Islet Dysfunction Research Articles

A CCR2+ myeloid cell niche required for pancreatic β cell growth.

Organ-specific patterns of myeloid cells may contribute tissue-specific growth and/or regenerative potentials. The perinatal stage of pancreas development marks a time characterized by maximal proliferation of pancreatic islets, ensuring the maintenance of glucose homeostasis throughout life. Ontogenically distinct CX3CR1+ and CCR2+ macrophage populations have been reported in the adult pancreas, but their functional contribution to islet cell growth at birth remains unknown. Here, we uncovered a temporally restricted requirement for CCR2+ myeloid cells in the perinatal proliferation of the endocrine pancreatic epithelium. CCR2+ macrophages are transiently enriched over CX3CR1+ subsets in the neonatal pancreas through both local expansion and recruitment of immature precursors. Using CCR2-specific depletion models, we show that loss of this myeloid population leads to a striking reduction in β cell proliferation, dysfunctional islet phenotypes, and glucose intolerance in newborns. Replenishment of pancreatic CCR2+ myeloid compartments by adoptive transfer rescues these defects. Gene profiling identifies pancreatic CCR2+ myeloid cells as a prominent source of IGF2, which contributes to IGF1R-mediated islet proliferation. These findings uncover proproliferative functions of CCR2+ myeloid subsets and identify myeloid-dependent regulation of IGF signaling as a local cue supporting pancreatic proliferation.

Engineered islet cell clusters transplanted into subcutaneous space are superior to pancreatic islets in diabetes.

An alternative route for pancreatic islet transplantation is the subcutaneous space; however, inadequate vascularization in the subcutaneous space limits the availability of oxygen and nutrients to the subcutaneously transplanted islets, which leads to the development of a necrotic core in the islets, thereby causing islet dysfunction. Thus, we aimed to prevent the early apoptosis of pancreatic islets after transplantation into subcutaneous space by preparing islet clusters of appropriate size. We prepared fully functional islet cell clusters (ICCs) by using the hanging-drop technique. We optimized the size of ICCs on the basis of viability and functionality after culture in an hypoxic environment. We transplanted ICCs into the subcutaneous space of diabetic mice and evaluated the viability of the islets at the transplantation site. In an hypoxic environment, ICCs exhibited improved viability and functionality compared with control islets. ICCs, upon transplantation into the hypoxic subcutaneous space of diabetic mice, showed better glycemic control compared with control islets. Live/dead imaging of the islets after retrieval from the transplanted area revealed significantly reduced apoptosis in ICCs. Transplantation of ICCs may be an attractive strategy to prevent islet cell apoptosis that results from nonimmune-mediated physiologic stress at the transplantation site.-Pathak, S., Regmi, S., Gupta, B., Pham, T. T., Yong, C. S., Kim, J. O., Yook, S., Kim, J.-R., Park, M. H., Bae, Y. K., Jeong, J.-H. Engineered islet cell clusters transplanted into subcutaneous space are superior to pancreatic islets in diabetes.

Exploring the molecular mechanisms underlying α- and β-cell dysfunction in diabetes.

Pancreatic islet dysfunction, including impaired insulin secretion in β cells and dysregulated glucagon secretion in α cells, is the chief pathology of diabetes. In β cells, oxidative stress, evoked by chronic hyperglycemia, was found to induce dysfunction of a critical transcription factor, PDX1, caused by its nucleocytoplasmic translocation via interactions with the insulin and JNK signaling pathways and another transcription factor, FOXO1. The significance of α-cell insulin signaling in the physiological and pathological regulation of α-cell biology was demonstrated in α-cell-specific insulin receptor knockout mice, which exhibited dysregulated glucagon secretion. Moreover, a high-glucose load directly induced excessive glucagon secretion in a glucagon-secreting cell line and isolated islets, together with impairment of insulin signaling. These findings indicate that disordered insulin signaling is central to the pathophysiology of islet dysfunction in both α and β cells. On the other hand, certain beneficial effects of GLP-1 on dysfunctional α and β cells indicate that it has therapeutic potential for diabetes patients who exhibit insulin resistance in islets. These studies, involving basic medical research approaches, have-at least in part-clarified the molecular mechanisms underlying α- and β-cell dysfunction in diabetes, and offer important clues that should aid the development of future therapeutic approaches to the disease.

Statins and New-Onset Diabetes Mellitus: LDL Receptor May Provide a Key Link.

Numerous studies have noted that populations treated with statins have increased risk for new-onset diabetes mellitus; however, the underlying molecular mechanisms are not fully understood. Interestingly, familial hypercholesterolemia (FH) patients with mutations in the low-density lipoprotein receptor (LDLR) gene are protected against diabetes mellitus (DM), despite these patients being subjected to long-term statin therapy. Since the common pathway between FH and statin therapy is LDLR-mediated cellular cholesterol uptake, the arising question is whether the LDLR plays an important role in the diabetogenic effect of statins. Indeed, given that statins can regulate the LDLR expression in liver and peripheral tissue, there is a possible mechanism that the increased LDLR causes cellular cholesterol accumulation and dysfunction in pancreatic islets, explaining why statins fail to increase the risk of DM in FH patients. In this paper, with regarded to recent literatures, we highlight the role of LDLR in the pathophysiology of cholesterol-induced pancreatic islets dysfunction, which may provide the key link between statins treatment and the increased risk of new-onset diabetes mellitus.

Effect of Empagliflozin on Tacrolimus-Induced Pancreas Islet Dysfunction and Renal Injury.

An inhibitor of sodium glucose co-transporter type 2 (SGLT-2) is recommended in type 2 diabetes mellitus (DM) but its use is still undetermined in tacrolimus (TAC)-induced DM. We evaluated the effect of empagliflozin (Em) on TAC-induced pancreatic islet dysfunction and renal injury in an experimental model of TAC-induced DM and invitro. TAC induced a twofold increase in SGLT-2 expression, while Em decreased SGLT-2 expression and further increased urinary glucose excretion compared to the TAC group. Em reduced hyperglycemia and increased plasma insulin level, pancreatic islet size, and glucose-stimulated insulin secretion compared to the TAC group. In kidney, Em alleviated TAC-induced renal dysfunction and decreased albumin excretion and histological injury compared with the TAC group. Increased oxidative stress and apoptotic cell death by TAC was remarkably decreased with Em in serum and pancreatic and renal tissues. In invitro study, TAC decreased cell viability and increased reactive oxygen species (ROS) production in both insulin-secreting beta-cell derived (INS-1) and human kidney-2 (HK-2) cell lines. Addition of Em increased cell viability and decreased ROS production in HK-2 but not in INS-1 cell lines. This suggests that Em is effective in controlling TAC-induced hyperglycemia and has direct protective effect on TAC-induced renal injury.

A systematic survey on the diagnosis strategy and patient management of type 1 diabetes by Chinese physicians.

The qualification of physicians is a key factor in controlling type 1 diabetes (T1D) since they provide crucial information to their patients about self-management. To investigate whether Chinese physicians' medical strategies influence the control of T1D in their patients, we designed a questionnaire to survey Chinese physicians, which covered their diagnosis and patient-management strategies for T1D. A total of 442 completed questionnaires were received from 35 public hospitals in 12 cities. The results showed Chinese physicians mainly diagnosed T1D based on the clinical features and islet dysfunction. One-third of physicians in this study still prescribed non-basal-bolus insulin regimens to their T1D patients. More than 80% of the doctors prescribed alpha-glucosidase inhibitors as adjunctive therapy, in addition to insulin therapy. Moreover, most of the physicians in China did not pay attention to identify coexistent autoimmune diseases. T1D patients in China were not armed with self-management knowledge and skills, which should be provided by their doctors. One of the circumstances leading to insufficient disease control in Chinese T1D patients is the ineffective therapeutic strategy prescribed by their physicians. We need to promote knowledge of efficient strategies among physicians in China to achieve better disease control in Chinese T1D patients in the future.

The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes

The pancreatic islet is highly vascularised, with an extensive capillary network. In addition to providing nutrients and oxygen to islet endocrine cells and transporting hormones to the peripheral circulation, islet capillaries (comprised primarily of islet endothelial cells) are an important source of signals that enhance survival and function of the islet beta cell. In type 2 diabetes, and animal models thereof, evidence exists of morphological and functional abnormalities in these islet endothelial cells. In diabetes, islet capillaries are thickened, dilated and fragmented, and islet endothelial cells express markers of inflammation and activation. In vitro data suggest that this dysfunctional islet endothelial phenotype may contribute to impaired insulin release from the beta cell. This review examines potential candidate molecules that may mediate the positive effects of islet endothelial cells on beta cell survival and function under normal conditions. Further, it explores possible mechanisms underlying the development of islet endothelial dysfunction in diabetes and reviews therapeutic options for ameliorating this aspect of the islet lesion in type 2 diabetes. Finally, considerations regarding differences between human and rodent islet vasculature and the potentially unforeseen negative consequences of strategies to expand the islet vasculature, particularly under diabetic conditions, are discussed.

Orphan nuclear hormone receptor Small Heterodimer Partner plays a protective role in diet‐induced islet dysfunction

Our early study found that deficiency of small heterodimer partner (SHP, NR0B2) protected the mice from diet‐induced obesity due to increased fatty acid oxidation but exacerbated glucose tolerance due to impaired glucose‐stimulated insulin secretion upon a 6‐month western diet regimen. Current study explored potential roles of SHP in the development of glucose intolerance furthermore. We assessed islet function using illumina beadchip array and morphometric measurement of pancreatic sections. Beadchip array revealed that many exocrine specific genes (for example, CUB and Zona Pellucida‐Like Domains (cuzd1), pancreas specific transcription factor 1a (ptf1a), trypsin 4 (try4) and pancreatic carboxyl ester lipase (cel) etc.) were markedly down‐regulated in the islets of SHP null mice in either chow or western diet‐fed condition. However, expression of major genes involved in insulin secretion and islet function were similar between WT and SHP null mice. Results from quantitative real‐time PCR analysis agreed with majority of beadchip array results except Glut2, which was decreased in SHP null islets. Corroborating with impaired insulin secretion and lower Glut2 mRNA level, glucose‐stimulated Ca2+ influx was greatly diminished in SHP null islets. Islet size was also decreased in SHP null mice fed either diet. The observed diabetic phenotype and pancreatic exocrine insufficiency in whole body SHP−/−mice was recapitulated in the pancreas specific SHPKO (PSHPKO) mice, where SHP deletion is confirmed in both endocrine and exocrine tissues. Interestingly the lean phenotype was reproduced only in liver‐specific SHPKO mice but not in PSHPKO mice. Even though detailed underlying molecular mechanisms for the observed phenotypes by SHP deletion remain to be elucidated, current data suggest that SHP plays distinctive and tissue‐specific role in the development of obesity and diabetes.Support or Funding InformationThis work had been supported by the National Institutes of Health 344 Grant R01DK093774 (to YKL)

VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins.

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type2 diabetes mellitus.

Increased vimentin in human α- and β-cells in type 2 diabetes.

Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; P < 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.

Exposure to chronic hyperglycemic conditions results in Ras-related C3 botulinum toxin substrate 1 (Rac1)-mediated activation of p53 and ATM kinase in pancreatic β-cells.

Chronic hyperglycemia (HG) promotes pancreatic islet dysfunction which leads to the onset of T2DM. This study is aimed at defining regulatory roles of Rac1, a small G-protein, in the activation of p53 and ATM kinase in pancreatic β-cells, under the duress of HG conditions. We report significant stimulatory effects of HG (20mM; 24h) on p53 activation in INS-1 832/13 cells, normal rodent and human islets. Pharmacological inhibition of Rac1 (EHT1864 or NSC23766) significantly suppressed HG-induced p53 activation in INS-1 832/13 cells and rat islets, suggesting novel roles for this small G-protein in the activation of p53. Inhibition of Rac1 geranylgeranylation with simvastatin or GGTI-2147, significantly attenuated HG-induced p53 activation, suggesting requisite roles for this signaling step in HG-mediated effects on β-cells. HG-induced p53 activation was also suppressed by SB203580, a known inhibitor of p38MAPK. Additionally, we observed increased activation of ATM kinase under HG conditions, which was blocked in presence of EHT1864. Furthermore, pharmacological inhibition of ATM kinase (KU55933) reduced activation of ATM kinase, but not p53, suggesting that HG-mediated activation of p53 and ATM could represent independent pro-apoptotic events. In conclusion, these data indicate that sustained activation of Rac1-p38MAPK signaling axis leads to activation of p53 leading to β-cell dysfunction under the duress of chronic hyperglycemic conditions.

RNA Sequencing Exposes Adaptive and Immune Responses to Intrauterine Growth Restriction in Fetal Sheep Islets.

The risk of type 2 diabetes is increased in children and adults who exhibited fetal growth restriction. Placental insufficiency and intrauterine growth restriction (IUGR) are common obstetrical complications associated with fetal hypoglycemia and hypoxia that reduce the β-cell mass and insulin secretion. In the present study, we have defined the underlying mechanisms of reduced growth and proliferation, impaired metabolism, and defective insulin secretion previously established as complications in islets from IUGR fetuses. In an IUGR sheep model that recapitulates human IUGR, high-throughput RNA sequencing showed the transcriptome of islets isolated from IUGR and control sheep fetuses and identified the transcripts that underlie β-cell dysfunction. Functional analysis expanded mechanisms involved in reduced proliferation and dysregulated metabolism that include specific cell cycle regulators and growth factors and mitochondrial, antioxidant, and exocytotic genes. These data also identified immune responses, wnt signaling, adaptive stress responses, and the proteasome as mechanisms of β-cell dysfunction. The reduction of immune-related gene expression did not reflect a change in macrophage density within IUGR islets. The present study reports the islet transcriptome in fetal sheep and established processes that limit insulin secretion and β-cell growth in fetuses with IUGR, which could explain the susceptibility to premature islet failure in adulthood. Islet dysfunction formed by intrauterine growth restriction increases the risk for diabetes.

Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal manner

Although p53 is not essential for normal embryonic development, it plays a pivotal role in many biological and pathological processes, including cell fate determination-dependent and independent events and diseases. The expression and activity of p53 largely depend on its two biological inhibitors, MDM2 and MDMX, which have been shown to form a complex in order to tightly control p53 to an undetectable level during early stages of embryonic development. However, more delicate studies using conditional gene-modification mouse models show that MDM2 and MDMX may function separately or synergistically on p53 regulation during later stages of embryonic development and adulthood in a cell and tissue-specific manner. Here, we report the role of the MDM2/MDMX-p53 pathway in pancreatic islet morphogenesis and functional maintenance, using mouse lines with specific deletion of MDM2 or MDMX in pancreatic endocrine progenitor cells. Interestingly, deletion of MDM2 results in defects of embryonic endocrine pancreas development, followed by neonatal hyperglycemia and lethality, by inducing pancreatic progenitor cell apoptosis and inhibiting cell proliferation. However, unlike MDM2-knockout animals, mice lacking MDMX in endocrine progenitor cells develop normally. But, surprisingly, the survival rate of adult MDMX-knockout mice drastically declines compared to control mice, as blockage of neonatal development of endocrine pancreas by inhibition of cell proliferation and subsequent islet dysfunction and hyperglycemia eventually lead to type 1 diabetes-like disease with advanced diabetic nephropathy. As expected, both MDM2 and MDMX deletion-caused pancreatic defects are completely rescued by loss of p53, verifying the crucial role of the MDM2 and/or MDMX in regulating p53 in a spatio-temporal manner during the development, functional maintenance, and related disease progress of endocrine pancreas. Also, our study suggests a possible mouse model of advanced diabetic nephropathy, which is complementary to other established diabetic models and perhaps useful for the development of anti-diabetes therapies.

Whole-Genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis.

Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited. Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes. Our aim was to characterize the whole-genome DNA methylation landscape in human pancreatic islets, to identify differentially methylated regions (DMRs) in diabetic islets, and to investigate the function of DMRs in islet biology. Here, we performed whole-genome bisulfite sequencing, which is a comprehensive and unbiased method to study DNA methylation throughout the genome at a single nucleotide resolution, in pancreatic islets from donors with T2D and control subjects without diabetes. We identified 25,820 DMRs in islets from individuals with T2D. These DMRs cover loci with known islet function, e.g., PDX1, TCF7L2, and ADCY5 Importantly, binding sites previously identified by ChIP-seq for islet-specific transcription factors, enhancer regions, and different histone marks were enriched in the T2D-associated DMRs. We also identified 457 genes, including NR4A3, PARK2, PID1, SLC2A2, and SOCS2, that had both DMRs and significant expression changes in T2D islets. To mimic the situation in T2D islets, candidate genes were overexpressed or silenced in cultured β-cells. This resulted in impaired insulin secretion, thereby connecting differential methylation to islet dysfunction. We further explored the islet methylome and found a strong link between methylation levels and histone marks. Additionally, DNA methylation in different genomic regions and of different transcript types (i.e., protein coding, noncoding, and pseudogenes) was associated with islet expression levels. Our study provides a comprehensive picture of the islet DNA methylome in individuals with and without diabetes and highlights the importance of epigenetic dysregulation in pancreatic islets and T2D pathogenesis.

Marked augmentation of PLGA nanoparticle-induced metabolically beneficial impact of γ-oryzanol on fuel dyshomeostasis in genetically obese-diabetic ob/ob mice

Our previous works demonstrated that brown rice-specific bioactive substance, γ-oryzanol acts as a chaperone, attenuates exaggerated endoplasmic reticulum (ER) stress in brain hypothalamus and pancreatic islets, thereby ameliorating metabolic derangement in high fat diet (HFD)-induced obese diabetic mice. However, extremely low absorption efficiency from intestine of γ-oryzanol is a tough obstacle for the clinical application. Therefore, in this study, to overcome extremely low bioavailability of γ-oryzanol with super-high lipophilicity, we encapsulated γ-oryzanol in polymer poly (DL-lactide-co-glycolide) (PLGA) nanoparticles (Nano-Orz), and evaluated its metabolically beneficial impact in genetically obese-diabetic ob/ob mice, the best-known severest diabetic model in mice. To our surprise, Nano-Orz markedly ameliorated fuel metabolism with an unexpected magnitude (∼1000-fold lower dose) compared with regular γ-oryzanol. Furthermore, such a conspicuous impact was achievable by its administration once every 2 weeks. Besides the excellent impact on dysfunction of hypothalamus and pancreatic islets, Nano-Orz markedly decreased ER stress and inflammation in liver and adipose tissue. Collectively, nanotechnology-based developments of functional foods oriented toward γ-oryzanol shed light on the novel approach for the treatment of a variety of metabolic diseases in humans.

Pancreatic islet dysfunction is partially attenuated by replacement of dietary saturated fatty acids with monounsaturated fatty acids

Pancreatic islet dysfunction is partially attenuated by replacement of dietary saturated fatty acids with monounsaturated fatty acids

Inhibition of TLR4 protects rat islets against lipopolysaccharide-induced dysfunction.

Oxidative stress leads to dysfunction in pancreatic cells, causing a reduction in insulin secretion following exposure to glucose. Toll-like receptor4 (TLR4) may be activated by exposure to lipopolysaccharide (LPS) stress. TLR4 may mediate the initiation of inflammatory and immune defense responses; however, the importance of the LPS/TLR4 interaction in apoptosis induced by oxidative stress in pancreatic βcells remains to be elucidated. The present study aimed to investigate the importance of TLR4 during LPS‑induced oxidative stress, apoptosis and dysfunction of insulin secretion in isolated islets of rats. LPS‑induced stimulation of TLR4 increased the production of reactive oxygen species and promoted apoptosis by upregulating the expression levels of caspase‑3, poly ADP ribose polymerase and altering the expression ratio of B‑cell lymphoma‑2 (Bcl‑2)/Bcl‑2 associated X protein. Additionally, the insulin secretion of islets cells was reduced. Anti‑TLR4 antibody and a knockdown of TLR4 by TLR4‑short hairpin RNA were used to inhibit TLR4 activity, which may reverse LPS‑induced events. The present study determined that in islets exposed to LPS oxidative stress, dysfunction may be partly mediated via the TLR4 pathway. Inhibition of TLR4 may prevent dysfunction of rat islets due to oxidative stress. The present study revealed that targeting the LPS/TLR4 signaling pathway and antioxidant therapy may be a novel treatment for the severely septic patients with hyperglycemia stress.

Decrease in Circulating Fatty Acids Is Associated with Islet Dysfunction in Chronically Sleep-Restricted Rats

Previous studies have shown that sleep restriction-induced environmental stress is associated with abnormal metabolism, but the underlying mechanism is poorly understood. In the current study, we investigated the possible lipid and glucose metabolism patterns in chronically sleep-restricted rat. Without changes in food intake, body weight was decreased and energy expenditure was increased in sleep-restricted rats. The effects of chronic sleep disturbance on metabolites in serum were examined using 1H NMR metabolomics and GC-FID/MS analysis. Six metabolites (lipoproteins, triglycerides, isoleucine, valine, choline, and phosphorylcholine) exhibited significant alteration, and all the fatty acid components were decreased, which suggested fatty acid metabolism was impaired after sleep loss. Moreover, increased blood glucose, reduced serum insulin, decreased glucose tolerance, and impaired glucose-stimulated insulin secretion of islets were also observed in sleep-restricted rats. The islet function of insulin secretion could be partially restored by increasing dietary fat to sleep-disturbed rats suggested that a reduction in circulating fatty acids was related to islet dysfunction under sleep deficiency-induced environmental stress. This study provides a new perspective on the relationship between insufficient sleep and lipid/glucose metabolism, which offers insights into the role of stressful challenges in a healthy lifestyle.

The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model.

We believe this study is important and of interest to the biomaterials and transplant community for several reasons: 1) it provides an optimized protocol for the PEGylation of islets, with minimal impact on the coated islets, which can be easily translated for clinical applications; 2) this optimized protocol demonstrates the benefits of islet PEGylation in providing modest immunosuppression in a murine model; 3) this work demonstrates the combinatory impact of PEGylation with short-course immunotherapy (via LFA-1 blockage), illustrating the capacity of PEGylation to complement existing immunotherapy; and 4) it suggests macrophage phenotype shifting as the potential mechanism for this observed benefit.

Single-cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes.

Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type–specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis.