We reinvestigated the clinical usefulness of the modified NAFIC scoring system, modified by changing the weightage assigned to the fasting serum insulin level based on the importance of hyperinsulinemia in the pathogenesis of non-alcoholic steatohepatitis (NASH), in Japanese patients with non-alcoholic fatty liver disease (NAFLD) who had undergone liver biopsy.
The NAFIC score is conventionally calculated as follows: serum ferritin ≥200 ng/mL (female) or ≥300 ng/mL (male), 1 point; serum fasting insulin ≥10 μU/mL, 1 point; and serum type IV collagen 7 s ≥5.0 ng/mL, 2 points. A total of 147 patients with NAFLD who had undergone liver biopsies were included in the estimation group. To validate the modified scoring system, 355 patients from nine hepatology centers in Japan were also enrolled.
In the estimation group, 74 (50.3%) patients were histologically diagnosed as having NASH, whereas the remaining 73 (49.7%) were diagnosed as not having NASH. As the percentage of NASH patients increased not only among participants with serum insulin levels greater than 10 μU/mL, but also in those with serum levels greater than 15 μU/mL, we advocated use of the modified NAFIC score, as follows: serum fasting insulin 10–15 μU/mL, 1 point and ≥15 μU/mL, 2 points. The modified NAFIC score showed improved sensitivity and negative predictive value for the diagnosis of NASH. This finding was also confirmed in the validation group.
The modified NAFIC scoring system could be a clinically useful diagnostic screening tool for NASH.
We compared the morphometric features of corneal epithelial basal cells between patients with type 2 diabetes mellitus and healthy controls, and analyzed the relationship of these features with corneal nerve fiber pathology and clinical factors in the patients.
Corneal epithelial basal cells and corneal nerve fibers were visualized by corneal confocal microscopy in 75 patients with type 2 diabetes and 42 age-matched controls. Density, area and area variability of corneal epithelial basal cells, as well as the width of the intercellular space between neighboring cells, were evaluated for both groups.
Patients showed decreased density (P < 0.02) and area (P < 0.0001), larger area variability (P < 0.0001) and a wider intercellular space (P < 0.0001) compared with controls. Density correlated inversely with area (P < 0.0001), width of intercellular space (P < 0.03) and beading frequency (P < 0.03), whereas it correlated directly with prothrombin time (P < 0.002) and activated partial thromboplastin time (P < 0.03). Area correlated inversely with duration of diabetes (P < 0.05) and coefficient of variation of area (P < 0.01), whereas it correlated directly with beading frequency (P < 0.05). Area variability correlated inversely with area (P < 0.01) and prothrombin time (P < 0.01), whereas it correlated directly with fibrinogen level (P < 0.0001).
Type 2 diabetes induces morphometric changes in corneal epithelial basal cells; this seems to be related to the morbid period of diabetes, beading frequency of corneal nerve fibers and blood coagulation state.
To investigate trends over the past 20 years for the prevalence of obesity and glycemic control in association with a patient's first hospital visit for type 2 diabetes mellitus.
This was a historical, cross-sectional, time-series, single-center study carried out at Marunouchi Hospital. Data from type 2 diabetic patients who were never treated until their first hospital visit were analyzed for the following periods: 1986–1987 (group A, n = 453), 1996–1997 (group B, n = 547) and 2006–2008 (group C, n = 443). Data on each patient's body mass index (BMI), age, untreated duration and glycated hemoglobin levels were also collected.
Obesity in younger patients (below age 40 years and ages 40–49 years in group C) with poor glycemic control increased over time. Patients with a BMI of <21.0 kg/m2 or ≥23.0 kg/m2 showed worse glycemic control than those with a BMI of 21.0–23.0 kg/m2 in group C. Younger patients had worse glycemic control and shorter untreated durations in group C. A BMI ≥23.0 kg/m2 was an independent risk factor for glycated hemoglobin levels ≥8.4% in group C, even after correction for sex, age, untreated duration and symptoms.
In recent years, glycemic control has worsened in young, obese patients in urban Japan. Obesity is rapidly increasing in younger patients, and patients with a BMI ≥23.0 kg/m2 might be candidates for diabetes screening. This trial was registered with the University Medical Information Network Clinical Trials Registry (no. UMIN000005725).
Small dense low-density lipoprotein (sdLDL) has been suggested to be a potential risk factor for cardiovascular diseases (CVD).
We carried out a prospective nested case–control study in the Korean Health and Genome Study. Participants were men and women aged 40–69 years who developed CVD (n = 313), and were matched by age and sex to controls who remained free of CVD (n = 313) during the 8-years follow-up period (from 2001 to 2009). LDL subfractions were analyzed in frozen samples collected from the 626 participants using polyacrylamide tube gel electrophoresis.
Patients with CVD had a significantly higher glycated hemoglobin level compared with the controls (5.72 vs 5.56). The proportion of patients with diabetes mellitus (DM) was higher in those who developed CVD during follow up (8.0% vs 1.9%). The frequency of CVD according to each tertile of LDL particle size and the number of metabolic syndrome components did not differ significantly. In the multivariate analysis, DM (odds ratio 4.244, 95% confidence interval 1.693–10.640, P = 0.002) was the only independent predictive factor of CVD. LDL particle size was not associated with the risk for future CVD.
Small dense LDL might not be a significant predictor of CVD in this Korean community-based prospective cohort study.
Existing concepts and models for glucose-stimulated insulin secretion (GSIS) are overviewed and a newer perspective has been formulated toward the physiological understanding of GSIS. A conventional model has been created on the basis of in vitro data on application of a square wave high glucose in the absence of any other stimulatory inputs. Glucose elicits rapid insulin release through an adenosine triphosphate-sensitive K+ channel (KATP channel)-dependent mechanism, which is gradually augmented in a KATP channel-independent manner. Biphasic GSIS thus occurs. In the body, the β-cells are constantly exposed to stimulatory signals, such as glucagon-like peptide 1 (GLP-1), parasympathetic inputs, free fatty acid (FFA), amino acids and slightly suprathreshold levels of glucose, even at fasting. GLP-1 increases cellular cyclic adenosine monophosphate, parasympathetic stimulation activates protein kinase C, and FFA, amino acids and glucose generate metabolic amplification factors. Plasma glucose concentration gradually rises postprandially under such tonic stimulation. We hypothesize that these stimulatory inputs together make the β-cells responsive to glucose independently from its action on KATP channels. Robust GSIS in patients with a loss of function mutation of the sulfonylurea receptor, a subunit of KATP channels, is compatible with this hypothesis. Furthermore, pre-exposure of the islets to an activator of protein kinase A and/or C makes β-cells responsive to glucose in a KATP channel- and Ca2+-independent manner. We hypothesize that GSIS occurs in islet β-cells without glucose regulation of KATP channels in vivo, for which priming with cyclic adenosine monophosphate, protein kinase C and non-glucose nutrients are required. To understand the physiology of GSIS, comprehensive integration of accumulated knowledge is required.
Previous studies have suggested that chromium (Cr) is an essential cofactor for normal carbohydrate metabolism and affects insulin sensitivity, especially in rodent models. Several factors, such as insulin challenge, high carbohydrate intake, and response to stress (e.g., in obesity), alter Cr excretion or distribution. Glucagon is known to regulate carbohydrate metabolism and hyperglucagonemia plays a role in the development of hyperglycemia in diabetic subjects.
In the present study we investigated possible modulation of Cr levels by glucagon using an obese mouse model. Mice were kept on a high-fat diet and then used as an obesity model. These obese mice were injected with one dose of glucagon or insulin and Cr levels in their tissues were determined.
In obese mice, glucagon challenge significantly increased Cr levels in bone but decreased them in the fat and liver. In contrast, insulin challenge significantly decreased Cr levels in bone but increased them in the fat, liver and muscle.
The results show that glucagon and insulin have opposite effects on Cr levels in bone, fat, liver, and muscle.
To realize the effectiveness of a novel system for measuring glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET), outpatients undergoing oral glucose tolerance tests (OGTT) were investigated for the efficacy of screening for glucose intolerance using this system.
Fifty outpatients scheduled to undergo a 75-g OGTT for medical reasons were recruited to the study. An area of skin on the forearm was pretreated with microneedle arrays before the application of hydrogels for interstitial fluid extraction. Plasma glucose (PG) levels were measured every 30 min for 2 h to calculate reference (actual) AUC. The AUC was predicted by MIET on the basis of glucose extracted by the hydrogel using sodium ion levels as the internal standard.
Good correlation between MIET-predicted and reference AUCs obtained using PG levels was confirmed for a wide AUC range. By introducing a threshold level for AUC to separate glucose intolerance with peak glucose ≥180 mg/dL from normal glucose tolerance, the system was demonstrated to provide better screening accuracy compared with conventional methods that use HbA1c and fasting PG levels. The results of a questionnaire-based survey administered to the subjects suggested that this system was readily accepted by the majority as a painless monitoring method.
The findings suggest that our glucose AUC measurement system using MIET would be useful for screening of glucose intolerance. In the future, this system may prove to be a useful aid as a screen for glucose intolerance before performing an OGTT for diagnosis.
Dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antidiabetic drugs that increase incretin hormone levels to enhance blood sugar level-dependent insulinotropic effects, suppress glucagon action, and reduce bowel motility. These incretin effects are ideal for blood sugar control. However, the safety profile of DPP-4 inhibitors is not yet established. Herein, we present three cases of ileus, considered to be closely related to the use of DPP-4 inhibitors, in diabetic patients. Each of the three patients exhibited some risk of a deficiency in bowel movement; the onset of ileus was within 40 days after strengthened inhibition of DPP-4. The use of a DPP-4 inhibitor could be safe, although the cases presented herein enable us to inform the scientific community to some of the potential adverse effects of the use of DPP-4 inhibitors in select populations.
Non-alcoholic fatty liver disease (NAFLD) describes a spectrum of liver conditions from simple steatosis, steatohepatitis to end-stage liver disease. The prevalence of NAFLD has been on the rise in many parts of the world, including Asia, and NAFLD is now the liver disease associated with the highest mortality, consequent to the increased risk of cardiovascular diseases and hepatocellular carcinoma. Whereas NAFLD is an independent risk factor for type 2 diabetes, increased hepatic and peripheral insulin resistance contribute to the pathogenesis of both NAFLD and diabetes, which are associated with enhanced cardiovascular risk. Studies in humans and animal models have suggested obesity as the common link of these two diseases, likely mediated by adipose tissue inflammation and dysregulated adipokine production in obesity. In the present review, we discuss recent advances in our understanding of the role of several novel adipokines (adiponectin, adipocyte fatty acid binding protein and fibroblast growth factor-21) in the pathophysiology of NAFLD and diabetes, as well as their use as potential biomarkers and therapeutic targets for dysglycemia in NAFLD patients.
Our primary objective was to assess changes in quality of life (QOL) associated with changes in insulin regimen in patients with type 2 diabetes mellitus. Secondary objectives were to assess the reasons for and patterns of changes in insulin regimen, and the effects on glycemic control.
This 12-week, observational study included patients with type 2 diabetes mellitus (n = 625) who planned to change insulin regimen (type of insulin, injection device and/or number of injections). The primary outcome measure was a change from baseline in QOL assessed by the Insulin Therapy-Related (ITR) QOL questionnaire. The secondary outcome measures included change from baseline in plasma glycated hemoglobin (HbA1c) level, the reasons for and pattern of insulin regimen change, and change from baseline in QOL assessed by Diabetes Treatment Satisfaction Questionnaire (DTSQ).
QOL did not worsen during the study. Improvements were seen in the ITR-QOL ‘daily activities’ subscale score (baseline: 12.7 ± 2.3; week 12: 12.9 ± 2.3; P = 0.038, n = 568) and the DTSQ ‘perceived frequency of hyperglycemia’ subscale score (baseline: 3.4 ± 1.6; week 12: 3.0 ± 1.7; P < 0.001, n = 573). Glycemic control improved, as evidenced by decreased plasma HbA1c levels (baseline: 8.21 ± 1.47%; week 12: 7.85 ± 1.31%; P < 0.001, n = 606).
It was suggested that insulin regimen changes might improve glycemic control in Japanese patients with type 2 diabetes mellitus without worsening QOL. This trial was registered with ClinicalTrials.gov (no. NCT01055808).
The aim of the present study was to investigate the association between diabetes and the risk of all type dementia (ATD), Alzheimer's disease (AD) and vascular dementia (VaD).
Prospective observational studies describing the incidence of ATD, AD and VaD in patients with diabetes mellitus were extracted from PubMed, EMBASE and other databases up to January 2012. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects model. Subgroup analyses and sensitivity analysis were also carried out.
A total of 28 studies contributed to the analysis. Pooled RR of developing ATD (n = 20) was 1.73 (1.65–1.82, I2 = 71.2%), AD (n = 20) was 1.56 (1.41–1.73, I2 = 9.8%) and VaD (n = 13) was 2.27 (1.94–2.66, I2 = 0%) in patients with diabetes mellitus. Higher and medium quality studies did not show any significant difference for pooled RR for ATD, AD or VaD. Sensitivity analyses showed robustness of pooled RR among ATD, AD and VaD, showing no single study had a major impact on pooled RR.
The results showed a 73% increased risk of ATD, 56% increase of AD and 127% increase of VaD in diabetes patients.
To define a set of criteria using indices of β-cell function, including results from the glucagon stimulation test, for liraglutide introduction in patients with type 2 diabetes.
In the present retrospective cohort study, patients were included in our analysis if their β-cell function had been evaluated with a glucagon stimulation test and a 24-h urinary C-peptide (U-CPR) excretion test before switching from insulin therapy to liraglutide monotherapy. The efficacy of liraglutide was determined by the extent to which glycemic control was achieved or if glycated hemoglobin levels were maintained at <7.0% after liraglutide monotherapy for 24 weeks.
Liraglutide was effective in 36 of 77 patients. In the liraglutide-effective cases, the following parameters were higher: fasting C-peptide (CPR0) levels, C-peptide levels 6 min after glucagon stimulation (CPR6), the C-peptide index (CPI; CPR0 × 100/fasting plasma glucose) and stimulated C-peptide index (S-CPI; CPR6 × 100/plasma glucose 6 min after glucagon stimulation). U-CPR did not differ between liraglutide-effective and liraglutide-ineffective cases. Using receiver operating characteristic analysis adjusted for baseline characteristics, the independent cut-off value for effective liraglutide introduction was 0.72 for CPI and 1.92 for S-CPI.
Evaluation of β-cell function using the glucagon stimulation test is useful for determining the efficacy of liraglutide introduction in patients with type 2 diabetes.
In earlier reports, we described that transgenic (Tg) mice ubiquitously expressing cryptochrome1 (CRY1) with a mutation in cysteine414 (CRY1-AP Tg mice) show an early-onset insulin-secretory defect of diabetes mellitus resembling human maturity-onset diabetes of the young (MODY). To clarify the yet undiscovered molecular pathogenesis of diabetes mellitus in which the mutant of CRY1 is involved, we examined age-dependent characteristics of islets of CRY1-AP Tg mice.
Immunohistochemical analyses of islets were carried out for 2-, 4- and 19-week-old mice. Insulin contents in the pancreas and glucose-stimulated insulin secretion of isolated islets of mice were measured at 4 weeks. Real-time polymerase chain reaction analyses using pancreases of mice at 4 and 21 weeks-of-age were carried out.
Already at a young stage, the proliferation of β-cells was reduced in CRY1-AP Tg mice. Insulin contents and the levels of glucose-stimulated insulin secretion were lower than those of wild-type controls in CRY1-AP Tg mice at the young stage. The expression of insulin and glucose-sensing genes was reduced at the young stage. At the mature stage, altered distribution and hyperplasia of α-cells were observed in the islets of CRY1-AP Tg mice.
Architectural abnormality in islets progressed with age in CRY1-AP Tg mice. The reduced expression of insulin and glucose-sensing genes, along with the lowered proliferation of β-cells from an early stage, is a possible primary cause of early-onset insulin-secretory defect in CRY1-AP Tg mice. Our results suggest that CRY1 is crucial for the maintenance of β-cell function.
The aim of the present study was to determine whether weight reduction is associated with improvement of glycemic control in non-obese and obese subjects with or without visceral fat accumulation, whose hemoglobin A1c (A1C) is 5.6–6.4%.
A total of 798 male subjects whose A1C levels were between 5.6% and 6.4% were divided into subgroups based on body mass index (BMI) and/or estimated visceral fat area (eVFA), and were analyzed with respect to the relationships between 1-year changes in BMI (ΔBMI) and A1C (ΔA1C).
In both the BMI ≥25 and BMI <25 groups, ΔA1C correlated positively with ΔBMI (BMI ≥25 (n = 321): r = 0.236, P < 0.0001; BMI <25 (n = 477): r = 0.095, P = 0.0387) although the r-value was very small for the latter group. In addition, for the group with eVFA ≥100 cm2 (n = 436), ΔA1C correlated positively with ΔeVFA (r = 0.150, P = 0.0017), but this correlation was not found for the eVFA <100 cm2 group (n = 339, P = 0.3505). Furthermore, ΔA1C positively correlated with ΔBMI for the groups in BMI ≥25 with eVFA >100 cm2 (n = 293, r = 0.256, P < 0.0001) and BMI <25 with eVFA ≥100 cm2 (n = 145, r = 0.250, P = 0.0024), but not for the groups in BMI ≥25 with eVFA <100 cm2 (n = 28, P = 0.6401) nor BMI <25 with eVFA <100 cm2 (n = 332, P = 0.6605).
These results suggest that the assessment of visceral fat, rather than BMI, might be more important in identifying subjects in whom lifestyle intervention aiming at weight reduction could be effective to prevent diabetes. This trial was registered with University Hospital Medical Information Network Clinical Trials Registry (no. UMIN 000002391).
Evidence is emerging that exposure to persistent organic pollutants (POPs) is a risk factor for obesity-related diseases and for diabetes mellitus (DM). We found that POPs could be measured by a cell-based arylhydrocarbon receptor (AhR)-dependent reporter assay. We tested if serum AhR transactivating (AHRT) activities are a risk factor for diabetic nephropathy in people with type 2 diabetes.
We enrolled diabetic patients with normoalbuminuria (n = 36), microalbuminuria (n = 29), macroalbuminuria (n = 8) and end-stage renal disease (n = 31). Sera were tested for their AHRT activities, which were standardized by an AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and expressed as TCDD equivalents (TCDDeq pmol/L).
Mean serum AHRT activities were higher in patients with microalbuminuria (40.1 ± 7.1 pmol/L), macroalbuminuria (37.4 ± 5.5 pmol/L) and end-stage renal disease (59.1 ± 20.0 pmol/L) than in subjects with normoalbuminuria (12.7 ± 5.4 pmol/L; P < 0.05 for all comparisons). Serum AhR ligands showed a correlation with estimated glomerular filtration rate (eGFR; r = −0.663, P < 0.001), serum creatinine level (r = 0.635, P < 0.001), systolic blood pressure (r = 0.223, P = 0.026), glycated hemoglobim (r = 0.339, P < 0.001) and diabetic duration (r = 0.394, P < 0.001). In a multiple regression analysis, diabetic nephropathy was found to be an independent risk factor for higher AHRT activity after controlling for the confounding factors.
The present findings suggest serum AHRT activity, thus serum AhR ligands, is a risk factor for diabetic nephropathy. Further studies are required to clarify if an accumulation of POPs in the body is causally related to diabetic nephropathy.
Type 2 diabetes is characterized by dysregulation of immunity, oxidative stress and reduced incretin effects. Experimental studies suggest that glucagon-like peptide (GLP-1) might have immunomodulating effects. We hypothesize that GLP-1 receptor agonist, exendin-4, might reduce inflammatory response in type 2 diabetes.
Using peripheral blood mononuclear cells (PBMC) sampled from 10 type 2 diabetes and 10 sex- and age-matched control subjects and supernatants from PBMC culture, the expression of phospho-mitogen activated protein kinase (MAPK) signaling pathways in CD4+ T helper lymphocytes and monocytes was analyzed using flow cytometry. Cytokines/chemokines and superoxide anion before and after treatment with exendin-4 were measured by cytometric bead array and chemiluminesence assay, respectively.
Compared with control subjects, PBMC from type 2 diabetes patients showed activated MAPK (P38, c-Jun NH2-terminal protein kinase and extracellular signal-regulated kinase) signaling pathway, elevated superoxide anion, increased pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) and chemokines (CCL5/regulated on activation normal T-cell expressed and secreted and CXCL10/interferon-γ-induced protein 10). These changes were attenuated by exendin-4, possibly through the suppression of p38 MAPK.
These results suggest that exendin-4 might downregulate pro-inflammatory responses and reduce oxidative stress by suppressing MAPK signaling pathways in type 2 diabetes.
The aim of the preset study was to investigate the effectiveness of structured self-monitoring of blood glucose (SMBG) in insufficiently controlled insulin-treated diabetes. A total of 86 insulin-treated patients were randomized to a routine testing group (RTG; n = 43) and a structured testing group (STG; n = 43). The STG used a chart to record seven-point blood glucose (BG) profile on three consecutive days per month. The primary end-point was the glycated hemoglobin (HbA1c) at 3 months and 6 months. There were no significant differences of HbA1c between the RTG and STG at 3 months. However, the STG had significantly improved HbA1c at 6-month follow-up compared with the RTG (P = 0.002). In the STG, HbA1c decreased by 0.5% from 7.9 (SD 0.5) to 7.4 (0.7)%, whereas it decreased by 0.1% in the RTG from 7.9 (0.5) to 7.8 (0.7)%. In the STG, 55% of the patients were willing to continue structured SMBG and they achieved a 0.7% decrease of HbA1c. The present findings suggest that structured SMBG significantly improves glycemic control.
The aim of the present study was to investigate whether non-surgical periodontal treatment reduces glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels in diabetic patients.
An electronic search was carried out on MEDLINE (through PubMed interface), EMBASE and the Cochrane Central Register of Controlled Trials. Randomized controlled trials with a minimum of 3 months follow up were included. The risk of bias was assessed for each study. A meta-analysis was carried out to evaluate the effect of non-surgical periodontal treatment on HbA1c and FPG levels. The effect of the adjunctive use of antimicrobials was also assessed.
A total of 15 studies were included. A reduction of −0.38% (95% confidence interval [CI] −0.23 to −0.53) after 3–4 months (P < 0.001) and of −0.31% (95% CI 0.11 to −0.74) after 6 months (P = 0.15) of follow-up was found for HbA1c, favoring the treatment group. Similarly, in treated patients, a significantly greater decrease in FPG was observed in respect to control participants. Such difference amounted to −9.01 mg/dL (95% CI −2.24 to −15.78) after 3–4 months (P = 0.009) and −13.62 mg/dL (95% CI 0.45 to −27.69) after 6 months (P = 0.06) from treatment, respectively. In participants treated with adjunctive antimicrobials, a non-significant increase of HbA1c was observed 3 months after treatment, whereas FPG decreased by 0.27 mg/dL (95% CI 39.56 to −40.11; P = 0.99).
The meta-analysis showed that non-surgical periodontal treatment improves metabolic control in patients with both periodontitis and diabetes.
The Kir6.2 E23K polymorphism was studied with a special reference to secondary sulfonylurea (SU) failure in non-obese patients with type 2 diabetes.
We recruited 278 non-obese (body mass index ≤30.0 kg/m2) Japanese patients with type 2 diabetes who had a history of SU treatment (for 11.2 ± 6.3 years) and compared the frequency of the secondary SU failure among the genotypes of the polymorphism. Genotyping of the Kir6.2 E23K was carried out by polymerase chain reaction-restriction fragment length polymorphism.
The genotype frequencies of the polymorphism were similar to those previously reported in Japanese patients with type 2 diabetes. The frequency with which patients deteriorated into secondary SU failure was significantly higher in those with the KK genotype than those with EE or EK genotypes. Among 214 patients who eventually received insulin therapy because of secondary SU failure, the period of SU treatment in those with the KK genotype was significantly shorter than those with the EE or EK genotype, although the period from diagnosis to the start of SU treatment was not significantly different.
These data suggest that the Kir6.2 E23K polymorphism is related to the acceleration of secondary SU failure in non-obese Japanese patients with type 2 diabetes.
We investigated the prevalence, treatment and control of diagnosed diabetes in Korean adults from 1998 to 2010.
The Korean Ministry of Health and Welfare carried out the Korean National Health and Nutrition Examination Survey (KNHANES) in the years 1998 (I), 2001 (II), 2005 (III), 2007–2009 (IV) and 2010 (V). We estimated the prevalence of diagnosed diabetes in Korean adults and the proportions of well-controlled diabetes, as defined by having glycosylated hemoglobin <7.0%, blood pressure <130/80 mmHg and low density lipoprotein (LDL) cholesterol <100 mg/dL according to the American Diabetes Association.
The prevalence of diagnosed diabetes increased significantly from 3.2% in 1998 to 6.4% in 2010 (P < 0.0001). The prevalence of adults with diagnosed diabetes achieving blood pressure and LDL cholesterol target levels increased from 23.8% to 54.2% (P < 0.0001), and 25.7% to 47.7% (P<0.0001), respectively. However, the percentage of patients achieving glycemic goals did not increase significantly from 42.5% to 49.1% (P = 0.3034). Furthermore, there were significant increases in the proportions of individuals achieving all three target levels, from 2.7% in 2005 to 8.7% in 2010 (P < 0.0001).
The prevalence of diagnosed diabetes in Korea increased significantly from 1998 to 2010. The percentages of those achieving all recommendations of the American Diabetes Association have increased, but are still not satisfactory.
To identify upper limit post-load 1-h plasma glucose (1-h PG) after 75-g oral glucose test in a Japanese population.
A total of 918 subjects were enrolled. We divided the subjects into two groups: normal 2-h post-load plasma glucose (2-h PG; <140 mg/dL) and impaired 2-h PG group (≥140 mg/dL).
A total of 417 subjects had normal 2-h PG and 501 had impaired 2-h PG. The receiver operating characteristic (ROC) curve showed that the optimal cut-off value of 1-h PG was 179 mg/dL (area under ROC curve = 0.89), providing that the sensitivity, specificity, and positive and negative predictive value were 85, 79, 82 and 83%, respectively. The subjects with 1-h PG < 179 mg/dL consisted of 0.5% diabetes and 99.5% non-diabetes, whereas those with 1-h PG ≥ 179 mg/dL consisted of 26.9% diabetes and 73.1% non-diabetes (P < 0.01). Furthermore, there was a significant correlation between 1-h PG and 2-h PG (r2 = 0.57, P < 0.01).
These data suggested that 179 mg/dL is the upper limit of the normal range of post-load of 1-h PG in a Japanese population. Thus, the subjects with 1-h PG ≥ 179 mg/dL might be at risk of developing future diabetes. Therefore, appropriate prospective study should be carried out to test this hypothesis.
Recently, patient-tailored statin therapy was proven effective for achieving target low-density lipoprotein (LDL) cholesterol levels. It is unclear, however, whether this therapeutic modality would be effective for atherogenic lipid profiles and inflammation in patients with type 2 diabetes.
The present study was an 8-week, multicenter, single-step titration trial of patient-tailored atorvastatin therapy (10, 20 and 40 mg) according to baseline LDL cholesterol levels in 440 patients with type 2 diabetes. We measured the LDL particle size by polyacrylamide gel electrophoresis, and used high-sensitivity C-reactive protein (hsCRP) and adiponectin as surrogate markers of inflammation.
In the intention-to-treat analysis, 91% of the patients achieved their LDL cholesterol targets (<2.6 mmol/L) at week 8. There were significant reductions at week 8 in total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (HDL) cholesterol, and the total cholesterol:HDL cholesterol ratio compared with the baseline values for all of the doses. The mean LDL particle size was significantly increased, and the small, dense LDL cholesterol levels were decreased in a dose-dependent manner over the study period. In addition, the hsCRP levels were decreased in those high-risk patients with baseline hsCRP levels over 3 mg/L (P < 0.001), and the adiponectin levels tended to increase with all of the doses (P = 0.004) at 8 weeks.
Patient-tailored atorvastatin therapy based on LDL cholesterol at baseline was effective in ameliorating atherogenic LDL particle size and inflammation, in addition to achieving the target LDL cholesterol level without an undesirable effect on glycemic control in patients with type 2 diabetes. This trial was registered with ClinicalTrials.gov (no. NCT01239849).
Sleep disturbances caused by painful diabetic neuropathy (PDN) might have substantial impacts on the multifaceted aspects of PDN, including quality of life. There are no convincing data on the validation or reliability of sleep problem measurements in patients with PDN in Korea. This large population-based cross-sectional study examined psychometric properties of the Medical Outcomes Study (MOS) Sleep Scale in patients with PDN in Korea.
Measurements of patient-reported outcomes (Brief Pain Inventory-short form, MOS Sleep Scale and EuroQoL Health [EQ-5D]) were documented. PDN was diagnosed if the average daily pain intensity was ≥4 based on the visual analog scale or if patients were taking medication for their current pain.
There were 577 patients with PDN (41.6% with diabetic peripheral neuropathy). The internal consistency of reliability for the MOS Sleep Scale was 0.80 as measured by Cronbach's alpha. The extent to which multiple items in a dimension were intercorrelated and formed a dimension measuring the same underlying concept (Pearson's correlation coefficient) ranged from 0.24 to 0.71 (all P < 0.001). Each item of the MOS Sleep Scale was significantly correlated with the average pain score and the pain interference score (Pearson's correlation coefficients ranged from 0.20 to 0.28 and from 0.29 to 0.40, respectively; all P < 0.001). The correlations between the EQ-5D index and the MOS Sleep Scale ranged from −0.27 to −0.31 (all P < 0.001).
The MOS Sleep Scale showed good reliability in the evaluation of PDN in Korean type 2 diabetic patients.
Islet amyloid polypeptide (IAPP) is a main component of islet amyloid in type 2 diabetes and cosecreted from β-cell with insulin. Clinical evidence from the patients with S20G mutation of the IAPP gene, as well as experimental evidence that insulin could inhibit amyloid formation of IAPP, suggests that a gradual reduction of insulin could be related to the cytotoxicity associated with S20G-IAPP through long-term deterioration of β-cells in type 2 diabetes. Our objective was to show an effect of human insulin on S20G-IAPP associated cytotoxicity.
We analyzed the cytotoxicity associated with S20G-IAPP by controlling human insulin expression using adenovirus vectors with micro ribonucleic acid specifically against human insulin in endocrine AtT-20ins cells, which express human insulin permanently. Additionally, we carried out a follow-up study of circulating IAPP and insulin in type 2 diabetic patients.
S20G-IAPP expression was associated with a decrease in viability and an increase in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling-positive cells in AtT-20ins cells. Furthermore, downregulation of human insulin enhanced the cytotoxicity associated with S20G-IAPP, and induced the cytotoxicity associated with wild-type (WT)-IAPP. Reduction of ubiquitin carboxy-terminal hydrolase L1 activity enhanced cytotoxicity under the downregulation of human insulin expression in both S20G- and WT-IAPP transduced cells. A 5-year follow up of type 2 diabetic patients showed a disproportionate increase of serum fasting IAPP-to-insulin ratio from baseline.
Human insulin plays a protective role against the cytotoxicity associated with S20G-IAPP, as well as WT-IAPP. The findings could suggest long-term deterioration of insulin secretion associates with IAPP linked cytotoxicity in type 2 diabetes.
The aim of the present study was to evaluate the predictive ability of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and body fat percentages (BF%) for the presence of cardiometabolic risk factors, namely type 2 diabetes (DM), hypertension (HTN), dyslipidemia and metabolic syndrome (MS).
A total of 2293 subjects aged ≥20 years from rural Bangladesh were randomly selected in a population-based, cross-sectional survey. The association of anthropometric indicators with cardiometabolic risk conditions was assessed by using receiver operating characteristic curve analysis and adjusted odds ratios (ORs) for DM, HTN, dyslipidemia and MS.
Area under the curve cut-off values showed that the association of WHR, BF% and WC was higher than that for other indices for DM, HTN and MS, respectively, for both sexes, and WHtR for men and WHR for women for dyslipidemia. The ORs were highest for WHR for DM and WC for MS for both sexes, and WHtR for men and WC for women for HTN and dyslipidemia, respectively. The optimal cut-off values for obesity for the present study in men and women showed BMIs of 22 and 22.8 kg/m2, WHRs of 0.93 and 0.87, WHtRs of 0.52 and 0.54, BF% of 21.4 and 32.4%, and WCs of 82 and 81 cm, except for MS, which were 90 for men and 80 for women.
Compared with BMI, measures of central obesity, particularly WHR, WC, WHtR and BF%, showed a better association with obesity-related cardiometabolic risk factors for both sexes.
The combination therapy of dipeptidyl-peptidase (DPP)-4 inhibitor and α-glucosidase inhibitors (α-GIs) is highly effective in suppressing postprandial hyperglycemia. The aim of the present study was to compare the effects of voglibose and miglitol on glucose fluctuation, when used in combination with DPP-4 inhibitor by using continuous glucose monitoring (CGM).
In a randomized cross-over study, 16 patients with type 2 diabetes who presented with postprandial hyperglycemia despite alogliptin (25 mg) were treated with voglibose (0.9 mg) or miglitol (150 mg). We measured standard deviation (SD); mean amplitude of glycemic excursions (MAGE), and mean, minimum and maximum glucose measured by CGM during three phases (alogliptin monotherapy, dual therapy of alogliptin and voglibose, and dual therapy of alogliptin and miglitol). The primary outcome measure was SD between α-GIs.
SD was significantly improved by the addition of either voglibose (18.9 ± 10.1) or miglitol (19.6 ± 8.2) to alogliptin monotherapy (36.2 ± 8.7). MAGE improved significantly with the addition of either voglibose (57.5 ± 26.1, P < 0.01) or miglitol (64.6 ± 26.2, P < 0.01) to alogliptin monotherapy (101.5 ± 21.5). There was no significant difference in glucose fluctuation between α-GIs. There were no differences between two groups in mean (132.6 ± 21.4 and 138.7 ± 25.4) and maximum (184.3 ± 48.7 and 191.9 ± 38.3). The minimum glucose under alogliptin plus voglibose (94.9 ± 20.2) was significantly lower than that under alogliptin and miglitol (105.3 ± 21.0).
Glucose fluctuation was improved by the addition of voglibose or miglitol to alogliptin. Glucose fluctuations and postprandial hyperglycemia were similar between α-GIs. This trial was registered with the University Hospital Medical Information Network (no. UMIN R000010028).
Recent studies have shown the association between blood pressure variability and cardiovascular events. The present study was designed to investigate the relationship between antihypertensive drug class and home blood pressure variability in patients with type 2 diabetes.
We compared home blood pressure variability among patients treated with calcium channel blockers (n = 44), with angiotensin II receptor blockers and/or angiotensin-converting enzyme inhibitors (n = 159), and with calcium channel blockers combined with angiotensin II receptor blockers and/or angiotensin-converting enzyme inhibitors (n = 183). Next, we analyzed the effect of calcium channel blockers on morning blood pressure variability using multiple linear regression analysis.
Coefficient variation of morning systolic blood pressure in patients treated with calcium channel blockers was significantly lower than that in patients treated with angiotensin II receptor blockers and/or angiotensin-converting enzyme inhibitors (P = 0.036). Multivariate linear regression analyses showed that treatment with calcium channel blockers was significantly correlated with coefficient variation of morning systolic blood pressure (β = −0.264, P = 0.001).
The present study implies a possibility for validity on selecting calcium channel blockers in hypertensive patients with type 2 diabetes to reduce home blood pressure variability.
We investigated the cut-off point of the Matsuda Index in Japanese according to the guideline from the Clinical and Laboratory Standards Institute. A total of 1,596 subjects free from medications for diabetes mellitus, dyslipidemia and/or hypertension, and without cardiovascular diseases or chronic renal failure underwent a health check-up and oral glucose tolerance test (OGTT). We recruited 204 healthy reference individuals with normal glucose tolerance without obesity, any component of metabolic syndrome or elevated alanine aminotransferase. The Matsuda Index was calculated with 0- and 120-min data during OGTT. As the index was not normally distributed (P < 0.001 by the Shapiro–Wilk test), the log-transformed value (P = 0.876 by the Shapiro–Wilk test) was used. The mean ± 2 standard deviations were taken as the reference limits. The lower reference limit of the Matsuda Index was then calculated to be 4.3. Our result shows that a Matsuda Index <4.3 indicates the presence of insulin resistance in Japanese.
We aimed at estimating the prevalence and at identifying the frequent comorbidities of diabetes mellitus in a region of northeastern Italy from administrative health data.
The prevalence was estimated according to two disease definitions, based on administrative health data. Association rule mining was used to detect comorbid diagnoses that coexisted with a diagnosis of diabetes among patients admitted to the regional hospitals.
The prevalence of known diabetes in 2010 was 6.0–8.1%, with great variations by age class (from approximately 2% <60 years to more than 20% in some elderly age groups). Of 155,494 patients admitted to the hospital in 2011, 9,358 had a diagnosis of diabetes. A total of 12 rules satisfied our criteria for support (>0.5%) and confidence (>5%), and identified nine frequent isolated comorbidities and three pairs of comorbid diagnoses. The rule with the highest support (2.4%) and confidence (39.5%) identified the combination of diabetes and essential hypertension.
Association rule mining was useful, because it showed the complexity of diabetic patients. Clinical management of those patients cannot neglect comorbidities.
To determine the prevalence and risk factors of retinopathy and validity of the current diagnostic cut-offs for diabetes by using data of health check-up examinees.
The study comprises 1,864 Japanese who participated in the general health check-up program and did not have a previous history of cardiovascular disease. Non-mydriatic 45° digital fundus photographs were taken twice annually. Multivariate logistic regression model was used to identify risk factors for retinopathy in participants without previously diagnosed diabetes.
The overall prevalence of retinopathy in participants with and without previously diagnosed diabetes were 23.3% (28/120) and 4.2% (74/1,744), respectively. Univariate logistic regression analysis identified age, systolic blood pressure (SBP), fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) as risk factors for retinopathy. Multivariate logistic regression analysis showed that FPG or both HbA1c and SBP were significant, positive and independent risk factors for retinopathy. The prevalence of retinopathy increased with deterioration of glucose categories (P < 0.001 for FPG or HbA1c). However, a statistically significant increased risk of retinopathy remained only in participants with FPG ≥ 7.0 mmol/L or HbA1c ≥ 6.5% compared with those with the lowest quartile of glucose in the participants without previously diagnosed diabetes after adjusting for age and SBP.
The prevalence of retinopathy was 4.2%, and FPG or both HbA1c and SBP were positive and independent risk factors for retinopathy in health check-up examinees without previously diagnosed diabetes. The FPG 7.0 mmol/L or HbA1c 6.5% seems to be appropriate to diagnose diabetes in view of its association with retinopathy.
‘Morningness’ and ‘eveningness’ represent the sleep–wake patterns of the circadian rhythm might also affect glycemic control in patients with type 2 diabetes. The aim of this study was to examine the relationship between the morningness–eveningness trait and metabolic parameters.
The study participants comprised 101 Japanese male workers with type 2 diabetes treated in an outpatient clinic. Blood samples were obtained, and a morningness–eveningness questionnaire (MEQ), where a high score represents morningness; and the Pittsburg Sleep Quality Index (PSQI), where the higher the score the worse the sleep quality, were carried out.
MEQ correlated positively with age, and high-density lipoprotein cholesterol (HDL-C), and negatively with glycated hemoglobin (HbA1c) and PSQI. Multivariate regression analysis showed that MEQ was significantly associated with HbA1c and HDL-C. In addition, we classified the study patients into three groups: ‘morning type’, ‘neither type’ and ‘evening type’ according to the sum of the MEQ score, and analyzed the difference between morning type (n = 32) and evening type (n = 11). We found that HbA1c, low-density lipoprotein cholesterol and PSQI of the morning type group were significantly lower than those of the evening type group.
The present study suggests that ‘eveningness’ type male Japanese workers with type 2 diabetes suffer inadequate glycemic control.
A growing body of evidence from observational studies and meta-analyses of the data suggest that diabetes mellitus is associated with an increased risk of cancer. Meta-analyses have shown that diabetes increases the risks of total cancer, and of site-specific cancers of the breast, endometrium, bladder, liver, colorectum and pancreas, and that it decreases the risk of prostate cancer. Insulin resistance and secondary hyperinsulinemia is the most frequently proposed hypothesis, and hyperglycemia itself might promote carcinogenesis. In addition to several facets of lifestyle including obesity, smoking and lack of exercise, treatment for diabetes might affect the risk of cancer. For instance, metformin, an insulin sensitizer, reportedly has a potential anticancer effect. In light of the exploding global epidemic of diabetes, even a modest increase in the cancer risk will translate into a substantial socioeconomic burden. The current insights underscore the need for clinical attention and better-designed studies of the complex interactions between diabetes and cancer.
Type 2 diabetes is one of the most common complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Recently, large-scale genome-wide association (GWA) studies have successfully identified genetic loci robustly associated with type 2 diabetes by searching susceptibility variants across the entire genome in an unbiased, hypothesis-free manner. The number of loci has climbed from just three in 2006 to approximately 70 today. For the common type 2 diabetes-associated variants, three features have been noted. First, genetic impacts of individual variants are generally modest; mostly, allelic odds ratios range between 1.06 and 1.20. Second, most of the loci identified to date are not in or near obvious candidate genes, but some are often located in the intergenic regions. Third, although the number of loci is limited, there might be some population specificity in type 2 diabetes association. Although we can estimate a single or a few target genes for individual loci detected in GWA studies by referring to the data for experiments in vitro, biological function remains largely unknown for a substantial part of such target genes. Nevertheless, new biology is arising from GWA study discoveries; for example, genes implicated in β-cell dysfunction are over-represented within type 2 diabetes-associated regions. Toward translational advances, we have just begun to face new challenges – elucidation of multifaceted (i.e., molecular, cellular and physiological) mechanistic insights into disease biology by considering interaction with the environment. The present review summarizes recent advances in the genetics of type 2 diabetes, together with its realistic potential.
Zinc-α2-glycoprotein (ZAG) is associated with the loss of adipose tissue in cancer cachexia, and has recently been proposed to be a candidate factor in the regulation of bodyweight. The aim of the study was to investigate the effects of ZAG on the proliferation and differentiation of 3T3-L1 preadipocytes.
3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) spectrophotometry, Oil Red O staining, intracellular triglyceride assays, real-time quantitative reverse transcription polymerase chain reaction and transient transfection methods were used to explore the action of ZAG.
Ectopic ZAG expression significantly stimulates 3T3-L1 cells proliferation in a dose- and time-dependent manner. The maximum influence of ZAG on proliferation was 1.43-fold higher than what was observed in control cells. This effect was observed 144 h after transfection with 0.16 μg of murine ZAG (mZAG) plasmid (P < 0.001). The intracellular lipids content in mZAG over-expressing cells were decreased as much as 37% when compared with the control cells after differentiation (P < 0.05, P < 0.01). The messenger ribonucleic acid levels of peroxisome proliferators-activated receptor-γ (PPARγ), CCAAT enhancer-binding protein-α (C/EBPα) and the critical lipogenic gene, fatty acid synthase (FAS), are also downregulated by up to 50% in fully differentiated ZAG-treated adipocytes. ZAG suppresses FAS messenger ribonucleic acid expression by reducing FAS promoter activity.
Zinc-α2-glycoprotein stimulates the proliferation and inhibits the differentiation of 3T3-L1 murine preadipocytes. The inhibitory action of ZAG on cell differentiation might be a result of the attenuation of the expression of PPARγ, C/EBPα and the lipogenic-specific enzyme FAS by reducing FAS promoter activity.
This cohort study of middle-aged Japanese participants investigated the relationship between family history of diabetes, the incident risk of type 2 diabetes and the interaction of these variables with other factors.
Study participants were 3,517 employees (2,037 men and 1,480 women) of a metal products factory in Japan. Baseline health examinations included questions about medical history, physical examination, anthropometric measurements, questions about lifestyle factors, such as smoking, alcohol consumption and habitual exercise, and a self-administered diet history questionnaire. Family history of diabetes was defined as having at least one-first-degree relative with diabetes. The incidence of diabetes was determined in annual medical examinations over a 7-year period. Hazard ratios (HRs) for type 2 diabetes were estimated by Cox proportional hazards analysis.
Of the 3,517 participants, 630 (18%) had a family history of diabetes mellitus. During the study, 228 participants developed diabetes. The age and sex-adjusted HR for type 2 diabetes in participants with a family history of diabetes was 1.82 (95% confidence interval 1.36–2.43) as compared with those without a family history of diabetes. HRs did not change after adjustment for body mass index and lifestyle factors. We found no interactions with body mass index, insulin resistance, pancreatic β-cell function or lifestyle factors.
Family history of diabetes was associated with the incident risk of diabetes, and these associations were independent of other risk factors, such as obesity, insulin resistance, and lifestyle factors in Japanese men and women.
The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel is a key component of insulin secretion in pancreatic β-cells. Activating mutations in ABCC8 encoding for the sulfonylurea receptor subunit of the KATP channel have been associated with the development of neonatal diabetes mellitus (NDM). The aim was to investigate clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent NDM (PNDM).
The coding regions and conserved splice sites of KCNJ11, ABCC8 and INS were screened for mutations in a 12-year-old girl diagnosed with PNDM. The functional property of the mutant channel identified was examined with patch-clamp experiments in COS-1 cells. We also investigated the difference of effectiveness between two groups of oral sulfonylureas in vitro and in the patient.
We identified a heterozygous missense mutation (c.3593 C>T, Pro1198Leu) in ABCC8. The mutated residue (P1198) is located within a putative binding site of sulfonylureas, such as tolbutamide or gliclazide. In patch-clamp experiments, the mutant channel was less ATP sensitive than the wild type. Furthermore, the sensitivity to tolbutamide was also reduced in the mutant channel. In addition to the tolbutamide/gliclazide binding site, glibenclamide is thought to also bind to another site. Glibenclamide was more effective than other sulfonylureas in vitro and in the patient. The treatment of the patient was finally able to be switched from insulin injection to oral glibenclamide.
We identified the Pro1198Leu ABCC8 mutation in a PNDM patient, and clarified the functional and clinical characterization. The present findings provide new information for understanding PNDM.
To assess the impact of smoking on impaired insulin secretion and insulin resistance in Japanese men.
This study included 1,199 men aged 30–79 years without diabetes, impaired insulin secretion and insulin resistance at baseline who underwent a comprehensive medical check-up between April 2006 and March 2007 at Saku Central Hospital. Smoking status was categorized as current, ex-smoker and never-smoker. Insulinogenic index and homeostasis model assessment-insulin resistance were determined using a standard 75-g oral glucose tolerance test. The Japan Diabetes Society criteria were used to define impaired insulin secretion and insulin resistance. Participants were followed up until March 2011.
A total of 449 and 99 men developed impaired insulin secretion and insulin resistance during 3,403 and 4,092 person-years follow up, respectively. The multivariable-adjusted hazard ratios (HRs) for impaired insulin secretion were 1.06 (95% confidence interval [CI] 0.84–1.33) in ex-smokers and 1.95 (95% CI 1.44–2.63) in current smokers compared with never-smokers after adjustment for age, familial history of diabetes, alcohol consumption, exercise, systolic blood pressure, triglyceride, γ-glutamyltransferase, waist circumference, leukocyte count, changes in smoking status and changes in waist circumference. The number of pack-years was positively associated with the risk for impaired insulin secretion in a dose-dependent manner (P-values for trend <0.001). The multivariable-adjusted HRs for insulin resistance were 0.95 (95% CI 0.56–1.61) in ex-smokers and 1.11 (95% CI 0.67–1.79) in current smokers compared with never-smokers.
Cigarette smoking is a modifiable risk factor for impaired insulin secretion. The findings might also be important for other Asian populations, which have low insulin secreting ability.
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.
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.
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.
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.
Many patients with diabetes now use 5-, 6- or 8-mm needles for insulin injection. However, it is unclear whether needle length, particularly for shorter needles, affects the pharmacokinetic properties of insulin.
This was a three-way, randomized, cross-over, single-center study involving 12 healthy Japanese adult males (age 27.4 ± 4.14 years; weight 64.2 ± 5.2 kg; body fat percentage 18.2 ± 1.5%). Participants received a subcutaneous (abdomen) dose of insulin lispro (1.5 U for participants weighing 55 to <65.0 kg; 2.0 U for participants weighing 65.0 to <80.0 kg) delivered using a 32-G × 4 mm (32G × 4), 31-G × 8 mm (31G × 8) or 32-G × 6 mm (32G × 6) needle with a 3–7-day washout between doses. Pharmacokinetic parameters of exogenous insulin were identified using non-linear least squares, where the total insulin concentration was fit to the measured plasma insulin concentration using an overall combined model that accounted for C-peptide/insulin secretion in addition to the injected dose.
Maximum concentration and area under the curve for 0 to infinity min for insulin were bioequivalent for the 32G × 4 needle relative to the 32G × 6 and the 31G × 8 needles. The time to the maximum insulin concentration was bioequivalent for the 32G × 4 needle relative to the 32G × 6 needle, but not the 31G × 8 needle.
The use of 4-mm needles is unlikely to change the pharmacokinetic properties of insulin when injected subcutaneously in adults. This trial was registered with UMIN-CTR (no. UMIN000004469).
The distinct effects of different statins on glycemic control have not been fully evaluated. In this open-label, prospective, cross-over clinical trial, we compared the effects of pitavastatin and atorvastatin on glycemic control in type 2 diabetic patients with hypercholesterolemia.
A total of 28 Japanese type 2 diabetics with hypercholesterolemia treated with rosuvastatin (2.5 mg/day) for at least 8 weeks were recruited to this quasi-randomized cross-over study. At study entry, the patients assigned to sequence 1 received pitavastatin (2 mg/day) for 12 weeks in period 1 and atorvastatin (10 mg/day) for another 12 weeks in period 2, whereas patients assigned to sequence 2 received atorvastatin (10 mg/day) for 12 weeks in period 1 and pitavastatin (2 mg/day) for another 12 weeks in period 2. Blood samples were collected at three visits (baseline, after 12 and 24 weeks).
Lipid control was similar in both statins. The difference in glycated hemoglobin between pitavastatin and atorvastatin treatments was −0.18 (95% confidence interval −0.34 to −0.02; P = 0.03). Compared with atorvastatin, pitavastatin treatment significantly lowered the levels of glycoalbumin, fasting glucose and homeostasis model assessment of insulin resistance.
Our results showed that treatment with pitavastatin had a more favorable outcome on glycemic control in patients with type 2 diabetes compared with atorvastatin. This trial was registered with UMIN (no. 000003554).
In order to characterize the impaired vascular function in type 2 diabetes (DM) patients, we evaluated the flow-mediated vascular dilation (FMD) with glyceryl trinitrate-mediated vascular dilation (NMD) using ultrasonography.
A total of 111 DM patients and 42 healthy control participants were studied. The maximal dilatation of FMD and NMD (%FMD and %NMD, respectively), the beginning time (T) of dilatation after stimulation and the velocity (V) of the vascular dilatation were also measured.
Among DM patients, 49% had impaired %NMD, which affects the results of %FMD. In DM patients with normal %NMD, the %FMD was also significantly lower than that in control participants, although the T and the V were not impaired. In contrast, both the T and the V were disturbed in the DM patients with low %NMD. Multiple linear regression analysis showed that %NMD was independently correlated with albuminuria. Our results indicate that the impaired FMD in DM is be affected by low NMD, and impaired endothelial function already exists even in DM patients whose vascular smooth muscle function is still retained, and also albuminuria is the clinical feature of DM with low %NMD.
Examination of NMD, not only FMD, should be carried out as it offers the possibility of clarifying vascular function in DM patients.
Discordant results about the relationship between diabetes complications and the risk of fragility fractures have been reported. Our aims were to analyze the factors related to morphometric vertebral fractures (VFs) in patients with type 2 diabetes mellitus, and to explore the association between the presence of VFs and the main cardiovascular risk factors.
We carried out a cross-sectional study including 123 patients with type 2 diabetes mellitus, and in 72 of these patients we recorded data about the risk factors for VFs and comorbidities of diabetes including diabetes-related microvascular disease and cardiovascular disease.
In the crude analysis, diabetic retinopathy (odds ratio [OR] 4.09, 95% confidence interval [CI] 1.01–12.5), ischemic heart disease (OR 5.02, 95% CI 1.1–9.7) and waist circumference (OR 1.06, 95% CI 1.006–1.114) were related to VFs. In the full model (adjusted for age, sex, body mass index), ischemic heart disease was the only determinant of VF (OR 3.33, CI 1.02–10.91, P = 0.047); whereas diabetic retinopathy did not reached significance (OR 2.27, CI 0.71–7.27, P = 0.16).
In summary, ischemic heart disease is associated with an increased risk of VFs in type 2 diabetes mellitus.
To compare the efficacy of spironolactone and trichlormethiazide, as add-on therapy to renin–angiotensin system (RAS) blockade, for reduction of albuminuria in diabetic patients with chronic kidney disease (CKD), we conducted this randomized, open-labeled, parallel-group, active-controlled, per-protocol-design study. Type 2 diabetic patients receiving an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, with persistent albuminuria (≥100 mg/g creatinine) were randomly assigned to either spironolactone (25 mg/day) or trichlormethiazide (2 mg/day). The primary outcome was the change in albuminuria at 24 weeks of treatment. In patients who completed 24 weeks of treatment with spironolactone (n = 18) and trichlormethiazide (n = 15), albuminuria decreased significantly by −57.6 ± 21.3% (SD) (P < 0.001) and −48.4 ± 27.1% (P < 0.001), respectively. There was no significant difference in the change in albuminuria between groups (P = 0.270). This pilot study suggests add-on therapy with spironolactone or trichlormethiazide to RAS blockade may be comparably beneficial to reducing albuminuria in type 2 diabetic patients. This trial was registered with UMIN-CTR (no. UMIN000008914).
Diabetes mellitus and periodontitis are closely related. A huge number of reports has addressed the effect of periodontal intervention therapy on glycemic control, but no reports have addressed the effect of glycemic intervention therapy on periodontal disease in type 2 diabetic patients. The aim of this study was to examine the effect of improved glycemic control by glycemic intervention therapy on periodontitis in type 2 diabetic patients.
A total of 35 patients underwent intervention therapy to improve glycemic control without periodontal treatment. Glycohemoglobin (HbA1c), high-sensitivity C-reactive protein (hs-CRP), bleeding on probing (BOP), probing pocket depth (PPD) and intraoral community periodontal index (CPI) codes of the World health Organization (WHO) were examined at baseline, and 2 and 6 months after the intervention therapy to improve glycemic control.
After the improvement of glycemic control, BOP lesions improved, but deep PPD lesions and WHO CPI codes did not improve. Subanalyses showed that effective glycemic control (average HbA1c reduction 1.8%) improved BOP lesions, but did not affect deep PPD lesions and WHO CPI codes. In addition, high BOP lesions at baseline responded more effectively to glycemic intervention. Further analysis of CPI codes in all individual periodontal sites independent of WHO CPI codes in 35 patients showed that only gingival inflammation without a deep periodontal pocket improved after glycemic intervention.
Effective glycemic control improves BOP lesions in type 2 diabetic patients with periodontitis through ameliorating inflammation at the gingival sites of periodontal tissue. This trial was registered with the University Hospital Medical Information Network (no. UMIN000007670).
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder including polycystic ovary morphology (PCOM), ovulatory dysfunction and hyperandrogenism. PCOS is frequently associated with type 2 diabetes mellitus; however, it is unknown whether PCOM and PCOS are prevalent in Japanese patients with type 1 diabetes mellitus. The purpose of our study was to determine the frequency of PCOM and PCOS in women with type 1 diabetes mellitus.
We evaluated clinical, hormonal and ovarian ultrasound data from 21 type 1 diabetes mellitus patients whose average glycated hemoglobin levels were 7.9 ± 1.5%.
Ultrasound identified PCOM in 11 patients (52.4%) and these patients also had higher levels of the androgen dehydroepiandrosterone sulfate (DHEA-S) than those without PCOM (P < 0.05). Of the patients with PCOM, five presented menstrual irregularities (45.5%) and three met the Japanese criteria for PCOS (27.2%); whereas all patients without PCOM had a normal menstrual cycle (P < 0.05).
Japanese premenopausal women with type 1 diabetes mellitus had a high frequency of PCOM as well as PCOS. This is the first research of this area carried out in an Asian population.