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A 51-year-old woman was admitted because of hypercalcemia. Neck ultrasonography and computed tomography revealed the presence of parathyroid cysts on both sides. After primary hyperparathyroidism was diagnosed by technetium-99m-methoxyisobutylisonitrile scintigraphy, the patient was successfully treated with total parathyroidectomy and autotransplantation. She also had a non-functioning pancreatic neuroendocrine tumor, prolactinoma, and adrenal tumors with subclinical Cushing's syndrome. Given these clinical features and her family history, multiple endocrine neoplasia type 1 (MEN1) was suspected, and germline DNA sequencing revealed a missense mutation (c.1013TC, [corrected] p.Leu338Pro) in exon 7 of MEN1. This case demonstrates the phenotypic and genetic diversity of MEN1.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Objectives Insulin-derived amyloidosis is a rare skin-related complication of insulin therapy. The purpose of this study was to show the effects of insulin-derived amyloidosis on blood glucose levels, insulin dose requirements, and insulin absorption. Methods Seven patients were found to have insulin-derived amyloidosis at the Tokyo Medical University Ibaraki Medical Center. The clinical characteristics and insulin therapy of the 7 patients were investigated. Insulin absorption was studied by comparing the serum insulin levels after insulin injections into insulin-derived amyloidosis sites versus injections into normal sites in 4 patients. Results When the insulin-derived amyloidosis was discovered, the mean hemoglobin A1c level was 9.3%, and the mean daily insulin dose was 57 units. After changing the injection sites to avoid the insulin-derived amyloidosis, the blood glucose concentrations improved, and the mean daily insulin dose could be reduced to 27 units (P = .035; 53% reduction). The insulin absorption at insulin-derived amyloidosis sites was 34% of that at normal sites (P = .030). Conclusions Insulin-derived amyloidosis caused poor glycemic control and increased insulin dose requirements because of impairments in insulin absorption.

Genetic data support the notion that polymorphisms in members of the matrix metalloproteinase (MMP) family of genes play an important role in extracellular matrix remodeling and contribute to the pathogenesis of vascular disease. To identify novel genetic markers for diabetic nephropathy (DN), we examined the relationship between MMP gene polymorphisms and DN in the Genetics of Kidneys in Diabetes (GoKinD) population. Genotypic data from the Genetic Association Information Network (GAIN) type 1 DN project were analyzed for associations across 21 MMP genes in 1,705 individual with type 1 diabetes, including 885 normoalbuminuric control subjects and 820 advanced DN case subjects. In total, we investigated the role of 1,283 SNPs (198 genotyped SNPs and 1,085 imputed SNPs) mapping to the MMP genes. We identified associations at several correlated SNPs across a 29.2 kb interval on chromosome 11q at the MMP-3/MMP-12 locus. The strongest associations occurred at 2 highly-correlated SNPs, rs610950 (OR = 0.50, P = 1.6×10−5) and rs1277718 (OR = 0.50, P = 2.1×10−5). Further examination of this locus identified 17 SNPs (2 genotyped SNPs and 15 imputed SNPs) in complete linkage disequilibrium associated with DN (P-values < 2.5×10−4), including a non-synonymous SNP (rs652438, Asn357Ser) located in exon 8 of MMP-12 that significantly reduced the risk of DN among carriers of the serine substitution relative to homozygous carriers of asparagine (OR = 0.51; 95% CI = 0.37–0.71, P = 6.2×10−5). Taken together, our study suggests that genetic variations within the MMP-3/MMP-12 locus influence susceptibility of DN in type 1 diabetes.

OBJECTIVE To examine the association between single nucleotide polymorphisms (SNPs) in the engulfment and cell motility 1 (ELMO1) gene, a locus previously shown to be associated with diabetic nephropathy in two ethnically distinct type 2 diabetic populations, and the risk of nephropathy in type 1 diabetes. RESEARCH DESIGN AND METHODS Genotypic data from a genome-wide association scan (GWAS) of the Genetics of Kidneys in Diabetes (GoKinD) study collection were analyzed for associations across the ELMO1 locus. In total, genetic associations were assessed using 118 SNPs and 1,705 individuals of European ancestry with type 1 diabetes (885 normoalbuminuric control subjects and 820 advanced diabetic nephropathy case subjects). RESULTS The strongest associations in ELMO1 occurred at rs11769038 (odds ratio [OR] 1.24; P = 1.7 × 10−3) and rs1882080 (OR 1.23; P = 3.2 × 10−3) located in intron 16. Two additional SNPs, located in introns 18 and 20, respectively, were also associated with diabetic nephropathy. No evidence of association for variants previously reported in type 2 diabetes was observed in our collection. CONCLUSIONS Using GWAS data from the GoKinD collection, we comprehensively examined evidence of association across the ELMO1 locus. Our investigation marks the third report of associations in ELMO1 with diabetic nephropathy, further establishing its role in the susceptibility of this disease. There is evidence of allelic heterogeneity, contributed by the diverse genetic backgrounds of the different ethnic groups examined. Further investigation of SNPs at this locus is necessary to fully understand the commonality of these associations and the mechanism(s) underlying their role in diabetic nephropathy.

OBJECTIVE Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS We genotyped ∼360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes-associated complications. RESULTS A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P < 1 × 10−5. The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 × 10−7). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 × 10−6). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression of both FRMD3 and CARS in human kidney. CONCLUSIONS We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes.

A 57-year-old man was referred to our outpatient clinic after interferon-beta (IFN-beta) treatment for 7 weeks. While IFN-beta therapy was continued in our outpatient clinic, his blood glucose level increased gradually, and he was admitted to our hospital for hyperglycemia. The patient was prescribed a 1,600-kcal diet and intensive insulin therapy was performed. GAD antibody became positive 15 months after the start of IFN therapy, and disappeared 27 months after the start of IFN therapy. Insulin secretion was depleted and the patient had HLA-DR4, B54, and DRB1*0405. This appears to be a case of type 1 diabetes mellitus induced by administration of IFN-beta alone.

Diabetic retinopathy is characterized by increased vascular permeability, ischemia, and neovascularization. Ischemia in the retina can induce neovascularization via induction of vascular endothelial growth factor (VEGF) expression by the transcription factor hypoxia-inducible factor-1 (1). Hypoxia is also the main stimulus for erythropoietin (EPO) gene expression. It has been reported that EPO may have not only erythropoietic (2) but also neuroprotective (3) and angiogenic (4) effects. EPO is expressed at a number of sites including kidney, liver, brain, uterus (5), and the adult mammalian retina, which also expresses EPO receptors (6). The aim of this study was to investigate whether EPO is elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and whether vitreous EPO levels are related to systemic levels of EPO, anemia, or nephropathy. Vitreous fluid samples were obtained from 59 PDR patients and 16 macular hole patients at the start of the vitrectomy procedure. Concentrations of EPO in vitreous fluid and serum samples were measured by an enzyme-linked immunosorbent assay for EPO (Toyobouseki, Osaka, Japan). Concentrations of VEGF were measured by an enzyme-linked immunosorbent assay for human VEGF (R & D Systems, Minneapolis, MN). Protein in vitreous fluid was determined using the method of Bradford (Bio-Rad, Hercules, CA). The Mann-Whitney U test was used to compare intravitreous concentrations of protein, VEGF, …

A 56-year-old patient with postsurgical hypothyroidism and hypoparathyroidism associated with gastrointestinal malabsorption syndrome was prescribed with L: -thyroxine and 1alpha(OH)D(3) at a massive daily dosage of 600 and 39 mug, respectively. Although the patient became nearly euthyroid, she had been hypocalcemic, requiring frequent intravenous injection of calcium gluconate to prevent tetany. Because the serum level of 1,25(OH)(2)D hardly increased after an oral intake of 21 microg 1alpha(OH)D(3), vitamin D(3) was administered intramuscularly. After stoss therapy (600,000 IU), the patient has been receiving 300,000 IU vitamin D(3) at intervals of 2-4 months so that she remained slightly hypocalcemic (7-8 mg/dl). At 1.5 years later, serum levels of 25(OH)D and 1,25(OH)(2)D were maintained at about 60 ng/ml and 30-50 pg/ml, respectively, and renal function was maintained well. These data suggest that intramuscular injection of 300,000 IU vitamin D(3) at an interval of a few months to maintain a slightly increased serum level of 25(OH)D and a slightly decreased serum level of calcium is a safe and cost-effective treatment in such a parathyroid hormone-deficient hypoparathyroid patient with malabsorption syndrome.

Objective To measure the amount and affinity of insulin antibodies, we performed a trial to establish a new method for quantitative and qualitative analysis of these antibodies by using surface plasmon resonance (BIAcoreTM system).Methods Real-time detection of insulin antibody interaction and kinetic analysis were performed using the BIAcoreTM system.Patients or Materials Eight diabetic patients with insulin antibodies and whose fasting total immunoreactive insulin levels were more than 100 μU/ml were selected. The patients with and without recurrent hypoglycemia were classified into hypoglycemic episode-positive or hypoglycemic episode-negative groups, respectively. Seven diabetic patients without insulin antibodies were selected as controls.Results In the 8 patients, the concentration of insulin antibodies ranged from 2.91 to 16.3 μg/ml and insulin antibodies were not detected in the control group. The apparent KD (dissociation constant) and kd (the dissociation rate constant) values of the patients were much larger than those seen for the anti-human insulin monoclonal antibody. The KD values were significantly higher in the hypoglycemic episode-positive group than in the hypoglycemic episode-negative group (p

We assessed the possibility of using myo-inositol as a marker of glucose intolerance.We measured urinary myo-inositol enzymatically before and 2 h after a 75-g oral glucose tolerance test in 564 volunteers, who were divided into four groups [normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM)]. Furthermore, we classified NGT into NGT-A (2-h blood glucose120 mg/dl and 2-h glucosuria50 mg/dl) and NGT-B (remaining NGT subjects). We then compared deltamyo-inositol (myo-inositol/creatinine ratio: 2-h after glucose load--before load) of each group to investigate the relationship between glucose intolerance and deltamyo-inositol.The glucose tolerance of NGT-B appeared to have deteriorated compared with NGT-A as determined by blood glucose, insulin, and glucosuria. There was very little effect of gender or age on deltamyo-inositol in NGT-A. deltamyo-inositol was significantly higher than that in NGT-A (0.5+/-7.1 mg/g Cr) not only in IFG (8.7+/-19.5 mg/g Cr, P0.0001), IGT (14.8+/-22.9 mg/g Cr, P0.0001) and DM (79.5+/-37.1 mg/g Cr, P0.0001), but in NGT-B (7.4+/-12.7 mg/g Cr, P0.0001). With 2 mg/g Cr as a tentative cut-off for deltamyo-inositol to detect NGT-A, sensitivity and specificity were 68% and 72%, respectively.The deltamyo-inositol can be use of a non-invasive and sensitive marker for glucose intolerance.