Yoshiyuki Hamamoto

Analysis of factors influencing pancreatic β-cell function in Japanese patients with type 2 diabetes: Association with body mass index and duration of diabetic exposure

AIMS To elucidate the clinical factors affecting beta-cell function, serum C-peptide immunoreactivity (CPR) levels of patients with type 2 diabetes were analyzed. METHODS Seven hundred Japanese patients with type 2 diabetes were enrolled. beta-Cell function was evaluated by fasting CPR (FCPR), 6 min after intravenous injection of 1mg glucagon (CPR-6 min), and the increment of CPR (DeltaCPR). Simple regression analysis between FCPR, CPR-6 min, and DeltaCPR and measures of variables and stepwise multiple regression analysis were carried out. RESULTS Years from diagnosis and BMI were the major independent variables predicting beta-cell function. Years from diagnosis was negatively correlated with CPR-6 min (P<0.0001, r=-0.271), and decrease in CPR-6 min was 0.050 ng/(ml year). BMI was positively correlated with CPR-6 min (P<0.0001, r=0.369). When subjects were divided according to BMI, the decrease in CPR-6 min per year in the high-BMI group (0.068 ng/(ml year)) was greater than that in the low-BMI group (0.035 ng/(ml year)). CONCLUSION A linear decline in endogenous insulin secretion over more than several decades of diabetes was confirmed by this cross-sectional study. The duration of diabetes exposure and BMI are thus major factors in beta-cell function in Japanese patients with type 2 diabetes.

Overexpression of Inducible Cyclic AMP Early Repressor Inhibits Transactivation of Genes and Cell Proliferation in Pancreatic β Cells

ABSTRACT Transcriptional control mediated by the cyclic AMP-responsive element (CRE) represents an important mechanism of gene regulation. To test our hypothesis that increased inducible cyclic AMP early repressor (ICER) Iγ inhibits function of CRE-binding proteins and thus disrupts CRE-mediated transcription in pancreatic β cells, we generated transgenic mice with β-cell-directed expression of ICER Iγ, a powerful repressor that is greatly increased in diabetes. Three transgenic lines clearly show that increased ICER Iγ expression in β cells results in early severe diabetes. From birth islets were severely disorganized with a significantly increased proportion of α cells throughout the islet. Diabetes results from the combined effects of impaired insulin expression and a decreased number of β cells. The decrease in β cells appears to result from impaired proliferation rather than from increased apoptosis after birth. Cyclin A gene expression is impaired by the strong inhibition of ICER; the suppression of cyclin A results in a substantially decreased proliferation of β cells in the postnatal period. These results suggest that CRE and CRE-binding factors have an important role in pancreatic β-cell physiology not only directly by regulation of gene trans-activation but also indirectly by regulation of β-cell mass.

Comparison of effects of amlodipine and angiotensin receptor blockers on the intima–media thickness of carotid arterial wall (AAA study: Amlodipine vs. ARB in atherosclerosis study)

Although there have been increasing reports, which suggest that angiotensin receptor blockers (ARBs) may have anti-atherogenic actions, most of them are performed in vitro and there are a few reports about anti-atherogenic action in vivo. Especially, in humans, there have been no reports about effect of ARBs on atheroslocerosis. On the other hand, there have been several reports, including ours, which indicate that amlodipine, a calcium channel blocker, has a unique property to cause a reduction in the intima-media thickness (IMT) of common carotid artery, which is established to be an indicator of early atherosclerotic lesion, in humans. The present study investigated which of amlodipine and/or ARBs might have more profound effect on IMT progression. The study included 104 hypertensive patients with type 2 diabetes. They were divided into the two groups: the amlodipine group (n=58), who received amlodipine (2.5-5mg/day) and the ARB group (n=46), who received losartan (25-50mg/day), candesartan (4-8 mg/day), valsaratan (40-80 mg/day) or telmisartan (20-40 mg/day). IMT changes were examined during an average of 56.9 weeks. The amlodipine group showed a significant decrease in IMT compared to the ARB group (-0.046 [S.E. 0.161] mm vs. 0.080 [S.E. 0.255] mm, P<0.05). These results suggest that amlodipine has an inhibitory effect on early atherosclerotic process, and that ARBs do not have any effect on it in hypertensive patients with type 2 diabetes.

Relationship Between Carotid Intima-Media Thickness and Silent Cerebral Infarction in Japanese Subjects With Type 2 Diabetes

OBJECTIVE We examined the relationship between intima-media thickness of common carotid artery (CCA-IMT) and silent cerebral infarction (SCI) with the magnetic resonance imaging (MRI) study in Japanese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS The brain MRI study and the carotid ultrasonography were performed in a total of 217 consecutive Japanese subjects with type 2 diabetes. Various risk factors for SCI were examined using multiple logistic analyses. RESULTS The SCI was found in 60.4% of the diabetic subjects. In the diabetic subjects, age, systolic blood pressure (SBP), pulse wave velocity, and CCA-IMT were significantly higher in the subjects with SCI than in those without it. Multiple logistic analyses indicated that age, SBP, and CCA-IMT were significant and independent risk factors of SCI in the diabetic subjects. CONCLUSIONS CCA-IMT, but not pulse wave velocity, was independently associated with SCI in Japanese subjects with type 2 diabetes.

Possible link of pioglitazone with bladder cancer in Japanese patients with type 2 diabetes

We retrospectively examined the frequency of bladder cancer in Japanese patients with type 2 diabetes in relation to use of pioglitazone. Among a total of 663 patients identified to be taking pioglitazone, 9 had bladder cancer (1.36%). Overall the hazard ratio of 1.75 [95% CI: 0.89-3.45] for pioglitazone for bladder cancer was not significant. However the prevalence of bladder cancer was 2.10% in patients taking pioglitazone for less than 24 months which was significant increased (HR 2.73 [95% CI: 1.11-6.72]).

Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia after ingestion of nutrients

AIMS Hypersecretion of glucagon and reduced insulin secretion both contribute to hyperglycemia in type 2 diabetes (T2DM). However, the relative contributions of impaired glucagon and insulin secretions in glucose excursions at the various stages of T2DM development remain to be determined. METHODS The responses of glucagon and insulin as well as those of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were examined before and after ingestion of glucose or mixed meal in Japanese subjects with normal or impaired glucose tolerance (NGT and IGT) and in non-obese, untreated T2DM of short duration. RESULTS In OGTT, T2DM showed a rise in glucagon at 0-30 min, unlike NGT and IGT, along with reduced insulin. In MTT, all three groups showed a rise in glucagon at 0-30 min, with that in T2DM being highest, while T2DM showed a significant reduction in insulin. Linear regression analyses revealed that glucose area under the curve (AUC)0-120 min was associated with glucagon-AUC0-30 min and insulin-AUC0-30 min in both OGTT and MTT. Total and biologically intact GIP and GLP-1 levels were similar among the three groups. CONCLUSIONS Disordered early phase insulin and glucagon secretions but not incretin secretion are involved in hyperglycemia after ingestion of nutrients in T2DM of even a short duration.

Sodium-glucose co-transporter-2 inhibitor use and dietary carbohydrate intake in Japanese individuals with type 2 diabetes: A randomized, open-label, 3-arm parallel comparative, exploratory study

This study investigated the safety and efficacy of the sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor luseogliflozin with differing carbohydrate intakes in Japanese individuals with type 2 diabetes (T2D). Participants were randomly assigned to 3 carbohydrate‐adjusted meals for 14 days (days 1‐14; a high carbohydrate [HC; 55% total energy carbohydrate] and high glycaemic index [HGI] meal; an HC [55% total energy carbohydrate] and low glycaemic index [LGI] meal; or a low carbohydrate [LC; 40% total energy carbohydrate] and HGI meal). All participants received luseogliflozin for the last 7 days (days 8‐14), continuous glucose monitoring (CGM) before and after luseogliflozin treatment (days 5‐8 and days 12‐15) and blood tests on days 1, 8 and 15. Luseogliflozin significantly decreased the area under the curve and mean of CGM values in all 3 groups similarly. Fasting plasma glucose, insulin and glucagon were similar at all time points. Ketone bodies on day 15 were significantly higher in the LC‐HGI group compared with the HC‐HGI and HC‐LGI groups. In conclusion, luseogliflozin has similar efficacy and safety in Japanese people with T2D when meals contain 40% to 55% total energy carbohydrate, but a strict LC diet on this class of drug should be avoided to prevent SGLT2 inhibitor‐associated diabetic ketoacidosis.

SGLT2 inhibitor use and dietary carbohydrate intake in Japanese individuals with type 2 diabetes: a randomized, open-label, 3-arm parallel comparative exploratory study.

This study investigated the safety and efficacy of the sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor luseogliflozin with differing carbohydrate intakes in Japanese individuals with type 2 diabetes (T2D). Participants were randomly assigned to 3 carbohydrate‐adjusted meals for 14 days (days 1‐14; a high carbohydrate [HC; 55% total energy carbohydrate] and high glycaemic index [HGI] meal; an HC [55% total energy carbohydrate] and low glycaemic index [LGI] meal; or a low carbohydrate [LC; 40% total energy carbohydrate] and HGI meal). All participants received luseogliflozin for the last 7 days (days 8‐14), continuous glucose monitoring (CGM) before and after luseogliflozin treatment (days 5‐8 and days 12‐15) and blood tests on days 1, 8 and 15. Luseogliflozin significantly decreased the area under the curve and mean of CGM values in all 3 groups similarly. Fasting plasma glucose, insulin and glucagon were similar at all time points. Ketone bodies on day 15 were significantly higher in the LC‐HGI group compared with the HC‐HGI and HC‐LGI groups. In conclusion, luseogliflozin has similar efficacy and safety in Japanese people with T2D when meals contain 40% to 55% total energy carbohydrate, but a strict LC diet on this class of drug should be avoided to prevent SGLT2 inhibitor‐associated diabetic ketoacidosis.

Olmesartan reduced microalbuminuria in Japanese subjects with type 2 diabetes

We investigated the effect of olmesartan on early diabetic nephropathy in hypertensive patients with type 2 diabetes by its replacement of other angiotensin II type 1 receptor blockers (ARBs) by olmesartan. The urinary albumin/creatinine ratio significantly decreased. The present result suggests a possibility that olmesartan may have more effect on early nephropathy than other ARBs.

GLP‐1 receptor agonist attenuates endoplasmic reticulum stress‐mediated β‐cell damage in Akita mice

Aims/Introduction:  Endoplasmic reticulum (ER) stress is one of the contributing factors in the development of type 2 diabetes. To investigate the cytoprotective effect of glucagon‐like peptide 1 receptor (GLP‐1R) signaling in vivo, we examined the action of exendin‐4 (Ex‐4), a potent GLP‐1R agonist, on β‐cell apoptosis in Akita mice, an animal model of ER stress‐mediated diabetes.