levels. Obvious fibrosis and congestion of blood vessels were noticed. Significant reductions in pancreatic islet number, volume, and surface area and diminished beta cell count and insulin immunoexpression were observed. After withdrawal of Cd, the whole pancreatic tissue still showed a serious impact. Concomitant treatment with VC or NS obviously reduced these degenerative changes and significantly improved pancreatic islet parameters and insulin immunoexpression. VC showed a better amendment than NS, but this difference was statistically insignificant. Therefore, VC and NS could be used as prophylactic agents that lessen Cd consequences on the pancreas.

Pancreatic beta cell function and insulin resistance profiles in first-degree relatives of patients with prediabetes and type 2 diabetes.

To evaluate insulin secretion and insulin resistance profiles in individuals with family history of prediabetes and type 2 diabetes. This was a cross-sectional study to evaluate clinical and metabolic profiles between individuals with type 2 diabetes, prediabetes and their relatives. There were 911 subjects divided into five groups: (i) normoglycemic (NG), (ii) type 2 diabetes, (iii) prediabetes, (iv) first-degree relatives of patients with type 2 diabetes (famT2D), and (v) first-degree relatives of patients with prediabetes (famPD); anthropometrical, biochemical and nutritional evaluation, as well as insulin resistance and pancreatic beta cell function measurement was performed by oral glucose tolerance to compare between groups. The most prevalent type 2 diabetes risk factors were dyslipidemia (81%), family history of type 2 diabetes (76%), central obesity (73%), male sex (63%), and sedentary lifestyle (60%), and most of them were progressively associated to prediabetes and type 2 diabetes groups. Insulin sensitivity was lower in famT2D groups in comparison to NG group (p < 0.0001). FamPD and famT2D had a 10% lower pancreatic beta cell function (DI) than the NG group (NG group 2.78 ± 1.0, famPD 2.5 ± 0.85, famT2D 2.4 ± 0.75, p˂0.001). FamPD and famT2D patients had lower pancreatic beta cell function than NG patients, highlighting that defects in insulin secretion and insulin sensitivity appear long time before the development of hyperglycemia in patients genetically predisposed.

Serum C-reactive Protein Levels about Insulin Resistance and Beta Cell Function in Iranian Women with Subclinical Hypothyroidism.

Subclinical hypothyroidism (SCH), is defined as an asymptomatic state characterized by a normal serum concentration of free thyroxine and elevated serum concentration of TSH. This study aims to investigate the complex interplay between hyperinsulinism, insulin resistance, beta cell function, and low-grade chronic inflammation in Iranian women with SCH. Eighty women with SCH and 80 healthy women as controls matched to the patient group for sex, age, and body mass index (BMI), were enrolled in this prospective cross-sectional study. TSH, free T3, free T4, highly sensitive C-reactive protein (hs-CRP), fasting insulin, fasting glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, Triglyceride, HOMA-IR index, Beta cell function (HOMA-B index) and insulin sensitivity were determined. Hs-CRP was not statistically different between the SCH patients and the control group (3.7±3.2 Vs 3.6±4.0, P>0.05). Total cholesterol and LDL-cholesterol were significantly higher; however, triglyceride and HDL-cholesterol were not statistically different in patients with SCH as compared with the control group. Fasting insulin levels and HOMA-IR and Beta cell function (HOMA-B) were significantly higher in SCH women compared to the control group. A positive correlation between HOMA-IR and HOMA-B with TSH levels was found (r=0.324, r=0.191, P<0.05 respectively). A positive correlation between insulin levels and hs-CRP (r=0.22, P<0.05), also between insulin levels and TSH (r=0.312, P<0.05) and LDL- LDL-cholesterol was obtained (r=0.27, P<0.05). Iranian women with SCH may exhibit elevated atherogenic parameters (hyperinsulinemia, LDL-cholesterol, and total cholesterol), HOMA-IR, and HOMA-B.

A longitudinal study of glucose tolerance in cystic fibrosis: the central role of beta cell functional mass.

The pathophysiological mechanisms underlying the natural history of glucose intolerance and its fluctuations in subjects with cystic fibrosis (CF) are still unclear. To investigate the relationship between longitudinal changes in glucose tolerance and concomitant changes in the main parameters of insulin secretion/metabolism/action determining glucose regulation in CF subjects. Insulin sensitivity and glucose-stimulated insulin secretion (GSIS, a biomarker of beta cell functional mass), as estimated by the Oral Glucose Sensitivity Index (OGIS) and by a sophisticated mathematical model, respectively, and insulin clearance were assessed in 127 CF subjects, aged 10-25 years, who underwent two OGTT tests over at least 1-year follow-up period. Subjects were classified a posteriori as regressors (improved glucose tolerance), stable, or progressors (worsened glucose tolerance). The interplay between beta cell compensatory action and insulin sensitivity over time was analyzed by vector plots of insulin clearance adjusted GSIS (PCadj) versus OGIS. OGIS decreased in progressors and stable. Insulin clearance decreased in both regressors and progressors. GSIS (beta cell functional mass) improved in regressors and worsened in progressors, whereas it did not change in stable. Vector plot analysis confirmed that glucose regulation changed differently in each group. Multinomial logistic regression analysis showed that baseline glucose tolerance and GSIS changes were the only significant predictors of the changes in glucose tolerance (p<0.02, R2Nagelkerke=0.55), whereas age, gender, z-BMI, CF genotypes, and baseline PCadj were not. In CF subjects, changes in beta cell functional mass are associated with favorable or detrimental changes of glucose tolerance over time.

Risk and factors determining diabetes after mild, nonnecrotizing acute pancreatitis.

Diabetes mellitus (DM) is relatively common following acute pancreatitis (AP), even after mild acute pancreatitis (MAP), the most frequent AP presentation, in which there is no overt beta cell injury. Post-AP related diabetes is widely misdiagnosed, resulting in potentially inappropriate treatment and worse outcomes than type 2 diabetes (T2D). Thus, it is important to understand risk across the spectrum of AP severity. Biological mechanisms are unclear and may include local and systemic inflammation leading to beta cell dysfunction and insulin resistance, altered gut barrier and/or gut peptides and possibly islet autoimmunity, though no studies have specifically focused on MAP. While studies examining clinical risk factors on MAP exclusively are lacking, there are studies which include MAP. These studies vary in scientific rigor, approaches to rule out preexisting diabetes, variable AP severity, diagnostic testing methods, and duration of follow-up. Overall, disease related factors, including AP severity, as well as established T2D risk factors are reported to contribute to the risk for DM following AP. Though numerous studies have explored risk factors for DM after AP, few studies specifically focused on MAP, highlighting a key knowledge gap that is relevant to the majority of patients with AP.

MiRNA-122 as a biomarker for insulin resistance and risk of cardiovascular diseases in obese children

BackgroundObesity in children is a major worldwide concern that has several negative health consequences in both the short and long term. The objective of this study was to evaluate the expression level of microRNA-122 in obese Egyptian children and investigate its potential associations with insulin resistance and cardiovascular diseases. MethodsThe study included 70 obese and 30 age-matched normal-weight control children. Anthropometric measurements, systolic, and diastolic blood pressures were assessed, and quantitative real-time polymerase chain reaction was used to determine the expression of circulating microRNA-122. Pancreatic beta cell function (HOMA2-%B), insulin resistance (HOMA2-IR), and insulin sensitivity (HOMA2-%S) was assessed by the homeostasis model assessment version 2 (HOMA2). McAuley index and single-point insulin sensitivity estimator (SPISE) was used to further evaluate insulin sensitivity. Levels of serum biochemical parameters were measured. ResultsThe obese group showed significantly higher levels of microRNA-122, fasting blood glucose, triglycerides, total cholesterol, LDL, VLDL, non-HDL cholesterol, cardiac risk ratios, atherogenic coefficient, atherosclerotic index, insulin levels, HOMA2-%B, and HOMA2-IR compared to the control group. In obese children, microRNA-122 exhibited a significant negative correlation with HDL while a significant positive correlation with the cardiac risk ratio 1 and the atherogenic coefficient. MicroRNA-122 had predictive ability for insulin resistance and cardiovascular diseases risk in obese children. However, a significant decrease in HDL levels, HOMA2-%S, McAuley, and SPISE insulin sensitivity indices was found in obese children. ConclusionsModifications in blood levels of microRNA-122 in obese children may indicate a possible role in the etiology of childhood obesity and its associated consequences. As a result, it could function as a preliminary biomarker and potential indicator of further metabolic diseases.

RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function

Aims/hypothesisRegulatory factor X 6 (RFX6) is crucial for pancreatic endocrine development and differentiation. The RFX6 variant p.His293LeufsTer7 is significantly enriched in the Finnish population, with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 and gestational diabetes. However, the precise mechanism of this predisposition remains unknown.MethodsTo understand the role of this variant in beta cell development and function, we used CRISPR technology to generate allelic series of pluripotent stem cells. We created two isogenic stem cell models: a human embryonic stem cell model; and a patient-derived stem cell model. Both were differentiated into pancreatic islet lineages (stem-cell-derived islets, SC-islets), followed by implantation in immunocompromised NOD-SCID-Gamma mice.ResultsStem cell models of the homozygous variant RFX6−/− predictably failed to generate insulin-secreting pancreatic beta cells, mirroring the phenotype observed in Mitchell–Riley syndrome. Notably, at the pancreatic endocrine stage, there was an upregulation of precursor markers NEUROG3 and SOX9, accompanied by increased apoptosis. Intriguingly, heterozygous RFX6+/− SC-islets exhibited RFX6 haploinsufficiency (54.2% reduction in protein expression), associated with reduced beta cell maturation markers, altered calcium signalling and impaired insulin secretion (62% and 54% reduction in basal and high glucose conditions, respectively). However, RFX6 haploinsufficiency did not have an impact on beta cell number or insulin content. The reduced insulin secretion persisted after in vivo implantation in mice, aligning with the increased risk of variant carriers to develop diabetes.Conclusions/interpretationOur allelic series isogenic SC-islet models represent a powerful tool to elucidate specific aetiologies of diabetes in humans, enabling the sensitive detection of aberrations in both beta cell development and function. We highlight the critical role of RFX6 in augmenting and maintaining the pancreatic progenitor pool, with an endocrine roadblock and increased cell death upon its loss. We demonstrate that RFX6 haploinsufficiency does not affect beta cell number or insulin content but does impair function, predisposing heterozygous carriers of loss-of-function variants to diabetes.Data availabilityUltra-deep bulk RNA-seq data for pancreatic differentiation stages 3, 5 and 7 of H1 RFX6 genotypes are deposited in the Gene Expression Omnibus database with accession code GSE234289. Original western blot images are deposited at Mendeley (https://data.mendeley.com/datasets/g75drr3mgw/2).Graphical

Human Pancreatic β Cell Regenerative Therapy: Exploring the Role of Chicoric Acid as a Phytochemical Candidate

Diabetes is a global health issue, impacting life expectancy and productivity. Pathogenesis of diabetes mellitus involves decreased functional beta cells, making beta cell replacement and regeneration a crucial area of research. However, current methods like whole pancreas transplant or stem cell-derived beta cells have limitations for diabetic patients. Exploring pharmacological approaches to stimulate regeneration of residual beta cells is valuable, as many diabetic patients retain some beta cells. Finding drugs that target and regenerate these cells effectively is a challenge, with no approved options available currently. Nature provides several therapeutic agents, and chicoric acid (CA) found in medicinal plants like Cichorium intybus, and shows potential for beta cell regeneration. Cichorium intybus possesses antioxidants, phenolics, and flavonoids, aiding its antidiabetic activity by targeting hyperglycemia, oxidative stress, inflammation, and hyperlipidemia. CA's multifaceted effects on glucose homeostasis are attributed to its involvement in various interconnected processes and pathways. This comprehensive review explores the molecular-level mechanisms through which chicoric acid facilitates beta cell regeneration, insulin release, and glucose uptake. The findings suggest that chicoric acid holds promise as a phytochemical agent for diabetes prevention and treatment. Its natural origin, antidiabetic properties, and multi-dimensional effects make it a potential candidate. Hence, further research to fully elucidate the efficacy and safety of chicoric acid for β cell regeneration as an antidiabetic agent is essential. In summary, this extensive review at the molecular level, concludes that chicoric acid is a phytochemical with great antidiabetic potential and may be indicated both as a preventive and therapeutic agent.

Correlation between TCF7L2 gene expression and certain biochemical parameters in type 2 diabetes mellitus

ObjectivesThe transcription factor 7-like 2 gene (TCF7L2) is associated with a predisposition to type 2 diabetes mellitus (T2DM) in different ethnic populations. This article investigated the relationship between TCF7L2 gene expression and several biochemical indexes among different age categories of T2DM in a sample of the Iraqi population. MethodsOne hundred and fifty blood samples were collected from three groups: young T2DM (10–35 years), old T2DM (40–80 years), and healthy control (10–65 years) groups. Both sexes were enrolled. qPCR was performed to explore the expression of the TCF7L2 gene. Biochemical tests were performed to assess hemoglobin A1C (HbA1c), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. The body mass index (BMI) was calculated. The results were statistically analyzed. ResultsPatients with T2DM had higher BMI, TG, and LDL, and lower HDL than the control group. There was a strong positive correlation between hemoglobin A1C (HbA1c) and BMI, TG, and LDL and a negative correlation between HbA1c and HDL. Expression of the TCF7L2 gene showed a significant difference between old and young patients by 1.68 and 0.207 fold, respectively. These results showed that old patients had higher gene expression than young patients. ConclusionTCF7L2 gene expression was affected by age, with higher expression in old T2DM patients. This may influence beta cell functions and insulin secretion.

Clinical and Laboratory Characteristics of MODY Cases, Genetic Mutation Spectrum and Phenotype-genotype Relationship

Maturity onset diabetes of the young (MODY) occurs due to mutations in genes involved in pancreatic beta cell function and insulin secretion, has heterogeneous clinical and laboratory features, and account for 1-5% of all diabetes cases. The prevalence and distribution of MODY subtypes vary between countries. The aim of this study was to evaluate the clinical and laboratory characteristics, mutation distribution, and phenotype-genotype relationship in a large case series of pediatric Turkish patients genetically diagnosed with MODY. MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. A total of 224 patients were included, of whom 101 (45%) were female, and the mean age at diagnosis was 9.4±4.1 years. Gene variant distribution was: 146 (65%) GCK; 43 (19%) HNF1A; 8 (3.6%) HNF4A, 8 (3.6%) KLF11 and 7 (3.1%) HNF1B. The remaining 12 variants were: PDX (n=1), NEUROD1 (n=3), CEL (n=1), INS (n=3), ABCC8 (n= 3) and KJNC11 (n=1). Of the cases, 197 (87.9%) were diagnosed with incidental hyperglycemia, 16 with ketosis (7%) and 7 (3%) with diabetic ketoacidosis (DKA), while 30% presented with classical symptoms of diabetes. Two-hundred (89%) had a family history of diabetes. Anti-GAD antibody was detected in 13 cases, anti-islet antibody in eight and anti-insulin antibody in four. Obesity was present in 16. Distribution of therapy was: 158 (71%) diet only; 23 (11%) intensive insulin treatment; 17 (7.6%) sulfonylureas; 10 (4.5%) metformin; and 6 (2.7%) insulin and oral anti-diabetic treatment. This was the largest genetically diagnosed series from Turkey. The most common gene variants were GCK and HNF1A with much lower proportions for other MODY types. Hyperglycemia was the most common presenting symptom while 11% of patients had diabetes-associated autoantibodies and 7% were obese. The majority of patients received dietary management only.

Mixed-Lineage Leukaemia Gene Regulates Glucose-Sensitive Gene Expression and Insulin Secretion in Pancreatic Beta Cells.

The escalating prevalence of diabetes mellitus underscores the need for a comprehensive understanding of pancreatic beta cell function. Interest in glucose effectiveness has prompted the exploration of novel regulatory factors. The myeloid/lymphoid or mixed-lineage leukaemia gene (MLL) is widely recognised for its role in leukemogenesis and nuclear regulatory mechanisms through its histone methyltransferase activity in active chromatin. However, its function within pancreatic endocrine tissues remains elusive. Herein, we unveil a novel role of MLL in glucose metabolism and insulin secretion. MLL knockdown in βHC-9 pancreatic beta cells diminished insulin secretion in response to glucose loading, paralleled by the downregulation of the glucose-sensitive genes SLC2a1 and SLC2a2. Similar observations were made in MLL heterozygous knockout mice (MLL+/-), which exhibited impaired glucose tolerance and reduced insulin secretion without morphological anomalies in pancreatic endocrine cells. The reduction in insulin secretion was independent of changes in beta cell mass or insulin granule morphology, suggesting the regulatory role of MLL in glucose-sensitive gene expression. The current results suggest that MLL interacts with circadian-related complexes to modulate the expression of glucose transporter genes, thereby regulating glucose sensing and insulin secretion. Our findings shed light on insulin secretion control, providing potential avenues for therapeutics against diabetes.