Pancreatic Β-cell Function Research Articles

Comparison of protective effects of teneligliptin and luseogliflozin on pancreatic β-cell function: randomized, parallel-group, multicenter, open-label study (SECRETE-I study)

AimsThe aim of this study is to directly compare the effects of SGLT2 inhibitors and DPP-4 inhibitors on β-cell function in patients with type 2 diabetes.Materials and methodsWe conducted a 26-week, randomized, open-label, parallel-group study, including a 1-2 week drug washout period, in patients with type 2 diabetes with HbA1c ≥7.0% and <9.0% and BMI ≥20 kg/m2 despite treatment with a drug naïve or other than DPP-4 inhibitors or SGLT2 inhibitors. A total of 103 subjects were randomly assigned to receive once daily oral luseogliflozin (L) or teneligliptin (T). The primary endpoint was the effect of L vs. T on the change in logarithmus naturalis (Ln) disposition index (DI) (DI 0-120min; combining measures of insulin secretion and sensitivity) from baseline to week 25-26 (post intervention), which was calculated by conducting an oral glucose tolerance test.ResultsLn DI 0-120min were improved in both groups: -0.46 ± 0.68 to -0.20 ± 0.59 (p=0.03) in L group and -0.26 ± 0.60 to -0.05 ± 0.62 (p=0.01) in T group. The change in Ln serum proinsulin/C-peptide ratio, a marker of β-cell dysfunction, was reduced in L group (1.63 ± 0.63 to 1.56 ± 0.68, p=0.16), but rather increased in T group (1.70 ± 0.75 to 1.90 ± 0.51, p=0.01), with significant difference between the two groups (-0.27; p=0.004).ConclusionsImprovement of disposition index in subjects with obese type 2 diabetes was comparable between luseogliflozin and teneligliptin. On the other hand, it is likely that alleviation of β-cell dysfunction is more effective with luseogliflozin compared to tenegliptin.Clinical trial registrationhttps://rctportal.niph.go.jp/en, identifier jRCTs061190008.

Pancreatic β-Cells, Diabetes and Autophagy.

Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis. We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management. Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression. Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function.

Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signalling pathway.

GPR119 agonists are being developed to safeguard the function of pancreatic β-cells, especially in the context of non-alcoholic fatty pancreas disease (NAFPD) that is closely associated with β-cell dysfunction. This study aims to employ a drug repurposing strategy to screen GPR119 agonists and explore their potential molecular mechanisms for enhancing β-cell function in the context of NAFPD. MIN6 cells were stimulated with palmitic acid (PA), and a NAFPD model was established in GPR119-/- mice fed with a high-fat diet (HFD). Terazosin, identified through screening, was utilized to assess its impact on enhancing β-cell function via the MST1-Foxo3a pathway and mitophagy. Terazosin selectively activated GPR119, leading to increased cAMP and ATP synthesis, consequently enhancing insulin secretion. Terazosin administration improved high blood glucose, obesity, and impaired pancreatic β-cell function in NAFPD mice. It inhibited the upregulation of MST1-Foxo3a expression in pancreatic tissue and enhanced damaged mitophagy clearance, restoring autophagic flux, and improving mitochondrial quantity and structure in β-cells. Nevertheless, GPR119 deficiency negated the positive impact of terazosin on pancreatic β-cell function in NAFPD mice and abolished its inhibitory effect on the MST1-Foxo3a pathway. Terazosin activates GPR119 on the surface of pancreatic β-cells, enhancing mitophagy and alleviating β-cell dysfunction in the context of NAFPD by suppressing the MST1-Foxo3a signalling pathway. Terazosin could be considered a priority treatment for patients with concomitant NAFPD and hypertension.

Chronic late gestation fetal hyperglucagonaemia results in lower insulin secretion, pancreatic mass, islet area and beta- and α-cell proliferation.

Fetal glucagon concentrations are elevated in the presence of a compromised intrauterine environment, as in cases of placental insufficiency and perinatal acidaemia. Our objective was to investigate the impact of late gestation fetal hyperglucagonaemia on in vivo insulin secretion and pancreatic islet structure. Chronically catheterized late gestation fetal sheep received an intravenous infusion of glucagon at low (5ng/kg/min; GCG-5) or high (50ng/kg/min; GCG-50) concentrations or a vehicle control (CON) for 8-10days.Glucose-stimulated fetal insulin secretion (GSIS) was measured following 3h (acute response) and 8-10days (chronic response) of experimental infusions. Insulin, glucose and amino acid concentrations were measured longitudinally. The pancreas was collected at the study end for histology and gene expression analysis. Acute exposure (3h) to GCG-50 induced a 3-fold increase in basal insulin concentrations with greater GSIS. Meanwhile, chronic exposure to both GCG-5 and GCG-50 decreased basal insulin concentrations 2-fold by day 8-10. Chronic GCG-50 also blunted GSIS at the study end. Fetal amino acid concentrations were decreased within 24h of GCG-5 and GCG-50, while there were no differences in fetal glucose. Histologically, GCG-5 and GCG-50 had lower β- and α-cell proliferation, as well as lower α-cell mass and pancreas weight, while GCG-50 had lower islet area. This study demonstrates that chronic glucagon elevation in late gestation fetuses impairs β-cell proliferation and insulin secretion, which has the potential to contribute to later-life diabetes risk. We speculate that the action of glucagon in lower circulating fetal amino acid concentrations may have a suppressive effect on insulin secretion. KEY POINTS: We have previously demonstrated in a chronically catheterized fetal sheep model that experimentally elevated glucagon in the fetus impairs placental function, reduces fetal protein accretion and lowers fetal weight. In the present study, we further characterized the effects of elevated fetal glucagon on fetal physiology with a focus on pancreatic development and β-cell function. We show that experimentally elevated fetal glucagon results in lower β- and α-cell proliferation, as well as decreased insulin secretion after 8-10days of glucagon infusion. These results have important implications for β-cell reserve and later-life predisposition to diabetes.

The effect of severe COVID-19 infection on biochemical markers (FBS, HbA1C, FA, INS, C-Pep) in diabetic patients

Background & objective: Several studies have been conducted around the world on the impact of COVID-19 on people with diabetes mellitus (DM). Any acute illness can cause stress and increased inflammatory reactions, which increase sympathetic outflow and produce catecholamines, growth hormones, cortisol, and cytokines, all of which raise the risk and severity of complications from diabetes. Diabetes is a significant risk factor for the severity of COVID-19. We conducted this study to identify whether severe COVID-19 infection has any effect on the biomarkers, including fasting blood sugar (FBS), HbA1C, FA, INS, C-Pep, in individuals with DM. Methodology: This study was simultaneously conducted at Department of Chemistry and Biochemistry, College of Medicine of Al-Nahrain University, and Department of Medicine of Mustansiriyah University College of Medicine, Baghdad, Iraq. During the months of February and March 2022, 50 COVID-19 patients with diabetes and 50 COVID-19 patients without diabetes were included in the study. The control group included 100 healthy, sexually identical people (age 50-80), collected under the supervision of the second supervisor from relatives and students of Mustansiriyah University, College of Medicine. Venous blood samples of 5 mL were taken from all participants and subjected to laboratory tests to detect the levels of the biomarkers. Results: Average FBS level in DM patients was 304.9 mg/dL, (range 132-545.9 mg/dL), which was remarkably higher than in non-DM patient groups (193.3 mg/dL), range (of 66.2–458). The DM patients' group had a significantly higher concentration of HbA1C (median = 6.70 mg/dL, range 5.2-8.1) than the non-DM patient group (median = 5.8, range 4.2–7.6) with a significant difference. Although The group of DM patients had significantly greater FA concentrations than the group of non-DM patients. In contrast, the median and range for insulin and c-peptide Displays non-significant differences for covid-19 patients (DM and non-DM), but it's significant with a control group. Conclusion: According to this study, COVID-19 patients with diabetes had greater biochemical indicator levels than non-diabetic people. Pre- and postprandial hyperglycemia and diabetic ketoacidosis were more common in COVID-19 DM patients than in non-infected DM patients. We found that COVID-19 increased the severity risk for T2DM patients and glucose level is raised and progresses in a vicious cycle exacerbated by insulin resistance (IR) and decreased pancreatic b-cell function. Keywords: COVID-19, Diabetes mellitus, FBS, HbA1C, FA, INS, C-Pep Citation: Yones MS, Al-Wasiti E, Al Qaseer AH, Al-Rubaiawi HK. The effect of severe COVID-19 infection on biochemical markers (FBS, HbA1C, FA, INS, C-Pep) in diabetic patients. Anaesth. pain intensive care 2024;28(5):804−808; DOI: 10.35975/apic.v28i5.2553 Received: June 01, 2024; Reviewed: June 19, 2024; Accepted: June 19, 2024

12614 Induction Of Gpt2 During Metabolic Stress Is Associated With Reduced Incretin Responsiveness And Decreased β-cell Resilience To Metabolic Stress

Abstract Disclosure: S. Sen: None. A.V. Rozo: None. M. Haemmerle: None. J. Roman: None. A.V. Scota: None. J.A. Christine: None. E.M. Morrow: None. S.A. Tersey: None. C.B. Newgard: None. N.M. Doliba: None. D.A. Stoffers: None. Elevated blood glucose and lipids compromise pancreatic β-cell survival and function, but the underlying molecular mechanisms are ill-understood. We previously found that mitochondrial glutamate-pyruvate transaminase 2 (GPT2) is induced by ER and glucolipotoxic (GLT) stress. Here, we find that islets from type 2 diabetic donors exhibited markedly elevated levels of GPT2 compared to those of non-diabetic donors. GLT stress induced GPT2 in MIN6 cells, primary murine, and human non-diabetic islets. We generated β-cell specific Gpt2-deficient (Gpt2βKO) and Gpt2 floxed control (Gpt2f/f) mice to study the in vivo role of Gpt2 in β-cells. Intraperitoneal (IP) glucose tolerance (GTT) of Gpt2βKO mice was minimally affected on chow diet; therefore, we placed Gpt2f/f and Gpt2βKO mice on 45 kcal% high-fat and matched control diets. At 1 week, HFD-fed Gpt2βKO mice exhibited reduced β-cell death, measured by droplet digital PCR of circulating unmethylated preproinsulin DNA and by TUNEL analysis. Over 37 weeks, HFD-fed Gpt2βKO mice showed lower random blood glucose similar to Gpt2f/f mice under a control diet. While IPGTT was modestly improved in HFD-fed Gpt2βKO compared to HFD-fed Gpt2f/f mice, insulin secretion was not enhanced. Remarkably, oral glucose administration markedly improved glucose tolerance and enhanced insulin secretion of control- and HFD-fed Gpt2βKO mice compared to Gpt2f/f mice, while GLP-1 and GIP levels were unaltered, suggesting enhanced incretin action on the β-cell. Indeed, Gpt2βKO mice (under both control and high-fat diets) were more responsive to administration of GLP1R agonist Exendin-4 (Ex4) than Gpt2f/f mice. Isolated Gpt2βKO islets secreted more insulin when stimulated by Ex4 and GIP but not acetylcholine. Perifusion assay revealed markedly enhanced insulin secretion of Gpt2βKO islets in response to a stepwise exposure to increasing Ex4 doses, indicating enhanced incretin sensitivity. Metabolic flux analysis of Gpt2βKO and Gpt2f/f islets exposed to uniformly labeled glucose (U-13C glucose) under low (2.8mM), high (12mM) glucose, and high glucose with Ex4 conditions revealed elevated levels of key TCA cycle intermediates in Gpt2βKO islets under high glucose and high glucose+Ex4 conditions, indicating increased TCA cycle flux that likely enhances insulin secretion. Gpt2βKO mice had higher β cell mass than Gpt2f/f littermates under control diet and HFD feeding. Bulk islet RNA-seq from Gpt2f/f and Gpt2βKO mice exposed to GLT revealed upregulation of genes responsible for cell cycle and division pathways and downregulation of apoptosis and ER stress genes, consistent with enhanced survival of Gpt2βKO islets under stress conditions. In summary, β-cell GPT2 is increased during metabolic stress and T2D. Its deficiency induces a metabolic reprogramming that improves incretin sensitivity and protects pancreatic β-cells from metabolic stress. Presentation: 6/2/2024

Near-infrared remote triggering of bio-enzyme activation to control intestinal colonization by orally administered microorganisms

Oral biotherapeutics hold significant promise, but their lack of controllability and targeting poses a major challenge, particularly for intestinal bacterial biotherapeutics. In response, we have developed a nanoencapsulation approach that responds to the release of enzyme activity in the organism and activates the enzyme in situ, allowing for controlled colonization of microbes in the gut. The nano-coating comprises a two-layer structure: an inner layer of polydopamine with photothermal and adhesive properties, and an outer layer of gelatin–sodium carboxymethylcellulose, which is hydrolyzed by cellulases in the gut following photothermal interaction with dopamine. We have successfully achieved controlled colonization of a wide range of microorganisms. Furthermore, in a diabetes model, this approach has had a profound impact on regulating glucagon-like peptide-1 (GLP-1) production, β-cell physiology, and promoting insulin secretion. This nanocoating is achieved by in situ activation of cellulase without the need for genetic or targeted molecular modification, representing a new paradigm and alternative strategy for microbial therapy. It not only enables precise and controlled colonization of probiotics but also demonstrates great potential for broader application in the field of oral biotherapy. Statement of significanceWe have developed a nano-encapsulation method that triggers enzyme activity in response to enzymatic activity, resulting in the controlled release and adhesion of a wide range of microorganisms in the gut. The nano coating comprises two layers: an inner layer of polydopamine with photothermal and adhesion properties, and an outer layer of a gelatin-sodium carboxymethylcellulose polymer, which can be hydrolyzed by cellulases in the intestine. Additionally, this method allows for the preparation of various microbial coatings. This approach holds significant promise for regulating GLP-1 production, the physiological function of pancreatic β-cells, and promoting insulin secretion in diabetes models.

Fam3a-mediated prohormone convertase switch in α-cells regulates pancreatic GLP-1 production in an Nr4a2-Foxa2-dependent manner

BackgroundFam3a has been demonstrated to regulate pancreatic β-cell function and glucose homeostasis. However, the role and mechanism of Fam3a in regulating α-cell function remain unexplored. MethodsGlucagon and glucagon-like peptide-1 (GLP-1) levels in pancreas and plasma were measured in global Fam3a knockout (Fam3a−/−) mice. Human islet single-cell RNA sequencing (scRNA-seq) datasets were utilized to analyze gene expression correlations between FAM3A and PCSK1 (encoding PC1/3, which processes proglucagon into GLP-1). Mouse pancreatic α-cell line αTC1.9 cells were transfected with Fam3a siRNA or plasmid for Fam3a knockdown or overexpression to explore the effects of Fam3a on PC1/3 expression and GLP-1 production. The downstream mediator (including Nr4a2) was identified by transcriptomic analysis, and its role was confirmed by Fam3a knockdown or overexpression in αTC1.9 cells. Based on the interacted protein of Nr4a2 and the direct binding to Pcsk1 promoter, the transcription factor Foxa2 was selected for further verification. Nuclear translocation assay and dual-luciferase reporter assay were used to clarify the involvement of Fam3a-Nr4a2-Foxa2 pathway in PC1/3 expression and GLP-1 production. Moreover, α-cell-specific Fam3a knockout (Fam3aα−/−) mice were constructed to evaluate the metabolic variables and hormone levels under normoglycemic, high-fat diet (HFD)-fed and streptozotocin (STZ)-induced diabetic conditions. Exendin 9–39 (Ex9), a GLP-1 receptor antagonist, was used to investigate GLP-1 paracrine effects in Fam3aα−/− mice and in their primary islets. ResultsCompared with wild-type mice, pancreatic and plasma active GLP-1 levels were increased in Fam3a−/− mice. Analysis of human islet scRNA-seq datasets showed a significant negative correction between FAM3A and PCSK1 in α-cells. Fam3a knockdown upregulated PC1/3 expression and GLP-1 production in αTC1.9 cells, while Fam3a overexpression displayed inverse effects. Transcriptomic analysis identified Nr4a2 as a key downstream mediator of Fam3a, and Nr4a2 expression in αTC1.9 cells was downregulated and upregulated by Fam3a knockdown and overexpression, respectively. Nr4a2 silencing increased PC1/3 expression, albeit Nr4a2 did not directly bind to Pcsk1 promoter. Instead, Nr4a2 formed a complex with Foxa2 to facilitate Fam3a-mediated Foxa2 nuclear translocation. Foxa2 negatively regulated PC1/3 expression and GLP-1 production. Besides, Foxa2 inhibited the transcriptional activity of Pcsk1 promoter at specific binding sites 10 and 6, and this inhibition was intensified by Nr4a2 in αTC1.9 cells. Compared with Flox/cre littermates, improved glucose tolerance, increased active GLP-1 level in pancreas and plasma, upregulated plasma insulin level in response to glucose, and decreased plasma glucagon level were observed in Fam3aα−/− mice. Primary islets isolated from Fam3aα−/− mice also showed an increase in active GLP-1 and insulin release. In addition, the insulinotropic effect of intra-islet GLP-1 was blocked by Ex9 in Fam3aα−/− mice and in their primary islets. Similarly, HFD-fed Fam3aα−/− mice also exhibited an improved glucose tolerance. Both HFD-fed and STZ-induced diabetic Fam3aα−/− mice showed an increased pancreatic active GLP-1 level, an elevated plasma insulin level and a reduced plasma glucagon level. ConclusionsFam3a deficiency in α-cells enhances pancreatic GLP-1 production to improve β-cell function via paracrine signaling in an Nr4a2-Foxa2-PC1/3-dependent manner. Our study unveils a novel strategy for reprogramming α-cell proglucagon processing output from glucagon to GLP-1 and deepen the understanding of crosstalk between α-cells and β-cells.

Metabolic perturbations associated with hIAPP-induced insulin resistance in skeletal muscles: Implications to the development of type 2 diabetes

The human islet amyloid polypeptide (hIAPP) tends to misfold and self-assemble to form amyloid fibrils, which has been associated with the loss of function and viability of pancreatic β-cells in type 2 diabetes mellitus (T2DM). The role of hIAPP in the development of insulin resistance (a hallmark of T2DM) in skeletal muscles – the major sites for glucose utilization – needs further investigation. Even though, insulin-resistant conditions have been known to stimulate hIAPP aggregation, the events that lead to the development of insulin resistance due to hIAPP aggregation in skeletal muscles remain unidentified. Here, we have attempted to identify metabolic perturbations in L6 myotubes that were exposed to increasing concentrations of recombinant hIAPP for different time durations. It was observed that hIAPP exposure was associated with increased mitochondrial and cellular ROS levels, loss in mitochondrial membrane potential and viability of the myotubes. Metabolomic investigations of hIAPP-treated myotubes revealed significant perturbations in o-phosphocholine, sn-glycero-3-phosphocholine and dimethylamine levels (p < 0.05). Therefore, we anticipate that defects in glycerophospholipid metabolism and the associated oxidative stress and membrane damage may play key roles in the development of insulin resistance due to protein misfolding in skeletal muscles. In summary, the perturbed metabolites and their pathways have not only the potential to be used as early biomarkers to predict the onset of insulin resistance and T2DM but also as therapeutic targets for the effective management of the same.

Vitamin D supplementation could enhance the effectiveness of glibenclamide in treating type 2 diabetes by improving the function of pancreatic β-cells through the NF-κB pathway

PurposeThe high morbidity and mortality associated with type 2 diabetes mellitus (T2DM) pose a significant global health challenge, necessitating the development of more efficient anti-diabetic drugs with fewer side effects. This study investigated the intervention of vitamin D3 combined with glibenclamide in rats with T2DM to elucidate its effects on pancreatic β-cells through the NF-κB pathway. MethodsTwenty-four healthy male Sprague-Dawley (SD) rats were randomly assigned to four groups: the control group (CG), the model group (MG), the glibenclamide group (GG), and the glibenclamide + vitamin D3 group (GDG). After inducing the T2DM model using high-fat and high-sugar diet and intraperitoneal injection of streptozotocin, the rats in the GG group were administered glibenclamide orally (0.6 mg/kg/day), while those in the GDG group received both glibenclamide (0.6 mg/kg/day) and vitamin D3 (500 IU/kg/day) in corn oil for a duration of 8 weeks. Biochemical indices were measured, and histopathological changes in pancreatic tissue and islet β cells were observed using hematoxylin and eosin staining. The expression of pancreatic nuclear factor κB (NF-κB), islet β-cells, and inflammatory cytokines were assessed using the TUNEL method and PCR. ResultsAccording to the data from this current study, the GDG group showed significant positive differences in plasma biochemical indices, as well as in the expression of β cells, NF-κB p65, TNF-α, IL-1β, INF-γ, and Fas, compared to the GG and CG groups (P < 0.05). ConclusionThe results suggest that vitamin D has beneficial effects on T2DM by improving the functions of islet β cells through inhibition of the NF-κB signaling pathway. Therefore, it is suggested that vitamin D supplementation, when used alongside antidiabetic drugs, may more effectively prevent and treat T2DM.

Lipocalin-2 as a fundamental protein in type 2 diabetes and periodontitis in mice.

Lipocalin-2 (LCN-2) is an osteokine that suppresses appetite, stimulates insulin secretion, regulates bone remodeling, and is induced by proinflammatory cytokines. The aim of this work was to investigate the participation of LCN-2 in periodontitis associated with type 2 diabetes (T2D) by evaluating alveolar bone loss, glycemic control, inflammation, and femur fragility. A murine model of periodontitis with T2D and elevated LCN-2 concentration was used. Functional LCN-2 inhibition was achieved using an anti-LCN-2 polyclonal antibody, and isotype immunoglobulin G was used as a control. The alveolar bone and femur were evaluated by micro-CT. Glucose metabolism was determined. Tumor necrosis factor (TNF-α) and receptor activator of nuclear factor kappa-B ligand (RANKL) levels in alveolar bone lysates were quantified using ELISA, and serum cytokines were quantified using flow cytometry. A three-point bending test was performed in the femur, and RANKL levels were measured in femur lysates using ELISA. Functional inhibition of LCN-2 in T2D-periodontitis mice decreased alveolar bone loss in buccal and palatal surfaces and preserved the microarchitecture of the remaining bone, decreased TNF-α and RANKL in alveolar bone, reduced hyperglycemia, glucose intolerance, and insulin resistance, and increased insulin production through improving the functionality of pancreatic β cells. Furthermore, this inhibition increased serum free-glycerol levels, decreased serum interleukin (IL)-6, increased serum IL-4, and reduced femur fragility and RANKL expression in the femur. LCN-2 participates in periodontitis associated with T2D. Inhibiting its function in mice with T2D and periodontitis improves pancreatic β-cell function, and glucose metabolism and decreases inflammatory cytokines and bone-RANKL levels, which results in the preservation of femoral and alveolar bone microarchitecture. In this study, we explored the role of a bone protein known as lipocalin-2 (LCN-2) in the connection between periodontitis and type 2 diabetes (T2D). Periodontitis is a destructive gum and alveolar bone disease. LCN-2 levels are increased in both T2D and periodontitis. Using a mouse model of T2D with periodontitis, we examined how blocking LCN-2 function affected various aspects of these two diseases. We found that this inhibition led to significant improvements. First, it reduced alveolar bone loss and preserved bone structure by decreasing local inflammation and bone resorption. Second, it improved glucose and lipid metabolism, leading to better blood-sugar control and decreased insulin resistance. Blocking the functions of LCN-2 also decreased systemic inflammation throughout the body and strengthened bone integrity. Overall, our results suggest that LCN-2 plays a crucial role in the periodontitis associated with T2D. By inhibiting LCN-2 function, we were able to improve pancreatic function, improve glucose metabolism, reduce inflammation, and enhance bone health. Targeting LCN-2 could be a promising strategy for the harmful effects of T2D and periodontitis.

Buddleoside-rich Chrysanthemum indicum L. extract modulates macrophage-mediated inflammation to prevent metabolic syndrome induced by unhealthy diet

BackgroundMetabolic syndrome (MetS) is a precursor to the development of many diseases (atherosclerosis, diabetes, etc.). It is marked by disruptions in glucose and lipid metabolism, along with hypertension. Numerous types of risk factors contribute to the development of the MetS, inflammation and insulin resistance are present throughout the metabolic abnormalities. Chrysanthemum indicum L. is a traditional Chinese plant used for both tea and medicine, known for its high content of total flavonoids, which are important secondary metabolites. Our research led to the extraction of a Buddleoside-Rich Chrysanthemum indicum L. extract (BUDE) which has demonstrated anti-inflammatory properties. Nonetheless, the specific role and mechanism of BUDE in preventing MetS remain unclear.MethodsThe study initially evaluated the role of BUDE in preventing MetS. Subsequently, it investigated the anti-inflammatory properties of BUDE in the liver and pancreas in response to unhealthy diets. It then examined the level of insulin resistance and pancreatic β-cell function induced by inflammation. Additionally, an lipopolysaccharide (LPS)-induced macrophage inflammation model was used to further investigate the ameliorative effects of BUDE in inflammation.ResultsBUDE has hypotensive, hypoglycemic and hypolipidemic effects. It can also resolve the imbalance between macrophage subpopulations, impede the triggering of the NF-κB signaling pathway, reduce the secretion of inflammatory mediators, ameliorate insulin resistance, and safeguard organs such as the liver and pancreas from inflammatory damage. These effects collectively contribute to preventing the development of MetS.DiscussionBUDE has the ability to modulate macrophage-mediated inflammation, leading to improved insulin resistance. Additionally, it delivers antihypertensive, hypoglycemic, and hypolipidemic effects, offering a potential for preventing MetS.

The different associations of serum gamma-glutamyl transferase and alanine aminotransferase with insulin secretion, β-cell function, and insulin resistance in non-obese Japanese

The present study investigated the associations of serum gamma-glutamyl transferase (GGT), a marker of fatty liver and oxidative stress, and ALT/AST, a marker of fatty liver, with percentage trunk fat and postload glucose, insulin resistance, and β-cell function in middle-aged Japanese individuals, whose BMI averaged < 23.0 kg/m2. Pancreatic β-cell function was assessed using the disposition index calculated by a product of the insulinogenic index (IGI) and Matsuda insulin sensitivity index, a biomarker of early-phase glucose-stimulated insulin secretion and whole-body insulin sensitivity, respectively. Multivariate linear regression analyses revealed that the disposition index was associated inversely with GGT independently of percentage trunk fat, homeostasis model assessment insulin resistance (HOMA-IR), a marker of insulin resistance, and Matsuda index. When IGI was included instead of the disposition index, IGI (inversely) and HOMA-IR were associated with GGT independently of percentage trunk fat and Matsuda index. When the area under the glucose concentration curve (AUCg) during an oral glucose tolerance test was included instead of the disposition index, AUCg and HOMA-IR emerged as independent determinants of GGT. ALT/AST was associated with HOMA-IR alone. Results suggest a different pathophysiologic basis between GGT and ALT/AST in predicting diabetic risk in non-obese Japanese.

Unlocking the Insightful Antidiabetic Effects of Lemongrass (Cymbopogon citratus): A Comprehensive Review

Lemongrass (Cymbopogon citratus) has emerged as a noteworthy contender in traditional medicine for its aromatic and therapeutic attributes, yet its potential as an antidiabetic agent remains largely unexplored in the literature. To address this gap, this study endeavors to provide a comprehensive overview of lemongrass role in diabetes management and the underlying pathways involved. Rich in bioactive compounds such as citral, flavonoids, and essential oils, lemongrass boasts a diverse array of medicinal properties. Research indicates its capability to modulate blood glucose levels, improve insulin sensitivity, and fortify pancreatic β-cell function primarily through antioxidant and anti-inflammatory mechanisms. Animal studies have demonstrated substantial reductions in fasting blood glucose and enhanced glucose tolerance, ascribed to heightened insulin signaling and inhibition of carbohydrate metabolism enzymes. Additionally, lemongrass exhibits a positive impact on lipid profiles, thereby mitigating cardiovascular risks associated with diabetes. Limited human trials have corroborated these findings, showcasing improvements in glycemic control and lipid metabolism following lemongrass consumption. In conclusion, lemongrass emerges as a promising adjunctive therapy for diabetes management, owing to its natural composition and multifaceted mechanisms. Nonetheless, further investigation, particularly through rigorous clinical trials, is imperative to determine optimal dosages, long-term safety, and efficacy, thereby facilitating its seamless integration into conventional diabetes treatment protocols.

Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells.

Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell-selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors (TFs) important for β-cell identity, such as FOXA, MAFA or RFX6, and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.

MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants.

Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype-phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype-phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients.

Therapeutic Potential of Blocking Nephrin Phosphorylation to Improve Pancreatic β-cell Function.

The phosphorylation of the transmembrane protein nephrin has been shown to play an important role in signaling in kidney podocytes, and it has now been shown to also play a key role in regulating pancreatic β-cell function. Williamson et al have recently shown that the loss of nephrin tyrosine phosphorylation on its 3 cytoplasmic YDxV motifs can enhance insulin release in aged female mice. These studies suggest that blocking nephrin phosphorylation may be an effective treatment option for improving β-cell function.

Deciphering the role of classical oestrogen receptor in insulin resistance and type 2 diabetes mellitus: From molecular mechanism to clinical evidence

The biological actions of oestrogen are mediated by the oestrogen receptor α or β (ERα or ERβ), which are members of a broad nuclear receptor superfamily. Numerous in vivo and in vitro studies have demonstrated that loss of circulating oestrogen modulated by classical ERα and ERβ led to rapid changes in pancreatic β-cell and islet function, GLUT4 expression, insulin sensitivity and glucose tolerance, dysfunctional lipid homeostasis, oxidative stress, and inflammatory cascades. Remarkably, 17β-oestradiol (E2) can completely reverse these effects. This review evaluates the current understanding of the protective role of classical ER in critical pathways and molecular mechanisms associated with insulin resistance and type 2 diabetes mellitus (T2DM). It also examines the effectiveness of menopausal hormone therapy (MHT) in reducing the risk of developing T2DM in menopausal women. Clinical trials have shown the protective effects of MHT on glucose metabolism, which may be useful to treat T2DM in perimenopausal women. However, there are concerns about E2's potential side effects of obesity and hyperlipidaemia in menopausal women. Further studies are warranted to gain understanding and find other oestrogen alternatives for treatment of insulin resistance and T2DM in postmenopausal women.

CREB activates the MafA promoter through proximal E-boxes and a CCAAT motif in pancreatic β-cells.

MafA is a key transcriptional regulator of pancreatic islet β-cell function. Its target genes include those encoding preproinsulin and the glucose transporter Glut2 (Slc2a2); thus, MafA function is essential for glucose-stimulated insulin secretion. Expression levels of MafA are reduced in β-cells of diabetic mouse models and human subjects, suggesting that β-cell dysfunction associated with type 2 diabetes is attributable to the loss of MafA. On the other hand, MafA is transcriptionally upregulated by incretin hormones through activation of CREB and its co-activator CRTC2. β-cell-specific expression of MafA relies on a distal enhancer element. However, the precise mechanism by which CREB-CRTC2 regulates the enhancer and proximal promoter regions of MafA remains unclear. In this report, we analyzed previously published ChIP-seq data and found that CREB and NeuroD1, a β-cell-enriched transactivator, bound to both the promoter and enhancer regions of human MAFA. A series of reporter assays revealed that CREB activated the enhancer through a conserved cAMP-responsive element (CRE) but stimulated MAFA promoter activity even when the putative CRE was deleted. Two E-box elements and a CCAAT motif, which bind NeuroD1 and ubiquitous NF-Y transcription factors, respectively, were necessary for transcriptional activation of the MAFA promoter by CREB. Genome-wide analysis of CREB-bound loci in β-cells revealed that they were enriched with CCAAT motifs. Furthermore, promoter analysis of the Isl1 gene encoding a β-cell-enriched transcription factor revealed that a CRE-like element and two CCAAT motifs, but not the E-box, were necessary for activation by CREB. These results provide clues to elucidate the detailed mechanism by which CREB regulates MafA as well as β-cell-specific genes.

Low muscle mass is associated with low insulin sensitivity, impaired pancreatic β cell function, and high glucose excursion in nondiabetic nonobese Japanese women

AimWe tested whether skeletal muscle mass is associated with insulin sensitivity, pancreatic β-cell function, and postglucose glycemia. MethodsAppendicular skeletal muscle mass (ASM) (relative to body size, %ASM) by DXA, surrogate measures of insulin sensitivity, insulin secretion and the disposition index (insulin sensitivity adjusted insulin secretion: a product of the insulinogenic index and Matsuda insulin sensitivity index) inferred from serum insulin kinetics during a 75 g oral glucose tolerance test (OGTT) were evaluated in 168 young and 65 middle-aged women, whose BMI averaged <23.0 kg/m2 and HbA1c ≦ 5.5 %. ResultsIn two groups of women, %ASM was associated negatively with homeostasis model assessment insulin resistance (HOMA-IR) and 2-h insulin (both p < 0.01 or less). In middle-aged women not in young women, %ASM was associated inversely with the Matsuda index (p < 0.001). In middle-aged women only, it also showed a positive association with the disposition index (p = 0.02) and inverse associations with 1-h and 2-h glucose (both p < 0.01) and area under the glucose concentration curve during OGTT (p = 0.006). On multivariate linear regression analyses, 2-h insulin emerged as a determinant of %ASM independently of HOMA-IR in young women (standardized β: 0.287, p < 0.001, R2 = 0.077). In middle-aged women, the Matsuda index emerged as a determinant of %ASM (standardized β: 0.476, p < 0.001) independently of HOMA-IR, log ODI and AUCg and explained 21.3 % of %ASM variability. Post-glucose glycemia and AUCg were higher and log ODI was lower in middle-aged women with low compared with high %ASM. ConclusionLow skeletal muscle mass (relative to body size) was associated with low insulin sensitivity in young and middle-aged Japanese women who were neither obese nor diabetic. Middle-aged women with low muscle mass had low disposition index, an early marker of inadequate pancreatic β-cell compensation, and hence high glucose excursion. Low skeletal muscle mass may be associated with the development of type 2 diabetes at a much lower BMI in Japanese people.