Pancreatic Islet Cell Function Research Articles

Evidence map analysis of randomized controlled trial of commonly used Chinese patent medicines in treatment of type 2 diabetes mellitus in recent five years

This study systematically combed the randomized controlled trial(RCT) of Chinese patent medicines in treatment of type 2 diabetes mellitus(T2DM) in recent five years by using the method of evidence map. It understood the distribution and quality of evidence in this field and found the existing Chinese patent medicines in treatment of T2DM and the problems in its research. The study collected the commonly used Chinese patent medicines for the treatment of T2DM from three drug catalogs, retrieved Chinese and English databases to obtain RCT literature related to Chinese patent medicines in recent five years, and extracted information such as sample size, study drug, combination medication, course of treatment, and outcome indicators from the literature. It also conducted quality evaluation based on the Cochrane collaborative network bias risk assessment tool and used charts to display the analysis results. A total of 19 kinds of Chinese patent medicines are collected, of which 13 kinds of Chinese patent medicines are mentioned in 131 articles related to RCT. The literature concerning Shenqi Jiangtang Capsules/Granules, Jinlida Granules, and Xiaoke Pills accounts for a large proportion. Outcome indicators include blood glucose, blood lipids, pancreatic islet cell function, and clinical symptoms. In terms of literature quality, 75 articles have correct random methods, and 1 article performs allocation hiding and blind methods. Therefore, the clinical orientation of Chinese patent medicines for the treatment of T2DM is broad, failing to reflect their own characteristics and lacking safety information. Insufficient attention has been paid to TCM syndrome scores, quality of life, and blood lipid outcome indicators that reflect the characteristics of traditional Chinese medicine(TCM). The number of studies on the treatment of T2DM by Chinese patent medicines varies greatly among varieties, and the quality of the studies is low. It is suggested that the holders of the marketing license of T2DM Chinese patent medicines should carry out a post-marketing re-evaluation of the varieties of traditional Chinese patent medicines for treating T2DM according to the relevant requirements of the State Food and Drug Administration, standardize the clinical positioning, and revise and improve the safety information in the instructions. It is recommended that researchers construct a core indicator dataset for Chinese patent medicine treatment of T2DM, improve the efficacy evaluation system, and develop an experimental plan based on CONSORT before conducting RCT.

Exploring lncRNAs associated with human pancreatic islet cell death induced by transfer of adoptive lymphocytes in a humanized mouse model.

Long noncoding RNA (lncRNA)-mediated posttranscriptional and epigenetic landscapes of gene regulation are associated with numerous human diseases. However, the regulatory mechanisms governing human β-cell function and survival remain unknown. Owing to technical and ethical constraints, studying the direct role of lncRNAs in β-cell function and survival in humans in vivo is difficult. Therefore, we utilized humanized mice with human islets to investigate lncRNA expression using whole transcriptome shotgun sequencing. Our study aimed to characterize lncRNAs that may be crucial for human islet cell function and survival. Human β-cell death was induced in humanized mice engrafted with functional human islets. Using these humanized mice harboring human islets with induced β-cell death, we investigated lncRNA expression through whole transcriptome shotgun sequencing. Additionally, we systematically identified, characterized, and explored the regulatory functions of lncRNAs that are potentially important for human pancreatic islet cell function and survival. Human islet cell death was induced in humanized mice engrafted with functional human islets. RNA sequencing analysis of isolated human islets, islet grafts from humanized mice with and without induced cell death, revealed aberrant expression of a distinct set of lncRNAs that are associated with the deregulated mRNAs important for cellular processes and molecular pathways related to β-cell function and survival. A total of 10 lncRNA isoforms (SCYL1-1:22, POLG2-1:1, CTRB1-1:1, SRPK1-1:1, GTF3C5-1:1, PPY-1:1, CTRB1-1:5, CPA5-1:1, BCAR1-2:1, and CTRB1-1:4) were identified as highly enriched and specific to human islets. These lncRNAs were deregulated in human islets from donors with different BMIs and with type 2 diabetes (T2D), as well as in cultured human islets with glucose stimulation and induced cell death induced by cytokines. Aberrant expression of these lncRNAs was detected in the exosomes from the medium used to culture islets with cytokines. Islet-enriched and specific human lncRNAs are deregulated in human islet grafts and cultured human islets with induced cell death. These lncRNAs may be crucial for human β-cell function and survival and could have an impact on identifying biomarkers for β-cell loss and discovering novel therapeutic targets to enhance β-cell function and survival.

The SSBP3 co-regulator is required for glucose homeostasis, pancreatic islet architecture, and beta-cell identity

ObjectiveTranscriptional complex activity drives the development and function of pancreatic islet cells to allow for proper glucose regulation. Prior studies from our lab and others highlighted that the LIM-homeodomain transcription factor (TF), Islet-1 (Isl1), and its interacting co-regulator, Ldb1, are vital effectors of developing and adult β-cells. We further found that a member of the Single Stranded DNA-Binding Protein (SSBP) co-regulator family, SSBP3, interacts with Isl1 and Ldb1 in β-cells and primary islets (mouse and human) to impact β-cell target genes MafA and Glp1R in vitro. Members of the SSBP family stabilize TF complexes by binding directly to Ldb1 and protecting the complex from ubiquitin-mediated turnover. In this study, we hypothesized that SSBP3 has critical roles in pancreatic islet cell function in vivo, similar to the Isl1::Ldb1 complex. MethodsWe first developed a novel SSBP3 LoxP allele mouse line, where Cre-mediated recombination imparts a predicted early protein termination. We bred this mouse with constitutive Cre lines (Pdx1- and Pax6-driven) to recombine SSBP3 in the developing pancreas and islet (SSBP3ΔPanc and SSBP3ΔIslet), respectively. We assessed glucose tolerance and used immunofluorescence to detect changes in islet cell abundance and markers of β-cell identity and function. Using an inducible Cre system, we also deleted SSBP3 in the adult β-cell, a model termed SSBP3Δβ-cell. We measured glucose tolerance as well as glucose-stimulated insulin secretion (GSIS), both in vivo and in isolated islets in vitro. Using islets from control and SSBP3Δβ-cell we conducted RNA-Seq and compared our results to published datasets for similar β-cell specific Ldb1 and Isl1 knockouts to identify commonly regulated target genes. ResultsSSBP3ΔPanc and SSBP3ΔIslet neonates present with hyperglycemia. SSBP3ΔIslet mice are glucose intolerant by P21 and exhibit a reduction of β-cell maturity markers MafA, Pdx1, and UCN3. We observe disruptions in islet cell architecture with an increase in glucagon+ α-cells and ghrelin+ ε-cells at P10. Inducible loss of β-cell SSBP3 in SSBP3Δβ-cell causes hyperglycemia, glucose intolerance, and reduced GSIS. Transcriptomic analysis of 14-week-old SSBP3Δβ-cell islets revealed a decrease in β-cell function gene expression (Ins, MafA, Ucn3), increased stress and dedifferentiation markers (Neurogenin-3, Aldh1a3, Gastrin), and shared differentially expressed genes between SSBP3, Ldb1, and Isl1 in adult β-cells. ConclusionsSSBP3 drives proper islet identity and function, where its loss causes altered islet-cell abundance and glucose homeostasis. β-Cell SSBP3 is required for GSIS and glucose homeostasis, at least partially through shared regulation of Ldb1 and Isl1 target genes.

IL-6 Levels Analysis Controlled in Type 2 Diabetes Mellitus Patients and Uncontrolled

Interleukin 6 (IL-6) is one of the pro-inflammatory cytokines responsible for inducing tissue-specific and/or systemic inflammation, which is a major contributor to the induction of inflammation of pancreatic islet cells. Inflammation of pancreatic cells causes impaired insulin secretion and Type 2 Diabetes Mellitus (T2DM). This study aims to determine the levels of IL-6 in T2DM patients with different levels of severity. A cross-sectional study of 46 subjects was performed with 21 in the controlled T2DM group and 25 in the uncontrolled T2DM group. Interleukin-6 levels were measured using the ELISA method. The statistical tests used were the Mann-Whitney test and the Spearman test. The test results were significant if the p-value <0.05. The level of IL-6 in uncontrolled T2DM was higher (64.00±77.65 pg/mL) than in controlled T2DM (31.25±11.04 pg/mL). Although the levels in both groups were different, the value was not statistically significant (p=0.120). There was no significant correlation found between HbA1c and IL-6 (p=0.125, r =0.230). Several experimental studies have shown that IL-6 inhibits glucose-stimulated insulin secretion from pancreatic islets in experimental animals. However, some of them revealed that acute exposure to IL-6 did not appear to affect pancreatic islet cell function, which is still controversial today. This study found a tendency of increased IL-6 in high-severity T2DM compared to low-severity T2DM although not statistically significant. Further studies with more clinically homogeneous samples are still needed.

Gunryeong-tang extracts protect against diabetes and heart dysfunction by reducing levels of inflammation and fibrosis in db/db mice

Diabetes mellitus (DM) is one of the most common metabolic disorders known to result from abnormal secretion of insulin and/or resistance to insulin. DM is characterized by hyperglycemia, decreased function of pancreatic islet cells and reduced insulin secretion. DM causes many types of complications, among which heart complications are a serious cause of death in people with diabetes. Gunryeong-tang (GRT, 君苓湯) is a traditional oriental herbal formula for the treatment of acute and chronic nephritis, which is used to promote water retention and reduce swelling. However, no study has been conducted on the cardioprotective effects of GRT in diabetes, so this study was investigated whether GRT alleviated diabetes and diabetic heart injury in db/db mice. The experiment was conducted for 8 weeks, distributed into four different groups: db/m control, db/db control, db/db treated with vildagliptin (50 mg/kg/day) or db/db treated with GRT (200 mg/kg/day). As a result, GRT has an impact in lowering high blood glucose levels and insulin resistance in db/db mice. GRT significantly improved cardiac function in db/db mice by inhibiting LDH, CK-MB, and CPK. After 8 weeks of GRT-treatment, M-mode echocardiography was performed to confirm whether GRT had effect on cardiac function. GRT significantly up-regulated impaired LV EF and FS in db/db mice. In addition, GRT was also confirmed to improve histopathological changes (hypertrophy, fibrosis and inflammation) and protein expression levels of related factors caused by diabetes. Furthermore, GRT remarkably improved the expression of factors involved in cardiac apoptosis in db/db mice. Taken together, our results suggest that GRT improves cardiac function and diabetic complications through suppression of cardiac fibrosis and inflammation. Therefore, it is believed that GRT can be developed as a new treatment for diabetes, especially heart complications. This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean government (MSIP) (2017R1A5A2015805) (2021R1C1C2009542). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cordycepin protects islet β-cells against glucotoxicity and lipotoxicity via modulating related proteins of ROS/JNK signaling pathway

Type 2 diabetes mellitus (T2DM) is a common and multiple endocrine metabolic disease. When pancreatic β cell in case of dysfunction, the synthesis and secretion of insulin are reduced. This study is to explore the effect of cordycepin (the molecular formula C10H13N5O3), a natural adenosine isolated from Cordyceps militaris, on high glucose/lipid-induced glucotoxicity and lipotoxicity in INS-1 cells. Our results showed that cordycepin improved cell viability, improved cell energy metabolism and promoted insulin synthesis and secretion. The mechanism may be related to that cordycepin reduces intracellular reactive oxygen species (ROS), increases ATP content in cells, causes membrane depolarization and balances the steady state of Ca2+ concentration, cordycepin inhibits cell apoptosis, which may be related to the downregulation of proteins level of c-Jun N-terminal kinases (JNK) phosphorylation, cytochrome c (Cyt-c), Cleaved Capase-3, the mRNA level of JNK, Cyt-c, Capase-3 and upregulation of proteins/mRNA level of pancreatic and duodenal homeobox factor-1 (PDX-1). These results suggest that cordycepin can inhibit cell apoptosis and protect cell number by downregulating ROS/JNK mitochondrial apoptosis pathway under high glucose/lipid environment, thereby improving the function of pancreatic islet cells, providing a theoretical basis for the related research on the prevention and control of cordycepin on T2DM.

Study on the Effect of PDA-PLGA Scaffold Loaded With Islet Cells for Skeletal Muscle Transplantation in the Treatment of Diabetes.

At present, islet cells transplantation was limited by the way in which islet cells are implanted into the body, their ability to adapt to the microenvironment and the maintenance time for relieving diabetic symptoms. In order to solve this problem, we made PDA-PLGA scaffold loaded with islet cells and used it for skeletal muscle transplantation to investigate its therapeutic effect in the treatment of diabetes. The PLGA scaffold was prepared by the electrospinning method, and modified by polydopamine coating. A rat diabetic model was established to evaluate the efficacy of PDA-PLGA scaffold loaded with RINm5f islet cells through skeletal muscle transplantation. The results showed that the PDA-PLGA scaffold has good biosafety performance. At the same time, transplantation of the stent to the skeletal muscle site had little effect on the serum biochemical indicators of rats, which was conducive to angiogenesis. The PDA-PLGA scaffold had no effect on the secretory function of pancreatic islet cells. The PDA-PLGA scaffold carrying RINm5f cells was transplanted into the skeletal muscle of type I diabetic rats. 1 week after the transplantation of the PDA-PLGA cell scaffold complex, the blood glucose of the treatment group was significantly lower than that of the model group (p < 0.001) and lasted for approximately 3 weeks, which further indicated the skeletal muscle transplantation site was a new choice for islet cell transplantation in the future.

Moderate Exercise Training Combined With a High-Fat and Sucrose Diet Protects Pancreatic Islet Function in Male C57BL/6J Mice.

Obesity is mainly caused by excess energy intake and physical inactivity, and the number of overweight/obese individuals has been steadily increasing for decades. Previous studies showed that rodents fed westernized diets exhibit endocrine pancreas deterioration and a range of metabolic disorders. This study evaluated the effects of moderated aerobic treadmill exercise training on pancreatic islet cell viability and function in mice consuming a high-fat and sucrose diet. In the present study, 60-day-old male C57BL/6J mice were divided into four groups: control (C), fed a standard diet AIN-93M (3.83 kcal/g; 70% carbohydrate (cornstarch and dextrinized starch were chosen as the major source of carbohydrate for the AIN-93 diet. In addition, a small amount of sucrose), 20% protein (casein), and 10% fat (soybean) with no training (i.e., sedentary); C + training (CTR, fed the standard diet with eight weeks of exercise; high-fat diet + sucrose (HFDS), fed a high fat and sucrose diet (5.2 kcal/g; 20% carbohydrate (cornstarch and dextrinized starch were chosen as the major source of carbohydrate), 20% protein (casein), 60% fat (Lard was chosen as the major source of fat and a small amount of soybean) + 20% sucrose diluted in drinking water with no training; and HFDS + training (HFDSTR). After eight weeks, the HFDS mice displayed increased body weight (P<0.001) and epididymal, inguinal and retroperitoneal adipose tissue mass (P<0.01). These mice also presented insulin resistance (P<0.01), glucose intolerance (P<0.001), impaired glucose-stimulated insulin secretion (GSIS) and were less responsive to the physiological net ROS production induced by glucose stimulus. The HFDS group’s pancreatic islet cells were 38% less viable and 59% more apoptotic than those from the C group (P<0.05). The HFDSTR improved glucose tolerance, body mass, insulin sensitivity and GSIS (P<0.05). Furthermore, HFDSTR mice had 53% more viable isolated pancreatic islets cells and 29% fewer apoptotic cells than the HFDS group (P<0.01). Thus, exercise training may slow down and/or prevent adverse metabolic effects associated with consuming a westernized diet.

Upregulating Human Cathelicidin Antimicrobial Peptide LL-37 Expression May Prevent Severe COVID-19 Inflammatory Responses and Reduce Microthrombosis.

COVID-19 is characterized by hyperactivation by inflammatory cytokines and recruitment of macrophages, neutrophils, and other immune cells, all hallmarks of a strong inflammatory response that can lead to severe complications and multi-organ damage. Mortality in COVID-19 patients is associated with a high prevalence of neutrophil extracellular trap (NET) formation and microthrombosis that are exacerbated by hyperglycemia, diabetes, and old age. SARS-CoV-2 infection in humans and non-human primates have revealed long-term neurological consequences of COVID-19, possibly concomitant with the formation of Lewy bodies in the brain and invasion of the nervous system via the olfactory bulb. In this paper, we review the relevance of the human cathelicidin LL-37 in SARS-CoV-2 infections. LL-37 is an immunomodulatory, host defense peptide with direct anti-SARS-CoV-2 activity, and pleiotropic effects on the inflammatory response, neovascularization, Lewy body formation, and pancreatic islet cell function. The bioactive form of vitamin D and a number of other compounds induce LL-37 expression and one might predict its upregulation, could reduce the prevalence of severe COVID-19. We hypothesize upregulation of LL-37 will act therapeutically, facilitating efficient NET clearance by macrophages, speeding endothelial repair after inflammatory tissue damage, preventing α-synuclein aggregation, and supporting blood-glucose level stabilization by facilitating insulin release and islet β-cell neogenesis. In addition, it has been postulated that LL-37 can directly bind the S1 domain of SARS-CoV-2, mask angiotensin converting enzyme 2 (ACE2) receptors, and limit SARS-CoV-2 infection. Purposeful upregulation of LL-37 could also serve as a preventative and therapeutic strategy for SARS-CoV-2 infections.

The relationship between thyroid hormone levels, insulin resistance and body mass index, in patients with subclinical hypothyroidism andeuthyroid patients

Background. Hypothyroidism is a common thyroid disorder with female predominance. In general population its prevalance is 2–5% while 10 times higher in female than in men. Insulin resistance, one of the most discussed issues recently, is an inadequate response to insulin in peripheral tissues despite the normal secretory function of pancreatic islet cells. In this study, we analyzed relationship between thyroid hormone levels, body mass index and insulin resistance calculated with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index (QUICKI) and Atherogenic Index of Plasma (AIP) in SCH and euthyroid patients under levothyroxine treatment. Materials and methods. The clinical and laboratory data of approximately 14000 patients between the ages of 18–60 were retrospectively evaluated. After these exclusion criteria were applied, 371 eligible individuals were included in the study. All 371 individuals divided into three groups according to TSH levels. Group 1 is eutyhroid patients under levothyroxine treatment with TSH levels between 0.27–4.2μIU/mL. Group 2 is subclinical hypothyroid patients with TSH levels between 4.2–10 μIU/mL. Group 3 is healthy control group with TSH levels between 0.27–4.2 μIU/mL. Results. The euthyroid patient group has the highest (25.66±3.36 kg/m2) mean BMI. On the other hand the mean BMI was higher in SCH (24.0400±3.8436kg/m2) group than in control group (22.48±2.74 kg/m2) (p&lt;0.05). Fasting plasma glucose (FPG), serum triglyserid, low density lipoprotein (LDL), anti-thyroid peroxidase (TPO) and insulin levels were significantly higher in euthyroid patient and SCH groups (p&lt;0.05). Notably, total cholesterol, LDL and TPO levels were higher in euthyroid patient group (p&lt;0.05). On the other hand, there were no difference between euthyroid patients and SCH group. Conclusions. This study found significantly elevated insulin resistance and cholesterol levels in SCH patients, so we hypothesized that SCH is also a risk factor for insulin resistance disorders such as cardiovascular diseases and metabolic syndrome. As a consequence, lipid metabolism defects and insulin resistance should be screened and treated in SCH patients. Thanks to the strong and significant correlation between HOMA and QUICKI in our study, we suggest the combined use of HOMA and QUICKI in these patients. Further and large-scale studies are needed to evaluate the relationship of HOMA, QUICKI, AIP, and BMI in detecting insulin resistance in SCH patients.

Using adipose‐derived mesenchymal stem cells to fight the metabolic complications of obesity: Where do we stand?

SummaryObesity is a critical risk factor for the development of metabolic diseases, and its prevalence is increasing worldwide. Stem cell‐based therapies have become a promising tool for therapeutic intervention. Among them are adipose‐derived mesenchymal stem cells (ADMSCs), secreting numerous bioactive molecules, like growth factors, cytokines, and chemokines. Their unique features, including immunosuppressive and immunomodulatory properties, make them an ideal candidates for clinical applications. Numerous experimental studies have shown that ADMSCs can improve pancreatic islet cell viability and function, ameliorate hyperglycemia, improve insulin sensitivity, restore liver function, counteract dyslipidemia, lower pro‐inflammatory cytokines, and reduce oxidative stress in the animal models. These results prompted scientists to use ADMSCs clinically. However, up to date, there have been few clinical studies or ongoing trails using ADMSCs to treat metabolic disorders such as type 2 diabetes mellitus (T2DM) or liver cirrhosis. Most human studies have implemented autologous ADMSCs with minimal risk of cellular rejection. Because the functionality of ADMSCs is significantly reduced in subjects with obesity and/or metabolic syndrome, their efficacy is questioned. ADMSCs transplantation may offer a potential therapeutic approach for the treatment of metabolic complications of obesity, but randomized controlled trials are required to establish their safety and efficacy in humans prior to routine clinical use.

Vesiculin derived from IGF-II drives increased islet cell mass in a mouse model of pre-diabetes

ABSTRACT Pancreatic islet-cell function and volume are both key determinants of the maintenance of metabolic health. Insulin resistance and islet-cell dysfunction often occur in the earlier stages of type 2 diabetes (T2D) progression. The ability of the islet cells to respond to insulin resistance by increasing hormone output accompanied by increased islet-cell volume is key to maintaining blood glucose control and preventing further disease progression. Eventual β-cell loss is the main driver of full-blown T2D and insulin-dependency. Researchers are targeting T2D with approaches that include those aimed at enhancing the function of the patient’s existing β-cell population, or replacing islet β-cells. Another approach is to look for agents that enhance the natural capacity of the β-cell population to expand. Here we aimed to study the effects of a new putative β-cell growth factor on a mouse model of pre-diabetes. We asked whether: 1) 4-week’s treatment with vesiculin, a two-chain peptide derived by processing from IGF-II, had any measurable effect on pre-diabetic mice vs vehicle; and 2) whether the effects were the same in non-diabetic littermate controls. Although treatment with vesiculin did not alter blood glucose levels over this time period, there was a doubling of the Proliferating Cell Nuclear Antigen (PCNA) detectable in the islets of treated pre-diabetic but not control mice and this was accompanied by increased insulin- and glucagon-positive stained areas in the pancreatic islets.

Pancreas-Brain Crosstalk.

The neural regulation of glucose homeostasis in normal and challenged conditions involves the modulation of pancreatic islet-cell function. Compromising the pancreas innervation causes islet autoimmunity in type 1 diabetes and islet cell dysfunction in type 2 diabetes. However, despite the richly innervated nature of the pancreas, islet innervation remains ill-defined. Here, we review the neuroanatomical and humoral basis of the cross-talk between the endocrine pancreas and autonomic and sensory neurons. Identifying the neurocircuitry and neurochemistry of the neuro-insular network would provide clues to neuromodulation-based approaches for the prevention and treatment of diabetes and obesity.

Glucose clearance and uptake is increased in the SOD1G93A mouse model of amyotrophic lateral sclerosis through an insulin-independent mechanism.

Metabolic disturbances are associated with the progression of the neurodegenerative disorder, amyotrophic lateral sclerosis (ALS). However, the molecular events that drive energy imbalances in ALS are not completely understood. In this study, we aimed to elucidate deficits in energy homeostasis in the SOD1G93A mouse model of ALS. SOD1G93A mice and their wild-type littermates underwent indirect calorimetry and intraperitoneal glucose/insulin tolerance tests at both the onset and mid-symptomatic stages of the disease. Glucose uptake and the plasma glucoregulatory hormone profiles were analyzed. Pancreatic islet cell mass and function were assessed by measuring hormone concentrations and secretion in isolated islets, and pancreatic α- and β-cell immunoreactive areas. Finally, we profiled liver glycogen metabolism by measuring glucagon concentrations and liver metabolic gene expressions. We identified that mid-symptomatic SOD1G93A mice have increased oxygen consumption and faster exogenous glucose uptake, despite presenting with normal insulin tolerance. The capacity for pancreatic islets to secrete insulin appears intact, however, islet cell insulin concentrations and β-cell mass were reduced. Fasting glucose homeostasis was also disturbed, along with increased liver glycogen stores, despite elevated circulating glucagon, suggesting that glucagon signaling is impaired. Metabolic gene expression profiling of livers indicated that glucose cannot be utilized efficiently in SOD1G93A mice. Overall, we demonstrate that glucose homeostasis and uptake are altered in SOD1G93A mice, which is linked to an increase in insulin-independent glucose uptake, and a loss of β-cells, insulin production, and glucagon sensitivity. This suggests that the hormonal regulation of glucose concentrations may contribute to the progression of disease in this ALS mouse model.

The Eye as a Transplantation Site to Monitor Pancreatic Islet Cell Plasticity.

The endocrine cells confined in the islets of Langerhans are responsible for the maintenance of blood glucose homeostasis. In particular, beta cells produce and secrete insulin, an essential hormone regulating glucose uptake and metabolism. An insufficient amount of beta cells or defects in the molecular mechanisms leading to glucose-induced insulin secretion trigger the development of diabetes, a severe disease with epidemic spreading throughout the world. A comprehensive appreciation of the diverse adaptive procedures regulating beta cell mass and function is thus of paramount importance for the understanding of diabetes pathogenesis and for the development of effective therapeutic strategies. While significant findings were obtained by the use of islets isolated from the pancreas, in vitro studies are inherently limited since they lack the many factors influencing pancreatic islet cell function in vivo and do not allow for longitudinal monitoring of islet cell plasticity in the living organism. In this respect a number of imaging methodologies have been developed over the years for the study of islets in situ in the pancreas, a challenging task due to the relatively small size of the islets and their location, scattered throughout the organ. To increase imaging resolution and allow for longitudinal studies in individual islets, another strategy is based on the transplantation of islets into other sites that are more accessible for imaging. In this review we present the anterior chamber of the eye as a transplantation and imaging site for the study of pancreatic islet cell plasticity, and summarize the major research outcomes facilitated by this technological platform.

Nifuroxazide improves insulin secretion and attenuates high glucose-induced inflammation and apoptosis in INS-1 cells

Inflammation and oxidative stress are important factors that cause islet β-cell dysfunction. STAT3 is not only a major factor in cell proliferation and differentiation, but also plays an important role in mediating inflammation. As a potent inhibitor of STAT3, the effect of Nifuroxazide (Nifu) on pancreatic islet cells in a high glucose environment has not been reported. In the present study, we used high concentration glucose-induced INS-1 cells to examine the effects of Nifu on high glucose-induced cell function by glucose-stimulated insulin secretion (GSIS). The effects of Nifu on high glucose-induced oxidative stress were recorded by oxidative factors and antioxidant factors. Simultaneously, the effect of Nifu on the inflammatory response, apoptosis, and STAT3/SOCS3 signal pathway were validated by quantitative real-time PCR (qRT-PCR) and Western blot. Our study indicated that Nifu significantly improved cell vitality and insulin secretion of INS-1 cells induced by high glucose. We found Nifu significantly inhibited pro-oxidative factors (ROS, MDA) and promoted anti-oxidative factors (SOD, GSH-PX, CAT). Meanwhile, qRT-PCR and Western blot results showed that inflammatory and apoptosis factors were remarkably inhibited by Nifu. Further research indicated that Nifu clearly suppressed the activation of the STAT3/SOCS3 signaling pathway. In conclusion, Nifu can significantly improve the insulin secretion function, protect oxidative stress injury, and reduce inflammatory response and apoptosis in high glucose-induced INS-1 cells. Therefore, Nifu has a new positive effect on maintaining the normal function of pancreatic islet cells in a high glucose environment and provides new drug candidates for the treatment and prevention of diabetes.

Anemarrhena asphodeloides modulates gut microbiota and restores pancreatic function in diabetic rats

Anemarrhena asphodeloides is an herb widely used to treat symptoms associated with diabetes in traditional Chinese medicine. However, its key components and metabolites have low bioavailability and poor host absorption. To clarify the anti-diabetic mechanism of A. asphodeloides extract (AAE), we examined the anti-diabetic effects of AAE in rats with diabetes induced by a high-fat diet and streptozotocin. Faeces levels of the main components and metabolites of AAE were significantly higher than levels in plasma, which indicated that gut microbiota might play important roles in its anti-diabetic effect. Microbiological studies showed that unabsorbed components increased the diversity of the gut microbiota, enriched potentially beneficial bacteria, and suppressed potentially harmful bacteria. In vitro studies showed that AAE promoted the proliferation of Blautia coccoides, a bacterium with positive implication for diabetes, in a dose-dependent manner. AAE also promoted pancreatic cell regeneration and restored the function of pancreatic islet cells via peroxiredoxin 4 overexpression. Overall, these results suggest that AAE alleviates diabetes via modulating gut microbiota and protein expression.

Effect of Glucose Metabolism-Associated Protein-1 on Exendin-4-Treated Pancreatic Islet Cell Function

Exendin-4 regulates blood sugar. Glucose metabolism-associated protein-1 (GMRP-1) regulates islet cell function. Therefore, this paper intends to analyze the effect of GMRP-1 on Exendin-4treated islet cells. The islet cell MIN6 cells were separated into control group, Exendin-4 group, GMRP-1 overexpressing+ Exendin-4 group, and GMRP-1 siRNA+ Exendin-4 group followed by analysis of the expression of GMRP-1 by quantitative real-time PCR and Western blot, cell proliferation by MTT, cell apoptosis by flow cytometry, Bcl-2, Bax, Fas and Fas-L expression by real-time PCR, as well as caspase-3 activity, reactive oxygen species (ROS) and superoxide dismutase (SOD) activity. Exendin-4 and GMRP-1 overexpression+ Exendin-4 significantly increased GMRP-1 expression and promoted cell proliferation, decreased apoptotic rate and Caspase-3 activity, increased Bcl-2 and Fas-L expression, reduced Fas and Bax expression, as well as decreased ROS generation and increased SOD activity (P &lt; 0 05), and the changes in GMRP-1 overexpression+ Exendin-4 group was more significant (P &lt; 0 01). However, GMRP-1 siRNA+ Exendin-4 group significantly down-regulated GMRP-1 expression, decreased MIN6 cell prolifer- ation, increased cell apoptosis and Caspase-3 activity, decreased Bcl-2 and Fas-L expression, elevated Fas and Bax expression, increased ROS content and decreased SOD activity compared to control group and Exendin-4 group (P &lt; 0 05). Up-regulation of GMRP-1 expression promoted Exendin-4-induced proliferation and inhibited apoptosis of islet cells. Down-regulation of GMRP-1 expression reversed Exendin-4's effect on islet cells.

Alterations in pancreatic islet cell function in response to small bowel resection.

After 50% proximal small bowel resection (SBR) in mice, we have demonstrated hepatic steatosis, impaired glucose metabolism without insulin resistance, and increased pancreatic islet area. We sought to determine the consequences of SBR on pancreatic β-cell morphology, proliferation, and expression of a key regulatory hormone, glucagon-like peptide-1 (GLP-1). C57BL/6 mice underwent 50% SBR or sham operation. At 10 wk, pancreatic insulin content and secretion was measured by ELISA. Immunohistochemistry was performed to determine structural alterations in pancreatic α-and β-cells. Western blot analysis was used to measure GLP-1R expression, and immunoassay was used to measure plasma insulin and GLP-1. Experiments were repeated by administering a GLP-1 agonist (exendin-4) to a cohort of mice following SBR. After SBR, there was pancreatic islet hypertrophy and impaired glucose tolerance. The proportion of α and β cells was not grossly altered. Whole pancreas and pancreatic islet insulin content was not significantly different; however, SBR mice demonstrated decreased insulin secretion in both static incubation and islet perfusion experiments. The expression of pancreatic GLP-1R was decreased approximately twofold after SBR, compared with sham and serum GLP-1, was decreased. These metabolic derangements were mitigated after administration of the GLP-1 agonist. Following massive SBR, there is significant hypertrophy of pancreatic islet cells with morphologically intact α- and β-cells. Significantly reduced pancreatic insulin release in both static and dynamic conditions demonstrate a perturbed second phase of insulin secretion. GLP-1 is a key mediator of this amplification pathway. Decreased expression of serum GLP-1 and pancreatic GLP-1R in face of no change in insulin content presents a novel pathway for enteropancreatic glucose regulation following SBR.NEW & NOTEWORTHY Metabolic changes occur following intestinal resection; however, the effects on pancreatic function are unknown. Prior studies have demonstrated that glucagon-like protein-1 (GLP-1) signaling is a crucial player in the improved insulin sensitivity after bariatric surgery. In this study, we explore the effect of massive small bowel resection on gut hormone physiology and provide novel insights into the enteropancreatic axis.

Patch-Seq Links Single-Cell Transcriptomes to Human Islet Dysfunction in Diabetes

Impaired function of pancreatic islet cells is a majorcause of metabolic dysregulation and disease in humans. Despite this, it remains challenging to directly link physiological dysfunction in islet cellsto precise changes in gene expression.Herewe show that single-cell RNA sequencing combined with electrophysiological measurements of exocytosis and channel activity (patch-seq) canbe used to link endocrine physiologyand transcriptomes at the single-cell level. We collected 1,369 patch-seq cells from the pancreataof 34 humandonors with and without diabetes. An analysis of function and gene expressionnetworks identifieda gene set associated withfunctional heterogeneity in β cells that can be used to predict electrophysiology. We also report transcriptional programs underlying dysfunction in type 2 diabetes and extend this approach to cryopreserved cells from donors with type 1 diabetes, generating a valuable resource for understanding islet cell heterogeneity in health and disease.