Increased alpha cell to beta cell ratio in patients with pancreatic cancer.

The development of pancreatic cancer (PC) is associated with worsening of glucose tolerance. However, there is limited information about the effects of PC on islet morphology. The aim of this study was to elucidate changes in alpha and beta cell mass in patients with PC. We enrolled 30 autopsy cases with death due to PC (9 with diabetes; DM) and 31 age- and BMI-matched autopsy cases without PC (controls, 12 with DM). Tumor-free pancreatic sections were stained for insulin and glucagon, and fractional beta cell (BCA) and alpha cell area (ACA) were quantified. In addition, expression of de-differentiation markers, i.e., ALDH1A3 and UCN3, was qualitatively evaluated. The pancreas of subjects with PC showed atrophic and fibrotic changes. There was no significant difference in BCA in subjects with PC compared to controls (1.53 ± 1.26% vs. 0.95 ± 0.42%, p = 0.07). However, ACA and ACA to BCA ratio were significantly higher in subjects with PC compared to controls (2.48 ± 2.39% vs. 0.53 ± 0.26% and 1.94 ± 1.93 vs. 0.59 ± 0.26, respectively, both p < 0.001). Increased ACA to BCA ratio was observed in subjects with PC irrespective of the presence of DM. Qualitative evaluation of ALDH1A3 and UCN3 expression showed no significant difference between the groups. In conclusion, in subjects with PC, alpha to beta cell mass ratio is increased, which may contribute to the increased risk of worsening glucose metabolism. Further studies are warranted to elucidate the mechanisms of increased alpha to beta cell mass in patients with PC.

Changes in glycemic variability, gastric emptying and vascular endothelial function after switching from twice-daily to once-weekly exenatide in patients with type 2 diabetes: a subpopulation analysis of the twin-exenatide study.

BACKGROUND: We investigated the changes in blood glucose fluctuation, gastric emptying, and vascular endothelial function by switching from an exenatide twice-daily formulation (BID) to a once-weekly formulation (QW) since the evaluation of postprandial glucose excursion and glycemic variability (GV) by continuous glucose monitoring (CGM) after switching was lacking. METHODS: Twenty-nine patients with type 2 diabetes treated with exenatide BID were included in this study and switched to exenatide QW for 24 weeks. GV assessed by CGM, gastric emptying (by 13 C-acetate breath test) and vascular endothelial function (by reactive hyperemia - peripheral arterial tonometry) were evaluated at baseline and 24 weeks after switching. RESULTS: HbA1c decreased significantly from the baseline to week 24, while postprandial glucose levels after breakfast and dinner significantly increased (both P <0.05). However, the increases in GV indices were modest and not statistically significant at week 24. Vascular endothelial function was also not significantly changed after switching (P >0.05). Gastric emptying was significantly accelerated at week 24 (Tmax 83.4 ± 12.1 min vs. 58.2 ± 16.4 min) (P <0.001) and correlated with increased postprandial glucose levels after breakfast and dinner (both P <0.05). CONCLUSIONS: Despite the increase in postprandial glucose associated with accelerated gastric emptying after switching from exenatide BID to QW, change in GV was modest and no significant deterioration in vascular endothelial function was observed after switching. These results support the superiority of treatment with exenatide QW over exenatide BID in clinical practice; however, attention should be paid to the monitoring and management of postprandial glucose levels when selecting exenatide QW. TRIAL REGISTRATION: Clinical trial registry number; UMIN000016390 and jRCTs031180320 . Approval date of Registry and the Registration: December 12, 2014.

Reduced beta cell number rather than size is a major contributor to beta cell loss in type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by reduced beta cell mass (BCM). However, it remains uncertain whether the reduction in BCM in type 2 diabetes is due to a decrease in size or number of beta cells. Our aim was to examine the impact of beta cell size and number on islet morphology in humans with and without type 2 diabetes. METHODS: Pancreas samples were obtained from 64 Japanese adults with (n = 26) and without (n = 38) type 2 diabetes who underwent pancreatectomy. Using pancreatic tissues stained for insulin, we estimated beta cell size based on beta cell diameter. Beta cell number was estimated from the product of fractional beta cell area and pancreas volume divided by beta cell size. The associations of beta cell size and number with islet morphology and metabolic status were examined. RESULTS: Both beta cell size (548.7 ± 58.5 vs 606.7 ± 65.0 µm3, p < 0.01) and number (5.10 × 108 ± 2.35 × 108 vs 8.16 × 108 ± 4.27 × 108, p < 0.01) were decreased in participants with type 2 diabetes compared with those without diabetes, with the relative reduction in beta cell number (37%) being greater than for beta cell size (10%). Beta cell number but not size was positively correlated with BCM in participants with and without type 2 diabetes (r = 0.97 and r = 0.98, both p < 0.01) and negatively correlated with HbA1c (r = -0.45, p < 0.01). CONCLUSIONS/INTERPRETATION: Both beta cell size and number were reduced in participants with type 2 diabetes, with the relative reduction in beta cell number being greater. Decrease in beta cell number appears to be a major contributor to reduced BCM in type 2 diabetes.

Relationship between daily and visit-to-visit glycemic variability in patients with type 2 diabetes.

The aim of the study was to explore the relationship between daily glycemic variability (GV) and visit-to-visit glycemic variability (VVV) in patients with type 2 diabetes (T2DM). A total of 156 outpatients with T2DM who had undergone continuous glucose monitoring (CGM) for 5 days were included in this study. Indices of GV, i.e., standard deviation and coefficient of variation (CV) of glucose, mean amplitude of glycemic excursion (MAGE) and mean of the daily differences (MODD) were calculated from the CGM data. VVV was calculated as CV of HbA1c or glycated albumin (GA) from HbA1c or GA measured for 3 years. Relationships among clinical parameters, GV and VVV were evaluated. Age was positively, and BMI and C-peptide index were inversely correlated with GV such as CV glucose and MAGE, while BMI was positively correlated with VVV. Mean glucose rather than GV was correlated with VVV. In contrast, time in range (TIR, 70-180 mg/dL) was correlated with both mean HbA1c or GA and VVV. In conclusion, GV and VVV were differently correlated with clinical parameters and were hardly correlated with each other. TIR was correlated with both mean HbA1c and VVV, suggesting that efforts to achieve optimal TIR are practical strategies to reduce VVV in patients with T2DM.

Associations of birthweight and history of childhood obesity with beta cell mass in Japanese adults.

AIMS/HYPOTHESIS: Low birthweight is associated with a high risk of diabetes, but there are no reports discussing birthweight and pancreatic tissues in humans. The purpose of this study was to examine the correlation between birthweight and beta and alpha cell mass in humans. METHODS: Sixty-four Japanese adults with and without diabetes who underwent pancreatectomy and were able to recall their weight history including birthweight were included. Pancreatic tissues were stained for insulin and glucagon, and fractional beta cell area (BCA) and alpha cell area (ACA) were quantified. Islet size and density and beta cell replication were also quantified and their associations with birthweight were evaluated. RESULTS: In participants without diabetes, there was a weak positive correlation between birthweight and BCA (R = 0.34, p = 0.03). The group with a history of childhood obesity, but not the group with a history of obesity in adulthood only, showed higher BCA compared with those without a history of obesity (1.78 ± 0.74% vs 0.99 ± 0.53%, p = 0.01), and the correlation coefficient between birthweight and BCA increased after excluding those with a history of childhood obesity (R = 0.51, p < 0.01). In those with diabetes, there was no correlation between birthweight and BCA. No correlation was found between birthweight and ACA in either those with or without diabetes. CONCLUSIONS/INTERPRETATION: Birthweight and beta, but not alpha, cell mass are positively correlated in non-diabetic adults, and a history of childhood obesity may affect beta cell mass. Graphical abstract.

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.