New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese adults with type 1 diabetes using basal and mealtime insulin: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 1).

AIM: To compare efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with that of insulin glargine 100 U/ml (Gla-100) in Japanese adults with type 1 diabetes. METHODS: The EDITION JP 1 study (NCT01689129) was a 6-month, multicentre, open-label, phase III study. Participants (n = 243) were randomized to Gla-300 or Gla-100 while continuing mealtime insulin. Basal insulin was titrated with the aim of achieving a fasting self-monitored plasma glucose target of 4.4-7.2 mmol/l. The primary endpoint was change in glycated haemoglobin (HbA1c) over 6 months. Safety measures included hypoglycaemia and change in body weight. RESULTS: Gla-300 was non-inferior to Gla-100 for the primary endpoint of HbA1c change over the 6-month period {least squares [LS] mean difference 0.13 % [95 % confidence interval (CI) -0.03 to 0.29]}. The annualized rate of confirmed (≤3.9 mmol/l) or severe hypoglycaemic events was 34 % lower with Gla-300 than with Gla-100 at night [rate ratio 0.66 (95 % CI 0.48-0.92)] and 20 % lower at any time of day [24 h; rate ratio 0.80 (95 % CI 0.65-0.98)]; this difference was most pronounced during the first 8 weeks of treatment. Severe hypoglycaemia was infrequent. The basal insulin dose increased in both groups (month 6 dose: Gla-300 0.35 U/kg/day, Gla-100 0.29 U/kg/day). A between-treatment difference in body weight change over 6 months favouring Gla-300 was observed [LS mean difference -0.6 kg (95 % CI -1.1 to -0.0); p = 0.035]. Adverse event rates were comparable between the groups. CONCLUSIONS: In Japanese adults with type 1 diabetes using basal plus mealtime insulin, less hypoglycaemia was observed with Gla-300 than with Gla-100, particularly during the night, while glycaemic control did not differ.

Aldose reductase C-106T gene polymorphism is associated with diabetic retinopathy in Japanese patients with type 2 diabetes.

It is likely that the C allele of the polymorphism at position -106 in the promoter of aldose reductase gene, which codes a rate-limiting enzyme of the polyol pathway, is a susceptibility allele for diabetic retinopathy in Japanese type 2 diabetic patients.

Combined effect of oxidative stress-related gene polymorphisms on atherosclerosis.

It is well known that oxidative stress plays critical roles in the pathogenesis of atherosclerosis. In this study, we enrolled 1746 type 2 diabetic subjects, determined 4 common genetic variants related to oxidative stress (glutamate-cysteine ligase modifier subunit (GCLM) C-588T, myeloperoxidase G-463A, human paraoxonase 1 Gln192Arg and NAD(P)H oxidase p22phox C242T polymorphisms), and measured carotid intima-media thickness (IMT) as a surrogate marker for atherosclerosis. GCLM C-588T polymorphism was associated with average IMT (AveIMT) (r=0.090, p=0.0008), but the association between the other 3 polymorphisms and AveIMT did not reach the statistical significance. However, AveIMT was significantly greater as the total number of 4 concomitant "pro-oxidant alleles" in each subject was increased (r=0.108, p<0.0001). Furthermore, the number of "pro-oxidant alleles" was a risk factor for a high AveIMT independently of conventional risk factors (p=0.0003). In conclusion, accumulation of oxidative stress-associated alleles was associated with carotid atherosclerosis in type 2 diabetic patients.

Association of soluble CD40 ligand with carotid atherosclerosis in Japanese type 1 diabetic patients.

AIMS/HYPOTHESIS: It has recently been shown that the soluble form of CD40 ligand (sCD40L) interacts with CD40 on vascular cells, leading to a variety of proinflammatory responses, and that serum sCD40L levels can be a predictive marker of cardiovascular events. The aim of this study was to estimate sCD40L levels in type 1 diabetic patients to examine a possible association with carotid atherosclerosis. SUBJECTS AND METHODS: Human sCD40L levels in serum and intima-media thickness (IMT) of carotid artery were examined in 80 Japanese type 1 diabetic patients (27 men and 53 women, age 22.8+/-3.4 years (mean+/-SD), duration of diabetes 13.2+/-6.1 years) and 20 healthy age-matched non-diabetic individuals. RESULTS: Serum sCD40L levels were significantly (p=0.0185) higher in subjects with type 1 diabetes (2.10+/-1.33 ng/ml) compared with non-diabetic subjects (1.35+/-0.88 ng/ml). The greatest IMT (Max-IMT) and averaged IMT (Mean-IMT) were also significantly greater in patients with type 1 diabetes than in control subjects (0.73+/-0.14 vs 0.64+/-0.07 mm, p=0.0041, 0.63+/-0.09 vs 0.57+/-0.06 mm, p=0.0066, respectively). Levels of sCD40L were statistically significantly associated with Max-IMT (r=0.383, p<0.001) and Mean-IMT (r=0.275, p=0.0058). Furthermore, stepwise multivariate regression analyses demonstrated that sCD40L is a determinant of both Max- and Mean-IMT, independently of conventional risk factors. CONCLUSIONS/INTERPRETATION: It is suggested that increased levels of serum sCD40L are associated with accelerated atherosclerotic change observed in young patients with type 1 diabetes.

Increased stress protein ORP150 autoantibody production in Type 1 diabetic patients.

AIMS: Various genetic and environmental stresses interfere with protein folding in the endoplasmic reticulum (ER), which leads to the induction of ER stress. It has recently been reported that ER stress is involved in the development of diabetes in diabetic animal models. The aim of this study is to estimate ER stress levels in Type 1 diabetic patients. METHODS: We recruited Type 1 diabetic patients undergoing periodic follow-up examinations (n = 91) and healthy non-diabetic individuals (n = 37), and measured their serum anti-oxygen-related protein (ORP)150 autoantibody levels. RESULTS: Anti-ORP150 autoantibody levels in Type 1 diabetic patients were significantly higher compared with those in healthy non-diabetic subjects. Furthermore, the serum autoantibody levels in Type 1 diabetic patients correlated with HbA(1c) (F > 3.0, P = 0.079), indicating that hyperglycaemia itself induces ER stress in diabetes. CONCLUSIONS: Anti-ORP150 autoantibody levels in Type 1 diabetic patients are higher compared with non-diabetic subjects, suggesting that ER stress is increased in Type 1 diabetes.

Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes.

AIM/HYPOTHESIS: Metformin is a well-known oral hypoglycaemic agent and has been commonly used, in combination with sulphonylurea, to treat type 2 diabetes. However, the advantageous effect of metformin plus sulphonylurea on diabetic macroangiopathy has yet to be clarified. To evaluate whether sulphonylurea or sulphonylurea plus metformin prevent diabetic macroangiopathy, we examined the progression of carotid artery intima-media thickness (IMT) as a surrogate end point. METHODS: Subjects with type 2 diabetes were divided into three groups, receiving the following treatments: (i) glibenclamide (n=59); (ii) gliclazide (n=30); and (iii) glibenclamide + metformin (n=29). Maximum IMT and average IMT (the greatest value among 6 average values of each 3 points including greatest thickness) were measured at the beginning and end of the observation period. RESULTS: For the follow-up period of 3 years, the annual change in average IMT of the glibenclamide plus metformin group (0.003+/-0.048 mm) was smaller than that of the glibenclamide group (0.064+/-0.045 mm) and gliclazide group (0.032+/-0.036 mm) (p<0.0001 and p=0.043 respectively). In the gliclazide group, average IMT increased during the follow-up period, but annual change in average IMT was significantly smaller than that of the glibenclamide group (p=0.005). Glibenclamide + metformin or gliclazide also attenuated the progression of maximum IMT, compared with that of glibenclamide (0.041+/-0.105, 0.044+/-0.106, 0.114+/-0.131 mm/year respectively, p=0.029 and p=0.035 respectively). Multivariable regression analysis implied that administration of metformin or gliclazide significantly and independently (p<0.05) reduces the progression of average IMT, compared with glibenclamide monotherapy. CONCLUSIONS/INTERPRETATION: These data indicate that metformin or gliclazide, rather than glibenclamide, have a potent anti-atherogenic effect in type 2 diabetes.

Association of (-)786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance.

AIMS/HYPOTHESIS: Endothelial derived nitric oxide synthase ( eNOS) gene polymorphisms affect eNOS activity and are associated with abnormal vasomotility and impaired local blood flow. A decrease in local blood flow has been reported to cause insulin resistance. The aim of this study was to examine a possible association of two eNOS polymorphisms, Glu298Asp (G894T) in exon 7 and (-)786T-C mutation with insulin resistance. METHODS: Genotypes of both Glu298Asp and (-)786T-C mutation were examined by the PCR-RFLP method. Plasma nitrate and nitrite concentrations were also measured. RESULTS: The allele frequencies of both polymorphisms showed no considerable differences in 233 non-diabetic subjects and 301 patients with Type II (non-insulin-dependent) diabetes mellitus. Non-diabetic subjects with the (-)786C allele had (p<0.05) higher fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the (-)786T/ (-)786T genotype. Diabetic subjects with (-)786C allele showed higher HbA(1c) than those with the (-)786T/(-)786T genotype. A euglycaemic hyperinsulinemic clamp study done on 71 of the 301 patients showed a lower glucose infusion rate in diabetic patients with the (-)786C allele than those without it. In diabetic patients with the (-)786C allele, plasma nitrate and nitrite concentrations were lower than in subjects without it (p=0.026). No differences were observed between mutant carriers of Glu298Asp and non-carriers among both non-diabetic subjects and Type II diabetic patients. CONCLUSIONS/INTERPRETATION: The (-)786T-C mutation of the eNOS gene is associated with insulin resistance in both Japanese non-diabetic subjects and Type II diabetic patients.

Heart rate elevation and diabetic retinopathy in patients with type 2 diabetes mellitus and normoalbuminuria.

To investigate the role of heart rate (HR) and blood pressure (BP) for diabetic retinopathy, 24-h ambulatory HR and BP were monitored for 162 in patients with type 2 diabetes and normoalbuminuria. The fundus was assessed as no retinopathy, simple diabetic retinopathy (SDR) and proliferative retinopathy (PDR). Comparing the highest with the lowest quartile of diabetic duration, the relative risk for retinopathy was 9.3 and for nocturnal HR, it was 3.6. Comparison among three retinopathy groups (no retinopathy, group 1, n=122; SDR, group 2, n=24; Pre-PDR or PDR, group 3, n=16) showed that 24-h and nocturnal HR were significantly higher in group 3 (80+/-9 and 71+/-9 beats per min) than in group 2 (73+/-8 and 64+/-8) and group 1 (72+/-7 and 60+/-7). In multiple logistic analysis, the odds ratio of diabetic duration and nocturnal HR to the existence of retinopathy was 1.17 (95% CI, 1.10-1.25, P=0.00001) and 1.11 (95% CI, 1.05-1.17, P=0.0002). We concluded that diabetic retinopathy is related to diabetic duration and high heart rate in type 2 diabetes mellitus with normoalbuminuria. Heart rate elevation may be a predictor of advanced retinopathy.

Carotid intima-media thickness in Japanese type 2 diabetic subjects: predictors of progression and relationship with incident coronary heart disease.

OBJECTIVE: To examine carotid intima-media thickness (IMT), predictors of its progression, and its relationship with incident coronary heart disease (CHD) in type 2 diabetic Japanese patients. RESEARCH DESIGN AND METHODS: Carotid IMT of 287 subjects with type 2 diabetes (mean age 61.6 years) without CHD or cerebrovascular disease was examined at baseline and after a mean follow-up of 3.1 years. RESULTS: The annual progression of IMT (means +/- SEM) was 0.04+/-0.004 mm/year. Stepwise multivariate analysis demonstrated that independent risk factors for progress of IMT were the initial IMT (P<0.001), the average HbA1c level (P<0.001), and age (P = 0.001). Both the initial IMT (odds ratio [OR] 4.9, 95% CI 1.7-14.1) and a low average HDL cholesterol (OR 0.2, 0.1-0.8) were identified as predictors of incident nonfatal CHD (angina pectoris or nonfatal myocardial infarction; 3-year incidence 10.1%) after adjusting for age, sex, average HbA1c, and other risk factors. CONCLUSIONS: The predictors of the progression of carotid IMT in Japanese type 2 diabetic subjects were its baseline thickness and the average HbA1c during the follow-up. Baseline carotid IMT and low HDL cholesterol predicted the incidence of nonfatal CHD.

Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment.

The study aim was to investigate the effect of the route of insulin treatment on the glucagon and glucose production (GP) responses to hypoglycemia in the diabetic rat. Experiments were performed in 4 groups of rats: (1) streptozotocin (STZ)-induced diabetic, untreated (D, n = 7), (2) diabetic treated with subcutaneous insulin (DSC, n = 8), (3) diabetic treated with intraperitoneal insulin (DIP, n = 6), and (4) normal control (N, n = 10). Slow-release insulin implants were used in DSC and DIP rats for 10 to 14 days (3 U/d). A hyperinsulinemic (120 pmol x kg(-1) x min(-1) insulin)-hypoglycemic (glycemia = 2.5 +/- 0.1 mmol/L) clamp following an isoglycemic basal period was performed in 5-hour fasted rats. Basal plasma glucose was normalized in both DSC and DIP rats; however, in DSC but not DIP rats, glucose normalization required peripheral hyperinsulinemia. Tracer-determined GP, which was elevated in D rats, was completely normalized in DIP but only partially corrected in DSC rats. Basal glucagon levels were similar in all groups. During hypoglycemia, GP was suppressed in D rats (delta, -28.9 +/- 5.0 micromol x kg(-1) x min(-1), moderately increased in DSC rats (delta, 6.1 +/- 5.6, P < .01 v D), but markedly increased in DIP and N rats (delta, 34.5 +/- 4.5 for DIP and 16.8 +/- 2.8 for N; P < .01 vD, P < .05 for DIP v DSC or N). Plasma glucagon increased 6-fold in N (945 +/- 129 pg/mL), only doubled in D (424 +/- 54), and tripled in DSC (588 +/- 83), but increased 5-fold in DIP rats (1,031 +/- 75, P < .05 v D and DSC). We conclude that in STZ-diabetic rats, (1) intraperitoneal but not subcutaneous insulin treatment normalizes basal GP, and (2) intraperitoneal insulin treatment as compared with subcutaneous treatment alleviates peripheral hyperinsulinemia and results in increased glucagon and GP responses to hypoglycemia.

Evaluation of gut motility in type II diabetes by the radiopaque marker method.

BACKGROUND: The clinical usefulness of the radiopaque marker method for detecting diabetic gastrointestinal motility disturbances, was evaluated by examining 21 type II diabetes subjects who did not have any neuropathic symptoms. METHODS: After administration of a Sitzmark capsule, markers were located using plain abdominal radiographs, and the transit time of the markers through seven areas of digestive tract was calculated by Arhan's methods. The plasma concentration of acetaminophen at 45 min after oral administration was measured to evaluate gastric emptying time. The coefficient of variation of R-R intervals on the electrocardiograms (CV(R-R)) was measured to evaluate parasympathetic autonomic function. RESULTS: In the diabetics, the average (+/- SD) transit time through upper digestive tracts was slightly but not significantly elongated compared with control subjects (14.4 +/- 8.3 vs 9.9 +/- 6.1 h). Significant elongation was observed in transit time through the lower digestive tracts or the whole gut (44.6 +/- 20.9 and 57.9 +/- 22.3 h, respectively) compared with control subjects (23.3 +/- 8.5 and 33.2 +/- 11.0 h). The transit time of the markers from stomach to small intestine was highly correlated (r = 0.693) with plasma concentration of acetaminophen. The transit time through either the whole colon (r = 0.564) or the whole gut (r = 0.630) was highly correlated with CV(R-R). CONCLUSIONS: These findings suggest that the radiopaque marker method is a useful tool for detecting the sections of the digestive tract responsible for gut motility disturbances. In type II diabetics with no neuropathic symptoms, the lower digestive tracts may deteriorate prior to the impairment of upper digestive tracts.

Antiplatelet drugs attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes.

The intima-media thickness of the carotid artery has been established as a surrogate of definite atherosclerosis in subjects with high risk of vascular events. This study was done to evaluate the effectiveness of long-term antiplatelet therapy in attenuating progression of the intima-media thickness of the carotid artery of subjects with type 2 diabetes. Subjects who had an intima-media thickness over the threshold of the normal subjects but showed no symptoms of vascular events were randomly divided into groups given antiplatelet drugs [ticlopidine (n = 34) or a small dose of aspirin (n = 40)] or no drugs (n = 74). For the follow-up period (3.0+/-0.06 years), the subjects not given antiplatelet drugs showed a significantly higher progression of intima-media thickness (0.067+/-0.009 mm/year) than those given ticlopidine (0.034+/-0.013 mm/year) or aspirin (0.033+/-0.010 mm/year). Stepwise multivariant regression analysis showed that long-term administration of ticlopidine or aspirin significantly reduced the progression of intima-media thickness of diabetic subjects by 0.041 mm/year or 0.032 mm/ year, respectively. These data indicated that despite differences of their pharmacological mechanisms, antiplatelet drugs could attenuate the progression of intima-media thickness of the carotid artery wall of asymptomatic type 2 diabetics who had early-stage carotid atherosclerosis.

Important role of the hepatic vagus nerve in glucose uptake and production by the liver.

We examined the role of the hepatic vagus nerve in hepatic and peripheral glucose metabolism. To assess endogenous glucose production (EGP), hepatic uptake of first-pass glucose infused intraportally (HGU), and the metabolic clearance rate of glucose (MCR), rats were subjected to hepatic vagotomy (HV, n = 7) or sham operation (SH, n = 8), after 10 days, they were then subjected to a euglycemic-hyperinsulinemic clamp together with a portal glucose load in the 24-hour fasting state. Metabolic parameters were determined by the dual-tracer method using stable isotopes. During the experiment, [6,6-2H2]glucose was continuously infused into the peripheral vein. To maintain euglycemia (4.5 mmol/L), insulin (54 pmol x kg(-1) x min(-1)) and glucose were infused peripherally after the 90-minute tracer equilibration and 30-minute basal periods, and glucose containing 5% enriched [U-13C]glucose was infused intraportally (50 micromol x kg(-1) x min(-1)) for 120 minutes (clamp period). EGP was significantly higher in HV rats versus SH rats during the basal period (64.3 +/- 7.6 v 43.6 +/- 5.3 micromol x kg(-1) x min(-1), P < .005)) and was comparable to EGP in SH rats during the clamp period (9.3 +/- 21.5 v 1.1 +/- 11.7 micromol x kg(-1) x min(-1)). HGU was reduced in HV rats compared with SH rats during portal glucose infusion (5.9 +/- 2.4 v 10.1 +/- 3.2 micromol x kg(-1) x min(-1)). The MCR in HV rats was significantly higher than in SH rats in the basal period (11.0 +/- 2.0 v 7.9 +/- 0.8 mL x kg(-1) x min(-1), P < .01)) and was comparable to the MCR in SH rats during the clamp period (41.9 +/- 10.0 and 36.6 +/- 5.7 mL x kg(-1) x min(-1)). We conclude that innervation of the hepatic vagus nerve is important for the regulation of hepatic glucose production in the postabsorptive state and HGU in the postprandial state.

Impaired diurnal cardiac autonomic function in subjects with type 2 diabetes.

OBJECTIVE: To assess diurnal cardiac sympathetic and parasympathetic nerve functions in diabetic subjects with variable diabetic neuropathy. RESEARCH DESIGN AND METHODS: Frequency domain analysis of 24-h Holter ECG was done for 132 diabetic subjects (84 without any symptomatic neuropathy; 37 with only symptomatic peripheral neuropathy; 11 with symptomatic autonomic neuropathy) and 57 normal volunteers to calculate the low frequency (LF) component representing the beta-adrenoceptor function and the high frequency (HF) component representing the cardiac parasympathetic nerve function. RESULTS: Cardiac LF and HF components in diabetic subjects without peripheral neuropathy showed values comparable to those of normal volunteers and a similar circadian rhythm. Diabetic subjects with peripheral neuropathy or autonomic neuropathy showed significantly depressed LF and HF components and loss of the circadian rhythm of LF and HF components compared with diabetic subjects without neuropathy. Impairment of the LF component in the afternoon could be accounted for by the duration of diabetes and elevated HbA1c level. Impairment of the HF component at night could be accounted for by the duration of diabetes but not an elevated HbA1c level. CONCLUSIONS: These data indicated that diabetic subjects with peripheral neuropathy and diabetic subjects with symptomatic autonomic neuropathy, but not diabetic subjects without neuropathy, showed a marked decrease in cardiac sympathetic and parasympathetic nerve functions and loss of circadian rhythm.

Identification of oxidative stress-regulated genes in rat aortic smooth muscle cells by suppression subtractive hybridization.

A suppression subtractive hybridization technique was used to identify reactive oxygen species (ROS)-regulated genes in rat vascular smooth muscle cells. Three genes out of 89 clones, identified as fibronectin, p105 coactivator and ECA39, showed increased expression after treatment with H(2)O(2). The mRNA expressions of these three genes were induced in a time- and dose-dependent manner, independent of protein kinase C activation. Immunohistochemical staining showed that the p105 coactivator expression was markedly induced in the neointima of balloon-injured rat carotid arteries. These results suggest that ROS may play an important role in the development of atherosclerosis by regulating the gene expressions we identified in this study.

Impaired splanchnic and peripheral glucose uptake in liver cirrhosis.

BACKGROUND/AIM: Patients with liver cirrhosis are insulin-resistant and frequently glucose-intolerant. Although peripheral glucose uptake has been shown to be impaired in liver cirrhosis, little is known about the significance of splanchnic (hepatic) glucose uptake after oral glucose load. METHODS/RESULTS: We performed an oral glucose tolerance test and euglycemic hyperinsulinemic clamp with oral glucose load for eight patients with liver cirrhosis and eight patients with chronic active hepatitis. The patients with liver cirrhosis had higher plasma glucose levels 2 h after glucose load than those with chronic active hepatitis (228+/-22 mg/dl vs. 102+/-9 mg/dl, p<0.01). Using the euglycemic hyperinsulinemic clamp with oral glucose load, we simultaneously measured peripheral and splanchnic glucose uptake. Peripheral glucose uptake in liver cirrhosis was 6.1+/-0.7 mg x kg(-1) x min(-1), which was lower than that in healthy volunteers (10.5+/-0.9 mg x kg(-1) x min(-1), p<0.05) and in chronic active hepatitis (8.4+/-0.3 mg x kg(-1) x min(-1), p<0.05). Furthermore, splanchnic glucose uptake in liver cirrhosis was much lower (20.1+/-3.4%) than in healthy volunteers (36.0+/-4.0%, p<0.05) and in chronic active hepatitis (37.2+/-3.1%, p<0.05). CONCLUSION: These results suggest that glucose intolerance in patients with liver cirrhosis is caused by a defect of the glucose uptake of both splanchnic and peripheral tissues.

Oxidative stress induces p21 expression in pancreatic islet cells: possible implication in beta-cell dysfunction.

AIMS/HYPOTHESIS: Prolonged poor glycaemic control in patients with Type II (non-insulin-dependent) diabetes mellitus often causes pancreatic beta-cell dysfunction accompanied by decreases in insulin biosynthesis and beta-cell proliferation. This is well known as a clinical concept called glucose toxicity. Whereas oxidative stress is provoked under diabetic conditions, we examined the possible implication of cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1/Sdi1) in beta-cell dysfunction mediated by oxidative stress. METHODS: Oxidative stress was induced in isolated rat pancreatic islet cells by treatment with H(2)O(2) and mRNA expression of p21 and insulin was examined by northern blot analyses. Also, the expression of p21 and insulin mRNA was examined in Zucker diabetic fatty rat. In islet cells p21 was overexpressed using adenovirus and its effect on insulin gene transcription was examined. RESULTS: When oxidative stress was charged on isolated rat pancreatic islet cells, p21 mRNA expression was induced whereas insulin mRNA was decreased. Also, when diabetes developed in Zucker diabetic fatty rats, p21 expression was induced and the insulin mRNA expression was reduced. As support for the implication of p21 in impairment of beta-cell function, the p21 overexpression in the islet cells suppressed the insulin gene transcription. CONCLUSIONS/INTERPRETATION: The expression of cyclin-dependent kinase inhibitor p21, which can be induced by oxidative stress, increases in pancreatic islet cells upon development of diabetes. By suppressing cell proliferation and insulin biosynthesis, the p21 induction is likely to be implicated in the beta-cell glucose toxicity.