Exercise, Dietary Habits, and Defecatory Dysfunction in Patients Living with Colorectal Cancer: A Preliminary Quantitative Study.

This study investigated the association of exercise and dietary habits with defecatory dysfunction in patients living with colorectal cancer. We recruited 61 adult patients who had undergone surgery within the past 20 years and attended outpatient clinics at designated cancer hospitals in Japan. Defecatory dysfunction was defined as any symptom caused by issues with colon and anal function, including fecal incontinence, evacuation difficulties, frequent stools, diarrhea, and constipation. Exercise and dietary habits were assessed via a quantitative questionnaire survey. Postoperative defecatory dysfunction occurred in all the patients. Multivariate analysis revealed no association between exercise habits and defecatory dysfunction; however, dietary fiber intake ≥4 times a week was associated with frequent stools (adjusted odds ratio, 5.11; 95% confidence interval, 1.10, 23.70). These findings suggest a need to alleviate defecatory dysfunction by improving one's dietary habits. Interventions aimed at alleviating defecatory dysfunction by improving the dietary habits in patients living with colorectal cancer are needed.

Home blood pressure is associated with cognitive impairment among elderly patients with type 2 diabetes: KAMOGAWA-HBP study.

BACKGROUND: This cross-sectional study was designed to examine the association between home blood pressure and cognitive impairment in elderly patients with type 2 diabetes. METHODS: Home blood pressure was measured in the morning and evening for 14 consecutive days in 749 patients with type 2 diabetes. A total of 231 patients were included in the study population. Cognitive function was evaluated using the Mini-Cog test, which is used as a screening for cognitive impairment in elderly patients. We performed a logistic regression analysis and measured the area under the receiver operating characteristic curve and estimated home blood pressure as a marker of cognitive impairment. RESULTS: The adjusted odds ratio (95% confidence interval) of evening systolic blood pressure for cognitive impairment was 1.24 (1.02-1.53). Evening systolic blood pressure showed the highest area under the receiver operating characteristic curve for cognitive impairment in both unadjusted and adjusted models. In all subgroup analyses except gender, home blood pressure showed higher area under the receiver operating characteristic curve than clinic blood pressure. CONCLUSION: Home blood pressure was associated with cognitive impairment in elderly patients with type 2 diabetes.

Prognostic significance of home pulse pressure for progression of diabetic nephropathy: KAMOGAWA-HBP study.

Pulse pressure (PP) has been noted as a potential independent risk factor for micro and macrovascular diabetic complications. We aimed to examine the prognostic value of home-measured PP (home PP) in patients with type 2 diabetes. This study is a 2-year prospective cohort study of 737 patients with type 2 diabetes. Home blood pressure measurements were performed for 14 consecutive days. We defined the progression of diabetic nephropathy as when the diabetic nephropathy stage advanced to a higher stage during the 2 years. Using logistic regression analyses, we investigated the relationship between home PP and home systolic blood pressure (SBP) in the morning and in the evening and the progression of diabetic nephropathy. Furthermore, we measured the area under the receiver-operating characteristic curve (AUC) to assess the predictive ability of the progression of diabetic nephropathy of home PP. During the 2-year study, progression of diabetic nephropathy was observed in 94 patients. The adjusted odds ratios (95% confidence interval (CI)) of home PP and home SBP to the progression of diabetic nephropathy were 1.23 (1.01-1.49) and 1.14 (0.98-1.33), respectively. The AUC (95% CI) of home PP to the progression of diabetic nephropathy was 0.624 (0.665-0.679). The optimal cut-off points, sensitivity and specificity for home PP that were associated with the progression of diabetic nephropathy were 57.7 mmHg, 0.649 and 0.580, respectively. Our findings suggest, for the first time, that home PP is an independent predictor of the progression of diabetic nephropathy in patients with type 2 diabetes.

Threshold value of home pulse pressure predicting arterial stiffness in patients with type 2 diabetes: KAMOGAWA-HBP study.

This cross-sectional multicenter study was designed to evaluate the threshold value of home pulse pressure (PP) and home systolic blood pressure (SBP) predicting the arterial stiffness in 876 patients with type 2 diabetes. We measured the area under the receiver-operating characteristic curve (AUC) and estimated the ability of home PP to identify arterial stiffness using Youden-Index defined cut-off point. The arterial stiffness was measured using the brachial-ankle pulse wave velocity (baPWV). AUC for arterial stiffness in morning PP was significantly greater than that in morning SBP (P < .001). AUC for arterial stiffness in evening PP was also significantly greater than that in evening SBP (P < .001). The optimal cut-off points for morning PP and evening PP, which predicted arterial stiffness, were 54.6 and 56.9 mm Hg, respectively. Our findings indicate that we should pay more attention to increased home PP in patients with type 2 diabetes.

Late-night-dinner is associated with poor glycemic control in people with type 2 diabetes: The KAMOGAWA-DM cohort study.

Skipping breakfast or irregular breakfast is associated with poor glycemic control. However, a relationship between the timing of dinner and glycemic control in people with type 2 diabetes remains indefinite. Therefore, we investigated the relationship between late-night-dinner and glycemic control in people with type 2 diabetes. We performed questionnaire survey for lifestyle factors in this cross-sectional study. We defined having dinner later than eight pm as late-night-dinner. We examined the differences in clinical and metabolic parameters between those who have late-night-dinner and those who do not have. We also examined the relationship between late-night-dinner and HbA1c, using multiple regression analysis. Ninety-five people (23.2%) had a late-night-dinner, among 409 people with type 2 diabetes. Metabolic parameters (mean (SD) or median (interquartile range)) of people with late-night-dinner were worse than those of without, including body mass index (BMI) (24.4 (4.0) vs. 23.2 (3.4) kg/m2, p = 0.006), triglycerides (1.5 (1.1-2.1) vs. 1.2 (0.8-1.7) mmol/L, p < 0.001), HDL-cholesterol (1.4 (0.4) vs. 1.6 (0.4) mmol/L, p = 0.004) and hemoglobin A1c (58.1 (13.3) vs. 55.2 (10.2) mmol/mol, (7.5 (1.2) vs. 7.2 (0.9) %), p = 0.023)). Late-night-dinner (standardized regression coefficient = 0.13, p = 0.028) was associated with hemoglobin A1c after adjusting for age, BMI, sex, duration of diabetes, smoking, exercise, alcohol, snacking after dinner, nighttime sleep duration, time from dinner to bedtime, skipping breakfast, and medication for diabetes. Late-night-dinner is independently associated with poor glycemic control in people with type 2 diabetes.

Prognostic significance of day-by-day variability of home blood pressure on progression to macroalbuminuria in patients with diabetes.

OBJECTIVES: Previously, we have shown in cross-sectional analysis of patients with type 2 diabetes mellitus that the presence of diabetic nephropathy is associated with increased home blood pressure (HBP) variability. We now examine the prognostic significance of HBP variability in substantially the same cohort. METHODS: We performed a prospective cohort study of type 2 diabetes patients. We analyzed 714 patients. Major exclusion criteria are missing data of urinary albumin excretion and newly prescribed or stopped renin-angiotensin system inhibitors during 2-year follow-up. Patients were instructed to perform triplicate morning and evening HBP measurements for 14 consecutive days. We computed day-by-day HBP variability as within-patient standard deviation (SD) and coefficient of variation (CV) of measurements. RESULTS: During the follow-up period of 2 years, 23 patients progressed to macroalbuminuria. The changing risk of progression to macroalbuminuria with increasing day-by-day variability of morning SBP was better depicted using smoothing spline analyses. Patients with greater SD of morning SBP tended to significantly progress to macroalbuminuria [odds ratio: 5.24 (95% confidence interval: 2.10-13.03; P > 0.001)]. Patients with greater CV of morning SBP also tended to significantly progress to macroalbuminuria [odds ratio: 3.36 (95% confidence interval: 1.39-8.12; P = 0.007)]. CONCLUSION: Day-by-day variability of morning SBP was proven as an independent predictor for progression to macroalbuminuria in patients with type 2 diabetes.

Protein Intake, Especially Vegetable Protein Intake, Is Associated with Higher Skeletal Muscle Mass in Elderly Patients with Type 2 Diabetes.

BACKGROUND/AIMS: Protein intake is important for maintaining muscle mass in general population. However, it remains to be elucidated the association between dietary protein intake and skeletal muscle mass in elderly patients with type 2 diabetes. METHODS: In this cross-sectional study of 168 elderly patients with type 2 diabetes, we investigated the relationship between skeletal muscle index (SMI) and protein intake. Bioimpedance analysis was used for measurement for skeletal muscle mass (kg) and SMI (%), which was defined as skeletal muscle mass (kg)/total body weight (kg) × 100. Habitual food and nutrient intake were estimated by a questionnaire. RESULTS: Protein intake was independently correlated with SMI after adjusting for age, hemoglobin A1c, C-peptide index, exercise, smoking, insulin treatment, total energy intake, and C-reactive protein (standardized regression coefficient = 0.664, P < 0.001 in men and standardized regression coefficient = 0.516, P = 0.005 in women). Additionally, the animal protein to vegetable protein ratio was negatively correlated with SMI after adjusting for covariates in men (standardized regression coefficient = -0.339, P = 0.005). CONCLUSIONS: We found that total protein intake, especially vegetable protein intake, was positively associated with skeletal muscle mass in elderly patients with type 2 diabetes.

Home Blood Pressure Variability From the Stored Memory Is Correlated With Albuminuria, but From the Logbook Is not.

BACKGROUND: The aim of this study was to evaluate whether the mean and the variability of home blood pressure (HBP) from the logbook correlate with albuminuria as well as HBP from the stored memory in patients with type 2 diabetes. METHODS: This study is a post hoc analysis of a cross-sectional multicenter study. HBP measurements were performed for 14 consecutive days in 276 patients with type 2 diabetes. Patients were requested to write down their HBP values in logbooks and were not informed about the memory function of their BP monitoring devices. RESULTS: HBP values from the logbook were significantly lower and less variable than those from the stored memory. The mean of morning systolic BP (SBP) from the logbook (adjusted ß = 0.326, P < 0.001) as well as that from the stored memory (adjusted ß = 0.336, P < 0.0001) was significantly associated with logarithm of urinary albumin excretion (UAE). The SD of morning SBP (adjusted ß = 0.134, P = 0.017) from the stored memory was significantly associated with logarithm of UAE, in contrast, the SD of morning SBP (adjusted ß = 0.104, P = 0.057) from the logbook was not associated with logarithm of UAE. CONCLUSIONS: Patients with type 2 diabetes might report inaccurate HBP measurements and, as a result, the variability of HBP from the logbook is underestimated and poorly correlates with albuminuria. The use of stored BP measurements is recommended to accurately evaluate the relationship with diabetic nephropathy.

Combined effect of body mass index and waist-height ratio on incident diabetes; a population based cohort study.

We investigated the impact of combined effect of body mass index and waist-to-height ratio on risk of diabetes. Overweight and abdominal obesity were defined as body mass index ≥23 kg/m2 and waist-to-height ratio ≥0.5, respectively. We divided participants into four groups according to presence of overweight and/or abdominal obesity. About 20% individuals with overweight did not complicated with an abdominal obesity. Among 3,737 participants, 286 participants had diabetes at baseline-examination. Adjusted odds ratios for prevalence of diabetes compared with non-overweight participants without abdominal obesity were as follow: 1.87 (95% confidence interval 1.09-3.14, p = 0.024) in non-overweight participants with abdominal obesity, 1.51 (0.87-2.55, p = 0.141) in overweight participants without abdominal obesity and 3.25 (2.37-4.52, p<0.001) in overweight participants with abdominal obesity. In the follow-up examination, 86 participants were diagnosed as diabetes among 2,263 participants. Adjusted odds ratios for incident diabetes were as follow: 2.59 (0.98-6.44, p = 0.056) in non-overweight participants with abdominal obesity, 1.65 (0.64-4.00, p = 0.288) in overweight participants without abdominal obesity and 2.77 (1.55-5.15, p<0.001) in overweight participants with abdominal obesity. Non-overweight individuals with abdominal obesity as well as overweight individuals with abdominal obesity was associated with diabetes compared with non-overweight individuals without abdominal obesity.

Maximum home blood pressure is a useful indicator of diabetic nephropathy in patients with type 2 diabetes mellitus: KAMOGAWA-HBP study.

OBJECTIVE: Maximum home systolic blood pressure has been shown to predict target organ damage. We aimed to clarify the association between maximum home systolic blood pressure and urine albumin to creatinine ratio, an indicator of early-phase diabetic nephropathy in patients with type 2 diabetes. METHODS: In 1040 patients, we assessed the relationship of mean or maximum home systolic blood pressure and urine albumin to creatinine ratio, and compared the area under the receiver operating characteristic curve of mean or maximum home systolic blood pressure for diabetic nephropathy (urine albumin to creatinine ratio ⩾30 mg/g Cr). RESULTS: Multivariate linear regression analyses indicated that mean morning systolic blood pressure ( ß = 0.010, p < 0.001) and maximum morning systolic blood pressure ( ß = 0.008, p < 0.001) were significantly associated with urine albumin to creatinine ratio. Area under the receiver operating characteristic curve (95% confidence interval) for diabetic nephropathy in mean and maximum morning systolic blood pressure was 0.667 (0.634-0.700; p < 0.001) and 0.671 (0.638-0.703; p < 0.001), respectively. CONCLUSION: Maximum home systolic blood pressure, as well as mean home systolic blood pressure, was significantly associated with diabetic nephropathy in patients with type 2 diabetes.

Olmesartan with azelnidipine versus with trichlormethiazide on home blood pressure variability in patients with type II diabetes mellitus.

The aim of the present study was to compare the effects of olmesartan combined with azelnidipine versus olmesartan combined with trichlormethiazide, on home blood pressure (BP) and pressure variability in type II diabetes mellitus patients using home BP telemonitoring system. We performed an open-label cross-over pilot study of 28 patients with type II diabetes mellitus. Patients received combination treatment with either olmesartan 20 mg plus azelnidipine 16 mg or olmesartan 20 mg plus trichlormethiazide 1 mg for more than 6 weeks each in a cross-over method. The coefficient of morning systolic BP variability in the olmesartan plus azelnidipine group was significantly lower than that in the olmesartan plus trichlormethiazide group (6.4 ± 1.9 vs. 7.5 ± 2.6, P = .004). There were no significant differences in mean morning systolic BP between the two groups. Using home BP telemonitoring for hypertensive patients with type II diabetes, this study revealed for the first time that the olmesartan with azelnidipine combination is superior to the olmesartan with trichlormethiazide combination in reducing home BP variability.

Optimal home SBP targets for preventing the progression of diabetic nephropathy in patients with type 2 diabetes mellitus.

OBJECTIVES: Home blood pressure control can reduce the risk of increased urinary albumin excretion in patients with diabetes mellitus. However, the optimal home blood pressure targets to prevent the onset or progression of diabetic nephropathy are not well defined. METHODS: We performed a retrospective cohort study of 851 patients with type 2 diabetes mellitus. Logistic regression models were used to evaluate the correlations of home SBP levels with progression of diabetic nephropathy. RESULTS: During the follow-up of 2 years, 86 patients had progression of diabetic nephropathy. Adjusted odds ratios (95% confidence interval) for progression of diabetic nephropathy in patients with morning SBP of 120-129  mmHg [2.725 (1.074-6.917), P = 0.035], 130-139  mmHg [3.703 (1.519-9.031), P = 0.004] and in those with morning SBP equal or more than 140  mmHg [2.994 (1.182-7.581), P = 0.021] were significantly higher than that in those with morning SBP less than 120  mmHg in multiple logistic analyses. CONCLUSION: The preferable morning SBP targets might be less than 120  mmHg for preventing the onset or progression of diabetic nephropathy in patients with type 2 diabetes mellitus.

Is home blood pressure reporting in patients with type 2 diabetes reliable?

The aim of this study was to evaluate the reliability of self-reported home blood pressure (HBP) in patients with type 2 diabetes by comparing the self-reported values with HBP measurements stored in the memory of the blood pressure (BP) monitor. We also examined what factors affect the reliability of HBP measurements. A cross-sectional study was conducted in 280 patients with type 2 diabetes. Patients were requested to perform triplicate morning and evening measurements over a span of 2 weeks and to enter their HBP values into logbooks. Patients were not informed about the memory function of their BP monitoring devices. The concordance rate of HBP reporting was 78.6%. A total of 51.4% of patients (n=144) had >90% concordant data, and 15.7% of patients (n=44) had ⩽50% concordant data. In general, HBP values from the logbook were significantly lower and less variable than those from the stored memory (P<0.05). The most common type of incorrect data was selected data that were reported in the logbooks that were randomly selected from multiple readings by the HBP monitors (55.8%). The concordance rate of HBP reporting significantly correlated with hemoglobin A1c levels (ß=-0.156; P=0.0149) and with smoking status (current vs. never, ß=-0.165; P=0.0184). In conclusion, HBP measurements from the patients' logbooks were lower and less variable than those from the stored memory in the BP monitors of patients with type 2 diabetes, and the reliability of HBP reporting was affected by glycemic control and smoking status. Repeated instructions regarding HBP measurement to the patients or the use of stored BP measurements is recommended to ensure accurate HBP measurements in patients with type 2 diabetes.

Low serum bilirubin concentration is a novel risk factor for the development of albuminuria in patients with type 2 diabetes.

OBJECTIVE: Bilirubin has been recognized as an important endogeneous antioxidant. Previous studies reported that bilirubin could prevent atherosclerosis. The aim of this study was to investigate if serum bilirubin concentration could be a predictor for the development of albuminuria in patients with type 2 diabetes. MATERIALS AND METHODS: We measured serum bilirubin in 320 consecutive patients with normoalbuminuria. We performed follow-up study to assess the development of albuminuria, mean interval of which was 3.2±0.9years. Cox proportional hazards regression was used to examine the relationship between serum bilirubin concentration and the development of albuminuria. RESULTS: During follow-up duration, 43 patients have developed albuminuria. In multivariate analysis, after adjusting for comprehensive risk factors, the risk of developing albuminuria was higher in the lowest quartile of serum bilirubin concentrations than that in the highest quartile of serum bilirubin concentrations (Hazard ratio, 5.76; 95% CI, 1.65 to 24.93). CONCLUSIONS: Low serum bilirubin concentration could be a novel risk factor for the development of albuminuria in patients with type 2 diabetes.

A difference in systolic blood pressure between arms is a novel predictor of the development and progression of diabetic nephropathy in patients with type 2 diabetes.

OBJECTIVE: Recent studies have suggested that a difference in systolic blood pressure (SBP) between arms is associated with both vascular disease and mortality. The aim of this study was to investigate the relationship between a difference in SBP between arms and change in urinary albumin excretion or development of albuminuria in patients with type 2 diabetes. METHODS: We measured SBP in 408 consecutive patients with type 2 diabetes, and calculated a difference in SBP between arms. We performed follow-up study to assess change in urinary albumin excretion or development of albuminuria, mean interval of which was 4.6 ± 1.7 years. We then evaluated the relationship of a difference in SBP between arms to diabetic nephropathy using multiple regression analysis and multiple Cox regression model. RESULTS: Multiple regression analyses demonstrated that a difference in SBP between arms was independently associated with change in urinary albumin excretion (ß = 0.1869, P = 0.0010). Adjusted Cox regression analyses demonstrated that a difference in SBP between arms was associated with an increased hazard of development of albuminuria; hazard ratio was 1.215 (95% confidence interval 1.077-1.376). Moreover, the risk of development of albuminuria was increased in patients with a difference in SBP of equal to or more than 10 mmHg between arms; hazard ratio was 4.168 (95% confidence interval 1.478-11.70). CONCLUSION: A difference in SBP between arms could be a novel predictor of the development and progression of diabetic nephropathy in patients with type 2 diabetes.

Visit-to-visit variability in systolic blood pressure is a novel risk factor for the progression of coronary artery calcification.

Recent studies have suggested that variability in the systolic blood pressure (SBP) is a risk factor for cardiovascular disease (CVD). The aim of this study was to investigate the relationship between variability in the SBP and the progression of coronary artery calcification (CAC), which is a useful marker for CVD. We measured SBP in 164 consecutive patients at every visit over the course of a year and calculated the coefficient of variation and s.d. of the SBP. We performed a follow-up study using multislice computed tomography to assess the progression of the CAC score, the mean interval of which was 3.93 ± 1.36 years. We then evaluated the relationship between variability in the SBP and progression of the CAC score. The coefficient of variation for the SBP correlated positively with the progression of the CAC score (r=0.4382, P<0.0001). Multiple regression analysis demonstrated that the coefficient of variation of the SBP (ß=0.3826, P<0.0001) was independently associated with the progression of the CAC score. The visit-to-visit variability in SBP could be a novel risk factor for the progression of CAC.

Morning pulse pressure is associated more strongly with elevated albuminuria than systolic blood pressure in patients with type 2 diabetes mellitus: post hoc analysis of a cross-sectional multicenter study.

AIMS: Recently, focus has been directed toward pulse pressure as a potentially independent risk factor for micro- and macrovascular disease. This study was designed to examine the relationship between pulse pressure taken at home and elevated albuminuria in patients with type 2 diabetes. METHODS: This study is a post hoc analysis of a cross-sectional multicenter study. Home blood pressure measurements were performed for 14 consecutive days in 858 patients with type 2 diabetes. We investigated the relationship between systolic blood pressure or pulse pressure in the morning or in the evening and urinary albumin excretion using univariate and multivariate analyses. Furthermore, we measured area under the receiver-operating characteristic curve (AUC) to compare the ability to identify elevated albuminuria, defined as urinary albumin excretion equal to or more than 30 mg/g creatinine, of systolic blood pressure or pulse pressure. RESULTS: Morning systolic blood pressure (ß=0.339, P<0.001) and morning pulse pressure (ß=0.378, P<0.001) were significantly associated with logarithm of urinary albumin excretion independent of other potential co-factors. AUC for elevated albuminuria in morning systolic blood pressure and morning pulse pressure were 0.668 (0.632-0.705; P<0.001) and 0.694 (0.659-0.730; P<0.001), respectively. AUC of morning pulse pressure was significantly greater than that of morning systolic blood pressure (P=0.040). CONCLUSIONS: Our findings implicate that morning pulse pressure is associated with elevated albuminuria in patients with type 2 diabetes, which suggests that lowering morning pulse pressure could prevent the development and progression of diabetic nephropathy.

Effects of liraglutide on postprandial insulin and glucagon responses in Japanese patients with type 2 diabetes.

This study assessed the endocrine pancreatic responses to liraglutide (0.9 mg once a day) during normal living conditions in Japanese patients with type 2 diabetes. The study included 14 hospitalized patients with type 2 diabetes. Meal tests were performed after improvement of glycemic control achieved by two weeks of multiple insulin injection therapy and after approximately two weeks of liraglutide treatment. Continuous glucose monitoring was performed to compare daily variation in glycemic control between multiple insulin injection therapy and liraglutide treatment. Liraglutide reduced plasma glucose levels after the test meals (60-180 min; p<0.05), as a result of significant increases in insulin secretion (0-180 min; p<0.05) and decreases in the incremental ratio of plasma glucagon (15-60 min; p<0.05). Continuous glucose monitoring showed that liraglutide treatment was also associated with a decrease in glucose variability. We also demonstrated that optimal glycemic control seen as a reduction in 24-h mean glucose levels and variability was obtained only with liraglutide monotherapy. In conclusion, liraglutide treatment increases insulin secretion and suppresses glucagon secretion in Japanese patients with type 2 diabetes under normal living conditions. The main therapeutic advantages of liraglutide are its use as monotherapy and its ability to decrease glucose variability.

Visit-to-visit blood pressure variability is a novel risk factor for the development and progression of diabetic nephropathy in patients with type 2 diabetes.

OBJECTIVE: Recent study has suggested that not only the presence of hypertension but also the variability in systolic blood pressure (SBP) are risk factors for vascular disease and organ damage. The aim of this study was to investigate the relationship between visit-to-visit variability in SBP and change in urinary albumin excretion (UAE) or development of albuminuria in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured SBP in 354 consecutive patients at every visit during 1 year and calculated the coefficient of variation (CV) of SBP. We performed a follow-up study to assess change in UAE or development of albuminuria, the mean interval of which was 3.76 ± 0.71 years. Then, we evaluated relationships of variability of SBP to diabetic nephropathy using multiple regression analysis and multiple Cox regression model. RESULTS: Multiple regression analysis demonstrated that CV of SBP was independently associated with change in UAE (ß = 0.1758; P = 0.0108). Adjusted Cox regression analyses demonstrated that CV of SBP was associated with an increased hazard of development of albuminuria; hazard ratio was 1.143 (95% CI 1.008-1.302). CONCLUSIONS: Visit-to-visit variability in SBP could be a novel risk factor for the development and progression of diabetic nephropathy in patients with type 2 diabetes.