Impaired Insulin Secretion Research Articles

Whole transcriptome sequencing analyses of islets reveal ncRNA regulatory networks underlying impaired insulin secretion and increased β-cell mass in high fat diet-induced diabetes mellitus.

Our study aims to identify novel non-coding RNA-mRNA regulatory networks associated with β-cell dysfunction and compensatory responses in obesity-related diabetes. Glucose metabolism, islet architecture and secretion, and insulin sensitivity were characterized in C57BL/6J mice fed on a 60% high-fat diet (HFD) or control for 24 weeks. Islets were isolated for whole transcriptome sequencing to identify differentially expressed (DE) mRNAs, miRNAs, IncRNAs, and circRNAs. Regulatory networks involving miRNA-mRNA, lncRNA-mRNA, and lncRNA-miRNA-mRNA were constructed and functions were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Despite compensatory hyperinsulinemia and a significant increase in β-cell mass with a slow rate of proliferation, HFD mice exhibited impaired glucose tolerance. In isolated islets, insulin secretion in response to glucose and palmitic acid deteriorated after 24 weeks of HFD. Whole transcriptomic sequencing identified a total of 1324 DE mRNAs, 14 DE miRNAs, 179 DE lncRNAs, and 680 DE circRNAs. Our transcriptomic dataset unveiled several core regulatory axes involved in the impaired insulin secretion in HFD mice, such as miR-6948-5p/Cacna1c, miR-6964-3p/Cacna1b, miR-3572-5p/Hk2, miR-3572-5p/Cckar and miR-677-5p/Camk2d. Additionally, proliferative and apoptotic targets, including miR-216a-3p/FKBP5, miR-670-3p/Foxo3, miR-677-5p/RIPK1, miR-802-3p/Smad2 and ENSMUST00000176781/Caspase9 possibly contribute to the increased β-cell mass in HFD islets. Furthermore, competing endogenous RNAs (ceRNA) regulatory network involving 7 DE miRNAs, 15 DE lncRNAs and 38 DE mRNAs might also participate in the development of HFD-induced diabetes. The comprehensive whole transcriptomic sequencing revealed novel non-coding RNA-mRNA regulatory networks associated with impaired insulin secretion and increased β-cell mass in obesity-related diabetes.

Glutathione Induces Keap1 S-Glutathionylation and Mitigates Oscillating Glucose-Induced β-Cell Dysfunction by Activating Nrf2.

Glutathione (GSH), a robust endogenous antioxidant, actively participates in the modulation of the redox status of cysteine residues in proteins. Previous studies have indicated that GSH can prevent β-cell failure and prediabetes caused by chronic oscillating glucose (OsG) administration. However, the precise mechanism underlying the protective effect is not well understood. Our current research reveals that GSH is capable of reversing the reduction in Nrf2 levels, as well as downstream genes Grx1 and HO-1, in the islet β-cells of rats induced by chronic OsG. In vitro experiments have further demonstrated that GSH can prevent β-cell dedifferentiation, apoptosis, and impaired insulin secretion caused by OsG. Additionally, GSH facilitates the translocation of Nrf2 into the nucleus, resulting in an upregulation of Nrf2-targeted genes such as GCLC, Grx1, HO-1, and NQO1. Notably, when the Nrf2 inhibitor ML385 is employed, the effects of GSH on OsG-treated β-cells are abrogated. Moreover, GSH enhances the S-glutathionylation of Keap1 at Cys273 and Cys288, but not Cys151, in OsG-treated β-cells, leading to the dissociation of Nrf2 from Keap1 and facilitating Nrf2 nuclear translocation. In conclusion, the protective role of GSH against OsG-induced β-cell failure can be partially attributed to its capacity to enhance Keap1 S-glutathionylation, thereby activating the Nrf2 signaling pathway. These findings provide novel insights into the prevention and treatment of β-cell failure in the context of prediabetes/diabetes, highlighting the potential of GSH.

High-Throughput Methods for the Discovery of Small Molecule Modulators of Pancreatic Beta-Cell Function and Regeneration.

The progression of type II diabetes (T2D) is characterized by a complex and highly variable loss of beta-cell mass, resulting in impaired insulin secretion. Many T2D drug discovery efforts aimed at discovering molecules that can protect or restore beta-cell mass and function have been developed using limited beta-cell lines and primary rodent/human pancreatic islets. Various high-throughput screening methods have been used in the context of drug discovery, including luciferase-based reporter assays, glucose-stimulated insulin secretion, and high-content screening. In this context, a cornerstone of small molecule discovery has been the use of immortalized rodent beta-cell lines. Although insightful, this usage has led to a more comprehensive understanding of rodent beta-cell proliferation pathways rather than their human counterparts. Advantages gained in enhanced physiological relevance are offered by three-dimensional (3D) primary islets and pseudoislets in contrast to monolayer cultures, but these approaches have been limited to use in low-throughput experiments. Emerging methods, such as high-throughput 3D islet imaging coupled with machine learning, aim to increase the feasibility of integrating 3D microtissue structures into high-throughput screening. This review explores the current methods used in high-throughput screening for small molecule modulators of beta-cell mass and function, a potentially pivotal strategy for diabetes drug discovery.

(+)-Catechin mitigates impairment in insulin secretion and beta cell damage in methylglyoxal-induced pancreatic beta cells.

The formation of advanced glycation end products (AGEs) is the central process contributing to diabetic complications in diabetic individuals with sustained and inconsistent hyperglycemia. Methylglyoxal, a reactive carbonyl species, is found to be a major precursor of AGEs, and its levels are elevated in diabetic conditions. Dysfunction of pancreatic beta cells and impairment in insulin secretion are the hallmarks of diabetic progression. Exposure to methylglyoxal-induced AGEs alters the function and maintenance of pancreatic beta cells. Hence, trapping methylglyoxal could be an ideal approach to alleviate AGE formation and its influence on beta cell proliferation and insulin secretion, thereby curbing the progression of diabetes to its complications. In the present study, we have explored the mechanism of action of (+)-Catechin against methylglyoxal-induced disruption in pancreatic beta cells via molecular biology techniques, mainly western blot. Methylglyoxal treatment decreased insulin synthesis (41.5%) via downregulating the glucose-stimulated insulin secretion pathway (GSIS). This was restored upon co-treatment with (+)-Catechin (29.9%) in methylglyoxal-induced Beta-TC-6 cells. Also, methylglyoxal treatment affected the autocrine function of insulin by disrupting the IRS1/PI3k/Akt pathway. Methylglyoxal treatment suppresses Pdx-1 and Maf A levels, which are responsible for beta cell maintenance and cell proliferation. (+)-Catechin could significantly augment the levels of these transcription factors. This is the first study to examine the impact of a natural compound on methylglyoxal with the insulin-mediated autocrine and paracrine activities of pancreatic beta cells. The results indicate that (+)-Catechin exerts a protective effect against methylglyoxal exposure in pancreatic beta cells and can be considered a potential anti-glycation agent in further investigations on ameliorating diabetic complications.

Imeglimin mitigates the accumulation of dysfunctional mitochondria to restore insulin secretion and suppress apoptosis of pancreatic β-cells from db/db mice

Mitochondrial dysfunction in pancreatic β-cells leads to impaired glucose-stimulated insulin secretion (GSIS) and type 2 diabetes (T2D), highlighting the importance of autophagic elimination of dysfunctional mitochondria (mitophagy) in mitochondrial quality control (mQC). Imeglimin, a new oral anti-diabetic drug that improves hyperglycemia and GSIS, may enhance mitochondrial activity. However, chronic imeglimin treatment’s effects on mQC in diabetic β-cells are unknown. Here, we compared imeglimin, structurally similar anti-diabetic drug metformin, and insulin for their effects on clearance of dysfunctional mitochondria through mitophagy in pancreatic β-cells from diabetic model db/db mice and mitophagy reporter (CMMR) mice. Pancreatic islets from db/db mice showed aberrant accumulation of dysfunctional mitochondria and excessive production of reactive oxygen species (ROS) along with markedly elevated mitophagy, suggesting that the generation of dysfunctional mitochondria overwhelmed the mitophagic capacity in db/db β-cells. Treatment with imeglimin or insulin, but not metformin, reduced ROS production and the numbers of dysfunctional mitochondria, and normalized mitophagic activity in db/db β-cells. Concomitantly, imeglimin and insulin, but not metformin, restored the secreted insulin level and reduced β-cell apoptosis in db/db mice. In conclusion, imeglimin mitigated accumulation of dysfunctional mitochondria through mitophagy in diabetic mice, and may contribute to preserving β-cell function and effective glycemic control in T2D.

KSRP improves pancreatic beta cell function and survival

Impaired insulin production and/or secretion by pancreatic beta cells can lead to high blood glucose levels and type 2 diabetes (T2D). Therefore, investigating new proteins involved in beta cell response to stress conditions could be useful in finding new targets for therapeutic approaches. KH-type splicing regulatory protein (KSRP) is a protein usually involved in gene expression due to its role in post-transcriptional regulation. Although there are studies describing the important role of KSRP in tissues closely related to glucose homeostasis, its effect on pancreatic beta cells has not been explored so far. Pancreatic islets from diet-induced obese mice (C57BL/6JUnib) were used to determine KSRP expression and we also performed in vitro experiments exposing INS-1E cells (pancreatic beta cell line) to different stressors (palmitate or cyclopiazonic acid—CPA) to induce cellular dysfunction. Here we show that KSRP expression is reduced in all the beta cell dysfunction models tested. In addition, when manipulated to knock down KSRP, beta cells exhibited increased death and impaired insulin secretion, whereas KSRP overexpression prevented cell death and increased insulin secretion. Taken together, our findings suggest that KSRP could be an important target to protect beta cells from impaired functioning and death.

A real-world disproportionality analysis of Everolimus: data mining of the public version of FDA adverse event reporting system.

Background: Everolimus is an inhibitor of the mammalian target of rapamycin and is used to treat various tumors. The presented study aimed to evaluate the Everolimus-associated adverse events (AEs) through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: The AE records were selected by searching the FDA Adverse Event Reporting System database from the first quarter of 2009 to the first quarter of 2022. Potential adverse event signals were mined using the disproportionality analysis, including reporting odds ratio the proportional reporting ratio the Bayesian confidence propagation neural network and the empirical Bayes geometric mean and MedDRA was used to systematically classify the results. Results: A total of 24,575 AE reports of Everolimus were obtained using data from the FAERS database, and Everolimus-induced AEs occurrence targeted 24 system organ classes after conforming to the four algorithms simultaneously. The common significant SOCs were identified, included benign, malignant and unspecified neoplasms, reproductive system and breast disorders, etc. The significant AEs were then mapped to preferred terms such as stomatitis, pneumonitis and impaired insulin secretion, which have emerged in the study usually reported in patients with Everolimus. Of note, unexpected significant AEs, including biliary ischaemia, angiofibroma, and tuberous sclerosis complex were uncovered in the label. Conclusion: This study provided novel insights into the monitoring, surveillance, and management of adverse drug reaction associated with Everolimus. The outcome of serious adverse events and the corresponding detection signals, as well as the unexpected significant adverse events signals are worthy of attention in order to improving clinical medication safety during treatment of Everolimus.

Caffeic Acid Dimethyl Ether Ameliorates Excessive Glucose and Lipid-Induced Insulin Secretion Dysfunction in Pancreatic Beta-Cells through the miR-378b–PI3K–AKT Pathway

An important factor in the progression of type 2 diabetes mellitus is the malfunctioning insulin production by β-cells in the pancreas. Caffeic acid dimethyl ether (CADE) reduces resistance to insulin in alcoholic fatty liver disease, but both the therapeutic effects of CADE on excessive glucose and lipid-induced insulin secretion disorders and the underlying mechanisms are unknown. The aim of this research was to (i) explore how CADE impacts insulin production issues caused by a surplus of glucose and lipids β-cells and (ii) elucidate the underlying mechanism. The results of our research demonstrated that insulin production was reduced in the pancreas of mice given a high-fat -diet and streptozotocin, as well as in human 1.1B4 pancreatic β-cells treated with high -glucose and high -fat, with increased activity of miR-378b and decreased expression levels of p110α, p-AKT1/2, insulin receptor, p-FoxO1, and PDX-1. However, treatment with CADE ameliorated the insulin secretion impairment by decreasing the miR-378b level and reversing the inhibitory effects on the aforementioned factors. Overexpression of miR-378b exacerbated the insulin secretion disorder and inhibited the PI3K-AKT signaling pathway, whereas miR-378b deficiency relieved the insulin secretion disorder, activating the PI3K-AKT pathway. In addition, CADE ameliorated the impairment of insulin secretion and reversed the miR-378b overexpression-induced PI3K-AKT pathway inhibition. In conclusion, our study demonstrates that CADE ameliorated insulin secretion dysfunction induced by excess lipid and glucose in β-cells by downregulating miR-378b expression, thus promoting PI3K-AKT activation.

Tyrosine nitration of glucagon impairs its function: Extending the role of heme in T2D pathogenesis

New studies raise the possibility that the higher glucagon (GCG) level present in type 2 diabetes (T2D) is a compensatory mechanism to enhance β-cell function, rather than induce dysregulated glucose homeostasis, due to an important role for GCG that acts directly within the pancreas on insulin secretion by intra-islet GCG signaling. However, in states of poorly controlled T2D, pancreatic α cell mass increases (overproduced GCG) in response to insufficient insulin secretion, indicating decreased local GCG activity. The reason for this decrease is not clear. Recent evidence has uncovered a new role of heme in cellular signal transduction, and its mechanism involves reversible binding of heme to proteins. Considering that protein tyrosine nitration in diabetic islets increases and glucose-stimulated insulin secretion (GSIS) decreases, we speculated that heme modulates GSIS by transient interaction with GCG and catalyzing its tyrosine nitration, and the tyrosine nitration may impair GCG activity, leading to loss of intra-islet GCG signaling and markedly impaired insulin secretion. Data presented here elucidate a novel role for heme in disrupting local GCG signaling in diabetes. Heme bound to GCG and induced GCG tyrosine nitration. Two tyrosine residues in GCG were both sensitive to the nitrating species. Further, GCG was also demonstrated to be a preferred target peptide for tyrosine nitration by co-incubation with BSA. Tyrosine nitration impaired GCG stimulated cAMP-dependent signaling in islet β cells and decreased insulin release. Our results provided a new role of heme for impaired GSIS in the pathological process of diabetes.

Long Suffering Type 1 Diabetes Mellitus During Metabolic Acidosis on Positiveness of Ketones in Urine Patients

Examination of ketones in the patient's urine and measuring the patient's blood sugar level will determine whether there will be metabolic acidosis in patients with type 1 diabetes mellitus, which is a metabolic disorder that can be caused by various etiologies, such as chronic hyperglycemia due to impaired insulin secretion or impaired insulin action. alone. Diabetes Mellitus type 1 itself is more caused by reduced insulin secretion due to damage to pancreatic -cells. This study was conducted to examine ketones in urine on the duration of suffering from type 1 diabetes mellitus when metabolic acidosis occurs Data collection in this study was carried out by accidental sampling method by researchers to collect secondary and primary data on urine ketones in patients with metabolic acidosis. Based on research that has been done, data obtained from 34 patients with type 1 diabetes mellitus at the Sigerongan Health Center, as many as 8 patients with positive results of urine ketones with a prevalence of +2 totaling 3 people and +3 totaling 5 people. Judging from the high level of glucose (hyperglycemia) that is > 200 mg/dl and the positivity of ketone bodies in the patient's urine as a sign of metabolic acidosis. With a long-susceptibility to suffer from diabetes mellitus 1-5 years and above. The results of measuring ketone levels in the patient's urine show that there is no relationship with the duration of suffering from diabetes mellitus in the urine but blood sugar levels.

Exosomes as Emerging Regulators of Immune Responses in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood glucose levels resulting from insulin resistance and impaired insulin secretion. Immune dysregulation-mediated chronic low-grade inflammation is a critical factor that poses a significant risk to the metabolic disorders of T2DM and its related complications. Exosomes, as small extracellular vesicles secreted by various cells, have emerged as essential regulators of intercellular communication and immune regulation. In this review, we summarize the current understanding of the role of exosomes derived from immune and nonimmune cells in modulating immune responses in T2DM by regulating immune cell functions and cytokine production. More importantly, we suggest potential strategies for the clinical applications of exosomes in T2DM management, including biomarkers for disease diagnosis and monitoring, exosome-based therapies for drug delivery vehicles, and targeted therapy for exosomes.

Monogenic diabetes.

Diseases in which genetic factors contribute to nearly 100% of the causation by single-gene mutations are referred to as monogenic disorders or Mendelian genetic diseases. These include neonatal diabetes mellitus (NDM), presenting within the first six months of life, maturity-onset diabetes of the young (MODY), developing later in childhood or adolescence, mitochondrial diabetes (MIDD), and insulin-resistant disorders, etc. On the other hand, common lifestyle-related diseases such as type 2 diabetes (T2DM), hypertension and dyslipidemia are multifactorial, emerging through complex interplay of genetic and environmental factors. The identification of causative genes for diabetes resulting from single-gene abnormalities not only unveils previously unknown mechanisms of insulin secretion and sensitivity at the molecular level but also reveals novel targets for drug development. Moreover, monogenic diabetes in which insulin secretion is impaired serve to clarify the pathophysiology and suggest therapeutic targets for the common multifactorial type 2 diabetes mellitus prevalent in the Japanese population, which is characterized by impaired insulin secretion. In this study, we characterize the various monogenic subtypes of diabetes so far identified.

Glucose intolerance in acromegaly is driven by low insulin secretion; results from an intravenous glucose tolerance test.

Insulin sensitivity (Si) and its role in glucose intolerance of acromegaly has been extensively evaluated. However, data on insulin secretion is limited. We aimed to assess stimulated insulin secretion using an intravenous glucose tolerance test (IVGTT) in active acromegaly. We performed an IVGTT in 25 patients with active acromegaly (13 normal glucose tolerance [NGT], 6 impaired glucose tolerance [IGT] and 6 diabetes mellitus [DM]) and 23 controls (8 lean NGT, 8 obese NGT and 7 obese IGT). Serum glucose and insulin were measured at 20 time points along the test to calculate Si and acute insulin response (AIRg). Medical treatment for acromegaly or diabetes was not allowed. In acromegaly, patients with NGT had significantly (p for trend < 0.001) higher AIRg (3383 ± 1082 pmol*min/L) than IGT (1215 ± 1069) and DM (506 ± 600). AIRg was higher in NGT (4764 ± 1180 pmol*min/L) and IGT (3183 ± 3261) controls with obesity than NGT (p = 0.01) or IGT (p = 0.17) acromegaly. Si was not significantly lower in IGT (0.68 [0.37, 0.88] 106*L/pmol*min) and DM (0.60 [0.42, 0.84]) than in NGT (0.81 [0.58, 1.55]) patients with acromegaly. NGT (0.33 [0.30, 0.47] 106*L/pmol*min) and IGT (0.37 [0.21, 0.66]) controls with obesity had lower Si than NGT (p = 0.001) and IGT (p = 0.43) acromegaly. We demonstrated that low insulin secretion is the main driver behind glucose intolerance in acromegaly. Compared to NGT and IGT controls with obesity, patients with NGT or IGT acromegaly had higher Si. Together, these findings suggest that impaired insulin secretion might be a specific mechanism for glucose intolerance in acromegaly.

KCNH6 is essential for insulin secretion by regulating intracellular ER Ca2+ store.

Appropriate Ca2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca2+ signal, serves significant roles in physiological function of pancreatic β cells. To maintaining ER homeostasis, Ca2+ movement across the ER membrane is always accompanied by a simultaneous K+ flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic β-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 β-cell-specific knockout (βKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of βKO mice, which contributed to ER stress and ER stress-induced apoptosis in β cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic β cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in βKO mice, restored ER Ca2+ overload and attenuated ER stress in β cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca2+ stores and protect β cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes.

Cyb5r3 activation rescues secondary failure to sulfonylurea but not β-cell dedifferentiation.

Diabetes mellitus is characterized by insulin resistance and β-cell failure. The latter involves impaired insulin secretion and β-cell dedifferentiation. Sulfonylurea (SU) is used to improve insulin secretion in diabetes, but it suffers from secondary failure. The relationship between SU secondary failure and β-cell dedifferentiation has not been examined. Using a model of SU secondary failure, we have previously shown that functional loss of oxidoreductase Cyb5r3 mediates effects of SU failure through interactions with glucokinase. Here we demonstrate that SU failure is associated with partial β-cell dedifferentiation. Cyb5r3 knockout mice show more pronounced β-cell dedifferentiation and glucose intolerance after chronic SU administration, high-fat diet feeding, and during aging. A Cyb5r3 activator improves impaired insulin secretion caused by chronic SU treatment, but not β-cell dedifferentiation. We conclude that chronic SU administration affects progression of β-cell dedifferentiation and that Cyb5r3 activation reverses secondary failure to SU without restoring β-cell dedifferentiation.

The correlation between the neutrophil-to-lymphocyte ratio and random blood glucose in patients with type 2 diabetes mellitus in Prof. Dr. I G. N. G. Ngoerah Hospital

Background: Diabetes mellitus and complications related to this disease have become a great problem affecting one in eleven adults. Pathophysiologically, this disease occurs due to impaired insulin secretion, resulting from systemic dysfunction in metabolic homeostasis involving inflammatory processes. One marker that can be used to measure such chronic inflammation is the neutrophil-lymphocyte ratio. Therefore, this study aims to evaluate the association between the neutrophil-to-lymphocyte ratio (NLR) with random blood glucose in patients with type 2 diabetes mellitus in Prof. Dr. I G. N. G. Ngoerah Hospital Methods: Our study is a cross-sectional study with secondary data from medical records and involved 155 type 2 diabetes mellitus patients who received inpatient or outpatient care at Prof. Dr. I G. N. G. Ngoerah Hospital in the period of 2021-2022. Results: Our analysis found a significant correlation between the neutrophil-lymphocyte ratio with random blood sugar levels (r = 0.228; p = 0.004). Additionally, the analysis also found a significant difference in random blood sugar level between the normal with the high neutrophil-lymphocyte ratio groups (p = 0.023; median difference = 39.5 mg/dL). Conclusion: It can be inferred that there is a weak and significant correlation between NLR with random blood glucose level in type 2 diabetes mellitus patients.

Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity

ObjectiveLipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. MethodsMale and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10–12 and 16–18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. ResultsAll groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. ConclusionsTAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis.

Insulin resistance and impaired insulin secretion and gastrointestinal cancer risk in Korean adults: Preliminary results from Korean Genome and Epidemiology study.

761 Background: To date, few studies conducted on the effect of insulin resistance or insulin secretory function on cancer risk in non-diabetic population. This study evaluated whether insulin resistance and/or insulin secretory function affect gastrointestinal cancer risk in the Korean population. Methods: We analyzed data from Korean Genome and Epidemiology Study, Korea Association Resource dataset. It consists of 10,030 participants aged 40-69y observed from 2001 to 2018. The risk of all cancers, and gastrointestinal cancers were assessed. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Homeostasis Model Assessment of Beta-cell function (HOMA-β) were used as indicators of insulin resistance and insulin secretory function. Results: In the final dataset, 8,649 individuals without previous history of any cancers were included. During an average follow-up of 15 years, 415 subjects (4.8%) developed cancers. Compared to the low HOMA-IR/high HOMA-β group (reference), diabetic patients had the highest risk of overall cancers, followed by high HOMA-IR/low HOMA-β group (Adjusted hazard ratio[95% confidence interval]: 1.74 [1.11 - 2.75] and 1.40 [0.96 – 2.06], respectively) Among gastrointestinal cancers, the risk of gastric cancer was higher in the low HOMA-IR/low HOMA-β and high HOMA-IR/high HOMA-β groups (1.92 [1.06 - 3.47] and 2.27 [1.26 - 4.06], respectively) When further analyzed by HOMA-β stratified by quartiles, the lowest quartile (Q1) showed an increased risk of gastric cancer compared to the highest-quartile (Q4; 1.84 [0.98 – 3.46], p = 0.06) In contrast, no significant results were observed regarding the colorectal cancer risk, when analyzed based on HOMA-IR and HOMA-β. However, when further analyzed by HOMA-IR stratified by quartiles, the highest quartile (Q4) exhibited a significantly elevated colorectal cancer risk compared to the lowest quartile (Q1; 2.14 [1.11 - 4.11], P for trend = 0.04). Conclusions: Insulin resistance and impaired insulin secretion function may increase the risk of cancer, but the underlying mechanisms may differ by cancer type.

Dysregulation of autophagy activation induced by atorvastatin contributes to new-onset diabetes mellitus in western diet-fed mice

Background and aimsThe incidence of statin-induced new-onset diabetes (NOD) is increasing but its underlying mechanisms remain unclear. We aimed to investigate the effects of various doses of atorvastatin (ATO)-induced autophagy on the development of NOD. Methods and resultsThe isolated rat islets and MIN6 cells-treated with ATO, exhibited impaired glucose-stimulated insulin secretion, reduced insulin content, and induced apoptosis. Additionally, autophagy was induced at all doses (in vitro: 5, 10, 20 μM; in vivo: 10, 15, 20 mg/kg) in ATO-treated MIN6 cells or western diet (WD)-fed mice. In contrast to normal glucose-tolerant mice administered a low-dose (10 mg/kg) ATO, those treated with high-doses (15 or 20 mg/kg) exhibited impaired glucose tolerance. Furthermore, high-dose ATO-treated mice showed decreased β-cell mass and increased apoptosis compared to that of vehicle-treated mice. We also observed that the number of vesicophagous cells in the pancreas of 20 mg/kg ATO-treated WD-fed mice was higher than in vehicle-treated WD-fed mice. Inhibiting autophagy using 3-methyladenine (3-MA) and siAtg5 improved glucose tolerance in vivo and in vitro by preventing apoptotic β-cell death and restoring insulin granules. ConclusionThese results indicate that high doses of ATO induced hyperactivated autophagy in pancreatic cells, leading to impaired insulin storage, decreased cell viability, and reduced functional cell mass, ultimately resulting in NOD development.

Uji Efektivitas Ekstrak Daun Jambu Biji (Psidium guajava) dalam Menurunkan Kadar Gula Darah Mencit (Mus musculus)

Diabetes mellitus is a disorder of blood sugar metabolism chronically characterized by high blood sugar levels resulting from impaired insulin secretion, insulin resistance, or both. Treatment of diabetes mellitus consists of four pillars: education, medical nutrition therapy (MNT), and physical and pharmacological therapies. One of the plants that can be used as a medicinal ingredient is guava leaves. Guava (Psidium guajava L.) leaves are a group of herbal plants with a chemical content that is good for health. Therefore, guava (Psidium guajava L.) leaves are plants that are efficacious as medicine. This plant contains secondary metabolites that act as antidiabetics. Thus, the research aimed to determine the effectiveness of ethanol extract of guava (Psidium guajava L.) leaves on the decrease in blood sugar levels in male mice. The research method employed was maceration, phytochemical screening, and antidiabetic testing with the pre-test and post-test control group design methods to determine if there was a decrease after administration of the extract. The findings indicated that the phytochemical screening test found that guava (Psidium guajava L.) contained secondary metabolites, including alkaloids, flavonoids, and tannins. In contrast, the antidiabetic test revealed that three extracts with concentrations of 50 mg, 100 mg. and 200 mg could decrease blood sugar levels by 15%, 21%, and 47%, respectively. From these findings, it can be concluded that antidiabetic compounds which play a role in the ellanol extrict of guava (Psidium guajava L.) leaves are alkaloids, flavonoids, and tannins.