BACKGROUND: Pathogenesis of type 2 diabetes mellitus (T2DM) is combined from initial insulin resistance (IR) and subsequent β-cell dysfunction. Insulin therapy can replace β-cell function in advanced stages. However excessive insulin therapy increases IR and may expose the patients to risk of cardiovascular disease. We aim to assess β-cell function and IR in patients with type 2 diabetes on insulin therapy by fasting C-peptide to glucose ratio (FCPGR), and triglyceride glucose (TyG) index respectively to support treatment plans.
METHODS: A cross-sectional study was conducted at the Galiawa Diabetes and Endocrinology Teaching Center in Erbil City, Iraq, from June 2023 to January 2024. A convenient sample of 100 patients with T2DM on insulin-based therapy were included after obtaining informed written consent and excluding conditions such as acute illness, uncertain type of diabetes, etc. Each patient was evaluated for anthropometric parameters and current treatment details. Biochemical tests were then carried out to calculate metabolic syndrome (MetS) index score, FCPGR, and TyG index. Finally, patients were divided into four subgroups according to their FCPGR and TyG index and the data were analyzed statistically.
RESULTS: The data showed those patients with sufficient β-cell function were 60 (60%), and patients with high TyG index were 95 (95%). There was a significant negative correlation between FCPGR and hemoglobin A1c (HbA1c) (p-value=0.001), while there was a positive correlation between TyG index and HbA1C (p-value=0.001). None of these markers were correlated with BMI (p-value=0.297, and 0.976), duration of T2DM (p-value=0.258, and 0.458), and dose of insulin therapy (p-value=0.901, and 0.477). Patients with sufficient β-cell function and high TyG index had the lowest HbA1C.
CONCLUSIONS: The study provides valuable insights into the utility of FCPGR and TyG index as biomarkers for β-cell function and insulin resistance in T2DM patients on insulin therapy. The significant correlation with HbA1C underscores their potential in clinical practice. However, the lack of correlation with BMI, disease duration, and insulin dose suggests that further investigation is needed to fully understand these biomarkers\' implications across diverse patient profiles.

The dysfunction of pancreatic β-cells plays a pivotal role in the pathogenesis of type 2 diabetes mellitus (T2DM). Despite numerous studies demonstrating the anti-inflammatory and antioxidant properties of puerarin, the protective effects of puerarin on β-cells remain poorly understood. Hence, this study aimed to explore the effects of puerarin on β-cell dysfunction in a hyperglycemic environment via the PINK/Parkin-mediated mitochondrial autophagy pathway. The alterations in cell viability of MIN6 cells exposed to glucose concentrations of 5 mM, 10 mM, 20 mM, and 30 mM for 24 h, 48 h, and 72 h, respectively, were assessed using the CCK-8 assay to optimize the modeling conditions. Subsequently, cellular insulin secretion was measured using enzyme-linked immunosorbent assay (ELISA), apoptosis rate by flow cytometry, mitochondrial membrane potential alteration by JC-1, cellular ROS production by the DCFH-DA fluorescent probe, and fusion of cellular autophagosomes and lysosomes through adenoviral infection analysis. Furthermore, gene and protein expression levels of the PINK/Parkin-mediated mitochondrial autophagy pathway and mitochondrial apoptosis pathway were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. Results indicated a significant decrease in MIN6 cell viability following 48 h of exposure to 30 mM glucose concentration. Puerarin intervention markedly attenuated ROS production, restored mitochondrial membrane potential, induced PINK/Parkin-mediated mitochondrial autophagy, suppressed activation of the mitochondrial apoptotic pathway, mitigated apoptosis, and enhanced insulin secretion in a high glucose (HG) environment. The findings of this investigation contribute to a deeper understanding of the precise mechanism underlying the protective effects of puerarin on β-cells and offer a theoretical foundation for advancing puerarin-based therapeutics aimed at ameliorating T2DM.

Aim: Type II diabetes (T2D) stems from insulin resistance, with β-cell dysfunction as a hallmark in its progression. Studies reveal that β cells undergo apoptosis or dedifferentiation during T2D development. The transcription factor PAX4 is vital for β differentiation and survival, thus may be a potential enhancer of β-cell function in T2D islets. Materials & methods: Human PAX4 cDNA was delivered into T2D human islets with an adenoviral vector, and its effects on β cells were examined. Results: PAX4 gene delivery significantly improved β-cell survival, and increased β-cell composition in the T2D human islets. Basal insulin and glucose-stimulated insulin secretion in PAX4-expressing islets were substantially higher than untreated or control-treated T2D human islets. Conclusion: Introduced PAX4 expression in T2D human islets improves β-cell function, thus could provide therapeutic benefits for T2D treatment.
Type II diabetes (T2D) results from insulin resistance, with β-cell dysfunction playing a pivotal role in its progression. Deficits in β-cell mass and function have been attributed primarily to β-cell death through apoptosis; however, recent studies suggest β-cell failure can also arise from β-cell dedifferentiation – that is, β cells undergo a loss of mature identity, adopting either progenitor-like or glucagon-producing α cell states during T2D development. Therefore, a strategy preventing β-cell dedifferentiation while promoting its survival is beneficial for T2D treatment. In this study, we explored whether PAX4, a critical transcription factor for β differentiation and survival, could alleviate β-cell dysfunction in human islets derived from T2D patients. To accomplish that, human PAX4 cDNA was delivered into human islets isolated from T2D donors by an adenoviral vector-based vector, Ad5.Pax4 and its effects on β-cell function were evaluated. The results showed PAX4 expression significantly improved β-cell survival and increased β-cell composition in the T2D islets. Notably, PAX4-treated T2D islets exhibited significantly higher basal insulin secretion and glucose-stimulated insulin secretion than control-treated islets. The data demonstrate that PAX4 gene delivery into T2D human islets enhances β-cell mass and function, and thus may offer therapeutic benefits in the treatment of T2D.

UNASSIGNED: Type 2 diabetes mellitus (T2DM) is a major health problem worldwide. Earlier studies have reported that pancreatic fat content (PFC) and liver fat content (LFC) are risk factors for T2DM. The aim of the present study was to demonstrate the relationship between PFC, LFC and T2DM.
UNASSIGNED: A total of 70 T2DM subjects and 30 non-diabetic volunteers who underwent Dixon-based magnetic resonance imaging (MRI) method at Yixing People\'s Hospital between December 2018 to December 2020 were included in the study. The three-point Dixon (3p-Dixon) method was used to measure the fat content in the pancreas and liver. Clinical indices including gender, age, body mass index (BMI), total cholesterol, triglyceride, glucose and C peptide levels were collected. The association between PFC, LFC, and OGTT-derived parameters was examined by Pearson and Spearman correlation analyses.
UNASSIGNED: T2DM subjects had higher PFC and LFC than those measured in the non-diabetic subjects (p <0.05). PFC and LFC were associated positively with OGTT-derived parameters such as insulin secretion, insulin resistance, and early- and late-phase insulin secretion in the male T2DM subjects(p <0.05), but not in the non-diabetic and female T2DM subjects. The relationship between PFC and OGTT-derived parameters was also more obvious than that for LFC in overweight and obese male patients with T2DM whose BMI was >24 kg/m2.
UNASSIGNED: PFC and LFC were both associated with β-cell dysfunction and insulin resistance in males with T2DM. The relationship between PFC and β-cell dysfunction and insulin resistance was more obvious than that observed for LFC in overweight and obese male T2DM patients. More attention should therefore be paid to PFC in clinical settings.

OBJECTIVE: While the reduction of transient receptor potential channel subfamily M member 5 (TRPM5) has been reported in islet cells from type 2 diabetic (T2D) mouse models, its role in lipotoxicity-induced pancreatic β-cell dysfunction remains unclear. This study aims to study its role.
METHODS: Pancreas slices were prepared from mice subjected to a high-fat-diet (HFD) at different time points, and TRPM5 expression in the pancreatic β cells was examined using immunofluorescence staining. Glucose-stimulated insulin secretion (GSIS) defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate (Palm). Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm, and the TRPM5 expression was detected using qRT-PCR and Western blotting. Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown. The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5 (Ad-Trpm5).
RESULTS: HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets. Palm reduced TRPM5 protein expression in a time- and dose-dependent manner in MIN6 cells. Palm also inhibited TRPM5 expression in primary mouse islets. Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis. Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique to β cells.
CONCLUSIONS: Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreatic β cells both in vivo and in vitro and, in turn, drives β-cell dysfunction.

UNASSIGNED: To investigate the effects of β-cell dysfunction on IVF outcomes in women with PCOS.
UNASSIGNED: This retrospective cohort study includes 1,212 women with PCOS undergoing their first IVF cycle between September 2010 and December 2019. Beta-cell dysfunction was measured by homeostasis model assessment of β-cell function (HOMA-β) index.
UNASSIGNED: In quartiles of HOMA-β, the incidence of miscarriage dramatically increased from 10.2% (Q1) to 31.1% (Q4) (P for trend <0.001). Likewise, the incidence of miscarriage in quartiles of HOMA-β also showed a similar trend (P for trend <0.001). After adjusting for confounding factors, logistic regression analyses showed that high HOMA-IR values were independently associated with a high risk of miscarriage, with the odds ratios (OR) and 95% confidence intervals for quartiles 2-4 versus quartile 1 were 1.30 (0.69-2.46), 1.82 (0.97-3.43), and 3.57 (1.86-6.85), respectively (P for trend <0.001). When analyzed jointly, women in the highest HOMA-IR and highest HOMA-β group exhibited the highest risk for miscarriage compared with all other groups. Furthermore, higher HOMA-IR values were associated with higher risks of miscarriage among PCOS women regardless of HOMA-β values.
UNASSIGNED: β-cell dysfunction is independently associated with increased miscarriage rate and decreased live birth rate in women with PCOS. It also plays a synergistic role with IR in terms of the reproductive outcomes, while the influence of IR overweighs that of β-cell dysfunction.

The proinsulin-to-C-peptide (PI:C) ratio is an index applied during the early stage of pancreatic β-cell dysfunction. The aim of this study was to identify the characteristics associated with the PI:C ratio to discuss pancreatic β-cell dysfunction progression during the natural course of type 2 diabetes and its relationship with glycemic management. This multicenter, prospective observational study included 272 outpatients with type 2 diabetes. Continuous glucose monitoring was performed and fasting blood samples were collected and analyzed. We identified the clinical factors associated with the PI:C ratio by multiple regression analysis. The mean age of the cohort was 68.0 years, mean hemoglobin A1c 7.1% (54 mmol/mol), and mean body mass index 24.9 kg/m2. Multiple regression analysis showed that a prolonged time above the target glucose range (>180 mg/dL) and high body mass index contributed to a high PI:C ratio. However, no associations were found between the PI:C ratio and glucose variability indices. These findings suggested that the PI:C ratio is positively associated with a prolonged hyperglycemic time in type 2 diabetes, whereas its relationship with glucose variability remains unclear.

Recent studies have shown placenta-derived exosome (pdE) acts as an important mediator of organ-to-organ interplay regulating maternal metabolic alterations, however, the function and mechanisms of placental exosomes on pancreatic β-cell maladaptation in gestational diabetes mellitus (GDM) remain unclear. The purpose of this investigation was to ascertain how placental exosomes affected the β-cell dysfunction associated with the onset of GDM. Exosomes were isolated from chorionic villi explants of pregnant mice and humans with normal glucose tolerance (NGT) and GDM. The effects of pdE from GDM on glucose tolerance in vivo and islets function in vitro were determined. Isolated islets from mice fed on the chow diet displayed an increase in apoptosis and observed their glucose-stimulated insulin secretion (GSIS) greatly diminished by PdE from GDM mice. Mice that accepted PdE from mice with GDM possessed glucose intolerance.Based on miRNA microarray assay and bioinformatics analysis from human placental exosomes, we identified miR-320b selectively enriched in PdE secreted in GDM compared with NGT. Importantly, the level of placental miR-320b was positively correlated with the 1h-glucose and 2-h glucose of a 75 g oral glucose tolerance test (OGTT) during human pregnancies. Furthermore, miR-320 overexpression attributed to impaired insulin secretion and increased apoptosis in MIN6 cells and islets obtained from mice with normal insulin sensitivity. This study firstly proposed that altered miRNAs in pdE contribute to defective adaptation of β cells during pregnancy, which expands the knowledge of GDM pathogenesis. Exosomes from the placenta may be an emerging therapeutic target for GDM.

Age is the greatest risk factor for the development of type 2 diabetes mellitus (T2DM). Age-related decline in organ function is attributed to the accumulation of stochastic damage, including damage to the nuclear genome. Islets of T2DM patients display increased levels of DNA damage. However, whether this is a cause or consequence of the disease has not been elucidated. Here, we asked if spontaneous, endogenous DNA damage in β-cells can drive β-cell dysfunction and diabetes, via deletion of Ercc1, a key DNA repair gene, in β-cells. Mice harboring Ercc1-deficient β-cells developed adult-onset diabetes as demonstrated by increased random and fasted blood glucose levels, impaired glucose tolerance, and reduced insulin secretion. The inability to repair endogenous DNA damage led to an increase in oxidative DNA damage and apoptosis in β-cells and a significant loss of β-cell mass. Using electron microscopy, we identified β-cells in clear distress that showed an increased cell size, enlarged nuclear size, reduced number of mature insulin granules, and decreased number of mitochondria. Some β-cells were more affected than others consistent with the stochastic nature of spontaneous DNA damage. Ercc1-deficiency in β-cells also resulted in loss of β-cell function as glucose-stimulated insulin secretion and mitochondrial function were impaired in islets isolated from mice harboring Ercc1-deficient β-cells. These data reveal that unrepaired endogenous DNA damage is sufficient to drive β-cell dysfunction and provide a mechanism by which age increases the risk of T2DM.

Pancreatic β-cell dysfunction and eventual loss are key steps in the progression of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress responses, especially those mediated by the protein kinase RNA-like ER kinase and activating transcription factor 4 (PERK-ATF4) pathway, have been implicated in promoting these β-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in β-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts β-cell function via a downregulation of cAMP signaling. We found that β-cell-specific transgenic expression of ATF4 led to early β-cell dysfunction and loss, a phenotype that resembles accelerated T2D. Expression of ATF4, rather than C/EBP homologous protein (CHOP), promoted PDE4D expression, reduced cAMP signaling, and attenuated responses to incretins and elevated glucose. Furthermore, we found that β-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired β-cell function. Accordingly, pharmacological inhibition of the ATF4 pathway attenuated PDE4D expression in the islets and promoted incretin-simulated glucose tolerance and insulin secretion in db/db mice. Finally, we found that inhibiting PDE4 activity with selective pharmacological inhibitors improved β-cell function in both db/db mice and β-cell-specific ATF4 transgenic mice. In summary, our results indicate that ER stress causes β-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting β-cell function during the progression of T2D.NEW & NOTEWORTHY Endoplasmic reticulum stress has been implied to cause multiple β-cell pathologies during the progression of type 2 diabetes (T2D). However, the precise molecular events underlying this remain unknown. Here, we discovered that elevated ATF4 activity, which was seen in T2D β cells, attenuated β-cell proliferation and impaired insulin secretion via PDE4D-mediated downregulation of cAMP signaling. Additionally, we demonstrated that pharmacological inhibition of the ATF4 pathway or PDE4D activity alleviated β-cell dysfunction, suggesting its therapeutic usefulness against T2D.