Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study (PRIME-V study).

A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%-10%, and body mass index (BMI) ≥ 22 kg/m2 . Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000-1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12.06% vs. -3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)-resistance, and increased HDL-cholesterol levels. Metformin significantly reduced HbA1c and LDL-cholesterol levels and increased HOMA-beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase-4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.

Characteristics of non-alcoholic steatohepatitis among lean patients in Japan: Not uncommon and not always benign.

BACKGROUND AND AIM: To elucidate features of nonobese non-alcoholic fatty liver disease (NAFLD), we assessed Japanese patients with NAFLD stratified by body mass index (BMI) and by sex. METHODS: Biopsy-proven 762 NAFLD patients (404 men) were classified into three groups by the Japanese criteria: nonobese group (BMI < 25 kg/m2 ), obese group (25 to 30), and severely obese group (≥ 30). Clinicopathological features and single nucleotide polymorphism of patatin-like phospholipase 3 (PNPLA3) rs738409 were investigated, and body composition analysis was performed by bioelectrical impedance analysis and computed tomography. RESULTS: Over 25% of men and almost 40% of women were nonobese, but most of them had visceral fat obesity and/or insulin resistance. The median age (years) of the nonobese, obese, and severely obese men was 49.9, 46.8, and 40.5 (P < 0.01), respectively, while those of women was 60.2, 59.6, and 48.5 (P < 0.01), respectively. The prevalence of metabolic comorbidities and PNPLA3 risk alleles did not differ among these groups in both sexes. Also, the prevalence of non-alcoholic steatohepatitis was not significantly different in both sexes, although nonobese patients had a higher prevalence of mild steatosis. Advanced fibrosis showed a marked difference between men and women. Advanced fibrosis was significantly more frequent among severely obese men (nonobese: 31.0%, obese: 41.6%, severely obese: 60.9%; P < 0.01), but it was lower among severely obese women (51.4%, 62.9%, 33.7%; P < 0.01). Skeletal muscle mass was significantly lower in nonobese patients. CONCLUSIONS: Non-alcoholic fatty liver disease was not milder in nonobese patients. Histological steatosis was associated with BMI, but advanced fibrosis was not and showed a significant sex difference.

Effect of sitagliptin on blood glucose control in patients with type 2 diabetes mellitus who are treatment naive or poorly responsive to existing antidiabetic drugs: the JAMP study.

BACKGROUND: To investigate the ameliorating effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood glucose control in patients with type 2 diabetes mellitus who were previously untreated with or who have a poor responsive to existing antidiabetic drugs. METHODS: Sitagliptin (50 mg/day) was added on to the pre-existing therapy for type 2 diabetes and changes in the glycated hemoglobin (HbA1c) level after 3 months of treatment were compared with the baseline and performed exploratory analysis. RESULTS: HbA1c levels were significantly decreased after 1 month of treatment compared to baseline, with a mean change in HbA1c level from baseline of -0.73% (range, -0.80 to -0.67) in the entire study population at 3 months. Patients who received a medium dose of glimepiride showed the least improvement in HbA1c levels. The percentage of patients who achieved an HbA1c level of <7.0% significantly increased after 1 month of treatment, reaching 53.1% at 3 months. The percentage of patients who achieved a fasting blood glucose level of <130 mg/dL significantly increased after 1 month of treatment, reaching 50.9% at 3 months. CONCLUSIONS: Sitagliptin improved the HbA1c level and rate of achieving the target control levels in patients with type 2 diabetes mellitus who were previously untreated with, or poorly responsive to, existing antidiabetic drugs. Thus, sitagliptin is expected to be useful in this patient group. However, the additional administration of sitagliptin in patients treated with medium-dose glimepiride only slightly improved blood glucose control when corrected for baseline HbA1c level.

Association of morning fasting blood glucose variability with insulin antibodies and clinical factors in type 1 diabetes.

The fasting blood glucose concentration in type 1 diabetes may vary without being much affected by diet and exercise. This study aimed to identify association of morning fasting blood glucose concentration variability with insulin antibodies and clinical factors. The subjects in this study were 54 patients with type 1 diabetes who had high variation of fasting blood glucose. The insulin antibody level was measured, and correlations of glycemic variability with antibody levels, binding rates, and other clinical factors were investigated. The standard deviation (SD) of the 30-day morning self-monitored fasting blood glucose concentration (FBG SD) was evaluated as an index of glycemic variability. The mean glucose level was 159.8±42.1 mg/dL and the FBG SD was 47.5±22.0 mg/dL. Glycemic variability (FBG SD) was positively correlated with insulin antibody level, but not with insulin antibody binding rate, and had a negative correlation with C-peptide immunoreactivity/plasma glucose (CPR/PG) and positive correlations with diabetes duration, basal insulin dose and bolus insulin dose. Glycemic variability was not correlated with BMI, HbA1c or age. In multiple regression analysis of glycemic variability, CPR/PG was the only significant related factor. The results showed that glycemic variability was mainly influenced by endogenous insulin secretion capacity and was high in patients with high insulin antibody levels. In some patients with a high insulin antibody titer, the antibody may have an effect on the variability of the fasting glucose concentration in type 1 diabetes.

An autopsy case of macroglobulinemia complicated with syndrome of inappropriate secretion of ADH (SIADH) like hyponatremia, hypopituitarism and AL amyloidosis.

An 88-year-old male patient with macroglobulinemia was admitted to our hospital because of severe hyponatremia and unconsciousness. Laboratory findings showed decreased inhibition of antidiuretic hormone (ADH) and he was diagnosed with syndrome of inappropriate secretion of ADH (SIADH). Hyponatremia improved with only limitation of water intake and the patient was followed up on a continuing outpatient basis. However, soon after discharge from hospital, his legs started swelling with edema and hyponatremia worsened. He was re-admitted due to a fall at home. Hyponatremia was observed at re-admission. A CRH challenge test showed partial dysfunction of ACTH secretion. Corticosteroid therapy was performed, but the patient subsequently died from pneumonia. Pathological findings at autopsy revealed invasion of plasma cells and amyloid depositions in multiple organs, including the pituitary, adrenal cortex, heart, liver, kidney, lymph nodes and bone marrow. Consistent with these results, fibrosis was observed in the anterior lobe of the pituitary, suggesting that the autopsy findings were related to the clinical observations and diagnosis. This is the first reported case of macroglobulinemia complicated with multiple hormone dysfunction.

Risk factors for chronic kidney disease progression over 20 years for primary prevention in Japanese individuals at a preventive medicine research center: Focus on the influence of plasma glucose levels.

AIMS/INTRODUCTION: Chronic kidney disease (CKD) is a very important issue globally because of the risk of its progressing to end-stage renal disease. We aimed to identify factors contributing to long-term estimated glomerular filtration rate (eGFR) decline to determine an early diagnosis and prevent CKD progression. MATERIALS AND METHODS: From January 2003 to December 2006, 5,507 individuals underwent health checkups at our hospital's Preventive Medicine Research Center. We ultimately enrolled 2,175 individuals. The eGFR was ≥60 mL/min/1.73 m2 at the start of observation period, which was 20 years. The event onset time was the day that the eGFR became <30 mL/min during the 20-year period. Baseline risk factors - in particular, the effect of plasma glucose levels on the eGFR - were extracted and evaluated by using Fine and Gray analysis. RESULTS: During the 20-year observation, the hazard ratio (HR) of CKD progression was examined. A fasting plasma glucose (FPG) level ≥105 mg/dL was significantly associated with the risk of CKD progressing to an eGFR <30 mL/min. This trend was similar in the slope of eGFR. An FPG ≥105 mg/dL or an glycated hemoglobin level ≥6.5% was useful for intervening in CKD progression. Multivariate analysis showed that independent risk factors were an FPG level ≥105 mg/dL (HR 1.9; P < 0.001), age ≥60 years (HR 3.86; P < 0.001), obesity (HR 1.61; P < 0.01) and urinary protein (HR 1.55; P < 0.01). CONCLUSIONS: For early intervention against a reduction in the eGFR, detecting mild increases in FPG ≥105 mg/dL in patients with CKD with or without diabetes is useful.

Sex differences in predictive factors for onset of type 2 diabetes in Japanese individuals: A 15-year follow-up study.

AIMS/INTRODUCTION: The increase in the number of patients with type 2 diabetes mellitus is an important concern worldwide. The goal of this study was to investigate factors involved in the onset of type 2 diabetes mellitus, and sex differences in long-term follow up of people with normal glucose tolerance. MATERIALS AND METHODS: Of 1,309 individuals who underwent screening at our facility in 2004, 748 individuals without diabetes were enrolled. Correlations of metabolic markers including serum adiponectin (APN) with onset of type 2 diabetes mellitus were examined over 15 years in these individuals. RESULTS: The Kaplan-Meier curve for onset of type 2 diabetes mellitus for 15 years in the decreased APN group was examined. Hazard ratios for the APN concentration for onset of diabetes were 1.78 (95% confidence interval [CI] 1.20-2.63, P = 0.004) in all participants, 1.48 (95% CI 0.96-2.29, P = 0.078) for men and 3.01 (95% CI 1.37-6.59, P = 0.006) for women. During the follow-up period of 15 years, body mass index, estimated glomerular filtration rate, fatty liver, C-reactive protein and alanine aminotransferase in men were significant in univariate analysis, but only estimated glomerular filtration rate and fatty liver were significantly related to onset of type 2 diabetes mellitus in multivariate analysis. In women, body mass index, systolic blood pressure, triglyceride, fatty liver and APN were significant in univariate analysis, and APN was the only significant risk factor in multivariate analysis (P < 0.05). CONCLUSIONS: There are differences between men and women with regard to targets for intervention to prevent the onset of type 2 diabetes mellitus. Individuals requiring intensive intervention should be selected with this finding to maximize the use of limited social and economic resources.

A case of TSH-producing adenoma treated with octreotide in combination with thiamazole for the control of TSH and thyroid hormones after trans-sphenoidal neurosurgery.

While TSH-producing adenoma (TSHoma) is rare, the diagnosis is often delayed because the clinical features are heterogeneous. The patient was a 69-year-old woman who had been referred to the Yachiyo Medical Center in August 2008, because of dyspnea, loss of appetite, weight loss of 10 kg, and diarrhea that lasted 4 years. We diagnosed this patient with pituitary TSH-producing macroadenoma. Thyroid hormone concentration was increasing although the serum TSH level was within a normal range after trans-sphenoidal surgery. We considered that because of enlargement of the thyroid gland due to long-term stimulation by TSH, a low concentration of TSH could stimulate the thyroid gland to produce excess T3 or T4. The somatostatin analogue, octreotide was used to control the TSHoma and serum TSH concentration but not thyroid hormone. The octreotide in combination with thiamazole treatment for 14 months controlled thyroid hormone concentration and decreased the thyroid mass, and ultimately, the thiamazole could be stopped. To date, the use of combination therapy of octreotide with thiamazole in patients with remaining TSH-producing adenoma without Basedow's disease is rare, and we suggest that this treatment is one of the therapeutic means to treat recurrence of TSH-producing adenoma after surgery with progressive complications or large thyroid gland.

[A case of corpus callosum splenium encephalopathy and 2009 influenza A/H1N1].

Encephalopathy with reversible lesion of the corpus callosum splenium has a favorable prognosis, but that in 2009 influenza A/H1N1 is unknown. We report a case of clinically mild encephalopathy with a reversible lesion of the corpus callosum splenium in which 2009 influenza A/H1N1 virus was confirmed by laboratory tests. A 15-year-old Japanese girl seen at the emergency unit for loss of consciousness 18 hours after fever onset had been diagnosed with influenza A, and administered zanamivir. Diffusion-weighted magnetic resonance imaging (MRI) indicated lesions of the corpus callosum splenium, and electroencephalography showed slow basic activity, suggesting influenza A related to encephalopathy. She required intensive care with ventilation for two days. Her consciousness had become normal by day 6 after onset, and MRI findings improved on day 7. She recovered without adverse sequelae.

Hyperferritinemia Is a Predictor of Onset of Diabetes in Japanese Males Independently of Decreased Renal Function and Fatty Liver: A Fifteen-Year Follow-Up Study.

BACKGROUND: Type 2 diabetes is an important health concern worldwide. The disease etiology may depend on multiple environmental and genetic factors that cause insulin resistance, including dysregulation of iron storage. The goal of this study was to examine the relationship of the serum ferritin concentration with onset of diabetes over a long period. METHODS: Correlations of serum ferritin and metabolic markers with onset of diabetes mellitus were examined over 15 years in 150 males participating in a health screening program. RESULTS: HOMA-ß showed a gradual significant decrease in the first 4 years in subjects with ferritin > 190 ng/mL (group H) compared to those with ferritin ≤ 190 ng/mL, but there was no difference in HOMA-R between these groups. A significant number of cases with onset of diabetes was observed over 15 years (hazard ratio (HR): 3.97), and obesity, fasting blood glucose level, hemoglobin A1c (HbA1c), HOMA-R, fasting immunoreactive insulin (IRI) and C-peptide immunoreactivity (CPR) were all significant in univariate comparison between non-diabetes and diabetes-onset groups. In multivariate analysis, ferritin in group H (HR: 3.25), fatty liver (HR: 3.38), estimated glomerular filtration rate (eGFR) < 70 mL/min/1.73 m2 (HR: 3.48) and high-density lipoprotein (HDL) < 40 mg/dL (HR: 2.61) were significant predictive factors for onset of type 2 diabetes mellitus. CONCLUSIONS: These results suggest that the serum ferritin level is an important index for priority intervention in preventive medicine for reduction of onset of diabetes.

Effects of ipragliflozin versus metformin in combination with sitagliptin on bone and muscle in Japanese patients with type 2 diabetes mellitus: Subanalysis of a prospective, randomized, controlled study (PRIME-V study).

AIMS/INTRODUCTION: Recent randomized clinical trials have suggested that sodium-glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium-glucose cotransporter 2 inhibitors on bone and muscle are unclear. MATERIALS AND METHODS: A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m2 and hemoglobin A1c 7-10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000-1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated. RESULTS: After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs -10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption. CONCLUSIONS: There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin.

The over 50 year clinical course of a patient with slowly progressive type 1 diabetes (SPIDDM).

Type 1 diabetic patients who have endured their condition for prolonged periods are not uncommon, but there are few well-documented cases of type 2 diabetic patients with duration of over fifty years. In the present case study, we analyzed the history of a diabetic patient whose duration was 53 years. Her case was consequently diagnosed not as the common type 2 diabetes, but as the slowly progressive type 1 diabetes (SPIDDM) identified by Japanese medical researchers. The patient, now 73 years old, was first diagnosed with diabetes in 1953 when she was 17 years of age and started insulin injections. In 1962 she was referred to our hospital, and two years later she vaginally delivered a healthy baby (birth weight 3100 g) at the 40(th) week of gestation. She was the first case of a diabetic mother delivering an infant treated at Tokyo Women's Medical College Hospital. Her data shows that her C-peptide responses by meal tolerance test in 1978 was at least partly preserved though it decreased year by year. Her anti-GAD antibody was found to be positive in 2000 and remained so in 2009. This leads us to conclude that the etiology of her SPIDDM was most likely has insulin secretion exhaustion.

Analysis of the effect of seasonal administration on the efficacy of sitagliptin: Subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes Study.

AIMS/INTRODUCTION: Hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus fluctuate throughout the year. However, there are few studies that have evaluated the therapeutic effect of hypoglycemic agents while considering such fluctuations. In a multicenter study (Januvia Multicenter Prospective Trial in Type 2 Diabetes Study), pretreatment patients with type 2 diabetes mellitus were divided into seven groups and given sitagliptin for 1 year. The aim of the present study was to evaluate the differences in the therapeutic effect, and the efficacy of sitagliptin in patients with type 2 diabetes mellitus based on the month the administration of the drug began as a subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes Study. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus were divided into four groups according to the month of initiation of sitagliptin. Changes in HbA1c in each group were compared at 3 and 12 months after administration of sitagliptin. As a negative correlation has been reported between baseline HbA1c and the degree of change after administration of sitagliptin, an analysis using the residual error from the approximate line was carried out. RESULTS: In the analysis of the degree of change in HbA1c, patients in the group in which administration of sitagliptin was started between August and October had the lowest degree of improvement at 3 months after starting sitagliptin. However, there was no significant intergroup difference in improvement at 12 months after the start of sitagliptin. The same result was also obtained in residual analysis. CONCLUSIONS: The present study suggested that the season of administration of sitagliptin influenced the subsequent hypoglycemic effect even after analysis excluding the influence of HbA1c value at the start of treatment. This study provides possibility, showing that seasonal fluctuations have an effect on the efficacy of antidiabetic drugs.

Renal Function During an Open-Label Prospective Observational Trial of Sitagliptin in Patients With Diabetes: A Sub-Analysis of the JAMP Study.

BACKGROUND: The aim of the study was to determine the effects of sitagliptin on renal function in a diabetic population including patients with normal renal function. METHODS: We analyzed the association between 12-month, 50 mg/day sitagliptin and renal function in outpatients with type 2 diabetes mellitus and poor blood glucose control in a subset of patients in the larger Januvia Multicenter Prospective Trial in Type 2 Diabetes observational study. Stratified analyses of changes in estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were performed. Factors associated with changes in eGFR at 3 months were examined by multivariate regression analysis. RESULTS: Of the 779 patients enrolled, 585 were followed up for 12 months. eGFR decreased significantly from baseline at 3 and 12 months in patients with a baseline eGFR of ≥ 90 mL/min/1.73 m2 and in those with a baseline eGFR of ≥ 60 to < 90 mL/min/1.73 m2. Conversely, eGFR tended to increase at 3 and 12 months in patients with a baseline eGFR of ≥ 45 to < 60 mL/min/1.73 m2 and in those with a baseline eGFR of ≥ 30 to < 45 mL/min/1.73 m2. UACR decreased significantly (-21.6 (-46.8, 7.8)) at 3 months in patients with a baseline UACR of ≥ 30 mg/g Cre. Multivariate regression analysis of factors associated with changes in eGFR at 3 months revealed that higher baseline eGFR and greater decline in UACR were associated with more conspicuous decreases in eGFR. CONCLUSIONS: In this group of diabetic patients receiving sitagliptin, eGFR declined in patients with high baseline eGFR, but not in those with a low baseline eGFR.

Efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus and comparison of hypoglycemic action of concomitant medications: a subanalysis of the JAMP study.

PURPOSE: To determine the efficacy and safety of sitagliptin when used with some therapeutic drugs to treat elderly patients. METHODS: Sitagliptin (50 mg/day) was added to the pre-existing therapy for type 2 diabetes. Changes in the glycated hemoglobin (HbA1c) level after 3 months of treatment were compared with the baseline, and exploratory analysis was performed. These analyses were conducted as subanalyses of the JAMP study, which was an open-label observational study. RESULTS: For patients who were ≥65 years of age, the change in HbA1c level from baseline ranged from -0.50 to -0.87% at 3 months after starting treatment. There was no significant difference in the change in HbA1c level between the patients treated with different concomitant drugs. No significant difference in HbA1c variations at 3 and 12 months from baseline was noted among the three age groups (≥75, 65-74, and <65 years). Multiple regression analysis was performed, and it revealed that patients with higher HbA1c levels at baseline were likely to show decreased HbA1c levels, while those with higher triglyceride (TG) levels were unlikely to show decreased HbA1c levels. CONCLUSION: Sitagliptin has the potential to both improve glycemic control and prevent hypoglycemia, and can be considered a potent alternative drug.

Factors involved in decreasing the therapeutic effect of sitagliptin: a subanalysis of the JAMP study.

OBJECTIVE: As a subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes (JAMP study), we examined factors that decreased blood glucose control effect of sitagliptin after 3 months and patients requiring an addition or increase of diabetes treatment. METHODS: We selected patients in whom glycated hemoglobin (HbA1c) levels decreased by month 3 after initiation of sitagliptin treatment and conducted two analyses: (1) in patients who did not change drugs until month 12, we compared changes in HbA1c levels between concomitant drugs and examined factors that decreased blood glucose control effect of sitagliptin; (2) compared changes in HbA1c levels and backgrounds between patients who did and did not require an addition to or increased dose of the antidiabetic agent. RESULTS: Four hundred and ninety-eight patients were chosen. In 369 patients without drug change until month 12, changes in HbA1c levels during months 3-12 were not significantly different among concomitant drugs; factors causing rebound HbA1c were smoking and weight gain. Patient characteristics were compared between those who did and did not require an additional drug or a dose increase (n = 114) (n = 384). Drug changes were associated with longer disease duration, younger age, higher rate of smoking, and higher degree of insulin resistance but not with concomitantly administered drugs. CONCLUSION: Smoking and weight gain were factors that decreased the effect of sitagliptin on reducing blood glucose levels. Differences in concomitant drugs did not affect sitagliptin's effects on glycemic control. A dose increase or the addition of the antidiabetic drug was not associated with concomitant drugs.

Erratum to: Efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus and comparison of hypoglycemic action of concomitant medications: a subanalysis of the JAMP study.

[This corrects the article DOI: 10.1007/s13340-017-0330-2.].

Regulation of Src homology 2-containing protein tyrosine phosphatase by advanced glycation end products: the role on atherosclerosis in diabetes.

Advanced glycation end products (AGEs), among the most important causes of atherosclerosis in diabetes mellitus, stimulate the proliferation of smooth muscle cells (SMCs). Smooth muscle cells are central in the formation of atherosclerotic lesions, where they show both increased migration and accelerated proliferation. In investigating how AGEs stimulate SMC proliferation, we focused on protein tyrosine phosphatase, especially Src homology 2-containing protein tyrosine phosphatase (SHP2), which is considered important in regulating cell proliferation. Advanced glycation end products increased activity of SHP2 in the membrane fraction of rat aortic SMCs compared with control bovine serum albumin (P < .05). Upon characterizing the genomic and promoter structure of SHP2, we detected nuclear factor-kappaB (NF-kappaB) binding sites in the promoter area. Advanced glycation end product stimulation increased luciferase activity in cells transfected with SHP2 promoter region including NF-kappaB binding sites (P < .05) and increased SHP2 expression (P < .05). These data indicate that AGE stimulation appears to activate NF-kappaB. Activated NF-kappaB binds to sites on the SHP2 promoter, resulting in increased SHP2 expression, SHP2 activity, and, ultimately, SMC proliferation. It suggests that AGE stimulation induces SMC proliferation via SHP2, underscoring the importance of control of AGE for suppressing macroangiopathy in diabetes mellitus.

A patient with Werner syndrome and adiponectin gene mutation.

Werner syndrome is a premature aging disease characterized by genomic instability and increased cancer risk. Here, we report a 45-year-old diabetic man as the first Werner syndrome patient found to have an adiponectin gene mutation. Showing graying and loss of hair, skin atrophy, and juvenile cataract, he was diagnosed with Werner syndrome type 4 by molecular analysis. His serum adiponectin concentration was low. In the globular domain of the adiponectin gene, I164T in exon 3 was detected. When we examined effects of pioglitazone (15 mg/day) on serum adiponectin multimer and monomer concentrations using selective assays, the patient's relative percentage increased in adiponectin concentration was almost same as that in the 18 diabetic patients without an adiponectin mutation, but the absolute adiponectin concentration was half of those seen in diabetic patients treated with the same pioglitazone dose who had no adiponectin mutation. The response suggested that pioglitazone treatment might help to prevent future Werner syndrome-related acceleration of atherosclerosis. Present and further clinical relevant to atherosclerosis in this patient should be imformative concerning the pathogenesis and treatment of atherosclerosis in the presence of hypoadiponectinemia and insulin resistance.