Islet Β-cell Function Research Articles

Study on the correlation between the changes of TNFR1, TNF-α, and adiponectin in patients with gestational diabetes mellitus and insulin resistance

Gestational diabetes mellitus (GDM) refers to pregnant women with impaired glucose tolerance, which could bring high risk to the mother and fetus. However, the early diagnosis and treatment of GDM remained unclear. In this study, 60 patients with GDM were selected as the research group and 50 healthy pregnant women as the control group. Tumor necrosis factor receptor 1 (TNFR1), tumor necrosis factor-α (TNF-α), and adiponectin (ADP) in the serum were measured by enzyme-linked immunosorbent assays (ELISAs). The levels of fasting blood glucose (FBG), fasting insulin (FINS), and glycosylated hemoglobin (HbA1c) were also detected to calculate homeostasis model assessment insulin resistance index (HOMA-IR) and pancreatic β-cell function index (HOMA-HBCl). Compared with the control group, the serum levels of TNFR1, TNF-α, and HbA1c in research group were significantly increased ( P < 0.05), while ADP showed lower levels ( P < 0.01). Furthermore, FBG, FINS, and HOMA-IR were evidently increased ( P < 0.05), while homeostasis model assessment insulin secretion index (HOMA-β) and insulin sensitivity index (ISI) were decreased ( P < 0.05) in research group. TNFR and TNF-α were positively correlated with FBG, FINS, and HOMA-IR ( P < 0.05). In addition, there was a significant negative correlation between ADP and FINS and HOMA-IR ( P < 0.01). From logistic regression analysis, age, gestational age, FBG, FINS, TNFR1, TNF-α, and ADP ( P < 0.05) were shown to be risk factors to affect the function of islet β-cells. In conclusion, the high levels of TNFR1 and TNF-α and the low levels of ADP in the second trimester of pregnancy are the risk factors of GDM, which are related to the insulin resistance and impaired pancreatic β-cell function.

Methods to Investigate β-Arrestin Function in Metabolic Regulation.

Type II diabetes is one of the most serious worldwide public health problems, and its hallmark is insulin resistance, obesity associated with chronic inflammation, and defective islet β-cell function. β-Arrestins play important roles in diabetes pathogenesis through scaffolding insulin-induced AKT activation in the liver, suppressing peroxisome proliferator-activated receptor-γ-mediated adipogenesis and inflammatory responses in adipose tissue and through promoting GLP-1-induced insulin secretion in the islet. The current chapter provides detailed protocols for both in vitro and in vivo studies of the function of β-arrestins associated with type II diabetes.

Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally.

The sustained expression of the MAFB transcription factor in human islet β-cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet β-cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet β-cell population and that MafB expression is postnatally restricted in mouse β-cells by de novo DNA methylation. To gain insight into how MAFB affects human β-cells, we developed a mouse model to ectopically express MafB in adult mouse β-cells using MafA transcriptional control sequences. Coexpression of MafB with MafA had no overt impact on mouse β-cells, suggesting that the human adult β-cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet β-cell defects in a mouse mutant lacking MafA in β-cells. Of note, transgenic production of MafB in β-cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives the serotonin biosynthesis critical for adaptive maternal β-cell responses. Together, these studies provide novel insight into the role of MAFB in human islet β-cells.

MiR-128-3p accelerates cardiovascular calcification and insulin resistance through ISL1-dependent Wnt pathway in type 2 diabetes mellitus rats.

Vascular calcification is highly prevalent in patients with type 2 diabetes mellitus (T2DM), one of the most common chronic diseases with high morbidity and mortality. In recent years, microRNAs have been widely reported as potential biomarkers for the diagnosis and treatment of T2DM. We hypothesized that miR-128-3p is associated with cardiovascular calcification and insulin resistance (IR) in rats with T2DM by targeting ISL1 via the Wnt pathway. Microarray analysis was adopted to identify differentially expressed genes related to T2DM. T2DM models were induced in rats. Blood samples from normal and T2DM rats were used to detect islet β-cell function, islet sensitivity, and calcium content. Next, islet tissues were obtained to identify the expression of miR-128-3p, ISL1, and the Wnt signaling pathway- and apoptosis-related genes. Finally, apoptosis of islet β-cells was determined by flow cytometry. Through microarray analysis of GSE27382 and GSE23343, ISL1 was found to be downregulated in T2DM. In blood samples from T2DM rats, basic biochemical indicators, IR, and calcium content were increased, and islet sensitivity and islet β-cell function were decreased. Furthermore, upregulation of miR-128-3p and ISL1 gene silencing promoted the expression of Wnt-1, β-catenin, GSK-3β, and Bax and the phosphorylation of β-catenin and GSK-3β, inhibited c-fos, PDX-1, and Bcl-2 expression, and enhanced cell apoptosis. The key findings of our study demonstrate that miR-128-3p aggravates cardiovascular calcification and IR in T2DM rats by downregulating ISL1 through the activation of the Wnt pathway. Thus, miR-128-3p may serve as a potential target for the treatment of T2DM.

TRPV1 neurons regulate β-cell function in a sex-dependent manner

There is emerging evidence to support an important role for the transient receptor potential vanilloid type 1 (TRPV1) sensory innervation in glucose homeostasis. However, it remains unknown whether the glucoregulatory action of these afferent neurons is sex-biased and whether it is pancreatic β-cell-mediated. ObjectiveWe investigated in male and female mice whether denervation of whole-body or pancreas-projecting TRPV1 sensory neurons regulates adult functional β-cell mass and alters systemic glucose homeostasis. MethodsWe used a combination of pharmacological and surgical approaches to ablate whole-body or pancreatic TRPV1 sensory neurons and assessed islet β-cell function and mass, aspects of glucose and insulin homeostasis, and energy expenditure. ResultsCapsaicin-induced chemodenervation of whole-body TRPV1 sensory neurons improved glucose clearance and enhanced glucose-stimulated insulin secretion without alterations in β-cell proliferation and mass, systemic insulin sensitivity, body composition, and energy expenditure. Similarly, denervation of intrapancreatic TRPV1 afferents by pancreas intraductal injection of capsaicin or surgical removal of the dorsal root ganglia projecting into the pancreas lowered post-absorptive glucose levels and increased insulin release upon glucose stimulation. The beneficial effects of TRPV1 sensory denervation on glucose tolerance and β-cell function were observed in male but not female mice. ConclusionCollectively, these findings suggest that TRPV1 neurons regulate glucose homeostasis, at least partly, through direct modulation of glucose-induced insulin secretion and that this regulation operates in a sex-dependent manner.

Liraglutide protects β-cell function by reversing histone modification of Pdx-1 proximal promoter in catch-up growth male rats

AimsCatch-up growth after a period of nutritional deprivation in adulthood is related to the onset of metabolic disorders. This process involves chromatin remodelling of the Pdx-1 gene in pancreas. The objective of this study was to determine the chromatin remodelling mechanism of GLP-1 analogue Liraglutide upon Pdx-1 in catch-up growth rats in vivo and in vitro. MethodsFive-week-old male specific pathogen free (SPF) Wistar rats were randomly divided into normal group, catch-up growth group and Liraglutide group. Hyperglycemic clamp test and glucose-stimulated insulin secretion test were carried out to evaluate β-cell function in vivo and in vitro. The histone H3 modification changes at the Pdx-1 proximal promoter were assessed by chromatin immunoprecipitation. ResultsThe catch-up growth state was characterized by less recruitment of histone H3 lysine4 trimethylation and histone H3 acetylation and more recruitment of histone H3 lysine9 dimethylation at the Pdx-1 proximal promoter. Liraglutide treatment reversed these epigenetic changes and increased Pdx-1 expression, which could be abrogated by GLP-1 receptor antagonist Exendin 9-39. The β-cell function of catch-up growth rats was improved after Liraglutide treatment. ConclusionsThe protective effects of Liraglutide on pancreatic islet β-cell function may be related to histone H3 modification at the Pdx-1 proximal promoter during catch-up growth and could be used to treat catch-up growth-related metabolic disorders.

In vitro characterization of neonatal, juvenile, and adult porcine islet oxygen demand, β-cell function, and transcriptomes.

There is currently a shortage of human donor pancreata which limits the broad application of islet transplantation as a treatment for type 1 diabetes. Porcine islets have demonstrated potential as an alternative source, but a study evaluating islets from different donor ages under unified protocols has yet to be conducted. Neonatal porcine islets (NPI; 1-3days), juvenile porcine islets (JPI; 18-21days), and adult porcine islets (API; 2+years) were compared in vitro, including assessments of oxygen consumption rate, membrane integrity determined by FDA/PI staining, β-cell proliferation, dynamic glucose-stimulated insulin secretion, and RNA sequencing. Oxygen consumption rate normalized to DNA was not significantly different between ages. Membrane integrity was age dependent, and API had the highest percentage of intact cells. API also had the highest glucose-stimulated insulin secretion response during a dynamic insulin secretion assay and had 50-fold higher total insulin content compared to NPI and JPI. NPI and JPI had similar glucose responsiveness, β-cell percentage, and β-cell proliferation rate. Transcriptome analysis was consistent with physiological assessments. API transcriptomes were enriched for cellular metabolic and insulin secretory pathways, while NPI exhibited higher expression of genes associated with proliferation. The oxygen demand, membrane integrity, β-cell function and proliferation, and transcriptomes of islets from API, JPI, and NPI provide a comprehensive physiological comparison for future studies. These assessments will inform the optimal application of each age of porcine islet to expand the availability of islet transplantation.

Activation of imidazoline receptor I2, and improved pancreatic β-cell function in human islets

AimThe impact of BL11282, an imidazoline receptor (NISCH) agonist, on potentiation of glucose-stimulated insulin secretion (GSIS) from isolated human non-diabetic (ND) and type 2 diabetic (T2D) islets was investigated. MethodsAnalysis of mRNA was performed by RNA-sequencing and qPCR. Insulin and cAMP by RIA and ELISA respectively. ResultsRNA-sequencing data revealed that NISCH is highly expressed in fat tissues, islets, liver and muscles, with eight detectable splice variants of transcripts in islets. NISCH had a positive correlation with GLP-1 (GLP1R) and GIP (GIPR) receptor transcripts. The expression of NISCH was confirmed by qPCR in human islets. NISCH and GLP1R were comparably higher expressed in mouse islets compared to human islets. GSIS was dose-dependently potentiated by BL11282 from incubated islets of ND and T2D human islet donors. The insulinotropic action of BL11282 was associated with increased cAMP. While the harmful effect of high glucose on reductive capacity of islet cells was enhanced by glibenclamide during long-term culture, it was counteracted by BL11282 or Bt2-cAMP. BL11282 also increased proliferation of INS-1 cells during long-time culture. ConclusionOur data suggest that BL11282 potentiates GSIS by an action involving cAMP/PKA system and BL11282 could be an attractive insulinotropic and β-cell protective agent.

Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet β-cell de-differentiation

ObjectivePancreatic tissue, and islets in particular, are enriched in expression of the interleukin-1 receptor type I (IL-1R). Because of this enrichment, islet β-cells are exquisitely sensitive to the IL-1R ligands IL-1α and IL-1β, suggesting that signaling through this pathway regulates health and function of islet β-cells. MethodsHerein, we report a targeted deletion of IL-1R in pancreatic tissue (IL-1RPdx1−/−) in C57BL/6J mice and in db/db mice on the C57 genetic background. Islet morphology, β-cell transcription factor abundance, and expression of the de-differentiation marker Aldh1a3 were analyzed by immunofluorescent staining. Glucose and insulin tolerance tests were used to examine metabolic status of these genetic manipulations. Glucose-stimulated insulin secretion was evaluated in vivo and in isolated islets ex vivo by perifusion. ResultsPancreatic deletion of IL-1R leads to impaired glucose tolerance, a phenotype that is exacerbated by age. Crossing the IL-1RPdx1−/− with db/db mice worsened glucose tolerance without altering body weight. There were no detectable alterations in insulin tolerance between IL-1RPdx1−/− mice and littermate controls. However, glucose-stimulated insulin secretion was reduced in islets isolated from IL-1RPdx1−/− relative to control islets. Insulin output in vivo after a glucose challenge was also markedly reduced in IL-1RPdx1−/− mice when compared with littermate controls. Pancreatic islets from IL-1RPdx1−/− mice displayed elevations in Aldh1a3, a marker of de-differentiation, and reduction in nuclear abundance of the β-cell transcription factor MafA. Nkx6.1 abundance was unaltered. ConclusionsThere is an important physiological role for pancreatic IL-1R to promote glucose homeostasis by suppressing expression of Aldh1a3, sustaining MafA abundance, and supporting glucose-stimulated insulin secretion in vivo.

Islet β-cell function in patients with gout and hyperuricemia accompanied by increased 1h postload plasma glucose

All of 143 patients with gout or hyperuricemia were divided into type 2 diabetes(n=43), impaired glucose regulation(n=45), and normal glucose tolerance(n=55)groups. Moreover, a cut point of 8.6 mmol/L in one hour postload plasma glucose(1hPG)of oral glucose tolerance test was used to sub-divide the normal glucose tolerance group into 1hPG≥8.6 mmol/L(n=30)and 1hPG 0.05). The first-phase insulin secretion index revealed no significant difference between impaired glucose regulation and 1hPG≥8.6 mmol/L groups(P>0.05), but obviously decreased in these two groups compared with 1hPG<8.6 mmol/L group(P<0.05). The modified β cell function indexes were gradually decreased in 1hPG<8.6 mmol/L, 1hPG≥8.6 mmol/L, and impaired glucose regulation groups(P<0.05). These results suggest that when 1hPG of the patients with gout and hyperuricemia is over 8.6 mmol/L, the first-phase insulin secretion will be impaired. (Chin J Endocrinol Metab, 2018, 34: 300-303) Key words: Gout; Hyperuricemia; β-cell function

MicroRNA-30d preserves pancreatic islet β-cell function through negative regulation of the JNK signaling pathway via SOCS3 in mice with streptozotocin-induced diabetes mellitus.

The loss of pancreatic islet β-cell function represents the classical feature in the pathogenesis of type 2 diabetes mellitus (T2DM). Previous evidence has highlighted the involvement of the activated JNK pathway in relation to islet β-cell apoptosis. Hence, during the present study a streptozotocin-induced DM mice model was established in a bid to ascertain as to whether microRNA-30d (miR-30d) plays a regulatory role in the JNK pathway in relation to islet β-cell dysfunction. The collection and identification of the islet β cells from streptozotocin-induced mice was performed. Islet β cells with elevated or suppressed levels of miR-30 as well as knocked down SOCS3 were established in order to verify the regulatory mechanisms by which miR-30d governs SOCS3 in vitro. We found miR-30d was overexpressed among tissue samples obtained form streptozotocin-induced mice and their islet β cells, as well as increasing miR-30d expression when the JNK pathway was activated were found to promote islet β cell growth and cell cycle entry, and inhibit apoptosis. SOCS3, confirmed to be a miR-30d target, was decreased in the islet β cells following the promotion of miR-30d, while the JNK pathway was inhibited following SOCS3 knocdown. Furthermore, the effect of miR-30d inhibition was lost in islet β cells when SOCS3 was knocked down. The data of the present study support the notion that miR-30d-mediated direct suppression of SOCS3 acts to protect pancreatic β-cell functions through the JNK signaling pathway, emphasizing the potential of miR-30d as a novel pharmacological target for treatment and intervention of DM.

The association between elevated serum uric acid levels and islet β-cell function indexes in newly diagnosed type 2 diabetes mellitus: a cross-sectional study.

BackgroundSerum uric acid (UA) has been reported as a risk factor for type 2 diabetes mellitus (T2DM). However, whether serum UA is associated with insulin resistance and insulin secretion, and the effect of gender on it in the case of the existed association, both remain undefined.MethodsA cross-sectional study was designed and performed, which enrolled a total of 403 newly diagnosed T2DM patients (mean age, 50.21 ± 13.34 years (62.5% males)). Clinical characteristics and islet function indexes of all participants were analyzed based on gender-specific tertiles of serum UA levels. In addition, multiple linear regression analysis was conducted to investigate covariates associated with islet function indexes.ResultsThe mean levels of serum UA were 331.05 μmol/L (interquartile range (IQR): 60.6, 400.9 μmol/L) and 267.9 μmol/L (IQR: 204.7, 331.9 μmol/L) in men and women, respectively. The values of insulin secretion indexes involving AUCins30/glu30, AUCins120/glu120 and total insulin disposition index (DI120) in females were significantly higher than those in males. Apart from the homeostasis model assessment insulin resistance of men, serum UA was positively associated with insulin secretion and insulin resistance indexes both in men and women. Multivariable linear regression analysis showed serum UA exerted an independent impact on insulin secretion in females, but not on insulin resistance. In males, islet function was simultaneously affected by serum UA age, body mass index (BMI), and serum lipids.ConclusionSerum UA harbored a positive correlation with insulin secretion and insulin resistance indexes in newly diagnosed T2DM patients, which was influenced by gender, BMI, serum lipids. Hence, serum UA may be considered as a predictor for islet function in clinical practice.

Genetic Variability in eIF2α Gene Is Associated with Islet β-Cell Function in the Development of Diabetes in a Chinese Han Population.

Aims Protein kinase-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2 alpha (eIF2α) pathway mutations lead to failure of β-cell function. The aim of this article was to assess the association between eIF2α and the risk of glucose metabolism abnormalities. Methods Two eIF2α SNPs (rs9840992 T>C and rs13072593 A>G) were selected based on CHB data from HapMap, and 1466 unrelated nondiabetes individuals were genotyped. All subjects were examined by the 75 g oral glucose tolerance test, and 733 participated in a subsequent insulin release test. Various indicators of insulin resistance and islet β-cell function were examined. Results There were no significant differences in genotype distribution and allele frequency between the prediabetes and controls. CC genotype carriers at rs9840992 showed higher insulin levels at 120 min after a 75 g glucose load than noncarriers. Also, CC homozygotes had higher ΔI30/ΔG30 and ΔI120/ΔG120 than noncarriers, even after adjusting for insulin resistance. CC homozygotes had greater AUCi values than noncarriers. Subjects aged ≥ 65 yrs, those with a BMI ≥ 24 kg/m2 and those carrying the rs9840992 risk allele, had a 2.5-fold higher risk of glucose abnormalities than subjects who had none of these risk factors. Conclusion The eIF2α polymorphism is associated with islet β-cell function in a Chinese population.

LH-21 and abnormal cannabidiol improve β-cell function in isolated human and mouse islets through GPR55-dependent and -independent signalling.

To examine the effects of Abn-CBD (GPR55 agonist) and LH-21 (CB1 antagonist) on human and mouse islet function, and to determine signalling via GPR55 using islets from GPR55-/- mice. Islets isolated from human organ donors and mice were incubated in the absence or presence of Abn-CBD or LH-21, and insulin secretion, [Ca2+ ]i, cAMP, apoptosis, β-cell proliferation and CREB and AKT phosphorylation were examined using standard techniques. Abn-CBD potentiated glucose-stimulated insulin secretion and elevated [Ca2+ ]i in human islets and islets from both GPR55+/+ and GPR55-/- mice. LH-21 also increased insulin secretion and [Ca2+ ]i in human islets and GPR55+/+ mouse islets, but concentrations of LH-21 up to 0.1 μM were ineffective in islets from GPR55-/- mice. Neither ligand affected basal insulin secretion or islet cAMP levels. Abn-CBD and LH-21 reduced cytokine-induced apoptosis in human islets and GPR55+/+ mouse islets, and these effects were suppressed after GPR55 deletion. They also increased β-cell proliferation: the effects of Abn-CBD were preserved in islets from GPR55-/- mice, while those of LH-21 were abolished. Abn-CBD and LH-21 increased AKT phosphorylation in mouse and human islets. This study showed that Abn-CBD and LH-21 improve human and mouse islet β-cell function and viability. Use of islets from GPR55-/- mice suggests that designation of Abn-CBD and LH-21 as a GPR55 agonist and a CB1 antagonist, should be revised.

Decreased Serum Relaxin-2 Is Correlated with Impaired Islet β-Cell Function in Patients with Unstable Angina and Abnormal Glucose Metabolism.

Circulating relaxin (RLX) is altered in patients with diabetes mellitus (DM) or cardiovascular diseases. This study was designed to evaluate the changes of RLX in patients with unstable angina (UA) complicated with various categories of abnormal glucose metabolism.Patients who confirmed UA by angiographic and clinical standard were grouped according to the glucose metabolism status with oral glucose tolerance test (OGTT) and medical history categorized as normal, prediabetes, newly diagnosed type 2 DM (T2DM), and previously diagnosed T2DM. Serum RLX-2 was measured and islet β-cell function was evaluated. The severity of the coronary arterial lesions was evaluated with Syntax Scores.Serum RLX-2 was significantly higher in UA patients with prediabetes (median [quartiles]: 9.87 [7.48, 32.58] pg/mL) and newly diagnosed T2DM (18.36 [9.52, 48.08] pg/mL), compared with those with normal glucose tolerance (6.24 [4.02, 7.27] pg/mL, both P < 0.05). Interestingly, UA patients with previously diagnosed T2DM exhibited lower RLX-2 levels (4.17 [3.23, 5.72] pg/mL) compared with those with normal glucose tolerance (P < 0.05). Subsequent analyses indicated that serum RLX-2 was positively associated with parameters of islet β-cell function, C-peptide, and fasting insulin levels; however, it was negatively associated with the levels of fasting glucose, 2-hour postprandial blood glucose, HbA1c, and insulin sensitivity, suggesting a potential protective role of RLX-2 during abnormal glucose metabolism in UA patients. Serum RLX-2 was not correlated with the Syntax Scores in these patients.Serum RLX-2 is a potential marker for UA patients with early glucose metabolism abnormality, and increased RLX-2 level was correlated with preserved islet β-cell function.

Circulating LncRNAs Analysis in Patients with Type 2 Diabetes Reveals Novel Genes Influencing Glucose Metabolism and Islet β-Cell Function

Background/Aims: The islet is an important endocrine organ to secrete insulin to regulate the metabolism of glucose and maintain the stability of blood glucose. Long noncoding RNAs (lncRNAs) are involved in a variety of biological functions and play key roles in many diseases, including type 2 diabetes (T2D). The aim of this study was to determine whether lncRNA-p3134 is associated with glucose metabolism and insulin signaling in pancreatic β cells. Methods: LncRNA microarray technology was used to identify the differentially expressed circulating lncRNAs in T2D patients. RT-PCR analyses were performed to determine the expression of lncRNA-p3134 in 30 pairs of diabetic and non-diabetic patients. The correlation of lncRNA-p3134 to clinical data from T2D patients was analyzed. LncRNA-p3134 was overexpressed in Min6 cells and db/db mice by adenovirus-mediated technology. CCK-8, TUNEL, Western blot, glucose-stimulated insulin secretion (GSIS), ELISAs and immunochemistry were performed to determine the effect of lncRNA-p3134 on proliferation, apoptosis and insulin secretion both in vitro and vivo. Results: The circulating level of lncRNA-p3134 was higher in diabetic patients than in non-diabetic controls and was correlated with fasting blood glucose and HOMA-β levels. The lncRNA-p3134 had risen by 4 times in serum exosomes but nearly unchanged in exosome-free samples. The secretion of lncRNA-p3134 was dynamically modulated by glucose in both Min6 cells and isolated mouse islet cells. LncRNA-p3134 positively regulate GSIS through promoting of key regulators (Pdx-1, MafA, GLUT2 and Tcf7l2) in β cells. In addition, the overexpression of lncRNA-p3134 resulted in a decreased apoptosis ratio and partially reversed the glucotoxicity effects on GSIS function in Min6 cells. The restoration of insulin synthesis and secretion the increase of the insulin positive cells areas by upregulation of lncRNA-p3134 in db/db mice confirmed the compensatory role of lncRNA-p3134 to preserve β-cell function. Furthermore, a protective effect of lncRNA-p3134 on GSIS by positive modulation of PI3K/Akt/mTOR signaling was also confirmed. After blocking the PI3K/AKT signals with their specific inhibitor, the effect of overexpressed lncRNA-p3134 on insulin secretion was obviously attenuated. Conclusion: Taken together, the results of this study provide new insights into lncRNA-p3134 regulation in pancreatic β cells and provide a better understanding of novel mechanism of glucose homeostasis.

Clinical benefits of autologous haematopoietic stem cell transplantation in type 1 diabetes patients

Type 1 diabetes (T1D) is characterized by severe damage to pancreas islet function through immunological attack; therefore, it is also called ‘insulin-dependent diabetes’. The present study aimed to evaluate the safety and clinical efficacy of autologous haematopoietic stem cell transplantation (AHSCT) in adolescent patients with newly diagnosed T1D. A phase-II prospective, parallel-assignment, non-randomized trial was conducted from March 2008 to December 2011 with 40 T1D patients, of whom 20 received AHSCT therapy and 20 were treated only with insulin injections. Of these patients, 14 (70%) in the AHSCT group became insulin-independent for 1.5 to 48 months compared with only one patient in the Insulin group. Of these 14 AHSCT patients, 11 relapsed within a median time of 19.5 (range 5.5–1) months and resumed insulin use. By the end of the 4-year follow-up, the difference in daily insulin dosages between the AHSCT and Insulin groups had become smaller (0.49±0.32IU/kg/day vs. 0.79±0.18IU/kg/day, respectively; P<0.01). C-peptide levels increased significantly at 3 months in both groups and later decreased, with the insulin group showing more rapid deterioration. Most of the adverse events in the AHSCT group were transplantation complications. Our data suggest that AHSCT treatment was well tolerated and slowed deterioration of islet β-cell function while significantly decreasing daily insulin dosages. However, because of the high relapse rate, more information on longer-term outcomes is needed before AHSCT can be routinely considered for T1D patients. Significance: although this was a non-randomized clinical study, this phase-II trial demonstrated the beneficial effects of AHSCT in patients with newly diagnosed T1D by increasing C-peptide levels and inducing insulin independence, while showing its safety and good tolerability compared with conventional intensive insulin therapy. Thus, these results are helpful for increasing our understanding of the use of haematopoietic stem cell therapy in the treatment of T1D and for evaluating whether it can become more widespread in future.

Protective effects of dietary polyphenols from black soybean seed coats on islet and renal function in streptozotocin-induced diabetic rats.

The aim of this study was to investigate the antidiabetic effects of the crude polyphenol extract (BSCP) from black soybean seed coats (BSC) and the whole flour of BSC and illustrate the mechanism in terms of islet and renal protection. BSCP and BSC effectively controlled the increased blood glucose level and impaired glucose tolerance in streptozotocin (STZ)-induced diabetic rats after 8 weeks of treatment. They increased the concentrations of serum insulin, C-peptide and Glp-1 (P < 0.05) by improving the STZ-induced damage of islet β-cells and increasing their insulin expression (P < 0.05). Lipid profiles and antioxidant activities were also improved. Moreover, BSCP and BSC tended to decrease serum creatinine (0.05 < P < 0.1), and blood urea nitrogen was decreased by BSC significantly (P < 0.05). They also led to significantly lower glomerular volume (P < 0.05). Long-term intervention with BSC at a low dose of polyphenols plays a role in controlling blood glucose and lipids levels by promoting insulin secretion and restoring islet β-cell function, the same as BSCP. These benefits are accompanied by their potential protection of diabetic renal dysfunction. BSCP is mainly responsible for the antidiabetic effect of BSC. © 2017 Society of Chemical Industry.

Sodium-glucose co-transport 2 inhibitor decreases fasting plasma glucose level in impaired fasting glucose but not in normal glucose tolerance subjects

Renal sodium-glucose co-transport 2 inhibitor (SGLT2i) can reduce fasting plasma glucose (FPG) in patients with type 2 diabetes mellitus, but its effect on FPG and β-cell function in impaired fasting glucose (IFG) is unclear. The current article is the Chinses translation of an article entitled as Inhibition of Renal Sodium-Glucose Co-Transport with Empagliflozin Lowers Fasting Plasma and Improves Beta Cell Function in Subjects With Impaired Fasting Glucose , which was published in Diabetes in September [Diabetes, 2017, 66: 2495-2502], with the consent of Diabetes . Eight subjects with IFG and eight subjects with normal FPG (NFG) were included in the study. 9-stage high glucose clamp test was done before and 48 hours, 14 days after taking empagliflozin to quantitatively evaluate the effect of FPG reduction on islet β-cell function. The results showed that FPG concentration decreased only in IFG subjects from (110±2) to (103±3) mg/dl (P<0.01) after taking empagliflozin for 14 days, but the FPG remained unchanged [(95±2) to (94±2) mg/dl] in NFG subjects. The incremental area under the plasma C-peptide concentration curve during the hyperglycemic clamp increased by 22%±4% and 23%±4% in IFG subjects after 48 hours and 14 days, respectively (P<0.01); the plasma C-peptide response remained unchanged in NFG subjects. The insulin secretion/insulin sensitivity (disposition) index increased significantly in IFG, but not in NFG subjects. In conclusion, empagliflozin only reduces the FPG concentration and improves β-cell function in IFG. (Chin J Endocrinol Metab, 2017, 33: 874-879) Key words: Sodium-glucose co-transport 2 inhibitor; Empagliflozin; Fasting plasma glucose; β-cell function; Impaired fasting glucose.

Normal pancreatic β-cell function in mice with RIP-Cre-mediated inactivation of p62/SQSTM1.

Recent studies have suggested that decreased pancreatic β-cell function and mass are common features of patients with type 2 diabetes mellitus. Pancreatic β-cell homeostasis is regulated by various types of signaling molecules and stress responses. Sequestosome 1/p62 (SQSTM1, hereafter referred to as p62) is a ubiquitin-binding adaptor protein involved in cell signaling, oxidative stress, and autophagy. Because p62 appears to play an important role in maintaining mitochondrial quality control, it is possible that the loss of p62 in pancreatic β cells contributes to mitochondrial dysfunction, and thus leading to impaired glucose tolerance. In this study we investigated the physiological roles of p62 by inactivating p62 in a β-cell specific manner. We found that firstly, rat insulin-2 promoter-Cre (RIP-Cre)-mediated p62 inactivation did not cause body weight gain, although ubiquitous inactivation of p62 was previously shown to result in severe obesity. Secondly, we found no gross structural disorganization of the islets of p62-deficient mice. Consistent with normal islet morphology, no impairment in glucose tolerance was observed in mice with RIP-Cre-mediated p62 deletion. These results suggest that p62 is dispensable for normal islet organization and β-cell function.