Serum adiponectin is associated with fasting serum C-peptide in non-obese diabetic patients.

Circulating adiponectin (ADP) level in diabetic patients was mainly studied from a viewpoint of insulin action, with little being known about the regulation by pancreatic beta-cell function. We thus investigated the relationship between the serum ADP concentration and pancreatic beta-cell function in non-obese [body mass index (BMI) <30 kg/m(2)] diabetic patients. Serum ADP was measured in 239 type 2 diabetic patients, 61 type 1 diabetic patients and 159 non-obese and non-diabetic subjects with enzyme-linked immunosorbent assay. Serum ADP was analyzed separately by gender. In both males and females, the ADP level increased in conjugation with beta-cell dysfunction, estimated by fasting serum C-peptide, and showed marked increase in type 1 diabetic patients. Multivariate analysis in type 2 diabetic patients showed that the fasting serum C-peptide was extracted as an independent and significantly negative modulator for serum ADP in addition to BMI. The ADP level was not associated with the daily dose of injected insulin in the multivariate analysis using insulin treated patients with types 1 and 2 diabetes. These results indicate that pancreatic beta-cell function is one of a significant negative modulator for the circulating ADP level in non-obese diabetic patients and support the presence of an adipoinsular axis.

Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients.

Common uncoupling protein 2 (UCP2) promoter polymorphism -866G/A is reported to be associated with its expression in adipose tissue and the risk of obesity in Caucasians. On the other hand, several studies suggested that UCP2 expression in beta-cells is an important determinant of insulin secretion. In the Japanese population, morbid obesity is very rare, and insulin secretion capacity is relatively low as compared with Caucasians. Because UCP2 would link to insulin secretion and obesity, it might explain this ethnic difference. Here, we report that the UCP2 promoter with the A allele showed higher promoter activity in the INS-1 beta-cell line. The frequency of the A allele is higher in our Japanese study than that in Caucasians. Type 2 diabetic patients with the A allele need insulin therapy earlier and showed higher frequency of insulin treatment. Moreover glucose-induced early insulin secretion is significantly lower in patients with the A allele. However, there was no difference in allele frequency between obese and lean type 2 diabetic patients. In conclusion, UCP2 promoter polymorphism -866G/A does not affect obesity in Japanese type 2 diabetic patients but affects its transcription in beta-cells and modulates glucose-induced insulin secretion and eventually insulin requirement in Japanese type 2 diabetic patients. Higher A allele frequency in the Japanese population might partly explain the ethnic difference of insulin secretion capacity.

Molecular scanning of the betacellulin gene for mutations in type 2 diabetic patients.

Betacellulin (BTC), a member of the epidermal growth factor (EGF) family, is an important factor in the growth and/or differentiation of pancreatic beta cells. In this point of view, we determined the transcriptional start site of the human BTC gene and screened the protein-coding region for mutations. The transcriptional start site was located 347 bp upstream from the translational initiation codon. After screening the protein coding exons (exons 1-5), we identified two novel missense mutations, Cys (TGC) to Gly (GGC) at codon 7 (C7G) and Leu (TTG) to Met (ATG) at codon 124 (L124M), and a single nucleotide substitution (-31c/t) in the intron 2. The C7G was located in the signal peptide and the L124M in the transmembrane domain and this Leu at codon 124 was conserved among human, bovine, rat, and mouse. The frequencies of these variants, however, were similar between type 2 diabetic patients (n = 228) and non-diabetic control subjects (n = 170). These data suggest that genetic variations in the protein-coding region of the human BTC gene are unlikely to be a major contributor to development of type 2 diabetes.

Nonsense and missense mutations in the human hepatocyte nuclear factor-1 beta gene (TCF2) and their relation to type 2 diabetes in Japanese.

Mutations in transcription factors expressed in the pancreatic beta-cell are a major cause of maturity-onset diabetes of the young (MODY). They have also been found in patients diagnosed with type 1 and type 2 diabetes mellitus, which may highlight the difficulty in diagnosing these forms of diabetes or perhaps indicate a direct role in the development of multiple forms of diabetes. We have screened the hepatocyte nuclear factor-1 beta (HNF-1 beta/MODY5) gene for mutations in a group of 126 unrelated Japanese patients with type 2 diabetes and a family history of at least one first degree relative with diabetes. We identified one patient with a nonsense mutation (R276X) and another with a missense mutation (S465R). These mutations were present in the heterozygous state and were not found in 132 nondiabetic subjects (264 normal alleles). We identified a second patient with the S465R mutation on screening a second group of 272 randomly selected type 2 diabetic patients but not in another 122 nondiabetic subjects. Functional studies indicated that R276X-HNF-1 beta was inactive and S465R-HNF-1 beta exhibited a 22% reduction in activity compared with the wild-type protein. The S465R mutation may function in a dominant-negative manner. The subject with the R276X mutation had MODY5 misdiagnosed as common type 2 diabetes. He was diagnosed with diabetes at 13 yr of age and also had small kidneys with multiple bilateral renal cysts and decreased urinary concentrating ability. The two subjects with the S465R mutation had typical late-onset type 2 diabetes and no evidence of kidney disease. We have identified two novel mutations in human HNF-1 beta gene. The prevalence of MODY5 among our population of Japanese diabetes patients with a strong positive family of disease is 0.8%. The S465R mutation was found in 0.5% of our patients with common type 2 diabetes and thus may be a rare genetic risk factor contributing to the development of type 2 diabetes rather than MODY5.

History of obesity as a risk factor for both carotid atherosclerosis and microangiopathy.

As a westernized lifestyle becomes widespread in Japan, the number of individuals with obesity, as well as type 2 diabetes, is rapidly increasing. In this investigation, we studied the prevalence of obesity and its association with the development of diabetic macroangiopathy and microangiopathy. The clinical records of 634 patients in our hospital with type 2 diabetes were surveyed. The relationship between obesity and diabetic retinopathy and nephropathy and macroangiopathy (carotid artery intima-media thickness, IMT) was examined using univariate and multivariate analysis. A body mass index (BMI) > or = 25 kg/m2 was used as the diagnostic criterion for obesity. The prevalence of obesity at the time of the survey was 35% and a history of obesity was reported in 70% of the survey population. Multiple regression analysis revealed that the maximum BMI was significantly correlated with IMT thickening. The prevalence of nephropathy in previously obese patients was significantly higher than in non-obese patients. The maximum BMI was significantly associated with the development of retinopathy and nephropathy, as shown by logistic regression analysis. This suggests that a history of obesity may be an important risk factor for the development of micro- and macroangiopathy in Japanese with type 2 diabetes.

A rare case of autoimmune polyglandular syndrome type 3.

A 57-year-old female was admitted to our hospital suffering from a lower lip tumor, small ulcers in the arms and alopecia of the head. Because she had type 2 diabetes mellitus (DM) for the past 3 years, she was referred to our department of internal medicine for its treatment. Her endogenous insulin secretion was much decreased despite the short duration of diabetes. Glutamic acid decarboxylase antibodies (GADA) and islet cell antibodies (ICA) were both positive. Therefore, she was diagnosed as having slowly progressive form of type 1 DM. Type 1 DM is sometimes complicated with autoimmune disorders. After further examinations, she was diagnosed as having Sjögren's syndrome, Graves' disease and autoimmune neutropenia (AIN). According to the histological examinations of the lip tumor and peripheral site of the skin ulcer, the patient was diagnosed as having carcinoma spinocellulare and chronic cutaneous lupus erythematosus. The examination also showed positive anti-intrinsic factor and anti-ribonucleoprotein (RNP) antibodies. She is a rare case of an autoimmune polyglandullar syndrome (APS) type 3 simultaneously manifesting these seven diseases with multiple autoimmune antibodies.

Neurosarcoidosis with spinal root pain as the first symptom.

We report a 60-year-old woman with neurosarcoidosis. She was referred to our hospital for examination of the cause of pain in left Th4-6 dermatome. Chest X-ray and computed tomography (CT) revealed bilateral hilar and mediastinal lymphadenopathy, and her serum angiotensin converting enzyme (ACE) level was elevated. Histological finding of mediastinal lymph nodes consisted with sarcoidosis. Therefore, her pain was thought to be spinal root pain caused by neurosarcoidosis. With the administration of prednisolone, her symptom and bilateral hilar lymphadenopathy disappeared, and serum ACE level became normal. It is important to pay attention to neurosarcoidosis when patients show unknown spinal root symptom, although it is rare.

Increased arterial stiffness is closely associated with hyperglycemia and improved by glycemic control in diabetic patients.

AIMS/INTRODUCTION: Although arteriosclerotic diseases have been reported to be frequently complicated by diabetes mellitus (DM), a detailed relationship between hyperglycemia and arterial stiffness has not been fully clarified. We investigated the influence of hyperglycemia on arterial stiffness using the cardio-ankle vascular index (CAVI), which is a new method for estimating arterial stiffness. MATERIALS AND METHODS: CAVI values of 52 early-staged DM patients (duration <5 years, no microangiopathies) were compared with those of 43 age-matched non-diabetic (NDM) subjects. The association between CAVI and clinical background factors was evaluated. The effect of glycemic improvement on CAVI was examined in 36 DM patients who were hospitalized for 2 weeks to treat hyperglycemia. CAVI and clinical parameters were measured twice during hospitalization and again after 8 weeks. Additionally, we measured CAVI before and 2 h after breakfast in five DM and five NDM subjects. RESULTS: The CAVI of DM patients was significantly higher than that of NDM subjects. Multiple regression analysis showed that neither hypertension, obesity nor dyslipidemia, but aging and hemoglobin A1c (HbA1c) were significantly related to CAVI elevation. The CAVI, HbA1c and total cholesterol (TC) had significantly improved. Improvement of CAVI was significantly associated with HbA1c improvement. In contrast, no significant association was observed between the improvements of TC and CAVI. CAVI values before and after breakfast did not change significantly. CONCLUSIONS: CAVI elevation seems to be a sensitive arteriosclerotic marker, which is closely associated with hyperglycemia and improved by glycemic control.