Urinary C-peptide Immunoreactivity Research Articles

The effects of endurance physical exercise with fat-free milk intake as a therapy for metabolic syndrome and/or sarcopenia

Background: Nutrition and exercise are important factors for addressing metabolic syndrome and sarcopenia as they are related to insulin secretion. Proteins, particularly branched-chain amino acids (BCAAs), have insulinotropic effects, while exercise reduces insulin secretion. It is thus important to investigate the effects of protein intake and exercise alone and in combination to determine suitable dietary and exercise therapies for treating metabolic syndrome and sarcopenia. Methods: Eight healthy young adult female volunteers participated in a crossover trial consisting of two 5-day experiments. Days 1 and 2 comprised a body-weight-maintained adjustment period during which the participants consumed control diets (energy, 2,010 kcal; protein, 51.9 g). Days 3 to 5 comprised the treatment period during which the participants consumed experimental diets (energy, 2,010 kcal; protein 82.3 g) containing 402 kcal of fat-free milk, and either performed only normal daily activities (non-Ex) or performed normal daily activities and exercised on a bicycle with an ergometer at a target intensity of about 50% of the maximal oxygen intake, expending 402 kcal of additional energy (Ex). Total urine samples were collected during the daytime (6:45 to 18:45) and nighttime (18:45 to 6:45 the next morning). Fasting blood samples were collected early in the morning before and after the treatment period. Results: Plasma valine, leucine, and BCAA levels were significantly elevated after both the non-Ex and Ex periods. Serum insulin levels were significantly elevated only after the non-Ex period. Urinary C-peptide immunoreactivity excretion levels increased significantly during the non-Ex period, but they decreased significantly during the Ex period. After the Ex period, the serum triglyceride and remnant lipoprotein-cholesterol (RLP-C) levels were significantly decreased. Homeostatic model assessment for insulin resistance (HOMA-IR) and atherosclerosis index (AI) values were slightly, yet significantly, increased after the non-Ex period, but were unchanged after the Ex period. The degree of change (Δ) in the RLP-C level significantly and positively correlated with the Δ HOMA-IR and Δ AI.

1553-P: Postprandial C-Peptide–to–Glucose Ratio Is Valuable in Assessing Beta-Cell Function in Japanese Patients with Type 2 Diabetes

Onset of type 2 diabetes (T2D) is based on the insulin secretion (loss of β-cell function) and resistance. Residual β-cell function is a key factor in achieving optimal glycemic control in T2D patients. Glucagon stimulates insulin, therefore glucagon stimulation test (GST) is a reliable marker for β-cell function. Fasting C-peptide (CPR) to glucose ratio (CPR[ng/ml] to glucose[mg/dl] x100; F-CPR-index) is used as a marker of insulin secretion. We evaluated the efficacy of postprandial CPR to glucose ratio (P-CPR-index) for evaluating β-cell function in T2D. Japanese T2D patients with inadequate glycemic control (HbA1c>7.0) were enrolled in the study (n=500, insulin therapy=283). HbA1c, fasting CPR and glucose, postprandial (120 min after breakfast) CPR and glucose were measured, and F-CPR-index and P-CPR-index were calculated. GST was performed as follows: 1mg of glucagon was injected intravenously, CPR was determined before and 6 min after injection, GSTΔCPR (CPR[6 min] - CPR[0 min]) was calculated. Factors correlated with GSTΔCPR were analyzed using simple and multiple stepwise regression analysis. P value<0.05 was defined as statistically different. F-CPR-index, P-CPR-index and GSTΔCPR were 1.60±0.95, 2.67±1.92 and 1.93±1.21, respectively. Simple regression analysis showed that GSTΔCPR was significantly correlated with age, height, body weight (BW), BMI, waist circumference, duration of diabetes, retinopathy, insulin therapy, urinary CPR, F-CPR-index and P-CPR-index. Multiple stepwise regression analysis revealed that independent factors contributing to GSTΔCPR were BW (β=0.336), duration of diabetes (β= −0.107), presence of retinopathy (β= −0.121), use of DPP-4i (β= −0.099), metformin (β= −0.109), SGLT2i (β= −0.108, p=0.002) and P-CPR-index (β=0.432)(R2=0.453). Our date demonstrated that P-CPR-index was valuable and simple method in assessing residual β-cell function with/without insulin therapy in daily clinical practice. Disclosure Y.Matsuhashi: None. T.Abe: None. T.Fujita: None. S.Mizushiri: None. S.Chikazawa: None. M.Daimon: None.

Glucagon Test Is a Useful Predictor of Withdrawal From Insulin Therapy in Subjects With Type 2 Diabetes Mellitus.

There are many tests for evaluating endogenous insulin secretory capacity. However, there are only a limited number of studies that have examined in detail in clinical practice which method most accurately reflects the ability to secrete endogenous insulin especially in hyperglycemic state. The purpose of this study was to find the endogenous insulin secretory capacity and a possible predictor of insulin withdrawal in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia. In the endogenous insulin secretory test during hospitalization, CPR, CPR index, and ΔCPR after glucagon loading were all significantly higher in the insulin withdrawal group. On the other hand, there were no difference in fasting CPR index, HOMA-β, SUIT, and 24-hour urinary CPR excretion between the two groups. In the glucagon test of the insulin withdrawal group, the cutoff value of ΔCPR was 1.0 ng/mL, the withdrawal rate of ΔCPR of 1.0 ng/mL or more was 69.2%, and the withdrawal rate of less than 1.0 ng/mL was 25.0%. In conclusion, it is likely that glucagon test is the most powerful tool for predicting the possibility of insulin withdrawal as well as for evaluating endogenous insulin secretory capacity in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia.

Casual C peptide index: Predicting the subsequent need for insulin therapy in outpatients with type 2 diabetes under primary care.

BackgroundEvaluation of residual beta cell function is indispensable in patients with type 2 diabetes as it informs not only diagnoses but also appropriate treatment modalities. However, there is a lack of convenient biomarkers for residual beta cell function. Therefore, we evaluated endogenous insulin level as a biomarker in outpatients who were being treated with insulin therapy and in patients who were introduced to insulin therapy after 4 years.MethodsData of 174 outpatients with type 2 diabetes (50% male) whose glycemia was moderately controlled (glycated A1c 7.3% [5.2%–14.8%]) were reviewed. Twenty patients whose estimated glomerular filtration rate was lower than 30 ml/min/1.73 m2 were excluded from the evaluation of endogenous insulin level with both casual C‐peptide index (C‐CPI) and urinary C‐peptide/creatinine ratio (determined at any time, generally 1–2 h after breakfast). Patients were stratified based on the provision of insulin therapy.ResultsC‐CPI and UCPCR were significantly lower in the insulin‐treated patients than in the insulin‐untreated patients (0.9 vs. 2.2, p < 0.0001; 24.7 vs. 75.5, p = 0.0003, respectively). Moreover, C‐CPI were significantly lower in the insulin‐requiring patients for 4 years than in the insulin‐unrequiring patients (1.0 vs. 1.7, p = 0.0184). The multivariate logistic regression analysis revealed that both indicators of insulin secretion influenced the requirement for insulin therapy, but C‐CPI could serve as the most convenient and useful biomarker for not only current insulin therapy requirements (p = 0.0002) but also the subsequent requirement for insulin therapy (p = 0.0008).ConclusionsC‐CPI could be determined easily, and it was found to be a more practical marker for outpatients; therefore, our findings would have critical implications for primary care.

Clinical Utility of the Meal Tolerance Test in the Care of Patients with Type 2 Diabetes Mellitus.

Objective The measurement of C-peptide immunoreactivity (CPR) is essential for evaluating the pancreatic β-cell function and selecting appropriate therapeutic agents in patients with diabetes mellitus. The meal tolerance test (MTT) is simple to administer physiological insulin-stimulating test. Previous studies have reported that several CPR-related indices are useful markers for predicting insulin requirement in type 2 diabetes. In the present study, we investigated the serum CPR response during the MTT in hospitalized patients with type 2 diabetes mellitus in order to clarify the clinical utility of the MTT. Methods We performed the MTT using a test meal with timed measurements of the serum CPR level based on the oral glucose tolerance test over 180 minutes and tested the correlation of various CPR-related indices and clinical factors in patients with type 2 diabetes mellitus. Patients The subjects were patients with type 2 diabetes mellitus who had been admitted to our hospital for diabetes management and education. The final study population consisted of 68 patients. Results The fasting CPR level was correlated with the 24-hour urinary CPR excretion and body mass index. The serum CPR level at 120 minutes in the MTT was strongly correlated with the area under the curve of CPR during the MTT. The patients who needed insulin therapy at 6 months after hospitalization showed a significant lower incremental CPR value from 0 to 120 minutes in the MTT than those who did not need insulin therapy. Conclusion The plasma C-peptide levels at 0 and 120 minutes in the MTT provide essential information for the clinical management of patients with type 2 diabetes mellitus.

THE PROGNOSTIC IMPACT OF METABOLIC SYNDROME IN PATIENTS WITH TYPE 2 DIABETES

Objective: Metabolic syndrome (Met S) is involved in the development of cardiovascular disease by promoting arteriosclerosis. In recent years, it is reported that obesity is related to an increase in the risk of malignant tumors. We examined the prognostic impact of metabolic syndrome in patients with type 2 diabetes by 8-year follow-up. Design and method: Seventy-one patients with type 2 diabetes without antihypertensive drugs (47 men, age 50 (mean) years-old) were recruited. Patients with a history of cardiac and cerebrovascular disease, and with chronic kidney disease were excluded. In the echocardiogram, left ventricular inner diameter was measured and left ventricular mass and function (FS and A/E) were calculated. Visceral fat area and subcutaneous fat area were measured using a CT scan of the navel region, and adipocytokines and fasting IRI and 24 hour urine CPR were measured. The end point was an onset of cardiac disease, cerebrovascular disease, malignant tumors event. Results: Fourty-four patients were Met S. The average follow-up period was 6.6 years and the follow-up rate was 94%. In the Met S group, 12 patients (29%) had end point events, 6 cardiac disease, 3 cerebrovascular disease, 3 malignant tumors. In the non-Met S group, 2 patients (7%) had the events, cardiovascular disease and malignant tumors. In Kaplan-Meier survival analysis, the incidence rates in the Met S group significantly increased compared to the non Met S group (p < 0.05). When cardiac disease and cerebrovascular disease were combined, the incidence rate was higher in the Met S group than the non Met S group (p < 0.05). In Cox regression analysis, the presence of Met S, decreased eGFR were independent risk factors of the onset of the total event (p < 0.05). And decreased eGFR and decreased E / A were independent risk factors of the onset of cardiac and cerebrovascular disease (p < 0.05). Conclusions: It was suggested that Met S induced worsening of prognosis in patients with Type 2 diabetes mellitus compared to those without Met S in total events including malignant tumors as well as arteriosclerotic diseases.

2351-PUB: Influence of Short-Term Improvements in Glycemic Control with Intensive Insulin Therapy on Pancreatic a-Cell Function and the Relationship between Concurrent SGLT2 Inhibitor Therapy and Insulin Withdrawal

Objective: We investigated the relationship between insulin withdrawal (IW), endogenous insulin recovery, and concurrent SGLT2 inhibitor (SGLT2i) therapy. Patients and Methods: Of the 78 type 2 diabetic patients admitted for glycemic control and subjected to meal tolerance tests (MTT) on the next day after admission and immediately before discharge using the same diabetes diet while off treatment, 39 patients who had received intensive insulin therapy after admission were subjected to retrospective analysis. Of these, 26 patients in whom insulin withdrawal had been achieved during admission were divided into those who had received concurrent SGLT2i therapy (n=19) and those who had not (n=7). Insulin secretion in terms of ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2 h during the MTT was compared at admission and discharge. Results: 1) While there was no significant difference between those with IW and those without IW in their age, BMI, HbA1c, C-peptide index and urinary CPR excretion at admission, significantly more patients with IW had received SGLT2i than those without IW (P &amp;lt; 0.001). Again, ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2 h were significantly (p&amp;lt;0.001) increased in those with IW but not in those without IW. 2) In those with IW, while ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2 h were significantly (p&amp;lt;0.05) increased in both of those with SGLT2i and those without, the time to IW was shown to be significantly shorter (p&amp;lt;0.01), the maximum daily insulin dose lower, and the duration of hospital stay shorter, in those with SGLT2i therapy than in those without. Conclusions: Study results confirmed that endogenous insulin secretion was significantly restored in those with IW and that the time to IW was significantly shorter in those with concurrent SGLT2i therapy than in those without, suggesting a role for SGLT2i in achieving IW. Disclosure M. Matsui: None. H. Takahashi: None. S. Sawano: None. Y. Mori: None. K. Utsunomiya: None.

1214-P: Effect of Short-Term Improvements in Glycemic Control with SGLT2 Inhibitor Therapy on Insulin and Glucagon Secretion: How Does It Differ With or Without Concurrent DPP-4 Inhibitor Therapy

Objective: We investigated the effect of short-term improvements in glycemic control with SGLT2i therapy on insulin and glucagon secretion with or without concurrent DPP-4 inhibitor (DPP-4i) therapy. Patients and Methods: 78 type 2 diabetic patients admitted for glycemic control and subjected to meal tolerance tests (MTT) on the next day after admission and immediately before discharge using the same diabetes diet while off treatment were subjected to retrospective analysis. Of these, 41 patients were found to have received SGLT2i after admission, with 15 of these also found to have received concurrent DPP-4i. The patients were divided into those not receiving SGLT2i (n=37), those receiving SGLT2i without concurrent DPP-4i (n=26) and those receiving SGLT2i with DPP-4i (n=15) and were compared for changes in postprandial insulin and glucagon secretion. All patients were evaluated at admission and discharge for insulin secretion in terms of ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2h, and as well as for glucagon (G) secretion in terms of ΔG/ΔPG 0-30 min and AUC-G 0-2h during the MTT. Results: There was no significant difference between the 3 groups in their HbA1c, C-peptide index, and urinary CPR excretion at admission. With improvements in glycemic control, ΔCPR/ΔPG 0-30min and AUC-CPR 0-2h were significantly increased, and AUC-PG 0-2h were significantly decreased, in all groups. Again, with improvements in glycemic control, AUC-G 0-2h was significantly decreased in those not receiving SGLT2i, increased in those receiving SGLT2i without DPP-4i, and decreased in those receiving both SGLT2i and DPP-4i. Conclusions: Postprandial insulin secretion was shown to be restored after short-term improvements in glycemic control irrespective of SGLT2i or concurrent DPP-4i, while glucagon secretion was shown to be increased with SGLT2i without DPP-4i but decreased with combined SGLT2i and DPP-4i. Disclosure M. Matsui: None. H. Takahashi: None. S. Sawano: None. Y. Mori: None. K. Utsunomiya: None.

Characteristics and clinical course of type 1 diabetes mellitus related to anti-programmed cell death-1 therapy.

We conducted a national survey to clarify the characteristics and clinical course of type 1 diabetes related to anti-programmed cell death-1 therapy. We analyzed the detailed data of 22 patients that were collected using a Japan Diabetes Society survey and a literature database search. Among the 22 patients, 11 (50.0%) met the criteria for fulminant type 1 diabetes and 11 (50.0%) met the criteria for acute-onset type 1 diabetes. The average patient age was 63years. The mean duration between the date of the first anti-PD-1 antibody injection and development of type 1 diabetes was 155days and ranged from 13 to 504days. Flu-like symptoms, abdominal symptoms, and drowsiness were observed in 27.8, 31.6, and 16.7% patients, respectively. Mean ±standard deviation or median (first quartile-third quartile)glucose levels, HbA1c levels, urinary C-peptide immunoreactivity levels, and fasting serum C-peptide immunoreactivity levels were 617 ± 248mg/dl, 8.1 ± 1.3%, 4.1 (1.4-9.4) μg/day, and 0.46 (0.20-0.70) ng/ml, respectively. Seventeen of 20 patients (85.0%) developed ketosis, and 7 of 18 patients (38.9%) developed diabetic ketoacidosis. Ten of 19 patients (52.6%) showed at least one elevated pancreatic enzyme level at the onset and two of seven patients showed this elevation before diabetes onset. Only one of 21 patients was anti-glutamic acid decarboxylase antibody positive. Anti-programmed cell death-1 antibody-related type 1 diabetes varies from typical fulminant type 1 diabetes to acute-onset type 1 diabetes. However, diabetic ketoacidosis was frequently observed at the onset of diabetes. An appropriate diagnosis and treatment should be provided to avoid life-threatening metabolic alterations.

Clinical, Endocrinological and Immunological Characteristics of Japanese Patients With Autoimmune Polyglandular Syndrome Type 3a

Background: Autoimmune polyglandular syndrome (APS) is an autoimmune disease that involves multiple organ failure. In APS3, autoimmune thyroid disease occurs with other autoimmune diseases, but not with Addison disease. APS3a is defined as APS3 including autoimmune diabetes. The information about clinical backgrounds of APS3a is very limited. We studied to understand clinical, endocrinological and immunological characteristics of Japanese patients with APS3a. Methods: We reviewed our previously published case reports about APS3a, and picked up patients with type 1 diabetes and autoimmune diabetes, who showed the positivity for anti-glutamic acid decarboxylase antibody (anti-GAD ab) or anti-islet antigen 2 antibody (anti-IA2 ab) or anti-thyroglobulin antibody (anti-TG ab) or anti-thyroid peroxidase antibody (anti-TPO ab) or anti-thyroid stimulating hormone receptor antibody (anti-TR ab) between January 2010 and January 2016. We collected data including age, sex, anti-GAD ab, anti-IA2 ab, HbA1c, serum fasting C-peptide immunoreactivity (CPR), urinary CPR, treatment for diabetes, anti-TPO ab, anti-TG ab, anti-TR ab, thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), findings of thyroid ultrasonography and treatment for thyroid diseases. Results: Present study revealed a remarkable female predominance in APS3a. Among patients with autoimmune diabetes, slowly progressive insulin-dependent diabetes mellitus (SPIDDM) was the most common type of diabetes, and almost 80% of patients with APS3a showed the positivity for anti-GAD ab. Among patients with autoimmune thyroid diseases, almost 80% of patients had possible Hashimoto thyroiditis. Almost 70% of patients with APS3a showed the positivity for anti-TPO ab. Almost 20% of APS3a patients had possible Grave’s disease, and 83% of patients with possible Grave’s disease showed overt Grave’s disease. In patients with possible Grave’s disease, the positive rate of anti-TR ab was 100%. Conclusion: We revealed clinical, endocrinological and immunological characteristics of patients with APS3a in Japan. J Endocrinol Metab. 2016;6(2):46-51 doi: http://dx.doi.org/10.14740/jem348e

C-Peptide Level in Fasting Plasma and Pooled Urine Predicts HbA1c after Hospitalization in Patients with Type 2 Diabetes Mellitus.

In this study, we investigate how measures of insulin secretion and other clinical information affect long-term glycemic control in patients with type 2 diabetes mellitus. Between October 2012 and June 2014, we monitored 202 diabetes patients who were admitted to the hospital of Asahi Life Foundation for glycemic control, as well as for training and education in diabetes management. We measured glycated hemoglobin (HbA1c) six months after discharge to assess disease management. In univariate analysis, fasting plasma C-peptide immunoreactivity (F-CPR) and pooled urine CPR (U-CPR) were significantly associated with HbA1c, in contrast to ΔCPR and C-peptide index (CPI). This association was strongly independent of most other patient variables. In exploratory factor analysis, five underlying factors, namely insulin resistance, aging, sex differences, insulin secretion, and glycemic control, represented patient characteristics. In particular, insulin secretion and resistance strongly influenced F-CPR, while insulin secretion affected U-CPR. In conclusion, the data indicate that among patients with type 2 diabetes mellitus, F-CPR and U-CPR may predict improved glycemic control six months after hospitalization.

Relationships between the duration of illness and the current status of diabetes in elderly patients with type 2 diabetes mellitus.

The aim of the present study was to clarify the relationships between the duration of diabetes and the current statuses of diabetes in elderly (aged ≥65 years) patients with type 2 diabetes. Clinical characteristics were cross-sectionally examined in 1436 patients (684 elderly and 752 non-elderly) with type 2 diabetes. As the duration of diabetes increased, the patients' age, frequency of receiving insulin therapy and glycated hemoglobin value increased in both the elderly and non-elderly groups, whereas the urinary C-peptide immunoreactivity and glomerular filtration rate decreased. The duration of diabetes (years) was significantly associated with the prevalence of diabetic retinopathy (OR 1.05, 95% CI 1.03-1.07, P < 0.01), nephropathy (OR 1.03, 95% CI 1.01-1.05, P < 0.01) and neuropathy (OR 1.08, 95% CI 1.05-1.12, P < 0.01), but not with cerebrovascular disease (OR 1.01, 95% CI 0.99-1.03, P = 0.38), coronary heart disease (OR 1.02, 95% CI 1.00-1.04, P = 0.09) or peripheral artery disease (OR 1.02, 95%CI 0.99-1.05, P = 0.12) in the elderly patients after adjusting for the traditional risk factors of diabetic angiopathies. In contrast, the duration of diabetes showed a significant association with the prevalence of both diabetic micro- and macroangiopathies in the non-elderly patients. It should be noted that atherosclerotic diseases are present in the clinical setting for the management of elderly diabetic patients independent of the duration of diabetes. Geriatr Gerontol Int 2017; 17: 24-30.

Reduction in Endogenous Insulin Secretion is a Risk Factor of Sarcopenia in Men with Type 2 Diabetes Mellitus.

Sarcopenia has recently attracted widespread attention, because it increases risks of fall and bedridden. Although patients with type 2 diabetes mellitus (T2DM) are known to have lower muscle mass of limbs than healthy people, the mechanism is still unclear. We thus examined the association of muscle mass with parameters of endogenous insulin secretion such as fasting immunoreactive insulin, fasting C-peptide immunoreactivity (CPR), and daily urine CPR in 191 men with T2DM. Muscle mass of arms and legs was evaluated by dual-energy X-ray absorptiometry, and we calculated relative skeletal muscle index (RSMI), which is useful for the diagnosis of sarcopenia. Multiple regression analyses adjusted for age, duration of T2DM, serum creatinine, HbA1c, and insulin-like growth factor-I showed that each parameter of endogenous insulin was significantly and positively correlated with muscle mass of arms and legs as well as RSMI (p < 0.05). Moreover, logistic regression analyses adjusted for confounding factors mentioned above showed that each parameter of endogenous insulin was significantly lower in subjects with sarcopenia than those without it (p < 0.05). In conclusion, reduction in endogenous insulin secretion is an independent risk factor of sarcopenia in men with T2DM.

Effect of Alogliptin, a DPP-4 Inhibitor, on Markers of Lipid Metabolism in Type 2 Diabetic Patients

Background: DPP-4 inhibitor has been shown to improve not only blood glucose levels but also dyslipidemia, but the effect remains controversial. Further, there are few reports regarding the influence on Apo B, Apo A-1 and Apo B/Apo A-1 in alogliptin. Objective: Using the alogliptin, we focused on Apo B and Apo A-1, in addition to LDL-C, HDL-C and TG, and investigated the effect of alogliptin on markers predicting cardiovascular events, such as Apo B/Apo A-1 and LDL-C/Apo B. Methods: This study was carried out with a single arm in an open label manner. 45 consecutive cases that could enroll between September 2011 and March 2012 were selected as the subjects for randomization. Alogliptin 25 mg/day was administered for eight weeks and non-fasting blood samples were collected 2-3 hours after breakfast, once at the beginning of the study and once eight weeks later, and changes in glucose and lipid metabolism markers were compared. Results: Administration of alogliptin significantly reduced HbA1c levels and non-fasting blood glucose levels, and reduced LDL-C and non-fasting TG. Apo B was significantly reduced by alogliptin treatment but Apo A-1 was unchanged. The Apo B/Apo A-1 ratio was significantly decreased and the LDL-C/Apo B ratio significantly increased by alogliptin treatment. The change in the pre-administration Apo B/Apo A-1 ratio was positively correlated with body weight, TG, HbA1c, blood CPR and pooled urine CPR and negatively correlated with HDL-C Conclusion: Administration of alogliptin in type 2 diabetic patients significantly improved levels of blood glucose, in addition to those of lipid metabolism markers such as LDL-C and non-fasting TG, as well as sensitive predictive markers for the onset risk of cardiovascular events, such as the Apo B/Apo A-1 ratio and the LDL-C/Apo B ratio. These results suggest that alogliptin could potentially suppress atherosclerosis and prevent cardiovascular events (UMIN 000011470).

Walking for exercise brings acute decreasing effects on urinary C‐peptide immunoreactivity (CPR) excretion (LB436)

Although it is well known that hyperinsulinemia is improved by exercise, insulin secretion volume has not been examined in detail. We investigated the effects of walking exercise on urinary C‐peptide immunoreactivity (CPR) excretion levels. Methods: In trial 1, six adult female volunteers participated in four experiments over 24 hours. The participants performed either only normal daily activities or walking programs at the speed of 6 km/h for 60 or 120 or 180 min/day. Total urine samples for 12 hours were collected during day (8am to 8pm) and night (8pm to 8am) after the second morning (6am to 8am) urine collection. In trial 2, similar experiments were carried out and urine samples after 8am were collected every four hours until 8pm. Results: In trial 1, urinary CPR excretion levels during day were significantly lower in 120 and 180 min walking than in non‐walking experiment. Similarly in trial 2, urinary CPR excretion levels were significantly lower in 120 and 180 min walking experiment at all times between 8am and 8 pm. Urinary adrenaline, noradrenaline and free cortisol excretion levels during 4 experiments did not significantly differ. In both trials, further effects of 180 min walking on urinary CPR excretion levels were not obtained. Conclusions: Walking at 6 km/h for more than 2 hours decreases urinary CPR excretion levels without increasing physical stress.Grant Funding Source: a grant from Kanto Gakuin University

Association between beta cell function and future glycemic control in patients with type 2 diabetes

The aim of this study was to clarify the association between C-peptide immunoreactivity (CPR), a marker of beta cell function, and future glycemic control in patients with type 2 diabetes. We conducted a retrospective analysis of 513 consecutive patients with type 2 diabetes who were admitted to our hospital between 2000 and 2007 and followed up for 2 years. Serum and urinary CPR levels were measured during admission, and CPR index was calculated as the ratio of CPR to plasma glucose. The associations between these markers at baseline and glycemic control after 2 years were assessed by means of logistic regression models. After 2 years, 167 patients (32.6%) showed good glycemic control (HbA1c <6.9%). Baseline serum and urinary CPR indices were significantly associated with good glycemic control after 2 years, and the postprandial CPR to plasma glucose ratio (postprandial CPR index) showed the strongest association (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.12-1.50, P = 0.001) among CPR indices. Multivariate analyses showed consistent results (OR 1.23, 95%CI 1.03-1.48, P = 0.021). In conclusion, preserved beta cell function at baseline was associated with better glycemic control thereafter in patients with type 2 diabetes.

Postprandial serum C-peptide to plasma glucose ratio predicts future insulin therapy in Japanese patients with type 2 diabetes

Type 2 diabetes is a progressive disease, and most patients with type 2 diabetes eventually need insulin therapy to maintain glycemic control. Recent studies have shown that early insulin treatment improved beta cell function as well as insulin resistance in patients with type 2 diabetes[1], suggesting that early introduction of insulin treatment may delay disease progression and be able to maintain good glycemic control thereafter. However, since predictive biomarkers for future insulin therapy have not been established, the introduction of insulin treatment is often delayed in clinical settings [2]. We have recently reported that lower 2 h postprandial C-peptide immunoreactivity (CPR) to plasma glucose ratio (postprandial CPR index; PCPRI) was associated with subsequent need for insulin treatment in Japanese subjects with type 2 diabetes who were admitted to our hospital between 2000 and 2007 [3]. In that study, however, since most patients were started on insulin treatment during the baseline admission, the time-to-event relationship of insulin initiation could not be accounted for in the analysis. Here, we report a sub analysis of this cohort in whom insulin therapy had not been introduced at baseline (N = 190), to establish the predictive value of PCPRI for future insulin therapy using univariate and multivariate Cox proportional hazard models. In addition, the prognostic performance of PCPRI was estimated using receiver operating characteristic (ROC) curve analysis. Baseline characteristics of the subjects were as follows; male 57.9 %, age 65 ± 13 years (mean ± SD), duration of diabetes 10 ± 9 years, BMI 25.3 ± 4.7, HbA1c 9.5 ± 1.8 % (80 ± 20 mmol/mol), fasting CPR 2.14 ± 0.95 ng/ml, fasting CPRI 1.56 ± 0.74, PCPR 5.62 ± 2.59 ng/ml, PCPRI 2.72 ± 1.62 and urinary CPR 78.4 ± 54.7 lg/day. Of the subjects, 52.1 % were treated with a sulfonylurea at baseline. During the observation period (mean 4.2 ± 2.3 years, median 3.0 years), insulin therapy was introduced in 34 subjects (18 %). Higher PCPRI at baseline was associated with a lower risk of future insulin therapy (hazard ratio (HR) for 1 unit increase in PCPRI was 0.48, 95 % CI: 0.32 to 0.73, P \ 0.001). However, neither fasting CPRI nor urinary CPR predicted future insulin therapy (P = 0.30 and P = 0.72, respectively). After adjustment for age, sex, duration of diabetes, family history of diabetes, BMI, HbA1c and sulfonylurea use at baseline, PCPRI remained an independent predictor of future insulin therapy (HR = 0.42, 95 % CI: 0.25 to 0.70, P = 0.001). The optimal cutoff value of PCPRI for predicting insulin therapy was 2.16, with 70.6 % sensitivity and 64.1 % specificity (area under the curve (AUC) of ROC curve = 0.698, 95 % CI: 0.609 to 0.788, P \ 0.001). In the present study, PCPRI predicted future insulin therapy in patients with type 2 diabetes. Interestingly, neither fasting CPR index nor urinary CPR was significantly associated with future insulin therapy, suggesting that PCPRI is the superior marker for future insulin therapy Communicated by Renato Lauro.

Analysis of clinical factors contributing to the postglucagon increment in C-peptide levels in Japanese patients with type 2 diabetes: comparison with basal C-peptide levels and 24-h urinary C-peptide excretion

We investigated the clinical factors that affected routine laboratory tests of C-peptide levels (CPR) used for the evaluation of β-cell function in Japanese patients with type 2 diabetes. The study subjects were 215 Japanese patients with type 2 diabetes admitted to Juntendo University Hospital just for glycemic control. β-cell function was evaluated by ΔCPR (6-min postglucagon increment in CPR), CPR index (100 × fasting CPR divided by fasting glucose), and 24-h urinary CPR excretion (U-CPR). Stepwise multiple regression analyses of relationships between clinical parameters and these laboratory tests were carried out. The analysis identified BMI and treatment with insulin before admission, but not glycosylated hemoglobin at admission, as independent determinants of all β-cell function tests [BMI: Stdβ (standard regression coefficient) = 0.337, P < 0.01 for ΔCPR, Stdβ = 0.365, P < 0.01 for CPR index, and Stdβ = 0.207, P < 0.01 for U-CPR, and treatment with insulin before admission: Stdβ = −0.141, P = 0.023 for ΔCPR, Stdβ = −0.285, P < 0.01 for CPR index, and Stdβ = −0.258, P < 0.01 for U-CPR]. The estimated glomerular filtration rate (eGFR) was an independent determinant of U-CPR (Stdβ = 0.145, P = 0.023), but not ΔCPR. In conclusion, ΔCPR evaluates β-cell function without being affected by eGFR and glycemic control over the preceding 2–3 months.

Clinical heterogeneity of adult Japanese diabetes depending on titers of glutamic acid decarboxylase autoantibodies

Aims/Introduction: We examined whether levels of glutamic acid decarboxylase autoantibodies (GADAb) might show the clinical heterogeneity of adult Japanese diabetes. In this cross-sectional study, the serum levels of GADAb were measured in a total of 1857 consecutive adult diabetic patients aged 20 years or older. The patients with positive GADAb, arbitrarily defined as ≥1.5 U/mL, were divided into quartiles according to the number of patients. The age- and sex-matched diabetic patients without GADAb were selected as a control group. A total of 103 (5.5%) of the diabetic patients had GADAb, and showed higher HbA1c and serum high-density lipoprotein (HDL) cholesterol levels, lower body mass index (BMI), urinary C-peptide immunoreactivity (CPR), serum triglycerides (TG) and uric acid (UA) levels, and lower prevalence of metabolic syndrome than the control group (P < 0.05). Quartiles 3 and 4 (i.e. GADAb ≥4.6 U/mL) showed a higher HbA1c level, lower BMI, urinary CPR, serum TG and UA levels, quartile 2 (2.5 ≤ GADAb < 4.6 U/mL) showed a lower BMI level than the control group (P < 0.05). Among the clinical parameters, we observed significant upward trends for both HbA1c and serum HDL cholesterol levels, and significant downward trends for BMI, serum TG and UA, urinary CPR levels, and prevalence of metabolic syndrome across GADAb quartiles (P < 0.05 for trend). These results show that the clinical phenotype of adult Japanese diabetes correlates with GADAb levels, and that patients with GADAb (≥2.5 U/mL) show different characteristics from those without GADAb, although further longitudinal studies are required. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00190.x, 2011).

The lack of long-range negative correlations in glucose dynamics is associated with worse glucose control in patients with diabetes mellitus

Glucose dynamics measured in ambulatory settings are fluid in nature and exhibit substantial complexity. We recently showed that a long-range negative correlation of glucose dynamics, which is considered to reflect blood glucose controllability over a substantial period, is absent in patients with diabetes mellitus. This was demonstrated using detrended fluctuation analysis (DFA), a modified random-walk analysis method for the detection of long-range correlations. In the present study, we further assessed the relationships between the established clinical indices of glycemic or insulinogenic control of hemoglobin A1c (HbA1c), glycated albumin (GA), 1,5-anhydroglucitol, and urine C-peptide immunoreactivity and the recently proposed DFA-based indices obtained from continuous glucose monitoring in 104 Japanese diabetic patients. Significant correlations between the following parameters were observed: (1) HbA1c and the long-range scaling exponent α2 (r = 0.236, P < .05), (2) GA and α2 (r = 0.254, P < .05), (3) GA and the short-range scaling exponent α1 (r = 0.233, P < .05), and (4) urine C-peptide immunoreactivity and the mean glucose fluctuations (r = −0.294, P < .01). Therefore, we concluded that increases in the long-range DFA scaling exponent, which are indicative of the lack of a long-range negative correlation in glucose dynamics, reflected abnormalities in average glycemic control as clinically determined using HbA1c and GA parameters.