This study aimed at elucidating the effects of interferon (IFN)-alpha on glucose metabolism in patients with chronic hepatitis B and C infections. Twenty-eight biopsy-proven patients with chronic hepatitis B (ten cases) and hepatitis C (18 cases) were given IFN-alpha for a total of 24 weeks. The patients received a 75 g oral glucose tolerance test (OGTT), glucagon stimulation test, tests for type 1 diabetes-related autoantibodies and an insulin suppression test before and after IFN-alpha therapy. Ten of the 28 patients responded to IFN-alpha therapy. Steady-state plasma glucose of the insulin suppression test decreased significantly in responders (13.32+/-1.48 (S.E.M.) vs 11.33+/-1.19 mmol/l, P=0.0501) but not in non-responders (12.29+/-1.24 vs 11.11+/-0.99 mmol/l, P=0.2110) immediately after completion of IFN-alpha treatment. In the oral glucose tolerance test, no significant difference was observed in plasma glucose in either responders (10.17+/-0.23 vs 10.03+/-0.22 mmol/l) or non-responders (10.11+/-0.22 vs 9.97+/-0.21 mmol/l) 3 Months after completion of IFN-alpha treatment. However, significant differences were noted in C-peptide in both responders (2.90+/-0.13 vs 2.20+/-0.09 nmol/l, P=0.0040) and non-responders (2.45+/-0.11 vs 2.22+/-0.08 nmol/l, P=0.0287) before vs after treatment. The changes of C-peptide in an OGTT between responders and non-responders were also significantly different (P=0.0028), with responders reporting a greater reduction in C-peptide. No case developed autoantibodies during the treatment. In patients who were successfully treated with IFN-alpha, insulin sensitivity improved and their plasma glucose stayed at the same level without secreting as much insulin from islet beta-cells.
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- Abstract: Diabetes x
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TY Tai, JY Lu, CL Chen, MY Lai, PJ Chen, JH Kao, CZ Lee, HS Lee, LM Chuang and YM Jeng
A Alidibbiat, C E Marriott, K T Scougall, S C Campbell, G C Huang, W M Macfarlane and J A M Shaw
Generation of new β-cells from the adult pancreas or the embryonic stem cells is being pursued by research groups worldwide. Success will be dependent on confirmation of true β-cell phenotype evidenced by capacity to process and store proinsulin. The aim of these studies was to robustly determine endocrine characteristics of the AR42J rat pancreatic acinar cell line before and after in vitro transdifferentiation. β-cell phenotypic marker expression was characterised by RT-PCR, immunostaining, western blotting, ELISA and in human preproinsulin transgene over-expression studies in wild-type AR42J cells and after culture on Matrigel basement membrane matrix with and without growth/differentiation factor supplementation. Pancreatic duodenal homeobox 1 (PDX1), forkhead box transcription factor a2 (Foxa2), glucokinase, pancreatic polypeptide and low-level insulin gene transcription in wild-type AR42J cells were confirmed by RT-PCR. Culture on Matrigel-coated plates and supplementation of medium with glucagon-like peptide 1 induced expression of the β-cell Glut 2 with maintained expression of insulin and PDX1. Increased biosynthesis and secretion of proinsulin were confirmed by immunocytochemical staining and sensitive ELISA. Absence of the regulated secretory pathway was demonstrated by undetectable prohormone convertase expression. In addition, inability to process and store endogenous proinsulin or human proinsulin translated from a constitutively over-expressed preproinsulin transgene was confirmed. The importance of robust phenotypic characterisation at the protein level in attempted β-cell transdifferentiation studies has been confirmed. Rodent and human sensitive/specific differential proinsulin/insulin ELISA in combination with human preproinsulin over-expression enables detailed elucidatation of core endocrine functions of proinsulin processing and storage in putative new β-cells.
Xiaofeng Wang and Catherine B Chan
n-3 polyunsaturated fatty acids (PUFAs) are a subgroup of fatty acids with broad health benefits, such as lowering blood triglycerides and decreasing the risk of some types of cancer. A beneficial effect of n-3 PUFAs in diabetes is indicated by results from some studies. Defective insulin secretion is a fundamental pathophysiological change in both types 1 and 2 diabetes. Emerging studies have provided evidence of a connection between n-3 PUFAs and improved insulin secretion from pancreatic β-cells. This review summarizes the recent findings in this regard and discusses the potential mechanisms by which n-3 PUFAs influence insulin secretion from pancreatic β-cells.
Hongbin Liu, Anthony E Dear, Lotte B Knudsen and Richard W Simpson
Glucagon-like peptide-1 (GLP-1) administration attenuates endothelial cell dysfunction in diabetic patients and inhibits tumour necrosis factor α (TNF)-mediated plasminogen activator inhibitor type-1 (PAI-1) induction in human vascular endothelial cells. The short half-life of GLP-1 mediated via degradation by the enzyme dipeptidyl peptidase 4 mandates the clinical use of long-acting GLP-1 analogues. The effects of a long-acting GLP-1 analogue on PAI-1 and vascular adhesion molecule expression in vascular endothelial cells are unknown. In this report, we demonstrate for the first time that the treatment with liraglutide, a long-acting GLP-1 analogue, inhibited TNF or hyperglycaemia-mediated induction of PAI-1, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA and protein expression in a human vascular endothelial cell line. In addition, treatment attenuated TNF- or hyperglycaemia-mediated induction of the orphan nuclear receptor Nur77 mRNA expression. Taken together, these observations indicate that liraglutide inhibits TNF- or glucose-mediated induction of PAI-1 and vascular adhesion molecule expression, and this effect may involve the modulation of NUR77. These effects suggest that liraglutide may potentially improve the endothelial cell dysfunction associated with premature atherosclerosis identified in type 2 diabetic patients.
Tetsuhiro Kakimoto, Hirotaka Kimata, Satoshi Iwasaki, Atsushi Fukunari and Hiroyuki Utsumi
Type 2 diabetes is characterized by impaired insulin secretion from pancreatic β-cells. Quantification of the islet area in addition to the insulin-positive area is important for detailed understanding of pancreatic islet histopathology. Here we show computerized automatic recognition of the islets of Langerhans as a novel high-throughput method to quantify islet histopathology. We utilized state-of-the-art tissue pattern recognition software to enable automatic recognition of islets, eliminating the need to laboriously trace islet borders by hand. After training by a histologist, the software successfully recognized even irregularly shaped islets with depleted insulin immunostaining, which were quite difficult to automatically recognize. The results from automated image analysis were highly correlated with those from manual image analysis. To establish whether this automated, rapid, and objective determination of islet area will facilitate studies of islet histopathology, we showed the beneficial effect of chronic exendin-4, a glucagon-like peptide-1 analog, treatment on islet histopathology in Zucker diabetic fatty (ZDF) rats. Automated image analysis provided qualitative and quantitative evidence that exendin-4 treatment ameliorated the loss of pancreatic insulin content and gave rise to islet hypertrophy. We also showed that glucagon-positive α-cell area was decreased significantly in ZDF rat islets with disorganized structure. This study is the first to demonstrate the utility of automatic quantification of digital images to study pancreatic islet histopathology. The proposed method will facilitate evaluations in preclinical drug efficacy studies as well as elucidation of the pathophysiology of diabetes.
Yuichiro Takeuchi, Keishi Yamauchi, Junko Nakamura, Satoshi Shigematsu and Kiyoshi Hashizume
The biological effects of angiotensin II (AngII) are mediated by two major subtypes of AngII receptors, type 1 (AT1R) and type 2 (AT2R). In this study, we attempted to elucidate the role of AngII subtype receptor-specific regulation in migration and proliferation of mouse cultured mesangial (MSG) cells. We found that 100 nM AngII stimulated weak migration of MSG cells. Cell motility increased more in the presence of AT2R than in the presence of AT1R, and it was suppressed by guanylate cyclase inhibitors. On the other hand, the activation of AT1R resulted in increased cell numbers, while AT2R activation inhibited cell proliferation. Moreover, high concentrations of glucose (25 mM) stimulated the expression of AT2R but not AT1R. These results indicate that there are receptor subtype-specific roles in MSG cells, and it is therefore possible that the activation of AT2R stimulates repair of glomerular tissue defect, by regulation of migration and proliferation of MSG cells. Taken together, these results suggest that the relative concentrations of AT1R and AT2R are important factors in the regulation of AngII function in glomerular tissue, and alterations in the concentrations of these receptors may contribute to progression of or protection from diabetic nephropathy.
Marleen B Dommerholt, Derek A Dionne, Daria F Hutchinson, Janine K Kruit and James D Johnson
Caloric restriction (CR) is the only environmental intervention with robust evidence that it extends lifespan and delays the symptoms of aging, but its mechanisms are incompletely understood. Based on the prolonged longevity of knockout models, it was hypothesized that the insulin-IGF pathway could be a target for developing a CR mimic. This study aimed to test whether CR has additive effects on glucose homeostasis and beta-cell function in mice with reduced insulin gene dosage. To study models with a range of basal insulin levels, wild-type C57BL/6J and mice on an Ins2 − / − background, were put on 8 weeks of 40% CR at various ages. Both male and female mice rapidly lost weight due to a reduced WAT mass. Glucose tolerance was improved and fasting glucose levels were reduced by CR in both wild type and 45- and 70-week-old Ins2 − / − mice. The effects of CR and reduced insulin on glucose tolerance were non-additive in 20-week-old mice. Interestingly, mice on CR generally exhibited an inability to further depress blood glucose after insulin injection, pointing to possible alterations in insulin sensitivity. In conclusion, our results demonstrate that CR can cause weight loss in the context of reduced insulin production, but that CR-improved glucose homeostasis does not occur near the ‘insulin floor’ in young mice. Collectively, these data shed further light on the relationships between CR, insulin and glucose homeostasis.
P S Leung, H C Chan, L X M Fu and P Y D Wong
Previous studies have demonstrated the existence of several key components of the renin–angiotensin system in the pancreas. In the present study, the localization of angiotensin II receptor subtypes, type I (AT1) and type II (AT2), in the mouse and the rat pancreas was studied by immunocytochemistry using specific antipeptide antibodies against the second extracellular loops of AT1 and AT2 receptors in conjunction with confocal laser scanning microscopy. In the mouse, immunoreactivity for AT1 and AT2 was observed predominantly in the endothelia of the blood vessels and the epithelia of the pancreatic ductal system. Similar distribution of immunoreactivity for AT1 and AT2 was also observed. However, the intensity of immunoreactivity for AT1 and AT2 was stronger in the rat than that found in the mouse pancreas. Much weaker immunostaining for both AT1 and AT2, as compared with that found in ductal regions, was also found in the acini of the rodent pancreas. Together with the previous findings, the present results suggest that AT1 and/or AT2 receptors may play a role in regulating pancreatic functions in the rodent.
Journal of Endocrinology (1997) 153, 269–274
H Del Zotto, L Massa, R Rafaeloff, GL Pittenger, A Vinik, G Gold, A Reifel-Miller and JJ Gagliardino
The possible relationship between changes in islet cell mass and in islet neogenesis-associated protein (INGAP)-cell mass induced by sucrose administration to normal hamsters was investigated. Normal hamsters were given sucrose (10% in drinking water) for 5 (S8) or 21 (S24) weeks and compared with control (C) fed hamsters. Serum glucose and insulin levels were measured and quantitative immunocytochemistry of the endocrine pancreas was performed. Serum glucose levels were comparable among the groups, while insulin levels were higher in S hamsters. There was a significant increase in beta-cell mass (P<0.02) and in beta-cell 5-bromo-2'-deoxyuridine index (P<0.01), and a significant decrease in islet volume (P<0.01) only in S8 vs C8 hamsters. Cytokeratin (CK)-labelled cells were detected only in S8 hamsters. INGAP-positive cell mass was significantly larger only in S8 vs C8 hamsters. Endocrine INGAP-positive cells were located at the islet periphery ( approximately 96%), spread within the exocrine pancreas ( approximately 3%), and in ductal cells (<1%) in all groups. INGAP positivity and glucagon co-localization varied according to topographic location and type of treatment. In C8 hamsters, 49.1+/-6. 9% cells were INGAP- and glucagon-positive in the islets, while this percentage decreased by almost half in endocrine extra-insular and ductal cells. In S8 animals, co-expression increased in endocrine extra-insular cells to 36.3+/-9.5%, with similar figures in the islets, decreasing to 19.7+/-6.9% in ductal cells. INGAP-positive cells located at the islet periphery also co-expressed CK. In conclusion, a significant increase of INGAP-positive cell mass was only observed at 8 weeks when neogenesis was present, suggesting that this peptide might participate in the control of islet neogenesis. Thus, INGAP could be a potentially useful tool to treat conditions in which there is a decrease in beta-cell mass.
A Shirakami, T Toyonaga, K Tsuruzoe, T Shirotani, K Matsumoto, K Yoshizato, J Kawashima, Y Hirashima, N Miyamura, CR Kahn and E Araki
Insulin receptor substrate 1 (IRS-1) gene polymorphisms have been identified in type 2 diabetic patients; however, it is unclear how such polymorphisms contribute to the development of diabetes. Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. GTG injection resulted in approximately 30% weight gain in IRS-1(+/-) and wild type (WT) mice, compared with saline-injected controls. There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. The islets of obese IRS-1(+/-) were 1.4-fold larger than those of obese WT. The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity.