CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity

CFTR, a chloride channel and ion channel regulator studied mostly in epithelial cells, has been reported to participate in immune regulation and likely affect the risk of cancer development. However, little is known about the effects of CFTR on the differentiation and function of γδ T cells. In this study, we observed that CFTR was functionally expressed on the cell surface of γδ T cells. Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γ release by peripheral γδ T cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo. Interestingly, the molecular mechanisms underlying the regulation of γδ T cell IFN-γ production by CFTR were either TCR dependent or related to Ca²⁺ influx. CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling. In addition, CFTR was found to modulate TCR-induced Ca²⁺ influx and membrane potential (V_m)-induced Ca²⁺ influx and subsequently regulate the calcineurin-NFATc1 signaling pathway in γδ T cells. Thus, CFTR serves as a negative regulator of IFN-γ production in γδ T cells and the function of these cells in antitumor immunity. Our investigation suggests that modification of the CFTR activity of γδ T cells may be a potential immunotherapeutic strategy for cancer.     

Streptozotocin-induced diabetes in mice lacking αβ T cells

Multiple low-dose streptozotocin (MD-STZ) is widely used for the experimental induction of diabetes, but, as non-obese diabetic (NOD)-scid/scid mice have been found to display enhanced susceptibility to MD-STZ, whether or not the model is genuinely autoimmune and T cell-mediated has been unclear. Mice bearing a targeted mutation of the T cell receptor (TCR) α-chain were therefore used to assess whether TCR αβ⁺ cells are involved in the diabetogenic effects of MD-STZ injections. Young NOD mice lacking TCR αβ cells, when given five daily injections of 40 mg/kg STZ, developed diabetes at low frequency (2/12), despite the widespread destruction of pancreatic islet cells. By comparison, most normal control mice became hyperglycaemic (12/23). We conclude that whilst much of the tissue destruction observed in this model is due to the direct toxic effect of STZ, a significant amount is also due to the action of TCR αβ cells tipping the balance between tolerable and clinically damaging action on islet cells.     

Role of glucose metabolism and phosphoinositide hydrolysis in glucose-induced sensitization/desensitization of insulin secretion from mouse pancreatic islets

The role of glucose metabolism and phosphoinositide hydrolysis in glucose-induced sensitization/desensitization of insulin secretion was studied. A change in glucose concentration from 5.5 to 16.7 mM during 22–24 h of pre-exposure of mouse islets in TCM 199 culture medium (0.26 mM Ca²⁺) led to sensitization of glucose-induced insulin secretion. This change in islet responsiveness to glucose was not mediated by increases in glucose utilization ([5-³H]glucose conversion to ³H₂0) and glucose oxidation ([U-¹⁴C]glucose oxidation to ¹⁴C0₂). Glucose-induced sensitization of insulin secretion was associated with an increase in glucose-induced phosphoinositide hydrolysis, leading to a significant increase in inositol 1-monophosphate formation, but not in inositol 1,4-bisphosphate or in inositol 1,4,5-trisphosphate plus inositol 1,3,4-trisphosphate formation. Diacylglycerol, which may arise from both phosphoinositide hydrolysis and de novo from glucose metabolism, was, on the other hand, not increased during acute exposure to glucose and not changed after pre-exposure to glucose. At 16.7 mM glucose in TCM 199 medium, a change in Ca²⁺ concentration from 0.26 to 1.26 mM led to a reduction in glucose-induced insulin secretion. This Ca²⁺-dependent desensitization of insulin secretion in the presence of glucose was associated with a decrease in glucose-induced phosphoinositide hydrolysis, but not with a change in glucose metabolism or diacylglycerol accumulation. In conclusion, it is suggested that glucose-induced sensitization/desensitization of insulin secretion may involve changes in phosphoinositide hydrolysis, but may occur independently of concomitant changes in glucose metabolism or diacylglycerol accumulation.     

Neuropilin-2 is a novel marker expressed in pancreatic islet cells and endocrine pancreatic tumours

Neuropilin-2 (NP-2) is a cell surface transmembrane protein originally characterized as a receptor for the type 3 semaphorins, and more recently for a number of vascular endothelial growth factor (VEGF) isoforms. NP-2 expression has been recently localized to a subset of neuroendocrine cells in the gastrointestinal tract. The aim of this study was to define the expression pattern of NP-2 in normal pancreatic islets and to determine the utility of NP-2 expression as a diagnostic marker of pancreatic endocrine tumours. Paraffin-embedded tissue sections from 30 endocrine pancreatic tumours (EPTs) and from normal pancreas were immunostained with a rabbit polyclonal antibody generated towards NP-2. Nineteen of the tumours were hormonally functional (nine insulinomas, nine gastrinomas, and one glucagonoma). The NP-2 staining pattern was correlated with islet cell hormone expression. In addition, NP-2 expression was evaluated in other normal neuroendocrine tissues and neuroendocrine neoplasms. In normal pancreas, NP-2 stained a distinct subset of islet cells situated primarily at the islet periphery. Double immunohistochemical staining revealed co-localization with glucagon-expressing cells. Moderate to strong NP-2 staining was present in 27 of 30 EPTs. Serial staining of the pancreatic tumours with insulin, gastrin, glucagon, pancreatic polypeptide (PP) or somatostatin did not reveal a distinct pattern of co-localization. NP-2 expression was not detected in neuroendocrine cells outside the gastroenteropancreatic system, or in their corresponding neoplasms, except for focal staining in one bronchial carcinoid tumour. In conclusion, the vast majority of EPTs examined expressed NP-2, suggesting its utility as a diagnostic marker for these tumours. The function of NP-2 in islet cell biology or tumourigenesis remains to be elucidated.     

Enhancement of insulin secretion during selective blockade of α1, - and α2-adrenoceptors in the rat: Effects of somatostatin

The effects of somatostatin on plasma concentrations of insulin and glucose in the presence of the selective α₁-adrenoceptor blocking agent prazosin or the selective α₂-adrenoceptor blocking drug yohimbine were studied in vivo in anesthetized rats. Infusion of both prazosin (0.080 mg/min) and yohimbine (0.018 mg/min) increased plasma insulin levels within 10 min. Prazosin, but not yohimbine, caused a significant increment in plasma glucose concentration. Somatostatin (0.1 μg/min) promptly and extensively lowered plasma insulin concentrations during the infusion of both prazosin and yohimbine, suggesting that the inhibitory effect of somatostatin is not mediated via a direct action on α₁ or α₂-adrenoceptors. Plasma glucose concentration fell slightly during somatostatin administration. A marked increment in insulin release occurred in response to cessation of the somatostatin infusion, both during prazosin- and yohimbine-treatment. We conclude that somatostatin efficiently inhibits insulin secretion during selective α₁- and α₂-adrenoceptor blockade and, further, that the insulin off-response after somatostatin treatment is potentiated by α-adrenoceptor blockade. This study also indicates that blockade of α₁- as well as of α₂-adrenoceptors leads to an increased insulin secretion.     

Angiotensin II type 2 receptor regulates the development of pancreatic endocrine cells in mouse embryos

Background : We previously identified a local renin‐angiotensin system (RAS) regulating the differentiation of an isolated population of human pancreatic progenitor cells. Major RAS components that regulate organogenesis have been also described in embryos; however, it is not known whether a local RAS is present in the fetal pancreas. We now hypothesize that angiotensin II type 1 (AT₁) and type 2 (AT₂) receptors are expressed in mouse embryonic pancreas and involved in regulating endocrine cell development. Results: Differential expression of AT₁ and AT₂ receptors was observed in the mouse pancreata in late embryogenesis. Systemic AT₂, but not AT₁, receptor blockade during the second transition in pancreatic development (from embryonic day 12.0 onward) reduced the β‐cell to α‐cell ratio of the neonate islets, impaired their insulin secretory function and the glucose tolerance of the pups. Studies with pancreas explants ex vivo revealed regulation by AT₂ receptors of the differentiation of pancreatic progenitors into insulin‐producing cells and of the proliferation of the differentiated cell, actions that did not result from reduced angiogenesis as a secondary effect of AT₂ receptor antagonism. Conclusions: These data revealed an AT₂ receptor‐mediated mechanism regulating pancreatic endocrine cell development in vivo. Developmental Dynamics 243:415–427, 2014. © 2013 Wiley Periodicals, Inc.     

Myelin basic protein stimulates insulin and glucagon secretion from rat pancreatic islets in vitro and in vivo

The effect of myelin basic protein on insulin and glucagon secretion from rat pancreatic islets was studied in vivo and in vitro. The myelin basic proteins isolated from bovine, human and rat brains all stimulated insulin secretion in a similar fashion. In a static incubation of isolated pancreatic islets, myelin basic protein at doses of 15.6–250 μg in a 0.5-ml reaction volume (1.7 times 10^-8 to 2.7 times 10^-5 M) significantly stimulated hormone release. Maximal stimulation, obtained at the 250-μg dose, was 6.5-fold greater than control for insulin secretion and 6.7-fold greater than control for glucagon secretion. In the case of glucagon no saturation was observed, but saturation was obvious for insulin release at doses of myelin basic protein of 62.5–250μg, larger doses causing permeabilization of the islet membranes as indicated by leakage of acid phosphatase. At a 100-μg dose the time course of insulin secretion induced by myelin basic protein indicated a fast initial release, and after the first 2 h only a little more insulin was released. At the lower doses of myelin basic protein (11 and 33μg) the secretion rate was nearly constant after the first hour. Significant stimulation of glucagon release by myelin basic protein was seen after 60 min, the rate of release being roughly constant at 33-and 100-μg doses thereafter. At the 11-μg dose significant stimulation of hormone release was observed only after a 4-h incubation. Lowering the temperature from 37 to 27 and 20°C reduced both basal and stimulated hormone secretion, the extent of stimulation over the basal level remaining the same at all temperatures only for insulin secretion at a dose of myelin basic protein of 100 μg. A dose of 10 mg myelin basic protein injected intravenously into anaesthetized rats resulted 15 min after injection in a circulating concentration of myelin basic protein of 34.7 μg ml^-1 (1.7 times 10^-6 M) as measured by our radioimmunoassay. It stimulated insulin secretion (P < 0.01), having no significant effect on plasma glucagon levels. Since myelin basic proteins have been shown to display fusogenic properties in cell-free membrane systems, we propose that myelin basic protein exerts its hormone-releasing effect by aggregating and fusing the hormone-containing vesicles to the cell plasma membranes.     

Platelet-rich plasma improves impaired glucose hemostasis,disrupted insulin secretion,and pancreatic oxidative stress in streptozotocin-induced diabetic rat

Abstract

Our study aimed to investigate the effects of platelet-rich plasma (PRP) on impaired glucose homeostasis, disrupted islet insulin secretion, and pancreatic oxidative status in streptozotocin (STZ)-diabetic rats. A total of 64 Sprague-Dawley male were randomized to four groups including controls, diabetes, control-PRP, and diabetes-PRP. The rats received the PRP (0.5?ml/kg, SC injection) twice weekly for 4 weeks. Plasma glucose and insulin levels, pancreatic oxidative stress markers and islet insulin secretion and content were measured. Compared with the control group, in the diabetic group, increased plasma glucose and malondialdehyde (MDA) levels and decreased plasma insulin level, islet insulin secretion, pancreatic superoxide dismutase (SOD), and catalase activities were observed. PRP treatment significantly reduced plasma glucose and MDA levels and enhanced plasma insulin, antioxidant enzyme activity, islet insulin secretion, and content in the diabetic rats. These findings showed that PRP can improve pancreatic islet insulin secretion, pancreatic oxidative stress and regulate plasma insulin and glucose levels in diabetic rats.     

Integrins αvβ3 and α5β1 Mediate Attachment of Lyme Disease Spirochetes to Human Cells

Borrelia burgdorferi (sensu lato), the agent of Lyme disease, is able to cause chronic, multisystemic infections in human and animal hosts. Attachment of the spirochete to host cells is likely to be important for the colonization of diverse tissues. The platelet-specific integrin α_IIbβ₃ was previously identified as a receptor for all three species of Lyme disease spirochetes (B. burgdorferi sensu stricto, B. garinii, and B. afzelii). Here we show that B. burgdorferi also recognizes the widely expressed integrins α_vβ₃ and α₅β₁, known as the vitronectin and fibronectin receptors, respectively. Three representatives of each species of Lyme disease spirochete were tested for the ability to bind to purified α_vβ₃ and α₅β₁. All of the strains tested bound to at least one integrin. Binding to one integrin was not always predictive of binding to other integrins, and several different integrin preference profiles were identified. Attachment of the infectious B. burgdorferi strain N40 to purified α_vβ₃ and α₅β₁ was inhibited by RGD peptides and the appropriate receptor-specific antibodies. Binding to α_vβ₃ was also shown by using a transfected cell line that expresses this receptor but not α_IIbβ₃. Attachment of B. burgdorferi N40 to human erythroleukemia cells and to human saphenous vein endothelial cells was mediated by both α₅β₁ and α_vβ₃. Our results show that multiple integrins mediate attachment of Lyme disease spirochetes to host cells.     

Expression of functionally active α4β1 integrin by thymic epithelial cells

We have investigated the expression and function of the VLA-4 heterodimer α₄β₁, a member of the β₁ integrin subfamily, on human thymic epithelial cells (TEC) derived from cortical epithelium. The expression of the α₄ integrin chain was studied in four different cloned TEC lines derived from either fetal or post-natal human thymus by both flow cytometry and immunoprecipitation techniques with anti-α₄ MoAbs. All different cell lines assayed expressed significant levels of α₄, as revealed by their reactivity with MoAbs specific for distinct α₄epitopes. The α₄ subunit expressed by TEC was associated to β₁ but not to β₇ chain, and displayed the characteristic 80/70 kD pattern of proteolytic cleavage. The VLA-4 integrin in these cells was constitutively active in terms of adhesiveness to both fibronectin and vascular cell adhesion molecule-1 (VCAM-1). In addition, this heterodimer localized to punctate regions of the cell in the area of contact with the substratum, named point contacts assessed by staining with the anti-β₁ activation epitope 15/7 MoAb. According to the cortical origin of the TEC lines expressing VLA-4, human thymus sections stained with different anti-α₄ antibodies revealed the presence of cortical, and in smaller numbers medullary epithelial cells bearing α₄ integrin. The expression of α₄ in the thymus was also found in both adult and fetal rats, in which epithelial cells were also specifically stained. Altogether, our data show that VLA-4 is an additional component of the integrin repertoire of TEC, and suggest that it could have an important role in thymus epithelial cell–thymocyte interactions.     

Expression of hypoxia-inducible factors is correlated with the presence of a fibrotic focus and angiogenesis in pancreatic ductal adenocarcinomas

AIMS: To study the expression of hypoxia-regulated markers in pancreatic ductal adenocarcinomas (PA) in relationship to the presence of a fibrotic focus, angiogenesis quantification and clinical outcome. METHODS AND RESULTS: The expression of hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) was immunohistochemically detected in 50 PA and correlated with tumour characteristics, microvascular density (MVD) and survival. HIF-1alpha was expressed within tumour cells in 68%, HIF-2alpha in 46%, CA9 in 78% and VEGF in 52% of the cases. Stromal expression was also noted for HIF-2alpha and CA9 in, respectively, 42% and 48% of the cases. Tumour CA9 expression was associated with that of VEGF (P=0.004) and that of stromal HIF-2alpha (P=0.013), with the presence of a fibrotic focus (P=0.046) and with an increased MVD (P=0.034). Tumour VEGF expression correlated with the presence of a fibrotic focus (P=0.039) and a greater MVD (P=0.047). Both the presence of a fibrotic focus (P=0.0002) and high tumour CA9 expression (P=0.029) were associated with reduced overall survival. CONCLUSION: The strong association of the presence of a fibrotic focus with CA9 expression and lower survival demonstrates that hypoxia-driven angiogenesis plays an important role in the progression of PA.     

Nervous control of pancreatic endocrine secretion in pigs

The increases in the concentrations of insulin and pancreatic glucagon in portal venous and arterial plasma in response to electrical stimulation of the vagus nerves were studied in anesthetized splanchnicotomized young pigs. The responses were frequence dependent; threshold frequency was below 1 Hz and maximum response was reached at 8–12 Hz. With maximal stimulation responses of magnitudes comparable to the responses to maximal arginine (glucagon) and glucose stimulation (insulin) were observed. However, both the insulin and the glucagon response were critically dependent on the blood glucose concentration during the stimulation: the glucagon response was inversely correlated to blood glucose, whereas the insulin response was positively correlated to blood glucose at concentrations above 4.5 mmol · 1^-1. Below this glucose concentration there was no detectable insulin response and above 8.0 mmol ·^-1 no glucagon response to vagal stimulation. A stimulated secretion of glucagon as well as insulin was maintained for up to 30 min stimulation, but insulin secretion tended to decrease, whereas glucagon secretion tended to increase. Above blood glucose concentrations of 4 mmol · 1^-1, blood glucose concentrations increased slightly in response to vagal stimulation, whereas no change was noted during stimulations performed at lower blood glucose concentrations.     

Processing of Mycobacterium tuberculosis Bacilli by Human Monocytes for CD4+ αβ and γδ T Cells: Role of Particulate Antigen

Mycobacterium tuberculosis readily activates both CD4⁺ and Vδ2⁺ γδ T cells. Despite similarity in function, these T-cell subsets differ in the antigens they recognize and the manners in which these antigens are presented by M. tuberculosis-infected monocytes. We investigated mechanisms of antigen processing of M. tuberculosis antigens to human CD4 and γδ T cells by monocytes. Initial uptake of M. tuberculosis bacilli and subsequent processing were required for efficient presentation not only to CD4 T cells but also to Vδ2⁺ γδ T cells. For γδ T cells, recognition of M. tuberculosis-infected monocytes was dependent on Vδ2⁺ T-cell-receptor expression. Recognition of M. tuberculosis antigens by CD4⁺ T cells was restricted by the class II major histocompatibility complex molecule HLA-DR. Processing of M. tuberculosis bacilli for Vδ2⁺ γδ T cells was inhibitable by Brefeldin A, whereas processing of soluble mycobacterial antigens for γδ T cells was not sensitive to Brefeldin A. Processing of M. tuberculosis bacilli for CD4⁺ T cells was unaffected by Brefeldin A. Lysosomotropic agents such as chloroquine and ammonium chloride did not affect the processing of M. tuberculosis bacilli for CD4⁺ and γδ T cells. In contrast, both inhibitors blocked processing of soluble mycobacterial antigens for CD4⁺ T cells. Chloroquine and ammonium chloride insensitivity of processing of M. tuberculosis bacilli was not dependent on the viability of the bacteria, since processing of both formaldehyde-fixed dead bacteria and mycobacterial antigens covalently coupled to latex beads was chloroquine insensitive. Thus, the manner in which mycobacterial antigens were taken up by monocytes (particulate versus soluble) influenced the antigen processing pathway for CD4⁺ and γδ T cells.

Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is spread readily from person to person by inhalation of aerosolized mycobacteria (8). A hallmark of M. tuberculosis infection is the ability of most healthy individuals to control the infection by mounting an acquired immune response, in which antigen-specific T cells and mononuclear phagocytes arrest the growth of M. tuberculosis bacilli and maintain control over dormant bacilli within granulomas (reviewed in reference 25). This protective cellular immune response results in conversion of the tuberculin skin test from negative to positive and probably in increased resistance to reinfection with tubercle bacilli.CD4⁺ αβ-T-cell-receptor (αβ TCR)-bearing T cells (CD4⁺ T cells) are readily activated by mycobacterial antigens and have a dominant role in the protective immune response to M. tuberculosis in humans (2, 34). These CD4⁺ T cells not only secrete cytokines but also serve directly as cytotoxic effector cells against M. tuberculosis-infected macrophages (6). In addition to CD4⁺ T cells, M. tuberculosis antigens activate other human T-cell subsets such as γδ TCR⁺ T cells (γδ T cells) (15, 16, 18). Vδ2⁺ and Vγ9⁺ γδ T cells are particularly responsive to live M. tuberculosis (15). A role for both γδ and CD4⁺ T cells in protective immunity to acute M. tuberculosis infection has been demonstrated in murine models (20, 21, 26, 27). A recent study of humans suggests that Vγ9⁺ and Vδ2⁺ γδ T-cell numbers and function are reduced in tuberculosis patients (23).Functional comparisons of human CD4⁺ and γδ T-cell responses of healthy tuberculin-positive persons demonstrate that both T-cell subsets have similar cytotoxic effector functions for M. tuberculosis-infected monocytes and produce large amounts of gamma interferon (IFN-γ), with γδ T cells being slightly more efficient producers of IFN-γ than CD4⁺ T cells (37). Despite similarities in function, these two T-cell subsets differ in the mycobacterial antigens recognized by their TCRs and the manners in which antigens are presented to them by M. tuberculosis-infected mononuclear phagocytes. CD4⁺ T cells recognize a wide diversity of mycobacterial peptides in the context of class II major histocompatibility complex (MHC) molecules, which include secreted as well as somatic antigens (6, 13, 33, 37). In contrast, Vγ9⁺ and Vδ2⁺ γδ T cells, the dominant γδ TCR subsets activated by M. tuberculosis, recognize mycobacterial antigens in a non-MHC-restricted manner and the repertoire of antigens includes small phosphate-containing antigens such as TUBag’s (5, 9, 19, 22, 29, 36).Both blood monocytes and alveolar macrophages infected with M. tuberculosis are efficient antigen-presenting cells for mycobacterial antigen-specific CD4⁺ and γδ T cells (1, 5). However, little is known about how M. tuberculosis-infected mononuclear phagocytes process antigens for these two T-cell subsets. M. tuberculosis bacilli are taken up by mononuclear phagocytes through a variety of surface receptors, including complement receptor 4, mannose receptor, and complement receptor 3 (17, 31, 32). Within mononuclear phagocytes, the mycobacteria reside within phagosomes and modulate the phagosome by preventing fusion with acidic lysosomal compartments (7). Although the vacuolar membranes surrounding the phagosome acquire endosomal markers, the vesicular proton ATPase is actively excluded, resulting in an elevated pH of 6.3 to 6.5 compared to the normal lysosomal pH of 4.5 (7, 35). The elevated pH in the phagosome does not appear to inhibit the ability of mycobacterial antigens to be processed and presented to CD4⁺ and Vδ2⁺ γδ T cells. This study was undertaken to gain insight into the mechanisms used by monocytes infected with live M. tuberculosis bacilli to process mycobacterial antigens for presentation to both CD4⁺ and γδ T cells.     

Hypothalamo–pituitary–adrenal axis,glucose metabolism and TNF‐α in narcolepsy

Narcolepsy with cataplexy is caused by a deficiency in the production of hypocretin/orexin, which regulates sleep and wakefulness, and also influences appetite, neuroendocrine functions and metabolism. In this case–control study, 11 patients with narcolepsy with cataplexy and 11 healthy adults underwent an oral glucose tolerance test, and dexamethasone suppression/corticotropin‐releasing hormone stimulation test. The average age of patients and controls was 35.1 ± 13.2 and 41.0 ± 2.9 years, respectively, body mass index was 28.1 ± 6.6 and 25.5 ± 4.7 kg m^?2. We did not find evidence of a significantly increased prevalence of disturbed glucose tolerance in patients with narcolepsy. After hypothalamo–pituitary–adrenal axis suppression, the number of non‐suppressors did not differ between the groups, indicating normal negative feedback sensitivity. The level of cortisol after dexamethasone suppression was significantly lower in patients with narcolepsy, suggesting a slight basal downregulation and/or a slightly increased negative feedback sensitivity of the major endocrine stress system in narcolepsy. Following corticotropin‐releasing hormone stimulation, there were no significant differences in levels of adrenocorticotropic hormone or cortisol, and in adrenocortical responsivity to adrenocorticotropic hormone. Finally, patients with narcolepsy displayed significantly higher plasma levels of tumour necrosis factor alpha, soluble tumour necrosis factor receptor p55, soluble tumour necrosis factor receptor p75 and interleukin 6 after adjustment for body mass index. The present study confirms that narcolepsy by itself is not associated with disturbances of glucose metabolism, but goes along with a subtle dysregulation of inflammatory cytokine production. We also found that dynamic hypothalamo–pituitary–adrenal system response is not altered, whereas negative feedback to dexamethasone might be slightly enhanced.     

The investigation of glucose metabolism and insulin secretion in subjects of chronic hepatitis B with cirrhosis

Aims: To investigate the situations of abnormal glucose metabolism and dysfunction of pancreatic islet beta cells in subjects of chronic hepatitis B (CHB) with cirrhosis. Methods: 106 hepatitis B virus (HBV) positive subjects with liver cirrhosis as well as with different grade of Child-Pugh and 37 healthy subjects were included in this study. The oral glucose tolerance test (OGTT), C-peptide and insulin release test were detected. Plasma glucose and insulin levels were analyzed periodically for 2 h after oral glucose loading. Results: There was no significant difference in the level of fasting plasma glucose and C-peptide between cirrhosis group and control group (P>0.05). The levels of OGTT 2 h glucose, insulin and C peptide were significantly higher in cirrhosis group than control group (P<0.01). Peak plasma glucose levels were obtained at 60 min in normal group and cirrhosis group. The peak insulin and C-peptide response occurred at 60 min in normal group, whereas it was delayed to 120 min in cirrhosis group. There was a significant difference between two groups in the pattern of plasma glucose levels at corresponding time points (P<0.05). The OGTT 2 h glucose and insulin levels were positively correlated with Child-Pugh Score (r1 = 0.389, r2 = 0.508, P<0.01). Conclusion: These findings implied that there was a certain degree of insulin resistance and abnormal glucose metabolism in the patients with liver cirrhosis.