Journal Article Latent Carcinoma of the Thyroid Manifested by Cystic Supraclavicular Metastasis Get access Junichi Yoshida, Junichi Yoshida * 1Department of Surgery Wakamatsu Municipal Hospital8-3 Hakusan 1-Chome, Wakamatsu-ku, Kitakyushu 808 *For reprints and all correspondence Search for other works by this author on: Oxford Academic PubMed Google Scholar Mizuho Nakagawa, Mizuho Nakagawa 2Department of Pathology I, Kyushu University Faculty of MedicineFukuoka 1-1 Maidashi 3-Chome, Higashi-ku, 812 Search for other works by this author on: Oxford Academic PubMed Google Scholar Kazunori Yokohata, Kazunori Yokohata 1Department of Surgery Wakamatsu Municipal Hospital8-3 Hakusan 1-Chome, Wakamatsu-ku, Kitakyushu 808 Search for other works by this author on: Oxford Academic PubMed Google Scholar Hideki Kishikawa, Hideki Kishikawa 1Department of Surgery Wakamatsu Municipal Hospital8-3 Hakusan 1-Chome, Wakamatsu-ku, Kitakyushu 808 Search for other works by this author on: Oxford Academic PubMed Google Scholar Akiyo Shiroozu Akiyo Shiroozu 3Department of Medicine, Wakamatsu Municipal Hospital8-3 Hakusan 1-Chome, Wakamatsu-ku, Kitakyushu 808 Search for other works by this author on: Oxford Academic PubMed Google Scholar Japanese Journal of Clinical Oncology, Volume 20, Issue 2, June 1990, Pages 204–208, https://doi.org/10.1093/oxfordjournals.jjco.a039388 Published: 01 June 1990 Article history Received: 03 August 1989 Accepted: 27 November 1989 Published: 01 June 1990
Pancreatic and duodenal homeobox gene-1(PDX-1) is a transcription factor which regulates the insulin gene expression. In this study, we tried to elucidate the role of PDX-1 in the glucose-induced transcriptional activation of the human insulin gene promoter in MINE cells. Electrophoretic mobility shift assay (EMSA) and chloramphenicol acetyltransferase (CAT) assay demonstrated that both DNA-binding activity and transcriptional activity of PDX-1 were increased with 20mmol/l glucose more than with 2mmol/l glucose. The DNA-binding activity of PDX-1 induced by high glucose was blocked by phosphatase treatment, suggesting the involvement of PDX-1 phosphorylation in this event. In an in vitro phosphorylation study, PDX-1 was phosphorylated by protein kinase C (PKC), but not by cAMP dependent protein kinase (PKA) or mitogen-activated protein kinase (MAPK). Furthermore, increased PDX-1 function induced by high glucose was blocked by calphostin C, an inhibitor of all PKC isoforms, but unaffected by phorbol 12-myristate 13-acetate (PMA), an activator of classical and novel PKC, or Gö 6976, an inhibitor of classical and novel PKC, which suggested that the PKC family which activated PDX-1 in MINE cells was atypical PKC. Western blot and immunocytochemical studies with anti-PKCζ antibody confirmed the presence of PKC ζ, one of the isoforms of atypical PKC, in MIN6 cells. Furthermore, PKC ζ activity was significantly increased by glucose stimulation. These results suggest that high glucose increased DNA-binding activity of PDX-1 by activating atypical PKC including PKC ζ, resulting in transcriptional activation of the human insulin gene promoter.
OBJECTIVE—To evaluate urinary 8-hydroxydeoxyguanosine (8-OHdG) as a marker for the progression of diabetic macroangiopathic complications. RESEARCH DESIGN AND METHODS—The content of urinary 8-OHdG, common carotid intima-media thickness (IMT), the coronary heart disease (CHD) risk score, the severity of diabetic retinopathy, and urinary albumin excretion were examined in 96 patients with type 2 diabetes, including 32 patients who had been nominated for the Kumamoto Study [Shichiri M, et al. Diabetes Care 23 (Suppl 2):B21–B29, 2000]. In addition, the patients from the Kumamoto Study were further evaluated regarding the effect of intensive insulin therapy on urinary 8-OHdG excretion. RESULTS—The urinary 8-OHdG:creatinine ratio (U8-OHdG) was 2.5-fold higher in patients with increased HbA1c than in those with normal HbA1c (P < 0.05). In addition, U8-OHdG was 2.3-fold higher in patients with increased IMT (P < 0.005). A similar result was observed between U8-OHdG and CHD risk score (P < 0.01). U8-OHdG was significantly higher in patients with simple retinopathy (P < 0.05) and those with advanced retinopathy (P < 0.01) than in patients without retinopathy. Similarly, U8-OHdG was significantly higher in patients with albuminuria (P < 0.01). Furthermore, in the Kumamoto Study, U8-OHdG was significantly lower in the multiple insulin injection therapy group compared with the conventional insulin injection therapy group (P < 0.01). CONCLUSIONS—Hyperglycemia independently increases 8-OHdG in patients with type 2 diabetes. 8-OHdG is a useful biomarker of not only microvascular but also macrovascular complications in patients with type 2 diabetes.
We studied the effects of glycated lipoproteins of low-and high-density (LDL and HDL) on platelets and vascular endothelial cells. After pretreatment for 5 minutes at 37°C, the thrombininduced synthesis of thromboxane B2 in washed platelets was significantly increased by glycated LDL as compared with native LDL (198.9 ± 16.2 vs 90.3 ± 29.4ng/109 platelets, n = 8, p < 0.01). Platelet aggregation was also increased by glycated LDL as compared with native LDL. After treatment with platelet-rich plasma for 5 hours at 37°C, these values were suppressed by native HDL vs the control (buffer), but not by glycated HDL. Abnormalities in the release of 6-keto prostaglandin F1α and lactate dehydrogenase from vascular endothelial cells were also induced by glycated LDL and/or HDL. These observations suggest that abnormalities induced in platelets and vascular endothelial cells by glycated lipoproteins may play an important role in the development of atherosclerosis in patients with diabetes mellitus.(Internal Medicine 31 : 746-751, 1992)
Insulin receptor substrate-1 (IRS-1) is one of the major substrates of insulin receptor tyrosine kinase and mediates various insulin signals downstream. In this study, we have examined the impact of three natural IRS-1 mutations identified in NIDDM patients (G971R, P170R, and M209T) on insulin signaling. G971R is located near src homology 2 protein binding sites, and P170R and M209T are located in the phosphotyrosine binding domain of IRS-1. 32D-IR cells, stably overexpressing human insulin receptor, were transfected with wild-type human IRS-1 cDNA (WT) or three mutant IRS-1 cDNAs and analyzed. All the cell lines expressing mutant IRS-1 showed a significant reduction in [3H]thymidine incorporation compared with WT. Upon insulin stimulation, cells expressing G971R showed a 39% decrease (P < 0.005) in phosphatidylinositol 3-kinase (PI 3-kinase) activity, a 43% decrease (P < 0.01) in binding of the 85-kDa regulatory subunit of PI 3-kinase, and a 22% decrease (P < 0.05) in mitogen-activated protein kinase activity compared with those expressing WT. Cells expressing P170R and M209T showed slight but significant decreases in PI 3-kinase activity (17 and 14%, respectively; both P < 0.05) and in binding of p85 (22 and 16%, respectively; both P < 0.05) and a greater decrease in mitogen-activated protein kinase activity (41 and 43%, respectively; both P < 0.005) compared with WT. After insulin stimulation, cells expressing P170R and M209T showed significant decreases in IRS-1 phosphorylation (37 and 42%, respectively; both P < 0.05) and in IRS-1 binding to the insulin receptor (48 and 53%, respectively; P < 0.01) compared with WT. G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. These data suggest that the impaired mitogenic response of P170R and M209T was mainly due to reduced binding to the insulin receptor, whereas the impaired response of G971R was mainly due to reduced association with PI 3-kinase p85.
Glycated hemoglobin (HbA1c) reflects glycemic control over a period of a few months before examination, and thus is commonly used as an indicator and a goal for the treatment of diabetes. Several prospective studies have shown that good glycemic control evaluated by HbA1c could prevent the development and/or progression of diabetic microvascular complications, such as retinopathy and nephropathy1–3. Furthermore, good glycemic control might also prevent macrovascular complications, such as cardiovascular disease, when glycemic control was initiated in the early stages of the development of diabetes4,5. According to these data, the American Diabetes Society proposed that the goal for diabetic control be lower than a HbA1c level of 7.0%6. In contrast, several recent studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study7 and Veterans Affairs Diabetes Trial (VADT)8 failed to prove the effect of good glycemic control on the reduction of mortality and macrovascular disease in subjects with type 2 diabetes. Recently, Craig Currie et al reported that there was a U-shaped association between HbA1c and the hazard ratio of all-cause mortality in subjects with type 2 diabetes, and the lowest hazard ratio was a HbA1c level of approximately 7.5%9. Briefly, the authors obtained data from routine general practice in the UK from a proprietary health data resource: the General Practice Research Database (GPRD)9 from November 1986 to November 2008, and identified all patients who had a diagnosis of type 2 diabetes and whose treatment history included evidence of a specific escalation of their diabetes treatment. Then, they classified the patients into two groups, one was defined as patients with a newly identified switch from oral monotherapy to a combination oral regimen with a sulfonylurea plus metformin (cohort 1; n = 27,965) and the other was defined as those who were initiated on insulin with or without concomitant oral hypoglycemic agents (cohort 2; n = 20,005). The cohorts were divided into deciles by the rank of the mean of all post-index HbA1c values or yearly values where appropriate. The post-index HbA1c was calculated as the mean of all observations recorded between the index date (first prescription of intensified diabetes therapy) and the respective outcome event (death or large-vessel event) or the censoring point (further switching of treatment or the last recorded database observation). The primary outcome measure was all-cause mortality, and the secondary outcome measure was occurrence of a major cardiovascular event. Mean follow-up was 4.5 and 5.2 years in cohort 1 and 2, respectively. As the results, unadjusted mortality rates were 16.2 deaths per 1000 person-years of follow-up in cohort 1 and 27.2 deaths in cohort 2. The hazard ratio for all-cause mortality in subjects of cohort 2 (2834 deaths) vs cohort 1 (2035) was 1.49, and there were more deaths in cohort 2. In cohort 1, a significant increase of all-cause mortality was found only in deciles 1 and 10, whereas for cohort 2, significant differences were observed for deciles 1, 2, 3, 9 and 10 (Figure 1). Therefore, increased unadjusted mortality was found both in the lowest and highest HbA1c deciles in both cohorts, and patients included in a decile whose median HbA1c of 7.5% had the lowest hazard of death. Similar to the results of all-cause mortality, insulin treatment (cohort 2 vs cohort 1) was associated with an increased risk of progression to first large-vessel disease with an adjusted hazard ratio of 1.36. Taking these results, the authors suggested the revision of the diabetes guidelines include a minimum HbA1c. Hazard ratios for all-cause mortality by HbA1c deciles in type 2 diabetes subjects given oral combination and insulin-based therapies. Hazard ratios for all-cause mortality by HbA1c deciles in type 2 diabetes subjects given (a) sulfonylurea plus metformin regimen and (b) insulin-based regimen are shown. Vertical bars show hazard ratios (HR), and horizontal bars show HbA1c range. Red circle indicates each reference decile. *Truncated value at lower quartile, †truncated value at upper quartile. This figure is reprinted from an article by Currie et al9. with permission from Elsevier (License number 2491840027075). From the results of many prospective studies1–3, it is clear that better glycemic control is beneficial for the prevention of the development and progression of diabetic microvascular complications. In contrast, the impact of strict glycemic control on cardiovascular disease and/or mortality has not yet been clarified. The UKPDS, in which glycemic control was initiated at the point of the first diagnosis of type 2 diabetes, proposed the beneficial effect of good glycemic control on cardiovascular events and mortality5. Similarly, although the subjects studied were type 1 diabetes, the DCCT/EDIC studies also found that better glycemic control at an early stage of diabetes has beneficial effects on a reduction in cardiovascular disease outcomes4. In contrast, the ACCORD study showed that type 2 diabetes subjects (with cardiovascular disease or at least two risk factors for cardiovascular disease or severe atherosclerosis) who underwent intensive glycemic control (target HbA1c < 6.0%) showed rather increased mortality (hazard ratio 1.22) compared with those who received standard glycemic control (target HbA1c 7.0–7.9%), and thus warned of the unexpected risk of strict glycemic control7. The results by Currie et al.9 supported the results of the ACCORD study, and were different from those of UKPDS and DCCT/EDIC. The reason might be explained by the difference in the subjects studied, because the subjects that they investigated were selected from routine general practice and already had high HbA1c levels at baseline (mean HbA1c levels were 7.73 and 8.31% in cohort 1 and 2, respectively), and were more similar to those in the ACCORD study (mean HbA1c was 8.3%), but were different from those in UKPDS (mean HbA1c was 7.1%). The prevalence of previous macrovascular disease was also high (22 and 30% in cohort 1 and 2, respectively) and again was similar to that of the ACCORD study (35.2%), but was different from that in UKPDS (2.1%). Therefore, although the proposal by Currie et al. to revise the diabetes guidelines to include a minimum HbA1c level might be used for subjects with type 2 diabetes who already have elevated HbA1c levels and/or have a high risk of macrovascular diseases, it might not be suitable in subjects in early stages of diabetes. Another observation by Currie et al. was that subjects receiving insulin treatment showed higher hazard ratios for all-causes of death and for progression to first large-vessel disease than those receiving sulfonylurea plus metformin regimen, implying the risk of insulin treatment itself. The U-shaped association was more abundant in cohort 2, and in that cohort, all three deciles lower than a mean HbA1c level of 7.5% showed a significant increase of all-cause mortality. Although the rates of hypoglycemic episodes were not investigated in this study, increased hypoglycemia under insulin treatment might be one reason. It has been suggested that hypoglycemia could increase cardiovascular events for several reasons, such as the enhancement of the adrenergic response and the destabilization of atherosclerotic plaques through the increase of oxidative stress and of other stress responses. However, as the authors discussed in their report, it should be taken in account that there are several differences in the subjects in cohort 1 and 2, such as higher frequency of previous cardiovascular events and of progressed nephropathy in cohort 2. Further investigation to clarify the impact of insulin treatment on mortality with detailed analysis, such as causes of death and frequencies of hypoglycemia, would be necessary. According to the results from the report by Currie et al. and from the ACCORD study, the proposal to revise the diabetes guidelines to include a minimum HbA1c seems reasonable, especially in subjects with poor glycemic control and a high risk of macrovascular complications who are treated by insulin, but this might not be applicable for subjects at an early stage of diabetes or those with few risks of macrovascular disease. In Japan, a new health check-up system that aimed to prevent and early diagnose lifestyle related diseases including diabetes started in 2008. The Japan Diabetes Society also encourages the early diagnosis of diabetes, and thus included the HbA1c level of 6.5% in the diagnostic criteria of diabetes in 2010 (Journal of the Japan Diabetes Society 2010; 53: 450–467, in Japanese). Because early diagnosis followed by early intervention of diabetes has now been encouraged and been proven to prevent most diabetic complications, careful discussion should be carried out to revise the goal of glycemic control.
