Mayumi Yano

Glucose tolerance, insulin secretion, and insulin sensitivity in nonobese and obese Japanese subjects.

OBJECTIVE To investigate the relative contributions of insulin secretion and insulin resistance to the development of glucose intolerance in Japanese subjects. RESEARCH DESIGN AND METHODS A cross-sectional study of 756 Japanese subjects (530 nonobese, 226 obese) was performed. A 75-g oral glucose tolerance test (OGTT) was given, and subjects were classified according to the World Health Organization (WHO) criteria (normal glucose tolerance [NGT], impaired glucose tolerance [IGT], and diabetes). Early-phase insulin secretion was assessed by the insulinogenic index (the ratio of the increment of insulin to that of plasma glucose [PG] 30 min after a glucose load [ΔIRI0-30 min/Δ PG0-30 min]). Total insulin secretion was assessed by mean immunoreactive insulin (IRI) during the OGTT, and insulin resistance was assessed by use of the homeostasis model [HOMA(R)]. RESULTS Early-phase insulin secretion was significantly decreased in IGT, compared with patients with NGT, in both the nonobese and obese subjects (0.70 ± 0.05 vs. 0.37 ± 0.03, P < 0.01 and 1.36 ± 0.19 vs. 0.73 ± 0.08, P < 0.01, respectively). However, mean IRI and HOMA(R) in both nonobese and obese subjects with IGT and NGT were not statistically different. Subjects with diabetes showed a significant decline in early-phase and total insulin secretion and a significantly higher level of insulin resistance than did subjects with IGT. When the fasting glucose (FPG) exceeded 100 mg/dl, early-phase insulin decreased progressively. The graphed relationship between FPG and mean IRI did not show an inverted U-shape, and mean IRI decreased progressively when FPG exceeded 100–130 mg/dl. The pattern of changes in insulin secretion and insulin resistance associated with the progression of glucose intolerance was similar in both the nonobese and obese subjects. CONCLUSIONS The worsening from NGT to IGT in Japanese subjects may be associated with a decrease in early-phase insulin secretion in nonobese as well as in obese subjects. Hyperinsulinemia in IGT is not common. We suggest that impaired early-phase insulin secretion may be the initial abnormality in the development of glucose intolerance in Japanese people. Insulin resistance may be a consequence of hyperglycemia and/or obesity.

Autoantibodies to glutamic acid decarboxylase in patients with IDDM and autoimmune thyroid disease

Autoantibodies to glutamic acid decarboxylase (GAD), previously reported to be the 64,000-Mr (64K) islet cell protein, were measured by a radioimmunoassay using purified pig brain GAD in 29 insulin-dependent diabetes mellitus (IDDM) patients with autoimmune thyroid disease (AITD) and in 29 sex- and disease duration-matched IDDM patients without AITD. Islet cell antibodies (ICAs) and 64K antibodies were also determined. In IDDM patients with short-duration diabetes (<1 year), the prevalence and levels of GAD antibodies were 100% (8 of 8) and 609 ± 166 U (means ± SE), respectively, in IDDM patients with AITD and 81.8% (9 of 11) and 90 ± 51 U, respectively, in patients without AITD. In patients with long-standing IDDM (3–22 years), the prevalence and levels of GAD antibodies were 76.2% (16 of 21) and 193 ± 66 U, respectively, in patients with AITD and 50.0% (9 of 18) and 36 ± 14 U, respectively, in patients without AITD. For up to 6 years after the onset of IDDM, the levels of GAD antibodies in IDDM patients with AITD were significantly higher than in IDDM patients without AITD. A close and significant correlation was found between GAD antibodies and ICA or 64K antibodies in IDDM patients with AITD. Our results demonstrate that high levels of GAD antibodies were present in IDDM patients with AITD. The observed differences in GAD immunoreactivity between IDDM patients with and without AITD might help evaluate the role of GAD antibodies in IDDM.

Effects of voglibose on glycemic excursions, insulin secretion, and insulin sensitivity in non-insulin-treated NIDDM patients

OBJECTIVE To investigate the effects of voglibose, an α-glucosidase inhibitor, on daily glycemic excursions, insulin secretion, and insulin sensitivity in non-insulin-treated NIDDM patients. RESEARCH DESIGN AND METHODS An open prospective study was conducted in 27 NIDDM patients receiving diet therapy alone or treatment with a sulfonylurea drug. Of the study subjects, 14 patients were treated with voglibose; the remaining 13 patients served as the control group. The metabolic parameters were evaluated before treatment and at week 4 of treatment as follows: glycemic excursions by M-value and 1,5-anhydro-D-glucitol (1,5-AG), insulin secretion by area under the curve of daily serum insulin (AUCinsulin), and insulin sensitivity by the K index of the insulin tolerance test (KITT). RESULTS After the study treatment, HbA1c and plasma glucose in the patients who had received voglibose were comparable to those of patients in the control group. M-value was lower in the patients treated with voglibose than in the control subjects (5.7 ± 0.9 vs. 9.8 ± 1.2, P < 0.05). 1,5-AG was higher in the patients treated with voglibose than in the control subjects (12.2 ± 1.0 vs. 8.2 ± 0.7 μg/ml, P < 0.01). A statistically significant decrease in AUCinsuiin occurred after treatment with voglibose (2,223.5 ± 390.6 to 1,546.7 ± 303.4 pmol · l−1 · h, P < 0.05), but no change occurred in the control group (2,364.5 ± 315.4 to 2,464.2 ± 269.3 pmol · l−1 · h, P = 0.60). Insulin sensitivity (KITT) was improved to a statistically significant level in both the patients treated with voglibose and the patients in the control group. KITT in the patients after voglibose treatment was comparable to that of the control group (3.18 ± 0.30 vs. 3.21 ± 0.23%/min, P = 0.94). CONCLUSIONS The results suggest that voglibose lowers the daily glycemic excursions and inhibits overwork of the pancreatic β-cells but has little effect on insulin sensitivity in NIDDM patients.

Insulin Resistance and Arteriosclerosis Obliterans in Patients With NIDDM

OBJECTIVE To investigate the risk factors for arteriosclerosis obliterans (ASO) in NIDDM, we measured insulin sensitivity and other risk factors including lipoprotein(a) [Lp(a)] in NIDDM patients with and without ASO. RESEARCH DESIGN AND METHODS A case-control study in 100 patients with NIDDM, 35 with and 65 without ASO, was performed. Insulin sensitivity was assessed by the short insulin tolerance tests K index (KITT). Duration of diabetes, a history of smoking, prevalence of hypertension, prevalence of coronary artery disease (CAD), serum C-peptide, 24-h urinary C-peptide, serum lipids, and Lp(a) were compared in the two groups. RESULTS Age, BMI, HbA1c, and fasting plasma glucose were comparable in the two groups. Patients with ASO were significantly more insulin resistant than patients without ASO (KITT 2.16 ± 0.16 vs. 3.00 ± 0.13%/min, P < 0.0001, respectively), had a longer duration of diabetes (10.3 ± 1.2 vs. 7.5 ± 0.8 years, P < 0.05), included a greater number of smokers (68.6 vs. 40.0%, P < 0.01), had a higher prevalence of CAD (60.0 vs. 16.9%, P < 0.01), and had a greater percentage of insulin therapy (48.6 vs. 29.2%, P < 0.05). However, urinary and serum C-peptide levels, serum lipids, and Lp(a) levels were comparable in the two groups. Multiple logistic regression analysis indicated that a history of smoking (odds ratio 3.70, P = 0.011), insulin resistance (odds ratio 3.68, P < 0.001), and an elevated Lp(a) level (odds ratio 1.03, P = 0.020) were independently related to ASO. When patients with CAD were removed from the logistic regression analysis, insulin resistance was most strongly related to ASO (odds ratio 20.9, P < 0.001). CONCLUSIONS Patients with ASO were characterized by a higher prevalence of CAD, a greater percentage of smokers, a greater percentage of insulin therapy, and a higher insulin resistance than were patients without ASO. Insulin resistance, especially, may be the most powerfully related to ASO. Lp(a) may play a minor role in the development of ASO.

Relationships between apolipoprotein(a) phenotype and increase of lipoprotein(a) by troglitazone

Troglitazone is a new oral hypoglycemic agent that reduces insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). However, this agent increases serum lipoprotein(a) [Lp(a)], which is known as an atherogenic lipoprotein. The relationships between the response of Lp(a) to troglitazone and the apolipoprotein(a) [apo(a)] phenotype were investigated in this study. Nineteen NIDDM patients were treated with troglitazone for 4 weeks. Lp(a) increased significantly from 20.1+/-16.5 mg/dL to 44.1+/-31.9 mg/dL (P<.001) in all study patients. Lp(a) increased from 25.7+/-34.2 mg/dL to 50.1+/-38.7 mg/dL (P = .03) in patients with smaller apo(a) phenotypes (S1S4 to S2S4). Lp(a) also increased from 17.5+/-12.0 mg/dL to 41.3+/-29.6 mg/dL (P<.01) in patients with larger apo(a) phenotypes (S3 to S4). Therefore, the increase of Lp(a) by troglitazone may be independent of the apo(a) phenotype.

Increased insulin responsiveness after CS-045 treatment in diabetes associated with Werner's syndrome

Werners syndrome is a rare inheritated disorder characterized by accelerated aging and is often accompanied by diabetes mellitus or impaired glucose tolerance. Previous reports suggest that insulin resistance is involved in the development of diabetes associated with Werners syndrome. In the present study, CS-045((+/-)-5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmet hoxy)benzyl] - 2,4-thiazolidinedione, a new oral hypoglycemic agent which reportedly reduces insulin resistance, was administered to 2 Werners syndrome patients. The patients were hospitalized for the duration of the study. During a pretreatment period lasting 8 weeks the patients received a controlled diet, however, their previous treatment was unchanged. Throughout the 4-week treatment period, each subjects blood glucose level was measured 7 times each day (07:30, 10:00, 11:30, 14:00, 17:30, 20:00, 22:00) for 1 week at 8, 4, and 1 week before treatment and at 2 and 4 weeks after treatment. To assess insulin action, the euglycemic glucose clamp technique was performed in these subjects at insulin infusion rates of 20, 120 and 400 mU/kg/min before and after 4 weeks of treatment. After 4 weeks of treatment with CS-045, the mean blood glucose level at each time point measured in this study was markedly lower compared to the corresponding pretreatment level.(ABSTRACT TRUNCATED AT 250 WORDS)

Argatroban Increases Nitric Oxide Levels in Patients with Peripheral Arterial Obstructive Disease: Placebo-Controlled Study

Abstract. Intravenous argatroban infusion therapy is widely used for the restoration of peripheral microcirculation in patients with peripheral arterial obstructive disease (PAOD). We investigated the effect of argatroban infusion therapy on plasma levels of nitric oxide (NO) and nitrosylhemoglobin (HbNO) in patients with PAOD compared with a placebo-treated PAOD group. The chemiluminescence method was used to determine plasma NO and HbNO. Argatroban was administered as a continuous intravenous infusion for 60 minutes and repeated daily over a period of 2 weeks in 10 patients with PAOD. Treatment significantly improved the clinical signs and symptoms. Serial thermograms showed a 1–2°C rise in the temperature of the affected legs in all patients immediately after intravenous argatroban infusion therapy. Enhancement of the peripheral circulation was maintained after the end of argatroban infusion for up to 90 minutes despite elimination of argatroban from the circulation. Furthermore, there was a progressive and significant increase in the mean concentration of plasma NO in PAOD patients after commencement of argatroban infusion (baseline, 58.0 ± 13.7;90 minutes after infusion, 65.7 ± 13.4 µM; P < 0.01). HbNO significantly increased from a baseline value of 1063 ± 126 to 1460 ± 250 nM at 30 minutes after infusion (P < 0.01). However, the level of HbNo decreased thereafter, although it remained significantly elevated, even at 90 minutes after the end of argatroban infusion. Our results suggest that argatroban may lead to increased HbNO and plasma NO, and this may contribute to the improved microcirculation in PAOD patients.

Autoantibodies to glutamic acid decarboxylase (GAD), 64000-Mr islet cell protein (64K) antibodies and islet cell antibodies (ICA) in insulin-dependent diabetes mellitus with and without autoimmune diseases in Japan

IDDM is known to be a heterogeneous disease which is frequently complicated with other autoimmune diseases (AID). We previously reported that IDDM patients with AID were characterized by late onset of diabetes, persistent ICA-positivity and increased association with DR9, while those without AID were characterized by rapid decline of ICA with duration of diabetes and increased association with DR4. The present study was performed to investigate the prevalence of autoantibodies to glutamic acid decarboxylase (GAD), autoantibodies to 64KDa islet cell protein (64K antibodies) and islet cell antibodies (ICA) in Japanese IDDM patients with and without AID. In short-duration diabetes (< 1 year), the prevalence of GAD antibodies, 64K antibodies and ICA were 100%, 100%, and 100%, respectively, in IDDM patients with AID, and 82%, 64% and 82%, respectively, in patients without AID. In long-standing diabetes (3-28 years), the prevalence of GAD antibodies were 76%, 48% and 33%, respectively, in IDDM patients with AID, and 48%, 28% and 16%, respectively, in patients without AID. The mean levels of GAD antibodies, 64K antibodies and ICA in IDDM patients with AID was significantly higher than in those without AID. Furthermore, the prevalence of GAD antibodies were detected more frequently than ICA and 64K antibodies in long standing IDDM patients. Our results demonstrate that the prevalence of GAD antibodies in IDDM patients were as high as those reported in Caucasians, and high levels of GAD antibodies were observed in IDDM patients with AID.

Molecular analysis of insulin receptor gene in Werner's syndrome

Werners syndrome is characterized by premature aging and frequent impaired glucose tolerance or overt diabetes. Insulin resistance may play an important role and may be caused by a post-receptor defect or dysfunctional insulin receptor. The present study was undertaken to investigate the insulin receptor gene mutation in Werners syndrome. The genomic DNAs were obtained from four patients with Werners syndrome. Exons 2-22 of the insulin receptor gene except exon 1 were amplified from genomic DNA by the polymerase chain reaction and screened for nucleotide variation by examining for single-stranded conformational polymorphisms. There were no nucleotide variations in exons 2, 4-->7, 9 and 12-->22. Variants were thus found in exons 3, 8, 10 and 11 and each were sequenced. The variant in exon 8 was due to a silent polymorphism (GAT-->GAC/T, Asp519) and other variants in exons 3, 10 and 11 were caused by nucleotide substitutions in introns. These results suggest that the patients with Werners syndrome express normal insulin receptors and that the primary genetic lesion for insulin resistance is not in the insulin receptor gene. Insulin resistance in Werners syndrome is thus likely by a post-receptor defect.

Detection of recombinant GAD65 and GAD67 antibodies using a simple radioimmunoassay

Autoantibodies to glutamic acid decarboxylase (GAD) are useful diagnostic and predictive markers for Type 1 (insulin-dependent) diabetes mellitus. In the present study we describe a development of simple, reproducible, and quantitative radioimmunoassays for detecting GAD65 and GAD67 antibodies, and compare sensitivity and specificity of these assays with native GADAb radioimmunoassay. We used in vitro transcribed and translated recombinant human islet GAD65 and GAD67 as antigens, and anti-human IgG was used to separate free from antibody-bound ligand. By using these assays, GAD65Ab and GAD67Ab were detected in 65% and 25% of recent-onset Japanese patients with Type 1 diabetes, respectively, but none of 71 healthy control subjects tested were postive for GAD65Ab and GAD67Ab. Moreover, none of 48 patients with other autoimmune disease had GAD65Ab or GAD67Ab. There was a 100% correlation between the sensitivity and specificity of GAD65Ab assay and native GADAb assay. GAD65Ab and GAD67Ab were concordant in 28% of Type 1 diabetic sera and the levels of GAD65Ab in doubly positive patients were significantly higher than those in only GAD65Ab positive patients (P < 0.01). GAD65Ab are specific markers for Type 1 diabetes, and the radioimmunoassay using in vitro translated GAD and anti-human IgG, which is sensitive, convenient and low cost for detecting GAD antibodies, will facilitate large population screening of Type 1 diabetes.