Postabsorptive hyperglucagonemia in patients with type 2 diabetes mellitus analyzed with a novel enzyme-linked immunosorbent assay.

AIMS/INTRODUCTION: The aims of the present study were to investigate the performance of a novel sandwich enzyme-linked immunosorbent assay (ELISA) for measuring glucagon (1-29) with monoclonal antibodies against both the C- and N-terminal regions of glucagon (1-29), and to analyze the differences in plasma levels and responses of glucagon (1-29) to oral glucose loading in normal glucose tolerance (NGT) subjects and patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The cross-reactivity against proglucagon fragments using the ELISA kit and two types of conventional radioimmunoassay (RIA) kits was evaluated. A 75-g oral glucose tolerance test was carried out with NGT subjects and patients with type 2 diabetes mellitus, and the glucagon (1-29) concentration was measured using three types of kit. RESULTS: The ELISA kit clearly had the lowest cross-reactivity against miniglucagon (19-29) and glicentin (1-61). The oral glucose tolerance test was carried out with 30 NGT and 17 patients with type 2 diabetes mellitus. The glucagon (1-29) levels measured by the ELISA kit after glucose loading were significantly higher at all time-points in the type 2 diabetes mellitus group than in the NGT group. However, the glucagon (1-29) levels measured by one RIA kit were significantly higher in the NGT group, and those measured with the other RIA kit were approximately the same among the groups. CONCLUSIONS: The novel sandwich ELISA accurately determines plasma glucagon (1-29) concentrations with much less cross-reactivity against other proglucagon fragments than conventional RIA kits.

Insulin resistance and ß-cell function influence postprandial blood glucose levels in Japanese patients with gestational diabetes mellitus.

AIMS/INTRODUCTION: The aim of this study in patients with gestational diabetes mellitus (GDM) was to evaluate the relationship of insulin resistance and secretion to area-under-the-sensor glucose concentration-time curve from before to 120 min postmeal (CGM-AUC(0-120 min)) as determined with continuous glucose monitoring (CGM). MATERIALS AND METHODS: Immunoreactive insulin and HbA1c were determined in 22 Japanese patients with GDM undergoing a 75 g oral glucose tolerance test. Patients underwent CGM within 3 weeks of receiving a diagnosis of GDM. RESULTS: HbA1c (NGSP) was 5.5 ± 0.4%, BMI was 24.8 ± 5.3 kg/m(2), mean sensor glucose by CGM was 94.2 ± 10.3 mg/dL, standard deviation was 17.5 ± 4.4 mg/dL, and CGM-AUC(0-120 min) was 204.2 ± 23.8 h mg/dL. The insulin resistance indices the homeostasis model assessment ratio (HOMA-R), quantitative insulin sensitivity check index (QUICKI), and the Matsuda Index were correlated with CGM-AUC(0-120 min). The disposition index (DI), which was used to evaluate insulin secretion, was negatively correlated with CGM-AUC(0-120 min). CONCLUSIONS: Not only insulin resistance but also beta cell dysfunction contributes to postprandial hyperglycemia in Japanese patients with GDM.

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.

Evaluation of blood glucose fluctuation in Japanese patients with type 1 diabetes mellitus by self-monitoring of blood glucose and continuous glucose monitoring.

AIMS: Accurate assessment of blood glucose fluctuation is essential for managing blood glucose control while avoiding hypoglycemia in patients with diabetes mellitus. In this study, blood glucose was measured by continuous glucose monitoring (CGM) in patients with type 1 diabetes mellitus (T1DM) whom self-monitoring of blood glucose (SMBG) was carried out three or more times per day, and evaluation was performed using blood glucose fluctuation parameters obtained by CGM and SMBG. METHODS: Twenty-nine insulin-depleted patients with T1DM were enrolled. Their blood glucose fluctuations were measured at the same time by SMBG and CGM, and the correlations were evaluated. RESULTS: Correlations were found between the following values obtained by SMBG and CGM: mean and standard deviation of blood glucose levels, average daily risk range, Morbus value and high-blood-glucose index. The hypoglycemia duration and the nocturnal hypoglycemia duration showed no correlation with any of the blood glucose fluctuation parameters obtained by SMBG. CONCLUSIONS: The findings suggest that routine SMBG and glycated hemoglobin (HbA1c) measurement are sufficient for evaluation of hyperglycemia in T1DM. On the other hand, blood glucose fluctuation parameters obtained by SMBG and HbA1c have been shown to have no correlations with either hypoglycemia duration or nocturnal hypoglycemia duration.

Very short-term effects of the dipeptidyl peptidase-4 inhibitor sitagliptin on the secretion of insulin, glucagon, and incretin hormones in Japanese patients with type 2 diabetes mellitus: analysis of meal tolerance test data.

BACKGROUND: Sitagliptin inhibits dipeptidyl peptidase-4, which inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. To assess its antidiabetic potency, we used meal tolerance tests (MTTs) to determine the very short-term effects of sitagliptin on plasma concentrations of insulin and glucagon. METHODS: On day 1, patients with newly diagnosed or uncontrolled type 2 diabetes mellitus started a calorie-restricted diet. On day 2, the first MTT was performed, before treatment with sitagliptin 50 mg/day started later the same day. On day 5, a second MTT was performed. Area under the concentration-time curves (AUCs) of relevant laboratory values were calculated [AUC from time zero to 2 h (AUC0-2h) and from time zero to 4 h (AUC0-4h)]. RESULTS: Fifteen patients were enrolled. AUCs for postprandial plasma glucose were decreased after 3 days of sitagliptin treatment [AUC0-2h 457 ± 115 mg/dL·h (25.4 ± 6.4 mmol/L·h) to 369 ± 108 mg/dL·h (20.5 ± 6.0 mmol/L·h); AUC0-4h 896 ± 248 mg/dL·h (49.7 ± 13.8 mmol/L·h) to 701 ± 246 mg/dL·h (38.9 ± 13.7 mmol/L·h); both p < 0.001]. AUC0-2h and AUC0-4h for postprandial plasma glucagon also decreased: 195 ± 57 to 180 ± 57 pg/mL·h (p < 0.05) and 376 ± 105 to 349 ± 105 pg/mL·h (p < 0.01), respectively. The AUC0-2h [median with quartile values (25%, 75%)] for active GLP-1 increased: 10.5 (8.5, 15.2) to 26.4 (16.7, 32.4) pmol/L·h (p = 0.03). CONCLUSIONS: Very short-term (3-day) treatment with sitagliptin decreases postprandial plasma glucose significantly. This early reduction in glucose may result partly from suppression of excessive glucagon secretion, through a direct effect on active GLP-1. Improvement in postprandial plasma glucose, through suppression of glucagon secretion, is believed to be an advantage of sitagliptin for the treatment of patients with type 2 diabetes.

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.

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.

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.

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.