Fulminant type 1 diabetes is characterized by a rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetic complications. This review summarizes new findings related to the pathophysiology of accelerated β-cell failure in fulminant type 1 diabetes. Immunohistological examination revealed the presence of enterovirus in pancreatic islet cells and exocrine tissues and hyperexpression of pattern recognition receptors (PRRs) including melanoma differentiation-associated antigen 5 (MDA5), retinoic acid-inducible gene-I (RIG-I), Toll-like receptor (TLR)3 and TLR4, essential sensors of innate immunity, in islet cells and mononuclear cells (MNCs) infiltrating islets. Interferon (IFN)-α and IFN-β, products of PRR cascades, were expressed in both islet cells and infiltrating MNCs. Phenotypes of infiltrating cells around and/or into islets were mainly dendritic cells, macrophages and CD8+ T cells. Islet β-cells simultaneously expressed CXC chemokine ligand 10 (CXCL10), IFN-γ and interleukin-18, indicating that these chemokines/ cytotoxic cytokines mutually amplify their cytoplasmic expression in the islet cells. These positive feedback systems might enhance adaptive immunity, leading to rapid and complete loss of β-cells in fulminant type 1 diabetes. In innate and adaptive/autoimmune immune processes, the mechanisms behind bystander activation/killing might further amplify β-cell destruction. In addition to intrinsic pathway of cell apoptosis, the Fas and Fas ligand pathway are also involved as an extrinsic pathway of cell apoptosis. A high prevalence of anti-amylase autoantibodies was recognized in patients with fulminant type 1 diabetes, which suggests that Th2 T-cell reactive immunity against amylase might contribute to β-cell destruction in fulminant type 1 diabetes.
Dumping syndrome, or rapid gastric emptying, is a frequent complication after gastric surgery. In this case, the patient was a 47-year-old woman who 10 years previously had undergone distal gastrectomy with Billroth I reconstruction for early-stage gastric cancer. She presented with symptoms of weakness, headache, palpitation, sweating, dizziness and significant fatigue between one and two hours after a meal. Because a 75g oral glucose tolerance test (75g-OGTT) induced both acute postprandial tachycardia (within 1 hour) and postprandial hypoglycemia, we diagnosed this patient with early and late dumping syndrome. Dietary measures and acarbose improved symptoms of late dumping syndrome but did not prevent the symptoms of early dumping syndrome such as postprandial tachycardia, weakness, headache, palpitation, and dizziness. We therefore used the somatostatin analogue octreotide, which has been reported as an effective therapy for early dumping syndrome. Octreotide prevented the symptoms of early dumping syndrome, especially postprandial tachycardia, but caused postprandial hyperglycemia. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were completely suppressed during the 75g-OGTT following subcutaneous injection of octreotide. No change was observed in vasoactive intestinal polypeptide (VIP), which is the gastrointestinal peptide hormone generally responsible for early dumping syndrome, suggesting possible contribution of incretins in early dumping syndrome of this patient.
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by primary hypocortisolism and normal mineralocorticoid production. Recently, NNT encoding the nicotinamide nucleotide transhydrogenase has been identified as a causative gene for FGD. Thus, we examined NNT in six Japanese FGD patients with no recognizable mutation in the previously known four responsible genes for FGD (MC2R, MRAP, STAR, and MCM4), and identified a novel homozygous substitution (c.644T>C; p.Phe215Ser) in a single 17.5-year-old boy. His parents were heterozygous for this mutation. This substitution was absent from 120 Japanese control subjects and was not registered in public databases including JSNP Database. The phenylalanine residue at the 215th codon was evolutionally conserved, and the p.Phe215Ser was assessed to be a pathologic mutation by in silico protein function analyses. The results, in conjunction with the previous data, imply that NNT mutations account for 5-10% of FGD patients, and that underlying factor(s) still remains to be clarified in a substantial fraction of FGD patients.
The association of CYP11B2 gene polymorphisms with the risk of primary aldosteronism (PA) was controversial in previous studies. Here we selected two commonly studied CYP11B2 alleles: T-344C, A2718G to explore their associations with PA risk by meta-analyses of published case-control studies. Six electronic databases were searched for relevant studies up to November 2012. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random or fixed effects model. Seven studies (621 cases and 1027 controls) on T-344C polymorphism, three studies (327 cases and 336 controls) on A2718G polymorphism were finally included. Then significant association was observed between T-344C polymorphism and idiopathic hyperaldosteronism (IHA) under three genetic models (CC vs TT, OR=0.544, 95%CI=0.324~0.914; CT vs TT, OR=0.554, 95%CI=0.406~0.757; CC+CT vs TT, OR=0.542, 95%CI=0.402~0.731). But patients with aldosterone-producing adenoma had no significant association with T-344C polymorphism under all genetic models except CT vs TT model. Concerning A2718G polymorphism, a decreased PA risk was observed only under GG+GA vs AA model. But this association disappeared after removing the studies not in Hardy-Weinberg equilibrium. The evidence accumulated suggested that -344C allele may be associated with decreased risk of IHA and there was still no enough evidence to indicate the association of A2718G polymorphism with PA risk.
Although postoperative serum thyroglobulin (Tg) is a prognostic indicator for papillary thyroid carcinoma (PTC), it is unreliable when Tg antibody (TgAb) is positive. We evaluated the prognostic significance of changes in serum TgAb levels of pre- and post-total thyroidectomy in TgAb-positive PTC patients. We reviewed our medical charts of 225 TgAb-positive PTC patients in whom TgAb levels were measured before and 1–2 years after total thyroidectomy, performed between April 2002 and March 2007. We divided them into 3 groups based on changes in TgAb levels. Postoperative serum TgAb levels decreased by ≥50% in 181 patients (80.4%) (Group 1), by <50% in 22 patients (9.8%) (Group 2), and increased in 22 patients (9.8%) (Group 3). During the follow-up, 3 patients died of the disease and 14 patients had recurrences. All 3 patients who died of PTC were seen only in Groups 2 and 3. Groups 2 and 3 showed similar prognostic outcomes, thus were analyzed together as Group 2+3. Group 1 had significantly better lymph node recurrence-free survival and distant recurrence-free survival than Group 2+3 (96.9% vs. 90.5%, p <0.001, and 98.9% vs. 90.1%, p = 0.004, respectively at 5 years). Multivariate analyses on prognostic factors revealed that classification to Group 2+3 was the strongest indicator for poor prognosis. The present results suggest that changes in TgAb levels following total thyroidectomy can be an important dynamic prognostic factor of PTC patients. Prospective periodical measurements of TgAb are necessary to confirm these findings.
Previous reports highlight the role of systemic inflammation in the genesis of non-thyroidal illness syndrome and type 2 diabetes mellitus (T2DM). Our objective was to assess whether body mass index and the low-grade systemic inflammation would be associated with changes in thyroid hormone metabolism in patients with type 2 diabetes. This was a cross-sectional study of 104 subjects; 52 patients with type 2 diabetes and 52 in a control group, paired by age, gender and body mass index. We measured total (T) and free (F) thyroxine (T4) and triiodothyronine (T3), reverse T3 (rT3), the ratios FT3/rT3, FT3/FT4 and FT4/rT3, clinical parameters (age, gender, diabetes duration and complications, body mass index, waist circumference, hypertension, HbA1c), and high sensitivity C-reactive protein. Patients with DM presented lower levels of TT4 (p=0.006), TT3 (p<0.001) and FT3 (p<0.001) and higher of FT4 (p<0.001), waist circumference (p=0.047) and C-reactive protein (p<0.001). Body mass index was inversely correlated with FT4 (p=0.036) and TT3 (p=0.008). C-reactive protein was positively correlated with rT3 (p=0.001) and inversely with FT4/rT3 (p<0.001) and FT3/rT3 (p=0.014). Body mass index was an independent predictor for FT4 (B=-0.011, p=0.029) and TT3 levels (B=-1.118, p=0.003). Inflammation predicted the FT4/rT3 ratio (B=-0.190, p<0.001). C-reactive protein (B=0.235, p<0.001) and body mass index (B=-0.008, p=0.047) were independent predictors for rT3. In conclusion, type 2 diabetes was associated with a low T3 state. Body mass index and the low-grade systemic inflammation are related to the non-thyroidal illness syndrome in these patients, possibly by altering the activity of peripheral deiodinases.
Serum CA19-9 levels are often elevated in diabetic patients. To elucidate this mechanism, we investigated the metabolism of CA19-9 in diabetic patients without obvious cancer. Study 1 included 119 patients in whom HbA1c, glycated albumin (GA) and CA19-9 were measured at the time of hospital admission. Study 2 examined 6 patients with markedly elevated CA19-9 levels (≥100 U/mL). Their half-lives for HbA1c, GA, and serum CA19-9 were calculated using the data before and after diabetes treatment. Three diabetic patients with pancreatic cancer were also examined as controls. In Study 1, serum CA19-9 (logarithmically transformed value) was significantly correlated with fasting plasma glucose (FPG), HbA1c and GA. On multivariate analysis, GA and FPG, but not HbA1c, were significant explanatory variables for serum CA19-9. In Study 2, serum CA19-9 decreased together with HbA1c and GA after diabetes treatment. The calculated half-lives for HbA1c, GA, and serum CA19-9 were 33.8 days, 16.1 days, and 10.9 days, respectively. The half-life of serum CA19-9 was longer in the study patients than that reported in patients with malignant tumors. By contrast, in the diabetic patients with pancreatic cancer serum CA19-9 showed a marginal decrease after diabetes treatment. Taken all together, prolonged half-life of serum CA19-9 may contribute to the increase in serum CA19-9 levels in diabetic patients without obvious cancer.
A meta-analysis was performed to assess the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms [4b4a VNTR and G894T (rs1799983)] with type 2 diabetes mellitus (T2DM). A comprehensive search was conducted to identify all eligible articles. Fixed or random effect pooled measure was selected based on homogeneity test. Heterogeneity among studies was evaluated using the I2. Meta-regression was used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Egger’s linear regression test. 19 articles involving 8,009 subjects for 4b4a VNTR and 19 articles involving 8,600 subjects for G894T were included. After excluding articles that deviated from Hardy–Weinberg equilibrium in controls and sensitivity analysis, significant association was found between 4a and increased risk of T2DM considering dominant model [OR (95%CI)=1.32 (1.17-1.48)], a vs. b [OR (95%CI)=1.34 (1.21-1.48)], and aa vs. bb [OR (95%CI)=1.52 (1.05-2.22)]. The 894T allele was also found associated with increased risk of T2DM considering dominant model [OR (95%CI)=1.14 (1.03-1.26)], recessive model [OR (95%CI)=1.28 (1.06-1.54)], T vs. G [OR (95%CI)=1.18 (1.09-1.27)], and TT vs. GG [OR (95%CI)=1.33 (1.09-1.62)]. The findings were consistent in Asian population. The meta-analysis indicated that NOS3 gene 4b4a VNTR and G894T polymorphisms might be associated with T2DM risk.
Subclinical Cushing’s syndrome (SCS) associated with adrenal incidentaloma is usually characterized by autonomous cortisol secretion without overt symptoms of Cushing’s syndrome (CS). Although the diagnostic criteria for SCS differ among countries, the 1 mg dexamethasone suppression test (DST) is essential to confirm the presence and the extent of cortisol overproduction. Since 1995, SCS has been diagnosed in Japan based on serum cortisol levels ≥3 μg/dL (measured by radioimmunoassay [RIA]) after a 1 mg DST. However, the increasing use of enzyme immunoassays (EIA) instead of RIA has hindered the diagnosis of SCS because of the differing sensitivities of commercially available assays, particularly for serum cortisol levels of around 3 μg/dL. One way to overcome this problem is to lower the cortisol threshold level after a 1 mg DST. In the present study, we examined the clinical applicability of lowering the cortisol threshold to 1.8 μg/dL, similar to the American Endocrine Society’s guidelines for CS, by reanalyzing 119 patients with adrenal incidentaloma. Our findings indicate that serum cortisol levels ≥1.8 μg/dL after 1 mg DST are useful to confirm the diagnosis of SCS if both of the following criteria are met: (1) basal ACTH level <10 pg/mL (or poor plasma ACTH response to corticotrophin-releasing hormone) and (2) serum cortisol ≥5 μg/dL at 21:00 to 23:00 h. If only one of (1) and (2) are met, we recommend that other clinical features are considered in the diagnosis of SCS, including serum dehydroepiandrosterone sulfate levels, urine free cortisol levels, adrenal scintigraphy, and clinical manifestation.
Postprandial hyperglycemia and/or hyperlipidemia can contribute to development of atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to compare the effects of miglitol and sitagliptin on postprandial glucose and lipid metabolism in patients with T2DM. Thirty-five patients with T2DM were randomized to 2 groups receiving miglitol (150 mg/day) or sitagliptin (50 mg/day). Serum variables related to glucose and lipid metabolism were measured before and after treatment for 10 weeks and at 0, 60, and 120 min using a cookie-loading test (CLT). After 10 weeks of treatment, miglitol (n = 16) and sitagliptin (n = 18) caused a similarly significant decrease in hemoglobin A1c (mean: 7.6% to 7.3% versus 8.0% to 7.6%) and a significant increase in fasting insulin levels, with a greater increase observed in the miglitol group than in the sitagliptin group (p=0.03). In addition, a significant decrease in the change in glucose levels after the CLT was observed in both groups, with a greater decrease observed in the miglitol group than in the sitagliptin group (p=0.02). The miglitol group also showed a greater decrease in the change in insulin levels after the CLT than the sitagliptin group (p<0.01). The lipid and lipoprotein levels did not show any significant differences between the groups after the CLT. Our results suggested that miglitol and sitagliptin treatment resulted in similar glycemic control but that a greater decrease in postprandial glucose and insulin levels was observed with miglitol compared with sitagliptin in patients with T2DM.
The aim of the current study was to investigate whether obese subjects have different insulin secretory capacity compared to lean subjects with the same glucose tolerance in a Japanese population. We included a total of 1749 Japanese employees who underwent 75-g oral glucose tolerance test (OGTT). The study population was divided into deciles of 120-min glucose levels and the indices of insulin secretion and insulin sensitivity in each decile were compared between the subjects with and without obesity (body mass index ≥ 25 kg/m2). The indices used in the current study were Matsuda index, insulinogenic index, and disposition index. Obese subjects had significantly lower values of Matsuda index and significantly higher value of insulinogenic index than non-obese subjects in every decile (all p < 0.05). On the other hand, disposition index was not significantly different between non-obese and obese subjects in any decile of 120-min glucose level (all p > 0.05). Similar findings were observed when the study population was classified by waist circumference. In conclusion, disposition index derived from the data of 75-g OGTT was similarly decreased in obese Japanese subjects compared to non-obese Japanese subjects with the same post-load glucose levels. Future studies will be needed to confirm whether the development of glucose intolerance in obese Japanese subjects is accompanied by the same degree of pancreatic beta cell dysfunction as non-obese Japanese subjects.