This study investigated the effects of mitiglinide in 16 patients with type 2 diabetes mellitus treated with 30 mg/day mitiglinide, divided into three doses given just before each meal, for ...approximately 12 months. A 450 kcal meal tolerance test was performed at baseline and after 3, 6 and 12 months, and levels of plasma glucose and immunoreactive insulin were measured. Various parameters of glucose metabolism and lipid metabolism, urinary albumin and markers of atherosclerosis, coagulation and fibrinolysis were also determined. Mitiglinide showed a rapid stimulatory effect on insulin secretion and reduced the levels of plasma glucose. The free fatty acid level significantly decreased at 60 min after the meal tolerance test. Mitiglinide also significantly lowered glycosylated haemoglobin and raised 1,5-anhydroglucitol after 6 months, and significantly decreased urinary albumin after 12 months. These data indicate that mitiglinide may have beneficial effects not only on glycaemic control but also on lipid metabolism and urinary albumin excretion, and may have a role in the prevention of the vascular complications of diabetes.
Cytokines are thought to contribute to the induction of pancreatic beta-cell destruction in insulin-dependent diabetes mellitus. The molecular mechanisms that underlie beta-cell death were ...investigated by studying cytokine-induced cell death in beta-cell lines. A combination of three cytokines (interleukin-1 beta, tumour necrosis factor-alpha, and interferon-gamma) induced apoptotic cell death in the mouse pancreatic beta-cell line beta TC1, as judged from the appearance of cells with hypodiploid nuclei and oligonucleosomal DNA fragmentation. The same treatment also induced apoptosis in the mouse pancreatic alpha-cell line alpha TC1 and the NOD/Lt mouse beta-cell line NIT-1, although to a lesser extent than in beta TC1 cells. The abundance of endogenous Bcl-2 in beta TC1 cells was lower than that in the other two cell lines. Overexpression of human Bcl-2 in beta TC1 cells partially protected them from cytokine-induced cell death. These results suggest that apoptosis may be responsible, at least in part, for cytokine-induced beta-cell destruction and that Bcl-2 prevents apoptosis in pancreatic islet cells.
Mutations in the hepatocyte nuclear factor (HNF) 4α gene cause a form of maturity-onset diabetes of the young (MODY1), which is a monogenic form of type 2 diabetes characterized by impaired insulin ...secretion by pancreatic β-cells. HNF4α is a transcription factor expressed in the liver, kidney, intestine, and pancreatic islet. Multiple splice variants of the HNF4α gene have been identified and an isoform of HNF4α8, an N-terminal splice variant, is expressed in pancreatic β-cells. However, expression levels of HNF4α protein in pancreatic β-cells and the transcriptional activity of HNF4α8 are not yet understood. In the present study, we investigated the expression of HNF4α in β-cells and examined its functional properties. Western blotting and immunohistochemical analysis revealed that the expression of HNF4α protein in pancreatic islets and INS-1 cells was much lower than in the liver. A reporter gene assay showed that the transactivation potential of HNF4α8 was significantly weaker than that of HNF4α2, which is a major isoform in the liver, suggesting that the total level of HNF4α activity is very weak in pancreatic β-cells. We also showed that the N-terminal A/B region of HNF4α8 possessed no activation function and C-terminal F region negatively regulated the transcriptional activity of HNF4α8. The information presented here would be helpful for the better understanding of MODY1/HNF4α diabetes.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been recently identified as a member of the EGF family. EGF receptors to which HB-EGF can bind have been detected in some types ...of gastric epithelial cells. The aim of this study was to investigate whether HB-EGF is produced in gastric epithelial cells to maintain normal gastric mucosa.
Gene expression and production of HB-EGF protein were investigated using Northern hybridization and immunohistochemistry, and the types of cells producing this protein were determined in human gastric mucosa.
HB-EGF messenger RNA was detected in the body and antrum. Immunohistochemical staining showed that HB-EGF was localized mainly in parietal cells of fundic glands and in gastrin cells of pyloric glands. Also, the immunoreactivity of EGF receptors was observed in parietal cells and gastrin cells and faintly in surface epithelial cells and mucous neck cells of the proliferative zone.
The results suggest that HB-EGF is synthesized mainly in parietal cells and gastrin cells and may act in an autocrine and/or paracrine manner in the regulation of proliferation and differentiation of the gastric mucosal cells through their surface EGF receptors.
Growth factors are involved in the development and progression of cancer. The purpose of this study was to evaluate the possible role of heparin-binding epidermal growth factor-like growth factor ...(HB-EGF), which is a member of the EGF family, in the neoplastic transformation of hepatocytes.
Gene expression and protein production of HB-EGF were investigated in samples of human hepatocellular carcinoma (HCC) from 17 patients using Northern hybridization and immunohistochemical methods.
The amount of HB-EGF messenger RNA was increased in the patients' HCC specimens compared with the surrounding liver tissues. In noncancerous hepatic tissues, HB-EGF was faintly positive in hepatocytes. Immunoreactive HB-EGF-producing cells were identified in HCC cells of all 17 patients with HCC, indicating that HB-EGF was produced in HCC cells themselves. However, none of the specimens from 10 patients with metastatic adenocarcinoma in the liver was positive for HB-EGF. The EGF receptor, which binds to HB-EGF, was also expressed on HCC cells.
It is hypothesized that the enhanced expression of immunoreactive HB-EGF on the cell suggests a possible role of HB-EGF in the development or progression of human HCC in an autocrine and/or a juxtacrine manners.
We isolated the human adipose-specific and most abundant gene transcript, apM1 (Maeda, K., et al.,Biochem. Biophys. Res. Commun.221, 286–289, 1996). The apM1 gene product was a kind of soluble matrix ...protein, which we named adiponectin. To quantitate the plasma adiponectin concentration, we have produced monoclonal and polyclonal antibodies for human adiponectin and developed an enzyme-linked immunosorbent assay (ELISA) system. Adiponectin was abundantly present in the plasma of healthy volunteers in the range from 1.9 to 17.0 mg/ml. Plasma concentrations of adiponectin in obese subjects were significantly lower than those in non-obese subjects, although adiponectin is secreted only from adipose tissue. The ELISA system developed in this study will be useful for elucidating the physiological and pathophysiological role of adiponectin in humans.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Heparin-binding EGF-like growth factor (HB-EGF) is a potent chemoattractant and mitogen for smooth muscle cells (SMC) in culture. To elucidate whether HB-EGF is implicated in the pathogenesis of ...human atherosclerosis, we examined immunohistochemical localization of HB-EGF in human aortic walls and atherosclerotic plaques. The medial SMC of the aorta in babies and children synthesized HB-EGF protein, while the number of SMC producing HB-EGF was dramatically decreased in young and middle-aged adults. In atherosclerotic plaques, however, marked production of HB-EGF protein was detected in SMC and macrophages of the plaques. Furthermore, EGF receptors, to which HB-EGF is known to bind, were detected in plaque SMC. These data suggest that HB-EGF may be implicated in the migration and proliferation of SMC that occurs in the normal development of arterial walls, and in the formation of atherosclerotic plaques.
Glucose-6-phosphatase (G-6-Pase) hydrolyzes glucose-6-phosphate to glucose, reciprocal with the so-called glucose sensor, glucokinase, in pancreatic beta cells. To study the role of G-6-Pase in ...glucose-stimulated insulin secretion from beta cells, we have introduced rat G-6-Pase catalytic subunit cDNA and have established permanent clones with 3-, 7- and 24-fold G-6-Pase activity of the mouse beta-cell line, MIN6. In these clones, glucose usage and ATP production in the presence of 5.5 or 25 mM glucose were reduced, and glucose-stimulated insulin secretion was decreased in proportion to the increased G-6-Pase activity. In addition, insulin secretory capacity in response to d-fructose and pyruvate was unchanged; however, 25 mM glucose-stimulated insulin secretion and intracellular calcium response were completely inhibited. In the clone with 24-fold G-6-Pase activity, changes in intracellular NAD(P)H autofluorescence in response to 25 mM glucose were reduced, but the changes with 20 mM fructose and 20 mM pyruvate were not altered. Stable overexpression of G-6-Pase in beta cells resulted in attenuation of the overall glucose-stimulated metabolic responses corresponding to the degree of overexpression. This particular experimental manipulation shows that the possibility exists of modulating glucose-stimulated insulin release by thoroughly altering glucose cycling at the glucokinase/G-6-Pase step.
Defective glucose-stimulated insulin secretion is the main cause of hyperglycemia in type 2 diabetes mellitus. Mutations in HNF-1α cause a monogenic form of type 2 diabetes, maturity-onset diabetes ...of the young (MODY), characterized by impaired insulin secretion. Here we report that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1α in pancreatic β cells. Expression of collectrin was decreased in the islets of HNF-1α (−/−) mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in rat insulinoma INS-1 cells or in the β cells of transgenic mice enhanced glucose-stimulated insulin exocytosis, without affecting Ca
2+ influx. Conversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP-25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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