Cognitive dysfunction during hypoglycemia in an elderly subject without diabetes.

The aim of the present study was to examine whether an elderly subject without diabetes experiences hypoglycemia during his daily life or after an oral glucose tolerance test (OGTT), and investigate whether hypoglycemic episodes affect cognitive function. The 85-year-old healthy subject, who is a sports enthusiast, showed lower than normal (< 80 mg/dl) blood glucose levels on two occasions over 6 days in the early morning. The subject also experienced hypoglycemic episodes and blood glucose levels of 65 and 74 mg/dl, respectively, during the 6-h OGTT given after a 13-h fast. Cognitive function, as assessed using a numeracy test and a driving simulator test, deteriorated during the hypoglycemic episodes but recovered 0.5 h after ingestion of a confectionary product (two pieces of Dorayaki containing 247 kcal and 51.5 g of carbohydrate each). Cognitive dysfunction caused by mild hypoglycemia can be involved in a part of traffic accidents in elderly drivers.

Urinary IgG4 and Smad1 Are Specific Biomarkers for Renal Structural and Functional Changes in Early Stages of Diabetic Nephropathy.

Diabetic nephropathy (DN) is the major cause of end-stage kidney disease, but early biomarkers of DN risk are limited. Herein we examine urinary IgG4 and Smad1 as additional early DN biomarkers. We recruited 815 patients with type 2 diabetes; 554 patients fulfilled the criteria of an estimated glomerular filtration rate (eGFR) >60 mL/min and no macroalbuminuria at baseline, with follow-up for 5 years. Patients without macroalbuminuria were also recruited for renal biopsies. Urinary IgG4 and Smad1 were determined by enzyme-linked immunoassays using specific antibodies. The specificity, sensitivity, and reproducibility were confirmed for each assay. Increased urinary IgG4 was significantly associated with lower eGFR. The level of urinary IgG4 also significantly correlated with surface density of peripheral glomerular basement membrane (Sv PGBM/Glom), whereas Smad1 was associated with the degree of mesangial expansion-both classic pathological findings in DN. Baseline eGFR did not differ between any groups; however, increases in both urinary IgG4 and Smad1 levels at baseline significantly predicted later development of eGFR decline in patients without macroalbuminuria. These data suggest that urinary IgG4 and Smad1 at relatively early stages of DN reflect underlying DN lesions and are relevant to later clinical outcomes.

Nutritional counseling regulates interdialytic weight gain and blood pressure in outpatients receiving maintenance hemodialysis.

Maintenance hemodialysis outpatients must limit salt and water intake to maintain electrolyte balance and blood pressure. In Kawashima Hospital, nationally registered dietitians provide hemodialysis patients with monthly nutritional counseling. We investigated whether nutritional counseling affects interdialytic weight gain (IDWG) and blood pressure. We investigated 48 hemodialysis patients whose monthly average IDWG ratio to dry weight exceeded 5.1% and who had not had a long-term hospital admittance of > 1 month. After the 48-month nutritional counseling period, the IDWG ratio had improved in 37 of the patients (77.1%), significantly decreasing from 6.0±0.7 to 5.3±0.9%. Estimated salt and water intake decreased significantly from 13.3±2.7 to 11.8±2.4 g/day and 2528±455 to 2332±410 ml/day, respectively. During the intervention period, normalized protein catabolic rate and body mass index did not change substantially. Pre-hemodialysis systolic and diastolic blood pressures had significantly decreased from 149±19 to 134±18 mmHg, and 82±13 to 75±10 mmHg for 48 months after study initiation, respectively. The dosage of antihypertensive drugs had significantly decreased in the group that experienced improvement in the IDWG ratio. Long-term nutritional counseling by nationally registered dietitians may improve the IDWG ratio and blood pressure of hemodialysis patients by decreasing their salt and water intake. J. Med. Invest. 64: 129-135, February, 2017.

Association between periodontal condition and kidney dysfunction in Japanese adults: A cross-sectional study.

Recent studies have demonstrated that chronic kidney disease (CKD) may be associated with the progression of periodontal disease. Diabetes mellitus (DM) is a major risk factor for CKD. The objective of this study was to clarify the relationship between periodontal condition and kidney dysfunction in patients who had kidney failure with or without DM. One hundred sixty-four patients with kidney dysfunction were enrolled (male: N = 105; female: N = 59), and the relationship between periodontal condition and kidney dysfunction was analyzed in a cross-sectional study. The subjects were divided into three groups: (a) patients with DM, (b) dialysis patients with nephropathy due to various kidney diseases, and (c) dialysis patient with nephropathy due to DM (diabetic nephropathy). Then, the effect of DM on the periodontal condition was analyzed. The patients were also stratified by CKD stage (into G1-G5) using the estimated glomerular filtration rate (eGFR), and the G5 group was divided in patients with or without DM. Correlations between eGFR and parameters of periodontal condition were calculated in patients from G1 to G4. The number of missing teeth was significantly higher in dialysis patients with diabetic nephropathy than in patients with DM, whereas alveolar bone loss did not show a significant difference among the three groups. In addition, the G5 patients with DM had a significantly higher number of missing teeth than the other CKD groups, whereas alveolar bone loss did not show a significant difference. In G5 patients with DM, Community Periodontal Index and Oral Hygiene Index scores were significantly higher than in G1-4 patients with DM. There was a significant negative correlation between eGFR and the number of missing teeth. Patients with diabetic nephropathy have a higher rate of periodontal problems such as missing teeth in Japanese adults.

Glycated albumin (GA) is more advantageous than hemoglobin A1c for evaluating the efficacy of sitagliptin in achieving glycemic control in patients with type 2 diabetes.

OBJECTIVE: The aim of this study was to compare the utility of hemoglobin A1c (HbA1c) and glycated albumin (GA) for evaluating the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, in patients with type 2 diabetes. METHODS: Sitagliptin (50 mg) was administered orally once daily in 67 outpatients with type 2 diabetes. Drug effectiveness was deemed present if the HbA1c or GA level decreased by 5% at week 4 and week 12 relative to the baseline value. RESULTS: The mean HbA1c level decreased from 8.1 ± 1.0% at baseline to 7.8 ± 0.9% at week 4 and 7.2 ± 0.8% at week 12. The mean GA level decreased from 25.0 ± 4.5% at baseline to 22.2 ± 3.8% at week 4 and 20.8 ± 3.5% at week 12. At week 4 and week 12, the drug was effective in 37.8% and 71.6% of the patients, respectively, when assessed based on changes in HbA1c, and in 83.6% and 97.0% of the patients, respectively, when assessed based on changes in GA. CONCLUSION: GA is superior to HbA1c for evaluating the efficacy of sitagliptin treatment in patients with type 2 diabetes.

Lower value of glycated haemoglobin relative to glycaemic control in diabetic patients with end-stage renal disease not on haemodialysis.

BACKGROUND: Glycated haemoglobin (HbA1c) concentration is lower relative to glyacemic control in diabetic patients on haemodialysis. However, it is unknown as to whether this is also true for diabetic patients with end-stage renal disease but not on haemodialysis. METHODS: Correlations between HbA1c or glycated albumin (GA) and estimated glomerular filtration rate (eGFR) (determined by serum creatinine concentration, sex and age) were investigated in 86 diabetic patients with renal dysfunction not on dialysis. The mean values of HbA1c and of red blood cell (RBC) lifespan were compared among four groups of patients: Group 1 (n = 30, eGFR ≥ 60 mL/min/1.73 m(2)), Group 2 (n = 30, eGFR < 60 mL/min/1.73 m(2) but ≥30 mL/min/1.73 m(2)), Group 3 (n = 13, eGFR < 30 mL/min/1.73 m(2) but ≥15 mL/min/1.73 m(2)) and Group 4 (n = 13, eGFR < 15 mL/min/1.73 m(2) without haemodialysis). RBC lifespan was determined in each subject from the difference between alveolar carbon monoxide (CO) concentration and atmospheric CO concentration. RESULTS: HbA1c was significantly correlated with eGFR (r = 0.37, P = 0.0004), but GA was not. The HbA1c values in Group 3 (6.8 ± 0.6%) and Group 4 (6.3 ± 0.5%) were significantly lower than that in Group 1 (7.4 ± 0.8%), but there was no difference between Group 2 (7.2 ± 0.7%) and Group 1. There was a significant correlation between RBC lifespan and eGFR, and the mean RBC lifespan in Group 3 (96 ± 35 d) and Group 4 (94 ± 30 d) were significantly shorter than that in Group 1 (127 ± 30 d). CONCLUSIONS: Diabetic patients with stage 4 or 5 chronic kidney disease not on haemodialysis had significantly lower values of HbA1c and shorter RBC lifespan compared with diabetic patients without renal dysfunction.

Stringent glycaemic control prolongs survival in diabetic patients with end-stage renal disease on haemodialysis.

AIM: No suitable index or optimal target for diabetic control has been established for diabetic patients with end-stage renal disease (ESRD) undergoing haemodialysis. To address these issues, the single-centre observational study was conducted. METHODS: Two hundred and forty-five diabetic ESRD patients (23.3% female; age at initiation of haemodialysis 61.7 ± 10.7 years) at start of haemodialysis between 1 January 1995 and 31 December 2004 were enrolled. Subjects were grouped according to glycaemic control level throughout the observational period as follows: mean postprandial plasma glucose (PPG) <8.9 mmol/L, 8.9 mmol/L ≤ PPG < 10.0 mmol/L, 10.0 mmol/L ≤ PPG < 11.1 mmol/L, 11.1 mmol/L ≤ PPG < 12.2 mmol/L and PPG ≥ 12.2 mmol/L; and HbA1c < 6.0%, 6.0-6.4%, 6.5-6.9% and ≥ 7.0%. Survival was then followed until 31 December 2005. RESULTS: Cumulative survival of groups of 10.0 mmol/L ≤ PPG < 11.1 mmol/L, 11.1 ≤ PPG < 12.2 and PPG ≥ 12.2 mmol/L was significantly lower than that for PPG < 8.9 mmol/L as determined by Kaplan-Meier estimation (P = 0.016, 0.009 and 0.031, respectively; log-rank test). In both uni- and multivariate Cox proportional hazard models, mortality hazard ratios were significantly higher for PPG ≥ 10.0 mmol/L than for PPG < 8.9 mmol/L (P = 0.002-0.021). Kaplan-Meier survival curves grouped by HbA1c levels showed no correlation between HbA1c and survival during the observational period. No significant difference in mortality hazard ratios was seen for any HbA1c groups evaluated by Cox proportional hazard model. CONCLUSION: Intensive management of diabetic control at a stringent mean on-study PPG < 10.0 mmol/L will improve the life expectancy in diabetic dialysis patients. However, no range of HbA1c values obtained in this study showed any clear difference in clinical outcomes.

Evaluation of error levels in hemoglobin A1c and glycated albumin in type 2 diabetic patients due to inter-individual variability.

AIM: To evaluate error levels in hemoglobin A1c (A1C) and glycated albumin (GA) in type 2 diabetic patients due to inter-individual variability. METHODS: Type 2 diabetic patients with stable glycemic control and without complications affecting either A1C or GA were enrolled (n=154; age 68.4+/-9.9 years). Blood examination was performed 1-4h after breakfast or lunch every 2-3 months on > or =3 occasions. A1C data were changed to IFCC values for analysis. RESULTS: A1C and GA correlated significantly with postprandial plasma glucose. The correlation coefficient between A1C and GA was 0.728 (p<0.001) when calculated using raw data and 0.747 (p<0.001) when calculated using averaged data for each patient. The ratio R of GA to A1C was 3.88+/-0.50 for raw data and 3.88+/-0.47 for averaged data, indicating coefficients of variation of R (CV(R)) of 12.9% and 12.1%, respectively. Multiple regression analysis reduced CV(R) to 11.2%. After dividing CV(R)(2) into CV(A1C)(2) and CV(GA)(2), CV(A1C) and CV(GA) were calculated as 9.1% for raw data and 8.6% for averaged data, and were reduced to 7.9% after multiple regression analysis. CONCLUSIONS: Error levels in A1C and GA reach 7.9-9.1%, suggesting the existence of maximal 18% errors in A1C and GA levels.

Indicators for blood glucose control in diabetics with end-stage chronic renal disease: GHb vs. glycated albumin (GA).

Diabetics with end-stage renal disease (ESRD) exhibit abnormal life span of erythrocytes, and thus, HbAlc is not necessarily a good indicator for blood glucose control. The present study was conducted to reaffirm this point and determine whether glycated albumin (GA) can be used instead of HbAlc. The following three groups of patients with diabetes served as subjects: 49 predialysis patients with ESRD (predialysis group), 37 patients with ESRD on dialysis (dialysis group), and 40 patients without nephropathy (non-dialysis group). The profile set mean blood glucose was calculated by measuring blood glucose levels seven times a day. The relationship of profile set mean blood glucose with HbAlc and GA levels was then investigated. Corrected HbAlc levels were calculated by applying the profile set mean blood glucose of each ESRD patient to the regression formula for the HbAlc of non-dialysis patients. The actual and corrected HbAlc levels for the predialysis patients were 5.4+/-1.1 and 7.9+/-1.1%, respectively, while those for the dialysis patients were 5.6+/-1.0 and 7.5+/-0.9%, respectively (p<0.0001). The changes in GA levels in relation to the blood glucose control in the dialysis patients matched those in non-dialysis patients. HbAlc levels for diabetics with ESRD were lower than indicated by their blood glucose control. When assessing blood glucose control based solely on HbAlc, erroneous results may be obtained. In such cases, GA may be used instead of HbAlc.

Report of the Committee on the classification and diagnostic criteria of diabetes mellitus.

In 1995, the Japan Diabetes Society (JDS) appointed the Committee for the Classification and Diagnosis of Diabetes Mellitus. The Committee presented a final report in May 1999 in Japanese. This is the English version with minor modifications for readers outside Japan. CONCEPT OF DIABETES MELLITUS: Diabetes mellitus represents a group of diseases of heterogeneous etiology, characterized by chronic hyperglycemia and other metabolic abnormalities, which are due to deficiency of insulin effect. After a long duration of metabolic derangement, specific complications of diabetes (retinopathy, nephropathy, and neuropathy) may occur. Arteriosclerosis is also accelerated. Depending on the severity of the metabolic abnormality, diabetes may be asymptomatic, or may be associated with symptoms (thirst, polyuria, and weight loss), or may progress to ketoacidosis and coma. CLASSIFICATION: Both etiological classification and staging of pathophysiology by the degree of deficiency of insulin effect need to be considered. The etiological classification of diabetes and related disorders of glycemia includes, (1) type 1; (2) type 2; (3) those due to specific mechanisms and diseases; and (4) gestational diabetes mellitus. Type 1 is characterized by destructive lesions of pancreatic beta cells either by an autoimmune mechanism or of unknown cause. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Category (3) includes two subgroups; subgroup A is diabetes in which specific mutations have been identified as a cause of genetic susceptibility, while subgroup B is diabetes associated with other pathologic conditions or diseases. The staging of glucose metabolism includes normal, borderline and diabetic stages. The diabetic stage is further classified into three substages; non-insulin requiring, insulin-requiring for glycemic control, and insulin-dependent (ID) for survival. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment. DIAGNOSIS: The confirmation of chronic hyperglycemia is a prerequisite for the diagnosis of diabetes mellitus. The state of glycemia may be classified within three categories, diabetic type; borderline type; and normal type. Diabetic type is defined when fasting plasma glucose (FPG) is 7.0 mmol/l (126 mg/dl) or higher, and/or plasma glucose 2 h after 75 g glucose load (2hPG) is 11.1 mmol/l (200 mg/dl) or higher. A casual plasma glucose (PG) > or =11.1 mmol/l (200 mg/dl) also indicates diabetic type. Normal type is defined when FPG is below 6.1 mmol/l (110 mg/dl) and 2hPG below 7.8 mmol/l (140 mg/dl). Borderline type includes those who are neither diabetic nor normal types. These cutoff values are for venous PG measurements. The persistence of 'diabetic type' in a subject indicates that he or she has diabetes. For children, a dose of 1.75 g/kg (maximum, 75 g) is used for oral glucose tolerance test (OGTT). The procedure for clinical diagnosis is as follows. Diabetes mellitus is diagnosed when hyperglycemia meeting the criteria for 'diabetic type' is shown on two or more occasions examined on separate days. Diabetes can be diagnosed by a single PG test of 'diabetic type' if one of the following three conditions co-exists, (1) typical symptoms of diabetes mellitus; (2) HbA1c > or =6.5% by a standardized method; or (3) unequivocal diabetic retinopathy. If the above conditions ((1) or (2)) have been present in the past and well documented, the subject is diagnosed either to have diabetes or to be suspected of diabetes, even if the present level of glycemia does not reach that of 'diabetic type'. If the diagnosis of diabetes cannot be established by these procedures, re-testing of PG is recommended after an appropriate interval. The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions. EPIDEMIOLOGICAL ASPECTS AND SCREENING: In order to determine the prevalence of diabetes in a population, 'diabetic type' may be regarded as 'diabetes'. The use of 2hPG cutoff level of > or =11.1 mmol/l (200 mg/dl) is recommended. If this is difficult, the FPG cutoff level of > or =7.0 mmol/l (126 mg/dl) can be used, but is likely to lead to under-ascertainment. For screening, the most important point is not to overlook 'diabetes'. In addition to parameters of hyperglycemia, clinical information such as family history, obesity etc., should be regarded as indications for further testing. NORMAL TYPE AND BORDERLINE: Only FPG and 2hPG are adopted as cutoff values, but in clinical situations, it is recommended to measure PG also at 30 and 60 min during 75 g OGTT. Among people with normal type, those with 1hPG higher than 10.0 mmol/l (180 mg/dl) are at higher risk to develop diabetes than those with lower 1hPG. When OGTT is performed, the borderline type corresponds to the sum of impaired fasting glycemia (IFG) plus impaired glucose tolerance (IGT) according to the new WHO report. Subjects in this category are at higher risk of developing diabetes than those with 'normal type'. Those with low insulinogenic index (the ratio of increment of plasma insulin to that of PG at 30 min during OGTT) are at particularly high risk to develop diabetes. Microvascular complications are rare but arteriosclerotic complications are fairly frequent in this category. GESTATIONAL DIABETES MELLITUS (GDM): The current definition of GDM is ' any glucose intolerance developed or detected during pregnancy'. We adopt the proposal of the Japan Society of Gynecology and Obstetrics for the diagnosis of GDM (1984). GDM is defined when two or more values during a 75 g OGTT are higher than the following cutoff levels; FPG > or =5.5 mmol/l (100 mg/dl), 1hPG > or =10.0 mmol/l (180 mg/dl) and 2hPG > or =8.3 mmol/l (150 mg/dl). As a screening test, subjects with casual PG > or =5.5 mmol/l (100 mg/dl) are recommended for further testing. Patients who have had documented glucose intolerance before pregnancy, and who present as 'diabetic type' should be under closer supervision than those who develop GDM during pregnancy for the first time. HbA1c: There is a large overlap in the distribution of HbA1c between groups with 'normal type' and 'borderline type' and mild 'diabetic type'. Therefore, HbA1c is not a suitable parameter to detect mild glucose intolerance. HbA1c higher than 6.5% suggests diabetes, but HbA1c below 6.5% alone should not be taken as evidence against the diagnosis of diabetes. COMPARISON WITH REPORTS OF AMERICAN DIABETES ASSOCIATION (ADA) IN 1997 AND WHO IN 1999: The present report is unique in the following points when compared with those of the ADA 'Diabetes Care 20 (1997) 1183' and WHO 'Report of a WHO Consultation (1999)'. (1) Diabetes due to specific mechanisms and diseases is divided into two subgroups; diabetes in which genetic susceptibility is clarified at the DNA level and diabetes associated with other diseases or conditions. (2) Cutoff PG levels are the same as those of ADA and WHO, but a term 'type' is added to each glycemic category, because a single coding of 'diabetic type' hyperglycemia does not define diabetes. Diabetes is diagnosed when 'diabetic type' hyperglycemia is shown on two or more occasions. (3) A single 'diabetic type' hyperglycemia is considered sufficient for the diagnosis of diabetes, if the patient has typical symptoms, HbA1c > or =6.5%, or diabetic retinopathy. (4) OGTT is recommended for those with mild hyperglycemia, because FPG criteria alone would overlook many subjects with 'diabetic type' in Japan. High 1hPG without elevation of FPG and 2hPG is also considered to be a risk factor for future diabetes. (5) Borderline type in the present report corresponds to the sum of IFG and IGT by WHO when OGTT is performed. (6) New criteria for GDM by OGTT are proposed.