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.

Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes.

There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 ± 0.80% vs. -0.80 ± 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM.

Proatherogenic effect of interleukin-18 is exerted with high-fat diet, but not with normal diet in spontaneously hyperlipidemic mice.

AIM: It has been considered that interleukin (IL)-18, a T helper 1(Th1) type cytokine, has a promoting effect on atherosclerosis development. A previous mouse study demonstrated that short-term exogenous IL-18 promoted atherosclerosis through a Th1 type immune response; however, the serum IL-18 may have increased greatly beyond its physiological range, and the effect of increased serum IL-18 on atherosclerosis development has not been investigated under different conditions of dietary fat content. The purpose of this study was to reveal the effect of increased serum IL-18 within its physiological fluctuations on atherosclerosis development under different conditions of dietary fat content. METHODS: Spontaneously hyperlipidemic (SHL) mice were systemically supplied with IL-18 for 10 weeks by means of an in vivo gene transfer system with a high-fat diet containing 0.15% cholesterol or a normal diet. RESULTS: Serum IL-18 steadily elevated within its physiological fluctuations. An atherosclerotic lesion area in the aortic root significantly increased with a high-fat diet. Systemic cytokine balance shifted to a Th1-dominant state, and IL-12 mRNA in the arterial wall significantly increased with a high-fat diet; however, these findings were not observed with a normal diet. CONCLUSIONS: It was suggested that the proatherogenic effect of IL-18 is physiologically exerted exclusively with a high-fat diet through Th1 type immune responses, but not with a normal diet.

Induction of anti-whole GAD65 reactivity in vivo results in disease suppression in type 1 diabetes.

Most type 1 diabetes mellitus is caused by autoimmune pancreatic beta-cell destruction. Several antigens such as insulin, glutamic acid decarboxylase (GAD) and islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) are considered to take part in the autoimmune destructive process. Because the role of GAD in the disease process of type 1 diabetes is still controversial, we investigated the disease phenotype upon in vivo induction of whole GAD65 reactivity using a GAD65 homo knockout NOD splenocytes to NOD-scid transfer system. Splenocytes from 8 to 10-week-old female GAD65 homo knockout (=KOT splenocytes) or age-matched wild type (=WTT splenocytes) NOD mice were transferred into female NOD-scid recipients. As compared to recipients of WTT splenocytes, the onset of diabetes in recipients of KOT splenocytes was significantly delayed (p<0.001). Moreover, TGF-beta expression was enhanced in the pancreas from recipients of KOT splenocytes. Splenocytes from recipients of KOT splenocytes produced IL-10 (/IFN-gamma) upon GAD65 stimulation, whereas those from recipients of WTT splenocytes did not. Based upon these results, we propose that anti-whole GAD65-reactive T cells have the ability to regulate the development of type 1 diabetes.

Hyperplastic islets observed in "reversed" NOD mice treated without hematopoietic cells.

At the onset of type 1 diabetes, most of the insulin-producing pancreatic beta cells are destroyed by effector cells, and therefore, the following two factors, at a minimum, are necessary for "reversing" hyperglycemia in autoimmune diabetes; depletion of effector cells and enhancement of beta cell regeneration. In this study, we tried a novel approach for "reversing" autoimmune diabetes in a murine model. Here we show that remission could be achieved with a combination therapy of a single injection of complete Freund's adjuvant (CFA) and a single intraperitoneal injection of a pancreatic beta cell line, MIN6N-9a, in recent-onset diabetic NOD (non-obese diabetic) mice. Five out of seven mice (71%) receiving MIN6N-9a and CFA became normoglycemic within 120 days after treatment, whereas only two of nine (22%) receiving vehicle instead of MIN6N-9a achieved remission. Histological examination of pancreatic specimens from "reversed" mice showed decreased islet number, but each islet was markedly hyperplastic; being about six times larger than those from controls. Although it has been reported that hematopoietic cells such as splenocytes differentiate into insulin-producing cells and play a key role, our data indicate that they are not an absolute requirement for the "reversal" of autoimmune diabetes.

Improved Monitoring of the Hyperglycemic State in Type 1 Diabetes Patients by Use of the Glycoalbumin/HbA1c Ratio.

AIM: Generally, the level of glycoalbumin (GA) is approximately 3 times higher than that of HbA1c. However, in type 1 diabetic patients, we often find an even higher GA/HbA1c ratio of nearly 3.5. Therefore, this study was performed to examine the significance of a higher GA/HbA1c ratio. METHODS: 17 type 1 diabetic patients were enrolled in part 1 of the study and divided into two groups, one with a higher and the other with a lower GA/HbA1c ratio. In both groups, the correlation between GA or HbA1c level and each "4-point" capillary glucose level was analyzed. 80 type 1 diabetic patients were enrolled in part 2 of the study and the relationship between mean GA/HbA1c ratio in the past year and degree of diabetic retinopathy was analyzed. RESULTS: In part 1 of the study, we found positive correlations between GA and bedtime capillary glucose levels and between HbA1c and bedtime capillary glucose levels in the higher GA/HbA1c group (r = 0.86, p = 0.023; r = 0.95, p = 0.012, respectively), but not in the lower GA/HbA1c group. In part 2 of the study, a significant positive correlation between GA/HbA1c ratio and severity of retinopathy could be observed (r = 0.269, p = 0.017). CONCLUSIONS: A higher GA/HbA1c ratio may reflect a postprandial hyperglycemic state and simultaneous monitoring of GA and HbA1c may improve the management of diabetic patients.