Effects of liraglutide on intrapancreatic fat deposition in patients with type 2 diabetes.

BACKGROUND & AIMS: Ectopic fat deposition is associated with worsening of glycemic control. This study was conducted to determine whether liraglutide reduces ectopic fat deposition, especially in pancreas, in patients with type 2 diabetes (T2D). METHODS: We retrospectively recruited T2D patients who underwent abdominal unenhanced CT scans both before and after administration of liraglutide (N = 13) or glimepiride (N = 29). Using CT values of pancreas (P), liver (L) and spleen (S), we defined the indices of intrapancreatic and liver fat as P-S value and L-S value, respectively. Increase of each value suggests the reduction of each fat deposition. RESULTS: The values of HbA1c (p = 0.0017) and body weight (p = 0.0081) decreased, and L-S (p = 0.0024) increased significantly after administration of liraglutide compared with those at baseline. Similarly, P-S tended to increase in the liraglutide group (p = 0.0547) and increased significantly in the liraglutide subgroup with fatty pancreas (p = 0.0303), defined as having baseline P-S less than -5. In the glimepiride group, P-S did not increase regardless of baseline P-S. Among patients with fatty pancreas, administration of liraglutide tended to be a significant factor for the change in P-S after adjustment for the change in HbA1c (p = 0.1090) and the change in visceral fat area (p = 0.1030). CONCLUSIONS: Intrapancreatic fat deposition was decreased after treatment with liraglutide, but not glimepiride, in T2D patients with fatty pancreas. Liraglutide might reduce intrapancreatic fat deposition independently of decreases in HbA1c and visceral fat volume.

Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus.

Cardiovascular (CV) complications are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis being a common risk factor for prospective crisis of coronary artery diseases and/or cerebral infarction in DM subjects. From another point of view, asymmetric dimethylarginine (ADMA) has been established as an inhibitor of endogenous nitric oxide synthesis and the relationship between ADMA and arteriosclerosis has been reported. In our study with 87 type 2 DM (T2DM) patients, we have examined whether ADMA and other CV risk factors are the useful predictors of DMCV complications. After the measurement of the respective CV risk factors, we have followed the enrolled T2DM patients for 5 years. We have finally analyzed 77 patients. DMCV complications developed in 15 cases newly within 5 years, and 4 cases recurred. The concentrations of ADMA in plasma were markedly more elevated in 19 DM patients with CV complications than in 58 DM patients without CV complications. Urinary albumin (U-Alb), mean intimal-medial thickness (IMT) and ankle brachial index (ABI) were also higher in patients with CV complications. Multiple regression analyses showed that U-Alb had an influence on the high level of ADMA (standardized ß = 6.59, P = 0.00014) independently of age, systolic BP, fibrinogen, mean IMT, plaque score, and ABI. The review indicates what is presently known regarding plasma ADMA that might be a new and meaningful biomarker of CV complications in DM subjects.

[Current concept of insulin therapy intensification, and the role of human regular insulin and rapid-acting insulin analogs in insulin treatment].

The evolution of insulin therapy from animal insulin to recombinant human regular insulin has improved diabetes treatment. Generating of rapid-acting insulin analogs, mimicking physiologic insulin action enables us to provide better control of post-prandial glucose level and lower incidence of hypoglycemia compared with human regular insulin. These rapid-acting insulin analogs show lower susceptibility of insulin precipitation and catheter occlusions, and are suitable for insulin pump therapy of continuous subcutaneous insulin infusion. Insulin lispro and insulin aspart are also applicable for diabetic patients with pregnancy, requiring excellent glycemic control. In some studies, stepwise addition of prandial insulin, as well as full basal-bolus regimen can improve glycemic control with less hypoglycemia. Treatment intensification with rapid-acting insulin analogs may offer a proper method to reach glycemic goals.

Hepatocyte growth factor, a biomarker of macroangiopathy in diabetes mellitus.

Atherosclerotic involvements are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis (CA) being a common risk-factor for prospective crisis of coronary artery diseases (CAD) and/or cerebral infarction (CI) in DM subjects. From another point of view, several reports have supplied augmenting proof that hepatocyte growth factor (HGF) has a physiopathological part in DM involvements. HGF has been a mesenchymal-derived polyphenic factor which modulates development, motion, and morphosis of diverse cells, and has been regarded as a humor intermediator of epithelial-mesenchymal interplays. The serum concentrations of HGF have been elevated in subjects with CAD and CI, especially during the acute phase of both disturbances. In our study with 89 type 2 DM patients, the association between serum concentrations of HGF and risk-factors for macrovascular complications inclusive of CA were examined. The average of serum HGF levels in the subjects was more elevated than the reference interval. The serum HGF concentrations associated positively with both intimal-media thickness (IMT) (r = 0.24, P = 0.0248) and plaque score (r = 0.27, P = 0.0126), indicating a relationship between the elevated HGF concentrations and advancement of CA involvements. Multivariate statistical analysis accentuated that serum concentrations of HGF would be associated independently with IMT (standardized = 0.28, P = 0.0499). The review indicates what is presently known regarding serum HGF might be a new and meaningful biomarker of macroangiopathy in DM subjects.

Profile of saxagliptin in the treatment of type 2 diabetes: focus on Japanese patients.

Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as α-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.

Medium-term effects of insulin degludec on patients with type 1 diabetes mellitus.

OBJECTIVE: The aim of this study was to analyze the changes in daily blood glucose fluctuation and insulin dose in patients with type 1 diabetes mellitus (T1DM) undergoing basal-bolus therapy following a switching of basal insulin used from insulin glargine or detemir to insulin degludec. METHODS: Seven patients with T1DM were enrolled. All patients treated with insulin glargine or detemir twice daily were switched to insulin degludec with 80-90 % of the prior insulin dose. During the study period, the basal insulin doses were adjusted by the attending physician. The patients underwent continuous glucose monitoring before, 3 days after, and 24 weeks after switching to insulin degludec. The daily insulin dose was analyzed before, 3 days after, and 24 weeks after switching. Glycated hemoglobin levels were measured before and 24 weeks after switching. RESULTS: The blood glucose profile did not change significantly before and after switching. On the other hand, the total daily insulin dose and total daily basal insulin dose decreased significantly 24 weeks after switching. DISCUSSION: In patients with T1DM undergoing insulin glargine or detemir treatment, it is possible to achieve similar glycemic control in the medium term with a once daily, lower dose of insulin degludec.

Effects of exenatide on metabolic parameters/control in obese Japanese patients with type 2 diabetes.

The effects of exenatide on glycemic control, lipid metabolism, blood pressure, and gastrointestinal symptoms were investigated in obese Japanese patients with type 2 diabetes mellitus. Twenty-six outpatients were enrolled and administered 5 µg of exenatide twice daily. If there was insufficient weight loss and/or insufficient improvement in glycemic control, the dose was increased to 10 µg twice daily. Follow-up was continued until the 12th week of administration. Hemoglobin A1c, glycoalbumin, fasting plasma glucose, body weight, fasting serum C-peptide, serum lipids, blood pressure, and pulse rate were measured before and after the observation period. In the initial phase of exenatide therapy, each patient received a diary to record gastrointestinal symptoms. During treatment with exenatide, hemoglobin A1c decreased significantly and serum C-peptide increased significantly. Body weight, low-density lipoprotein cholesterol, and systolic blood pressure decreased significantly. Nausea was the most frequent gastrointestinal symptom and occurred in 16 patients. Its onset was noted at a mean of 1.7 h after injection, the mean duration was 1.1 h, and it continued for a mean of 9.3 days after the initiation of administration. Patients with nausea showed a significant decrease in hemoglobin Alc, glycoalbumin, or body weight compared with those without nausea. These findings suggest that a more marked improvement in metabolic parameters by exenatide can be partly dependent on the manifestation of gastrointestinal symptoms.

Effects of switching from insulin glargine or detemir to insulin degludec in patients with type 1 diabetes mellitus.

INTRODUCTION: Insulin degludec is a new, ultra-long-acting basal insulin. The aim of this study was to analyze the changes of basal insulin dose and blood glucose profile in basal-bolus therapy of type 1 diabetes mellitus (T1DM) at the switching of basal insulin from insulin glargine or detemir to insulin degludec. METHODS: Sixteen patients with T1DM were enrolled. The patients underwent continuous glucose monitoring before and after the switching of insulin glargine or detemir to degludec. Ten patients treated with insulin glargine or detemir twice daily, were switched to insulin degludec with 80-90% of the prior insulin dose. The remaining six patients treated with insulin glargine once daily, were switched to insulin degludec without down titration. The changes of daily insulin dose and glycated hemoglobin (HbA1c) were also examined for 12 weeks after switching to insulin degludec. RESULTS: In the patients switched from twice-daily basal insulin, no significant difference was found between before and after switching in the blood glucose profile. In the once-daily group, blood glucose levels showed a tendency to decrease after switching to the degludec treatment. During the study period, total daily insulin dose (TDD) and total daily basal insulin dose (TBD) decreased significantly in the twice-daily group, and TDD and TBD showed a tendency to decrease after switching to degludec in the once-daily group. In both groups, the changes of HbA1c were not significantly different. CONCLUSION: It is possible to achieve similar glycemic control with once-daily injection and lower doses of insulin degludec in patients with T1DM who have been treated with insulin glargine or detemir.

Effects of combination therapy with mitiglinide and voglibose on postprandial plasma glucose in patients with type 2 diabetes mellitus.

Patients with diabetes mellitus are at increased risk from cardiovascular-related morbidity and mortality as compared with healthy individuals. An association between the postprandial metabolic state and atherogenesis has been observed in patients with diabetes mellitus. In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), treatment with an α-glucosidase inhibitor (α-GI) in patients with impaired glucose tolerance not only reduced the rate of conversion from impaired glucose tolerance to type 2 diabetes mellitus (T2DM), but was also associated with a reduction in the risk of cardiovascular events. These results suggested the importance of treating postprandial hyperglycemia in the early stages of T2DM. Glinides are rapid and short-acting insulin secretagogues that bind to the sulfonylurea receptors on pancreatic ß-cells to facilitate rapid insulin secretion, restore postprandial early insulin secretion, and reduce the postprandial glucose spike. Moreover, α-GIs reduce postprandial hyperglycemia and insulin secretion by delaying the digestion of carbohydrates and polysaccharides in the small intestine. Then, both glinides and α-GI have beneficial effects for treating patients with T2DM and impaired glucose tolerance. Considering the ameliorating effects of these drugs on postprandial metabolic disorders, combinations of glinides and α-GI might constitute a promising therapeutic strategy for managing patients with T2DM, and also appear to be suitable for Japanese people, who consume more carbohydrates, such as polished rice, than Caucasians. It has recently been reported that combined use of mitiglinide and voglibose reduces postprandial insulin secretion and blunts diurnal glycemic changes in T2DM patients. This therapy can thus be regarded as being suitable for achieving strict postprandial glycemic control. In this report, we outline the effects of this combination therapy on postprandial plasma glucose and assess its safety.

Evaluation of a minimally invasive system for measuring glucose area under the curve during oral glucose tolerance tests: usefulness of sweat monitoring for precise measurement.

AIMS: We developed a system for measuring glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET). Sweat contamination during interstitial fluid glucose (IG) extraction affects the accuracy of glucose AUC measurement, because this technology uses extracted sodium ion levels as an internal standard. Therefore, we developed a sweat monitoring patch to reduce this effect and investigated its efficacy in volunteers undergoing oral glucose tolerance tests (OGTTs). MATERIALS AND METHODS: Fifty diabetes mellitus inpatients and 10 healthy subjects undergoing the 75 g OGTT were included. Two sites on the forearm were pretreated with microneedle arrays, then hydrogels for interstitial fluid extraction were placed on the treated sites. Simultaneously, hydrogels for sweat monitoring were placed on untreated sites near the treated sites. Plasma glucose (PG) levels were measured every 30 min for 2 h to calculate reference AUC values. Using MIET, IG AUC was calculated from extracted glucose and sodium ion levels after attachment of the hydrogel for 2 h. RESULTS: Good correlation between IG AUC measurements using MIET and reference AUCs measured using PG levels was confirmed over a wide AUC range (202-610 mg/h/dl) after correction for the sweat-induced error detected by the hydrogel patches on the nonpretreated skin. Strong correlation between IG AUC and peak glucose levels indicates that glucose spikes can be easily detected by this system. CONCLUSION: We confirmed the effectiveness of a sweat monitoring patch for precise AUC measurement using MIET. This novel, easy-to-use system has potential for glucose excursion evaluation in daily clinical practice.

Effects of the naturally-occurring disaccharides, palatinose and sucrose, on incretin secretion in healthy non-obese subjects.

AIMS/INTRODUCTION: Incretins might play some pathophysiological role in glucose metabolism in diabetes and obesity; it is not clear whether or not the amount and the pattern of incretin secretion vary with different types of sugars. To evaluate the effect of two types of disaccharides on glucose metabolism and the kinetics of incretin secretion, plasma levels were measured after palatinose or sucrose ingestion in non-obese healthy participants. MATERIALS AND METHODS: The study was carried out on healthy participants who were given a solution containing 50 g of palatinose or sucrose for ingestion. Blood samples were obtained before loading and after ingestion. Insulin, glucagon and incretins hormones were measured by the enzyme-linked immunosorbent assay method. RESULTS: When the data were compared between palatinose and sucrose ingestion, both plasma glucose values at 15, 30 and 60 min, and plasma insulin values at 15 and 30 min after palatinose loading were significantly lower than those after sucrose loading. Plasma levels of total glucose-dependent insulinotropic polypeptide at 15-90 min after palatinose loading were significantly lower than those after sucrose loading. Plasma levels of total and active glucagon-like peptide-1 at 90 min and the area under the curve (60-120 min) of the total glucagon-like peptide-1 were significantly higher with palatinose-loading than with sucrose loading. CONCLUSION: Compared with sucrose, palatinose appears to have a more favorable effect on glucose metabolism and protection of pancreatic islets as a result of less hyperglycemic and hyperinsulinemic potency.

Effect of additional administration of acarbose on blood glucose fluctuations and postprandial hyperglycemia in patients with type 2 diabetes mellitus under treatment with alogliptin.

Acarbose was administered at 300 mg/day to patients with type 2 diabetes mellitus (T2DM) who had been taking 25 mg/day of alogliptin, and levels of blood glucose were analyzed by continuous glucose monitoring (CGM) for 3 days. The mean blood glucose level with acarbose (136.4 ± 30.7 mg/dL) did not differ significantly from that without acarbose (141.7 ± 28.3 mg/dL). However, in the condition of the combination therapy, there were significant decreases in the standard deviation of the mean blood glucose levels for the 24-hour period (27.6 ± 9.1 vs. 16.2 ± 6.9 mg/dL, p<0.001) and mean amplitude of glycemic excursions (MAGE) (65.8 ± 26.1 vs. 38.8 ± 19.2 mg/dL, p=0.010). In addition, a meal tolerance test was conducted to monitor changes in insulin secretion and active GLP-1 and total GIP values. Ten subjects (5 males, 5 females) of 54.9 ± 6.9 years with BMI 25.9 ± 5.2 kg/m² and HbAlc 9.2 ± 1.2% were enrolled. In the meal tolerance test, active GLP-1 values before and after acarbose administration were 17.0 ± 5.8 and 24.1 ± 9.3 pmol·hr/mL (p=0.054), respectively, showing an increasing tendency, and total GIP(AUC0-180) values were 685.9 ± 209.7 and 404.4 ± 173.7 pmol·hr/mL, respectively, showing a significant decrease (p=0.010). The results indicate that the combined administration of both inhibitors is effective not only in decreasing blood glucose fluctuations and preventing postprandial insulin secretion. The beneficial effects may also protect the endocrine pancreas and inhibit body weight gain.

Estimation of HbA1c response to sitagliptin by change in glycated albumin level for 2 weeks.

UNLABELLED: Aims/Introduction: Since glycated albumin (GA) reflects shorter-term (about 2 weeks) control of plasma glucose levels compared with HbA1c, GA is thought to be a useful glycemic control indicator for the early period following commencement of the treatment of diabetes. In this study, we attempted to estimate HbA1c using the change in GA level before and after the first 2 weeks (ΔGA2w) of administration of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. MATERIALS AND METHODS: The study included 28 patients with type 2 diabetes who were administered sitagliptin at a dose of 50 mg/day for 12 weeks. RESULTS: At 2 weeks after administration of sitagliptin, GA markedly decreased, while HbA1c had only slightly decreased. A significant positive correlation was observed between the ΔGA2w and the change in HbA1c before and after the first 12 weeks of administration of sitagliptin (ΔHbA1c12w) (R = 0.793, P < 0.0001). The latter was about 0.6 times the former. The estimated HbA1c after 12 weeks of therapy was calculated by adding ΔGA2w × 0.6 to the baseline HbA1c. A significant positive correlation was observed between the estimated HbA1c and the measured HbA1c after 12 weeks (R = 0.735, P < 0.0001) and both were similar levels. CONCLUSIONS: HbA1c in the first 12 weeks after administration of sitagliptin could be estimated from the formula using the ΔGA2w. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00167.x, 2011).

Incretin responses to oral glucose load in Japanese non-obese healthy subjects.

INTRODUCTION: Recently, incretin-related therapy has been developed for the new treatment of diabetes mellitus; however, incretin response to glucose ingestion in normal glucose tolerant (NGT) subjects has not been clarified in detail with special reference to the role of incretin hormones, glucagon, and a family history of diabetes. METHODS: We conducted a 75 g oral glucose tolerance test in 30 NGT subjects. RESULTS: The total glucose-dependent insulinotropic peptide (GIP)-AUC(0-120) (area under the curve over a period of 0-120 minutes) was correlated with immunoreactive insulin (IRI)-AUC(0-120) (P<0.05), insulinogenic index (II; P<0.05), ΔIRI between 0 and 120 minutes (P<0.05). Active glucagon-like peptide-1 (GLP-1) AUC(0-120) was correlated inversely both with Δ glucose between 0 and 30 minutes (P<0.01) and with Δ immunoreactive glucagon between 0 and 30 minutes (P<0.05). Δ Total GIP between 0 and 15 minutes (P<0.01), Δ total GIP between 0 and 30 minutes (P<0.05), and the total GIP-AUC(0-120) (P<0.05) in the subjects with a family history of type 2 diabetes were significantly higher than those in the subjects without a family history. CONCLUSION: These results suggest that GIP possibly facilitates insulin secretion in response to oral glucose load directly and active GLP-1 may exert the glucoregulatory action via the suppression of glucagon secretion in NGT subjects. Notably, the subjects with a family history of diabetes exert significantly higher GIP response in the early phase of glucose load compared with those without a family history.

Effects of miglitol in combination with intensive insulin therapy on blood glucose control with special reference to incretin responses in type 1 diabetes mellitus.

To determine whether miglitol administration improves glycemic control and reduces the frequency of hypoglycemia in type 1 diabetes mellitus (T1DM) patients treated with intensive insulin therapy, we analyzed the effect of miglitol on daily insulin doses, body weight, hypoglycemia, and incretin hormone responses during meal tolerance tests (MTT). Eleven T1DM subjects (21-77 years) undergoing intensive insulin therapy, took 25 mg (weeks 0-4) and 50 mg miglitol (weeks 4-12) thrice daily, immediately before meals. At weeks 0 and 12, 9 of 11 subjects underwent MTT. In present study, mean HbA1c, glycoalbumin, and 1,5-anhydroglucitol levels were significantly improved. The blood glucose level 1 h after dinner was significantly lower at week 12 than at week 0 (p = 0.008). From week 0 to 12, there was a significant decrease in the body mass index (BMI; p = 0.0051), frequency of preprandial hypoglycemic events (p = 0.012), and daily bolus insulin dosage (p = 0.018). The change in active glucagon-like peptide-1 (GLP-1) at 120 min significantly increased at week 12 (p = 0.015). The change in total glucose-dependent insulinotropic peptide (GIP) significantly decreased in the MTT at week 12. These results demonstrate that addition of miglitol on intensive insulin therapy in T1DM patients has beneficial effects on reducing BMI, bolus and total insulin dosage, and frequency of preprandial hypoglycemic events. MTT findings suggest that this combination therapy improves blood glucose control by delaying carbohydrate absorption and modifying the responses of incretins, GIP, and GLP-1.

Comparison of efficacy of concomitant administration of mitiglinide with voglibose and double dose of mitiglinide in patients with type 2 diabetes mellitus.

UNLABELLED: Aims/Introduction: When monotherapy with an oral hypoglycemic agent (OHA) is not sufficiently effective for blood glucose control, combination therapy with OHA having different mechanisms of action might be indicated. MATERIALS AND METHODS: In the present study, we compared the efficacy of two options in type 2 diabetes mellitus patients whose blood glucose had not been well controlled with mitiglinide (30 mg/day) alone. A total of 20 patients were included in the study and divided into two groups: group A, in which mitiglinide was given concomitantly with the α-glucosidase inhibitor voglibose (0.6 mg/day); and group B, in which a double dose of mitiglinide was given (60 mg/day). Twelve weeks after changing the medication, HbA1c, glycoalbumin and 1,5-anhydroglucitol (1,5-AG) were measured. In addition, at weeks 0 and 12, a meal tolerance test was carried out, and plasma glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic polypeptide levels were measured. RESULTS: The plasma level of 1,5-AG improved in both groups at week 12. In group A, the plasma insulin level significantly decreased and the plasma active GLP-1 level significantly increased during the meal tolerance test at week 12; thus, bodyweight significantly decreased only in group A. CONCLUSIONS: Our findings suggested that concomitant administration of mitiglinide with voglibose could achieve better glycemic control, particularly in the postprandial period, without bodyweight gain and might have beneficial effects in type 2 diabetic patients at risk of macrovascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.0082.x, 2011).

Effects of gliclazide on platelet aggregation and the plasminogen activator inhibitor type 1 level in patients with type 2 diabetes mellitus.

Vascular complications are a common factor determining morbidity and mortality of diabetic patients. In vitro studies have revealed that gliclazide has antiplatelet activities. To clinically assess this action, we measured the effects of gliclazide on platelet activities and abnormal fibrinolysis in patients with type 2 diabetes mellitus. We studied 14 patients aged 38 to 72 years (9 men and 5 women) with type 2 diabetes mellitus who have been treated with glibenclamide in our hospital for more than 6 months. We switched from glibenclamide to gliclazide using the average ratio of the respective doses, 2.5 vs 40 mg. We titrated the dose of gliclazide to keep the glycemic control at the same level as the previous (glibenclamide) treatment. We measured 10 micromol/L serotonin-induced or 0.5 micromol/L adenosine diphosphate (ADP)-induced platelet aggregate formation by particle counting using light scattering at baseline and up to 6 months after the switch. After switching to gliclazide, platelet aggregate formation induced by serotonin was significantly reduced (P < .05, compared with the levels observed after glibenclamide treatment). The body mass index, fasting plasma glucose, immunoreactive insulin, homeostasis model assessment of insulin resistance, hemoglobin A(1c) (HbA(1c)), total cholesterol, triglycerides, high-density lipoprotein cholesterol, prothrombin time, activated partial thromboplastin time, fibrinogen, thrombin-antithrombin III complex, plasmin-alpha2-plasmin inhibitor complex, and plasma plasminogen activator inhibitor type 1 (PAI-1) were not changed. In the group with improved HbA(1c) (n = 5), ADP-induced platelet aggregate formation and plasma PAI-1 level were significantly reduced (P < .05, compared with the group with aggravated HbA(1c), n = 9). Multiple regression analysis showed that percentage change of ADP-induced platelet aggregate formation (standardized beta = 0.540, P < .05) was independently associated with percentage change of plasma PAI-1 level in addition to percentage change of HbA(1c) (standardized beta = 0.657, P < .05) (R = 0.939, P < .05) after switching to gliclazide. The other independent variants, like the final dose of gliclazide, homeostasis model assessment of insulin resistance, percentage change of prothrombin time, activated partial thromboplastin time, and total cholesterol, were not significantly associated with the percentage change of plasma PAI-1 level. These results indicate that gliclazide inhibits platelet aggregation via the serotonin pathway, independently of the metabolic control per se. Furthermore, in the patients with improved glycemic control, gliclazide could inhibit ADP-induced platelet aggregation and reduce PAI-I level. Taken together, the results show that gliclazide may be more useful for the prevention of diabetic vascular complications than glibenclamide.

Role of macrophages in the development of pancreatic islet injury in spontaneously diabetic torii rats.

Spontaneously diabetic Torii (SDT) rats were established from Sprague-Dawley (SD) rat and are used as an animal model of type 2 diabetes mellitus. In the present study, the mechanism of the development of injury in the pancreas of these rats was examined focusing on the role of monocytes/macrophages. The number of lymphocytes and monocytes in the circulation of SDT rats increased with age, reaching a plateau at around 9 weeks of age and remaining at that level thereafter. The number of leukocytes in SDT rats was almost twice that of wild-type SD rats. Serum IL-18 levels began to increase at 8 weeks of age, forming a prominent peak at 9 weeks of age. In parallel with this, serum levels of NO2/NO3 showed an abrupt rise and decline. Spleen cells prepared from 9-week-old SDT rats expressed high levels of IFN-gamma in response to IL-18, while those from 9-week-old wild-type SD rats did not. Immunohistochemical analysis revealed marked infiltration of CD68+ cells in the islets of SDT rats. Treatment of SDT rats with Cl2MDP-liposomes reduced the number of monocytes as well as levels of NO2/NO3 in the circulation. Consistent with this, the number of infiltrated CD68+ cells in the islets was reduced in SDT rats treated with Cl2MDP-liposomes. These results suggest that macrophages are involved in pancreatic islet injury in SDT rats through excess production of NO induced by IL-18 which increases transitorily at around 9 weeks of age.