Efficacy and safety of once-weekly exenatide after switching from twice-daily exenatide in patients with type 2 diabetes.

AIMS/INTRODUCTION: To evaluate the efficacy and safety of once-weekly (q.w.) extended-release exenatide after switching from twice-daily (b.i.d.) exenatide in patients with type 2 diabetes. MATERIALS AND METHODS: This was an investigator-initiated, prospective, single-arm, multicenter study. Individuals with type 2 diabetes who had been treated with exenatide b.i.d. for at least 3 months were enrolled and switched to exenatide q.w. for 24 weeks. The primary end-point was change in HbA1c at week 24 to test the glucose-lowering effect of exenatide q.w. versus exenatide b.i.d. RESULTS: A total of 58 Japanese individuals with type 2 diabetes completed the study. Glycated hemoglobin was reduced by 0.2% at week 24 (7.2 ± 1.2% vs 7.0 ± 1.2% [56 ± 13 vs 53 ± 13 mmol/mol], 95% confidence interval -0.4 to -0.03%, P < 0.005 for non-inferiority, P = 0.01 for superiority). Fasting plasma glucose was reduced by 12 mg/dL at week 24 (154 ± 46 vs 142 ± 46 mg/dL, P = 0.02). ß-Cell function assessed by homeostasis model assessment of ß-cell function and C-peptide index was significantly improved at week 24. The incidence of self-reported hypoglycemia was reduced, and treatment satisfaction assessed by the Diabetes Treatment Satisfaction Questionnaire and Diabetes Medication Satisfaction Questionnaire was improved at week 24, with no change in body weight. There was no serious adverse event related to the study drug. CONCLUSIONS: Switching from exenatide b.i.d. to exenatide q.w. resulted in a reduction in glycated hemoglobin, fasting plasma glucose and the incidence of hypoglycemia, and improvement in ß-cell function and treatment satisfaction in patients with type 2 diabetes. These findings will be useful for selecting optimal treatment in individuals with type 2 diabetes.

Pancreas Fat and ß Cell Mass in Humans With and Without Diabetes: An Analysis in the Japanese Population.

Context: The mechanisms by which ß cell mass is reduced in patients with type 2 diabetes remain unclear. It has been postulated that ectopic fat deposits in the pancreas induce ß cell apoptosis, leading to the development of diabetes. Objective: The aim of this study was to clarify the effects of intrapancreatic fat on ß and α cell mass in humans with and without diabetes. Design and Subjects: Using our tissue database, pancreas sections of 72 Japanese nondiabetic (NDM) autopsy cases and 50 diabetic and 49 age- and body mass index (BMI)-matched NDM patients who underwent pancreatic surgery were analyzed. In addition to histological grading, intrapancreatic fat area (IPFA) was quantified as fractional intralobular, but not interlobular, fat area to the whole pancreas area. Results: Although IPFA was positively correlated with age and BMI, there was no significant difference in IPFA between cases with and without diabetes. Moreover, no association was found between IPFA and either ß or α cell area, or glycated hemoglobin. Conclusion: These findings suggest that pancreatic fat deposits have little effect on ß cell mass and the development of diabetes in humans.

Effects of Obesity and Diabetes on α- and ß-Cell Mass in Surgically Resected Human Pancreas.

CONTEXT: The ethnic difference in ß-cell regenerative capacity in response to obesity may be attributable to different phenotypes of type 2 diabetes among ethnicities. OBJECTIVE: This study aimed to clarify the effects of diabetes and obesity on ß- (BCM) and α-cell mass (ACM) in the Japanese population. DESIGN, SETTING, AND PARTICIPANTS: We obtained the pancreases of 99 individuals who underwent pancreatic surgery and whose resected pancreas sample contained adequate normal pancreas for histological analysis. Questionnaires on a family history of diabetes and history of obesity were conducted in 59 patients. Pancreatic sections were stained for insulin or glucagon, and fractional ß- and α-cell area were measured. Islet size and density as well as ß-cell turnover were also quantified. RESULTS: In patients with diabetes, BCM was decreased by 46% compared with age- and body mass index-matched nondiabetic patients (1.48% ± 1.08% vs 0.80% ± 0.54%, P < .001), whereas there was no difference in ACM between the groups. There was no effect of obesity or history of obesity on BCM and ACM irrespective of the presence or absence of diabetes. There was a negative correlation between BCM, but not ACM, and glycated hemoglobin before and after pancreatic surgery. In addition, reduced BCM was observed in patients with pancreatic cancer compared with those with other pancreatic tumors. CONCLUSIONS: These findings suggest that the increase in BCM in the face of insulin resistance is extremely limited in the Japanese, and BCM rather than ACM has a major role in regulating blood glucose level in humans.

Effects of Glucocorticoid Treatment on ß- and α-Cell Mass in Japanese Adults With and Without Diabetes.

The aim of this study was 1) to clarify ß-cell regenerative capacity in the face of glucocorticoid (GC)-induced insulin resistance and 2) to clarify the change in ß- and α-cell mass in GC-induced diabetes in humans. We obtained the pancreases from 100 Japanese autopsy case subjects. The case subjects were classified according to whether or not they had received GC therapy before death and the presence or absence of diabetes. Fractional ß-cell area (%BCA) and α-cell area (%ACA) were quantified, and the relationship with GC therapy was evaluated. As a result, in case subjects without diabetes, there was no significant difference in %BCA between case subjects with and without GC therapy (1.66 ± 1.05% vs. 1.21 ± 0.59%, P = 0.13). %ACA was also not significantly different between the two groups. In case subjects with type 2 diabetes, %BCA and %ACA were both significantly reduced compared with control subjects without diabetes; however, neither %BCA nor %ACA was significantly decreased in case subjects with GC-induced diabetes. There was a significant negative correlation between %BCA and HbA1c measured before death; however, this relationship was attenuated in case subjects with GC therapy. In conclusion, the current study suggests that ß- and α-cell mass remain largely unchanged in the face of GC-induced insulin resistance in Japanese individuals, implying limited capacity of ß-cell regeneration in adult humans. The absence of apparent ß-cell deficit in case subjects with GC-induced diabetes suggests that GC-induced diabetes is mainly caused by insulin resistance and/or ß-cell dysfunction, but not necessarily a deficit of ß-cell mass.

Efficacy and safety of sitagliptin added to insulin in Japanese patients with type 2 diabetes: the EDIT randomized trial.

AIMS: To clarify the efficacy and safety of adding sitagliptin to insulin therapy in Japanese patients with suboptimally controlled type 2 diabetes (T2DM). STUDY DESIGN AND METHODS: This was a 24-week, prospective, randomized, open-labeled, controlled trial. Patients with T2DM who were suboptimally controlled despite receiving at least twice daily injection of insulin were enrolled in the study. The patients were randomized to continuation of insulin treatment (Insulin group) or addition of sitagliptin 50 to 100 mg daily to insulin treatment (Ins+Sita group). The primary outcome was change in HbA1c at week 24. RESULTS: Adding sitagliptin to insulin significantly reduced HbA1c from 7.9 ± 1.0% at baseline to 7.0 ± 0.8% at week 24 (P <0.0001), while there was no significant change in HbA1c in the Insulin group (7.8 ± 0.7% vs. 7.8 ± 1.1%, P = 0.32). The difference in HbA1c reduction between the groups was 0.9% (95% confidence interval, 0.4 to 1.5, P = 0.01). There was no significant weight gain in either group. Incidence of hypoglycemia was significantly reduced in the Ins+Sita group compared with the Insulin group. Treatment satisfaction was improved in the Ins+Sita group. Baseline HbA1c level and beta cell function were associated with the magnitude of reduction in HbA1c in the Ins+Sita group. CONCLUSION: Adding sitagliptin to insulin reduced HbA1c without weight gain or increase in hypoglycemia, and improved treatment satisfaction in Japanese patients with T2DM who were suboptimally controlled despite at least twice daily injection of insulin. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004678.

Relationship between body mass index and pancreas volume in Japanese people.

CONTEXT: The volume of the pancreas increases with obesity. OBJECTIVE: This study was aimed to explore the relationship between body mass index (BMI) and pancreas volume in Japanese. METHODS: The pancreas volume was examined in a total of 103 (60 men and 43 women) Japanese adults who had undergone abdominal computed tomography (CT) scan. The pancreas was outlined by hand in each CT image and the pancreas volume was computed by summing the product of pancreas area of each image and the CT section thickness. RESULTS: There was a significant positive correlation between BMI and pancreas volume (r = 0.41, P <0.001). This relationship was expressed by the following equation: y = 23.8 + 2.48x, where y is pancreas volume (cm3) and x is BMI. CONCLUSIONS: There is a positive correlation between BMI and pancreas volume in Japanese and this relationship is similar to that in Caucasians. This information will be useful to estimate the impact of obesity on pancreas volume in Japanese and for comparison among different ethnicities.

Islet number rather than islet size is a major determinant of ß- and α-cell mass in humans.

OBJECTIVE: The objective of the study was to clarify the relative contribution of islet number and islet size to ß- and α-cell mass in humans. RESEARCH DESIGN AND METHODS: We obtained the pancreas at autopsy from 72 Japanese adults with no history of diabetes or pancreatitis (aged 47 ± 12 years, body mass index 24.1 ± 5.0 kg/m(2)). Pancreatic sections were stained for insulin or glucagon, and fractional ß-cell area (%BCA) and α-cell area (%ACA) were measured. Islet number and islet size as well as ß-cell turnover were also quantified. Glycosylated hemoglobin measured within 1 year prior to death was obtained in 38 individuals. RESULTS: There was considerable interindividual variation in islet density and mean islet size, with a significant negative correlation between the two (r = -0.25, P = .03). There were significant positive correlations between islet density and %BCA or %ACA (r = 0.63, P < .001, and r = 0.41, P = .001), whereas mean islet size correlated with neither of them. Islet density as well as %BCA, but not mean islet size, was negatively correlated with glycosylated hemoglobin (r = -0.37, P = .02, and r = -0.36, P = .03). CONCLUSION: The present study suggests that islet number rather than islet size is a major determinant of ß- and α-cell mass in humans. Interindividual difference in islet number may contribute to susceptibility to development of glucose intolerance.

Change in ß-cell mass in Japanese nondiabetic obese individuals.

AIM: The aim of this study was to clarify the change in ß-cell mass in Japanese obese individuals. METHODS: We obtained the pancreas at autopsy from 39 lean and 33 obese Japanese nondiabetic individuals (aged 47 ± 13 vs 47 ± 12 y, P = .83, body mass index 20.4 ± 1.6 vs 28.5 ± 3.9 kg/m(2), P < .01). Pancreatic sections were stained for insulin, and ß-cell area (%BCA) was measured as the fraction of the ß-cell area to the total pancreas area. ß-Cell mass was then calculated as the product of %BCA and estimated pancreas weight. ß-Cell replication and apoptosis were assessed by double staining for insulin and Ki67 and insulin and single-stranded DNA, respectively. The frequencies of insulin-positive duct cells and scattered ß-cells were assessed as the surrogate markers of ß-cell neogenesis. The α-cell area (%ACA) was also measured, and the %ACA to %BCA ratio was determined. RESULTS: There was no increase in ß-cell mass in obese individuals compared with lean individuals (0.6 ± 0.4 vs 0.7 ± 0.4 g, P = .12). ß-Cell replication, ß-cell neogenesis, and ß-cell apoptosis were not significantly increased in the presence of obesity. There was no significant difference in %ACA to %BCA ratio between obese and lean individuals (0.91 ± 1.09 vs 0.75 ± 0.51, P = .47). CONCLUSION: There was no increase in ß-cell mass and no detectable change in ß-cell turnover in Japanese obese individuals.

Association between beta cell function and future glycemic control in patients with type 2 diabetes.

The aim of this study was to clarify the association between C-peptide immunoreactivity (CPR), a marker of beta cell function, and future glycemic control in patients with type 2 diabetes. We conducted a retrospective analysis of 513 consecutive patients with type 2 diabetes who were admitted to our hospital between 2000 and 2007 and followed up for 2 years. Serum and urinary CPR levels were measured during admission, and CPR index was calculated as the ratio of CPR to plasma glucose. The associations between these markers at baseline and glycemic control after 2 years were assessed by means of logistic regression models. After 2 years, 167 patients (32.6%) showed good glycemic control (HbA1c <6.9%). Baseline serum and urinary CPR indices were significantly associated with good glycemic control after 2 years, and the postprandial CPR to plasma glucose ratio (postprandial CPR index) showed the strongest association (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.12-1.50, P = 0.001) among CPR indices. Multivariate analyses showed consistent results (OR 1.23, 95%CI 1.03-1.48, P = 0.021). In conclusion, preserved beta cell function at baseline was associated with better glycemic control thereafter in patients with type 2 diabetes.

Postprandial serum C-peptide to plasma glucose ratio as a predictor of subsequent insulin treatment in patients with type 2 diabetes.

Type 2 diabetes is a progressive disease and most patients with type 2 diabetes eventually need insulin therapy. The objective of this study was to clarify C-peptide immunoreactivity (CPR), a marker of beta cell function, as a predictor of requirement for insulin therapy. We conducted a retrospective study of 579 consecutive subjects with type 2 diabetes who were admitted to our hospital from 2000 to 2007 and were able to be followed up for at least 6 months after discharge. Fasting and postprandial serum CPR and urinary CPR levels had been measured during admission. Information about insulin therapy at the last visit was obtained from medical records. At the last visit, 364 subjects (62.9%) were treated with insulin. Mean interval between discharge and the last visit was 4.5 ± 2.3 years. Serum and urine CPR levels at baseline were significantly associated with insulin treatment at the last visit (P<0.001 for all). Among CPR values, postprandial serum CPR to plasma glucose ratio (CPR index) showed the greatest area under the receiver operating characteristic (ROC) curve for insulin therapy. Multivariate logistic regression analysis evaluating the effect of postprandial CPR index adjusted for other confounders showed consistent results with unadjusted results. In conclusion, beta cell dysfunction is significantly correlated with future insulin therapy in patients with type 2 diabetes. Our study indicates that among CPR measurements, postprandial CPR index is the best predictive marker for future insulin therapy.