Correction to: Decline in the estimated glomerular filtration rate (eGFR) following metabolic control and its relationship with baseline eGFR in type 2 diabetes with microalbuminuria or macroalbuminuria.

[This corrects the article DOI: 10.1007/s13340-021-00517-2.].

Decline in the estimated glomerular filtration rate (eGFR) following metabolic control and its relationship with baseline eGFR in type 2 diabetes with microalbuminuria or macroalbuminuria.

AIMS: Relationship between baseline eGFR and the rate of decline in eGFR was investigated in diabetic kidney disease. MATERIALS AND METHODS: Patients with type 2 diabetes with microalbuminuria (MI) (n = 124) or macroalbuminuria (MA) (n = 81) received team-based medical care to prevent the development of diabetic kidney disease. The decline in eGFR over 4 years, divided into the first year and subsequent 3 years, was estimated by linear-mixed modeling. RESULTS: The eGFR showed a rapid decline during the first year, followed by a slower decline. On multiple regression analysis, the baseline eGFR was positively correlated with HbA1c in MI and negatively correlated with carotid plaque in MI and in MA. Subsequent eGFR decline following 1-year intervention was negatively correlated with the baseline eGFR and HbA1c level at 1 year in MI, whereas it was positively correlated with baseline eGFR and negatively correlated with the amount of proteinuria at 1 year in MA. Even in maintained baseline eGFR(≧ 60 ml/min/1.73 m2) at the first year, when HbA1c ≧ 7.5%, eGFR reduction rate and years to ESKD were much faster and shorter, compared to the group of HbA1c < 7.5% [- 3.44 (SE 1.137) vs. - 1.695 (SE 0.431) ml/min/1.73 m2/year, and 19.4 vs. 35.7 years, respectively]. In MA, lower eGFR (< 60 ml/min/1.73 m2) and higher proteinuria (≧ 2.25 g/gCre) had a much faster eGFR decline and shorter time to ESKD, compared to the group of maintained eGFR and lower proteinuria (< 2.25 g/gCre) [- 5.240 (SE 1.537) vs. - 2.67 (SE 0.997) ml/min/1.73 m2/year, and 4.41 vs. 22.8 years, respectively]. CONCLUSIONS: In MI, even in maintained eGFR, the continued increase in eGFR in response to hyperglycemia (HbA1c ≧ 7.5%) led to a faster decline in renal function and in MA, lower eGFR, with an increase in proteinuria, contributed to rapid decline of renal function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00517-2.

Usefulness of carotid plaque (sum and maximum of plaque thickness) in combination with intima-media thickness for the detection of coronary artery disease in asymptomatic patients with diabetes.

AIMS/INTRODUCTION: The usefulness of markers of carotid plaque, such as sum (PS) and maximum (P-max) of the plaque thickness, in combination with intima-media thickness in the common carotid artery (CIMT) for the detection of obstructive coronary artery disease (CAD) was investigated in patients with type 2 diabetes without known CAD. MATERIALS AND METHODS: B-mode ultrasonographic scanning of the carotid artery and multislice computed tomography coronary angiography were carried out in 332 asymptomatic patients with type 2 diabetes. RESULTS: For the presence of obstructive CAD when incorporating PS or P-max to standard risk factors in a multiple logistic regression model, the classification ability in PS and P-max increased greatly (area under the curve [AUC] 0.827 vs 0.720 [net reclassification index {NRI} = 0.652, P < 0.01] and AUC 0.820 vs 0.720 [NRI = 0.775, P < 0.01], respectively), and it in CIMT increased slightly (AUC 0.740 vs 0.720, NRI = 0.230, P = 0.041). Furthermore, the classification abilities for a model with interaction terms between PS* or P-max* and CIMT were statistically larger than those for a model without interaction terms (AUC 0.833 vs 0.827 [NRI = 0.411, P < 0.01] and 0.823 vs 0.820 [NRI = 0.269, P < 0.05], respectively). Partitioning showed the patients in the values of the PS <2.6 mm and CIMT <0.725 mm (100%), or in P-max <2.1 mm and CIMT <0.725 mm (95.4%), did not have obstructive CAD, whereas those in the values of PS ≧2.6 mm, presence of hyperlipidemia and CIMT ≧0.675 mm (84%) or those in the value of P-max ≧2.1 mm and body mass index ≧24 (91.7%) had obstructive CAD. CONCLUSIONS: Although the P-max and PS in the carotid artery were useful as detectors of CAD, combining them with CIMT provided a much superior first-line screening method in detecting CAD in asymptomatic patients with diabetes.

Pregnancy outcomes in women with type 1 and type 2 diabetes mellitus in a retrospective multi-institutional study in Japan.

The present study was performed to evaluate pregnancy outcomes in women with type 1 and type 2 diabetes mellitus (DM) in Japan. This multi-institutional retrospective study was conducted in 40 general hospitals in Japan during 2003-2009. We evaluated 369 and 579 pregnant women with type 1 and type 2 DM, respectively, and compared pregnancy outcomes between the two groups. Glycosylated hemoglobin levels in the first trimester did not differ significantly between the studied groups. Gestational weight gain was lower in type 2 DM than in type 1 DM. Although there were no significant differences in perinatal outcomes between the groups, the primary cesarean section rate was higher in type 2 DM than in type 1 DM. Multiple logistic regression analysis revealed that primigravida status, pre-gestational body mass index (BMI), gestational weight gain, chronic hypertension, and microvascular disease including diabetic retinopathy or nephropathy were associated with onset of pregnancy-induced hypertension. Further, pre-gestational BMI was associated with the need for primary cesarean section. This study demonstrated that no differences were observed in the rates of perinatal mortality and congenital malformation between pregnant women with type 1 DM and type 2 DM; however, women with type 2 DM displayed a higher risk of primary cesarean section.

Pregnancy outcomes of gestational diabetes mellitus according to pre-gestational BMI in a retrospective multi-institutional study in Japan.

The aim of this study was to determine the effects of pre-gestational body mass index on pregnancy outcomes of women with gestational diabetes in Japan. A multi-institutional retrospective study was performed. We examined pregnant women who met the former criteria for gestational diabetes in Japan, receiving dietary intervention with self-monitoring of blood glucose with or without insulin therapy. Women with gestational diabetes were divided into three groups according to pre-gestational body mass index: body mass index <25 (control group), 25 ≤ body mass index <30 (overweight group), body mass index ≥30 (obese group). Data from a total of 1,758 eligible women were collected from 40 institutions. Participants included 960 controls, 426 overweight women, and 372 obese women with gestational diabetes. Gestational weight gain was highest in the control and lowest in the obese group. The prevalences of chronic hypertension and pregnancy induced hypertension were higher in the overweight and obese groups than in the control group. Multiple logistic regression analysis revealed pre-gestational body mass index, gestational weight gain, chronic hypertension, and nulliparity to be associated with the onset of pregnancy induced hypertension, while the 75-g OGTT results were unrelated to pregnancy induced hypertension. The prevalence of large-for-gestational age was lower in infants born to obese women than in those born to overweight or control women. The present results suggest that medical interventions for obese women with gestational diabetes may contribute to reducing the prevalence of large-for-gestational age but would not achieve marked reductions in maternal complications.

Usefulness of sum of the thickness of plaque in the carotid artery for predicting the presence and the extent of the coronary artery disease in patients with type 2 diabetes mellitus without known coronary artery disease.

AIMS: The usefulness of the sum of plaque thickness in the carotid artery (plaque score; PS), as a prediction of coronary artery disease (CAD) was investigated in patients with type 2 diabetes mellitus. METHODS: B mode ultrasonographic scanning of the carotid artery and multislice computed tomography (MSCT) coronary angiography were performed in 227 diabetic patients without known cardiac disease. RESULTS: The PS was useful to predict the presence of diseased [nonobstructive and obstructive] CAD (≧3 segments) and obstructive (≧50%) CAD with cut-off value of 3.5mm (area under curve: 0.745 and 0.782, respectively), according to a receiver operating characteristics curve analysis. A multivariate logistic analysis of baseline risk factors showed that the PS was independent risk factor for the prediction of diseased and obstructive coronary artery disease (R(2)=0.2165, p<0.0001 and R(2)=0.2265, p<0.0001, respectively). The PS was most significant predictor of the number of diseased and obstructive segments of the coronary artery in a multiple regression analysis (R(2)=0.2022, p<0.0001 and R(2)=0.2209, p<0.0001, respectively). CONCLUSIONS: The PS in the carotid artery was useful for the prediction of the presence and the extent of CAD, and was most important as a screening test for the identification of a high risk group of asymptomatic diabetic patients.

Diabetic embryopathy: studies using a rat embryo culture system and an animal model.

The mechanism of diabetic embryopathy was investigated using in vitro experiments in a rat embryo culture system and in streptozotocin-induced diabetic pregnant rats. The energy metabolism in embryos during early organogenesis was characterized by a high rate of glucose utilization and lactic acid production (anaerobic glycolysis). Embryos uninterruptedly underwent glycolysis. When embryos were cultured with hypoglycemic serum, such embryos showed malformations in association with a significant reduction in glycolysis. In a diabetic environment, hyperglycemia caused an increased glucose flux into embryonic cells without a down-regulation of GLUT1 and an increased metabolic overload on mitochondria, leading to an increased formation of reactive oxygen species (ROS). Activation of the hexamine pathway, subsequently occurring with increased protein carbonylation and increased lipid peroxidation, also contributed to the increased generation of ROS. Hyperglycemia also caused a myo-inositol deficiency with a competitive inhibition of ambient glucose, which might have been associated with a diminished phosphoinositide signal transduction. In the presence of low activity of the mitochondrial oxidative glucose metabolism, the ROS scavenging system in the embryo was not sufficiently developed. Diabetes further weakened the antioxidant system, especially, the enzyme for GSH synthesis, gamma-GCS, thereby reducing the GSH concentration. GSH depletion also disturbed prostaglandin biosynthesis. An increased formation of ROS in a diminished GSH-dependent antioxidant system may, therefore, play an important role in the development of embryonic malformations in diabetes.

Apoptosis and its pathway in early post-implantation embryos of diabetic rats.

It has been reported that diabetes-induced inappropriate apoptosis in embryos during neurulation may be one of the mechanisms leading to neural tube defects. We studied apoptosis and the apoptotic pathway occurring in early post-implantation period embryos of non-diabetic and streptozotocin (STZ)-induced diabetic rats. In quantitative RT-PCR, bax mRNA was constantly expressed to similar degree in embryos of non-diabetic and diabetic rats, while the expression of bcl-2 mRNA was significantly decreased in diabetic rat embryos compared to non-diabetic rat embryos. The increased number of terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL)-positive cells occurred selectively in the primitive brains of diabetic rat embryos compared to non-diabetic rat embryos. Immunohistochemical studies revealed that, in mirror sections, the staining of Bax and activated caspase-3 were observed in the TUNEL-positive cell area, but the expression of Bcl-2 in these apoptotic cells was generally too low to be detected. These results suggest that a Bax-regulated mitochondrial cytochrome c-mediated caspase-3 activation pathway might be involved in the diabetic embryopathy.

Genome-wide linkage analysis of type 2 diabetes mellitus reconfirms the susceptibility locus on 11p13-p12 in Japanese.

Type 2 diabetes mellitus is a heterogeneous disorder, and the development of type 2 diabetes mellitus is associated with both insulin secretion defect and insulin resistance. The primary metabolic defect leading to type 2 diabetes mellitus has been thought to be varied among populations, especially in Japanese and Caucasians. Here, we have done the genome-wide scan for type 2 diabetes mellitus using 102 affected Japanese sib-pairs to identify the genetic factors predisposing to type 2 diabetes mellitus. Nonparametric linkage analysis showed one suggestive evidence for linkage to 11p13-p12 [D11S905: two-point maximum LOD score (MLS) of 2.89 and multipoint MLS of 2.32] and one nominally significant evidence for linkage to 6q15-q16 (D6S462: two-point MLS of 2.02). Interestingly, the 11p13-p12 region was reported to be a susceptibility locus for Japanese type 2 diabetes mellitus with suggestive evidence of linkage, and D11S905 was within 5 cM to D11S935 with the highest MLS in the previous linkage analysis reported. The only overlapped susceptibility region with suggestive evidence of linkage for Japanese type 2 diabetes mellitus was D11S935-D11S905 among the three reports including this study. These results taken together suggest that a susceptibility gene for type 2 diabetes mellitus in Japanese will reside in 11p13-p12.

Apoptosis in normal rat embryo tissues during early organogenesis: the possible involvement of Bax and Bcl-2.

Apoptosis commonly occurs in a variety of developmental processes in mammals. In this study, we investigated the relationship between apoptosis and the expression of both Bax and Bcl-2 during the early organogenesis period (9.5-11.5 days of gestation) of rat embryos. Apoptotic cells detected by the terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) method were extremely abundant in the foregut diverticulum at 9.5 days of gestation, while they largely disappeared at 10.5 and 11.5 days of gestation, although they were detected in newly formed mid- and hindgut diverticulum at these times. Real-time RT-PCR analysis of whole embryos revealed that the expression of bax mRNA was constant at days 9.5 to 11.5, while the expression of bcl-2 mRNA gradually increased. Immunohistochemical studies of Bax and Bcl-2 expression revealed that these apoptotic cells were exactly positive to Bax in mirror sections, while their expression of Bcl-2 was generally too low to be detected. A disappearance of apoptotic cells was associated with strong Bcl-2 expression in the foregut diverticulum at 10.5 and 11.5 days of gestation. It was similarly observed that apoptotic cells detected in the cardiogenic area at 9.5 days of gestation disappeared with the formation of the primitive heart tube--accompanied by a strong expression of both Bcl-2 and Bax--in the developmental process of the primitive heart. Apoptotic cells were also observed in the primitive brain vesicle, optic vesicle, otic vesicle, and thyroid primordium at 10.5 and 11.5 days of gestation during the developmental process, with a strong expression of Bax. These results indicate that the Bax and Bcl-2 may be important in regulating the induction of embryonic cell apoptosis during early organogenesis.