Key enzyme in charge of ketone reabsorption of renal tubular SMCT1 may be a new target in diabetic kidney disease.

OBJECTIVE: A ketogenic diet or mildly increased ketone body levels are beneficial for diabetic kidney disease (DKD) patients. Our previous study has found that sodium-coupled monocarboxylate transporter 1 (SMCT1), a key enzyme in charge of ketone reabsorption, possesses beneficial effects on the function of renal tubular epithelial cells (TECs) in energy crisis. Our present study is to investigate whether SMCT1 is important in maintaining the physiological function of renal tubular and plays a role in DKD. METHODS: We tested the expression of SMCT1 in kidney tissues from DKD patients receiving kidney biopsy as well as diabetes mice. We compared the difference of ß-hydroxybutyrate (ß-HB) levels in serum, urine and kidney tissues between diabetic mice and control. Using recombinant adeno-associated viral vector containing SMCT1 (encoded by Slc5a8 gene), we tested the effect of SMCT1 upregulation on microalbuminuria as well as its effects on mitochondrial energy metabolism in diabetic mice. Then we investigated the role of SMCT1 and its ß-HB reabsorption function in maintaining the physiological function of renal tubular using renal tubule-specific Slc5a8 gene knockout mice. Transcriptomes and proteomics analysis were used to explore the underlying mechanism. RESULTS: SMCT1 downregulation was found in DKD patients as well as in diabetic mice. Moreover, diabetic mice had a decreased renal ß-HB level compared with control, and SMCT1 upregulation could improve microalbuminuria and mitochondrial energy metabolism. In renal tubule-specific Slc5a8 gene knockout mice, microalbuminuria occurred early at 24 weeks of age, accompanied by ATP shortage and metabolic reprogramming in the kidney; however, supplementation with ß-HB precursor substance 1,3-butanediol in food alleviated kidney damage as well as energy metabolic reprogramming. CONCLUSIONS: Decreased SMCT1 expression and its ketone reabsorption function play an important role in the occurrence of DKD. SMCT1 may be a new promising target in treating DKD.

A J-shaped relationship between ketones and the risk of diabetic kidney disease in patients with type 2 diabetes: New insights from a cross-sectional study.

AIM: To investigate the association between circulating ß-hydroxybutyric acid (ßOHB) and diabetic kidney disease (DKD) risk in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 1388 patients with T2D were recruited. Participants were divided into high and normal ßOHB groups. Participants in the normal ßOHB group were divided into four subgroups according to ßOHB quartile (Q). The relationships of ßOHB with DKD and DKD subtype were analysed using chi-square and binary logistic regression. Restricted cubic splines were used to explore the non-linear correlation between ßOHB concentration and DKD risk in the total population. RESULTS: A higher prevalence of DKD was detected in the high compared with the normal ßOHB group (43.3% vs. 33.3%, P = .041). Participants in the Q4 group (ßOHB, 0.12-0.30 mM) had the lowest prevalence of DKD (P = .001). In the binary logistic regression model, the multivariable-adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for DKD risk were 2.30 (1.62-3.26) for Q1, 1.80 (1.23-2.62) for Q2 and 1.63 (1.10-2.41) for Q3 relative to Q4 (P < .001). Restricted cubic spline analyses suggested a J-shaped association of circulating ßOHB concentration with DKD risk. DKD risk was lowest at a serum ßOHB concentration of 0.183 mM (OR, 0.63; 95% CI, 0.52-0.77). CONCLUSIONS: A J-shaped relationship between circulating ketone level and DKD risk in patients with T2D was determined. Circulating ßOHB in the range of 0.12-0.30 mM was associated with a lower risk of DKD. Further studies are warranted to verify the causality and to elucidate the underlying mechanisms.

Identifying optimal ranges of weight gain at the end of the second trimester result from a population-based cohort study.

OBJECTIVE: To identify the optimal weight gain at the end of the second trimester. DESIGN: This was a population-based cohort study from the antenatal care system in Tianjin, China. We calculated gestational weight gain (GWG) based on the weight measured in the first trimester and the end of the second trimester. Restricted cubic spline analysis was performed to model the possible non-linear relationships between GWG and adverse outcomes. The optimal GWG was defined as the value of the lowest risk. Non-inferiority margins and the shape of the spline curves identified the recommended ranges in Chinese-specific BMI categories. SETTING: Tianjin Maternal and Child Health Cohort. PARTICIPANTS: Singleton pregnant women aged 18-45 years. RESULTS: In total, 69 859 pregnant women were included. Adverse outcome (including stillbirth, preterm birth, hypertensive disorders of pregnancy, gestational diabetes mellitus, small and large for gestational age) was significantly associated with GWG at the end of the second trimester. The risk score was non-linearly correlated with GWG in the underweight, normal weight and overweight groups. GWG at the end of the second trimester should not be < 7 kg in underweight group. For most normal-weight women, a GWG of about 8 kg is optimal. Pregnant women who are overweight should not have a GWG of more than 9 kg. We advised women with overweight and obesity to keep positive growth of GWG (> 0 kg) in the first and second trimesters. CONCLUSIONS: According to the comprehensive adverse maternal and infant outcomes, we recommend the optimal GWG at the end of the second trimester. This study may provide a considerable reference for weight management.

Relationship between inflammatory markers and mild cognitive impairment in Chinese patients with type 2 diabetes: a case-control study.

BACKGROUND: Several studies have indicated that inflammatory markers were associated with the risk of mild cognitive impairment (MCI) in type 2 diabetes (T2D). Serum folate was related to MCI as well as inflammation. However, no studies have investigated the association between inflammatory markers and MCI taking account of serum folate level in T2D patients. This study aimed to conduct a case-control study to evaluate the association between inflammatory markers and MCI taking account of serum folate level in Chinese patients with T2D. METHODS: This study consisted of 126 T2D patients (63 cases with MCI and 63 controls without MCI). Clinical parameters, serum folate, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) were measured. Spearman correlation analysis and logistic regression analysis were used to analyze the association between the inflammatory markers and the risk of MCI in T2D patients. RESULTS: There were higher serum hs-CRP, IL-6 and TNF-α in T2D cases with MCI compared with the controls. Serum folate was negatively correlated with hs-CRP, TNF-α, and IL-6 (P < 0.05). In multivariate analysis, there were significant associations between serum IL-6 or hs-CRP and MCI after adjusting for the confounding variables, however, the association between hs-CRP and MCI disappeared after further adjusting for serum folate. Further subgroup analysis revealed that the significant association between hs-CRP and MCI only existed in the low folate subgroup (< 7.0 µg/L; OR = 3.34, 95% CI: 1.05-10.64), not in the high folate subgroup (≥7.0 µg/L; OR = 2.16, 95% CI: 0.68-6.88) after adjusting for the confounding variables. CONCLUSIONS: Serum IL-6 and hs-CRP were associated with the risk of MCI in Chinese patients with T2D. Serum folate might modify the association between serum hs-CRP and MCI in T2D patients.

Triptolide prevents extracellular matrix accumulation in experimental diabetic kidney disease by targeting microRNA-137/Notch1 pathway.

MicroRNAs (miRNAs) are involved in multiple biological functions via suppressing target genes. Triptolide is a monomeric compound isolated from a traditional Chinese herb, which exerts protective roles in many kinds of glomerular diseases. However, our understanding of the triptolide effect on miRNAome is still limited. In this study, we found that triptolide significantly decreased albuminuria and improved glomerulosclerosis in rats with diabetic kidney disease (DKD). And triptolide also inhibited extracellular matrix (ECM) protein accumulation and the notch1 pathway activation under diabetic conditions. MiR-137 was significantly decreased in the HG (high glucose)-treated HRMCs and in the kidney tissues of the diabetic rats, but was upregulated by triptolide. In addition, overexpression of miR-137 exerted similar effects to those of triptolide, while miR-137 inhibition aggravated ECM protein accumulation. Luciferase reporter assay results demonstrated that miR-137 directly targets Notch1. Furthermore, the miR-137-dependent effects were due to Notch1 suppression that in turn inhibited ECM protein expression, key mediators of glomerulosclerosis. Finally, downregulation of miR-137 reversed the ECM inhibition role of triptolide in HG cultured HRMCs. Taken together, these findings indicate that triptolide is a potential therapeutic option for DKD and that miR-137/Notch1 pathway play roles in the anti-glomerulosclerosis mechanism of triptolide.

A randomized, open-label, multicentre, parallel-controlled study comparing the efficacy and safety of biphasic insulin aspart 30 plus metformin with biphasic insulin aspart 30 monotherapy for type 2 diabetes patients inadequately controlled with oral antidiabetic drugs: The merit study.

AIM: To confirm non-inferiority of biphasic insulin aspart 30 (BIAsp 30) plus metformin to BIAsp 30 in lowering glycated haemoglobin (HbA1c) in Chinese patients with inadequately controlled type 2 diabetes using oral antidiabetic drugs. MATERIALS AND METHODS: In this 16-week, prospective, randomized, open-label, multicentre, parallel-controlled study, patients aged 18-79 years with HbA1c ≥7% were randomized to BIAsp 30 plus metformin (n = 130) or BIAsp 30 (n = 127). Initially, 500 mg metformin was administered twice daily and BIAsp 30 was administered at 0.2-0.3 U/kg/d. Changes in HbA1c % from baseline to week 16 as well as secondary and safety endpoints were assessed. RESULTS: In total, 83.66% of patients in the BIAsp 30 plus metformin (n = 110) and the BIAsp 30 (n = 105) groups completed the study. Mean (±standard deviation) change in HbA1c from baseline to endpoint was -1.74 ± 1.64% and -1.32 ± 2.05% with BIAsp 30 plus metformin and BIAsp 30, respectively. Least squares mean treatment difference was -0.67% (95% CI, -1.06; -0.28). The upper limit of the 95% CI was <0.4 (non-inferiority margin). A significantly higher proportion of individuals reached HbA1c <7% with BIAsp 30 plus metformin than with BIAsp 30 (53.15% vs 35.19%; P = 0.0074). At endpoint, daily BIAsp 30 dose (P < 0.001) and weight gain were significantly lower (P < 0.05) in the BIAsp 30 plus metformin group compared with the BIAsp 30 group. No between-group differences in number of hypoglycaemic events were observed. CONCLUSION: BIAsp 30 plus metformin was non-inferior to BIAsp 30 in safely reducing HbA1c in this study.

[Correlation study between obesity and dawn phenomenon in patients with type 2 diabetes].

OBJECTIVE: To investigate the correlation between the frequency of dawn phenomenon and obesity in patients with type 2 diabetes. METHODS: This study was conducted in 98 patients with type 2 diabetes admitted to the Metabolic Disease Hospital of Tianjin Medical University from 2011 to 2014. The subjects were divided into 3 groups according to BMI: the normal weight (BMI 18.5-23.9 kg/m(2), n = 30), the overweight(BMI 24-27.9 kg/m(2), n = 33)and the obesity (BMI ≥ 28.0 kg/m(2), n = 35). All participants underwent continuous glucose monitoring for 72 h. Fasting plasma glucose(FPG), insulin and C-peptide were tested. Frequency of dawn phenomenon among the 3 groups was calculated, and the correlations between dawn phenomenon and its related factors were analyzed. RESULTS: The frequency of dawn phenomenon in type 2 diabetes increased with the increase of BMI in the 3 groups (P < 0.05) with 33.3% in the normal weight, 78.8% in the overweight and 88.6% in the obesity groups, respectively. The dawn phenomenon was positively correlated with BMI (r = 0.424, P < 0.05), Homeostasis model assessment of insulin resistance(HOMA-IR) (r = 0.781, P < 0.05), waist circumference (r = 0.394, P < 0.05), fasting C-peptide (r = 0.254, P < 0.05)and TG (r = 0.220, P < 0.05). It was negatively correlated with the course of diabetes mellitus (r = -0.278, P<0.05) and HDL-C (r = -0.268, P < 0.05). No correlation could be viewed between the dawn phenomenon and age, LDL-C, glycosylated hemoglobin A1c(HbA1c), TC and FPG (P > 0.05). CONCLUSIONS: The dawn phenomenon is closely associated with obesity and insulin resistance. The frequency of dawn phenomenon increases with BMI.

Liraglutide reduces the body weight and waist circumference in Chinese overweight and obese type 2 diabetic patients.

AIM: To investigate the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor activator, on body weight and waist circumference in Chinese overweight and obese type 2 diabetic patients. METHODS: A total of 328 Chinese overweight and obese type 2 diabetic patients were included in this multi-center, open-labeled and self-controlled clinical study. The patients were subcutaneously injected with liraglutide once daily for 24 weeks as add-on therapy to their previous hypoglycemic treatments. Statistical analyses were performed using SPSS software package version 11.5 for Windows. RESULTS: Liraglutide treatment caused significant reduction of the mean body weight (from 86.61±14.09 to 79.10±13.55 kg) and waist circumference (from 101.81±13.96 to 94.29±14.17 cm), resulting in body weight lose of 5%-10% in 43.67% patients, and body weight loss above 10% in 34.06% patients, who had significant lower plasma creatinine levels. Baseline waist circumference, BMI and HOMA-IR were independently correlated with the body weight loss. Furthermore, liraglutide treatment significantly decreased HbA1c levels (from 8.66%±2.17% to 6.92%±0.95%) with HbA1c<7.0% in 35.37% patients, who had a significantly lower baseline level of HbA1c, but higher baseline levels of C peptide and glucagon. Moreover, liraglutide treatment resulted in greater body weight loss in patients with a long duration of diabetes, and better glycemic control in patients with a short duration of diabetes. CONCLUSION: Liraglutide significantly reduces body weight and waist circumference in Chinese overweight and obese type 2 diabetic patients. Patients with apparent visceral obesity, insulin resistance and a long duration of diabetes may have greater body weight loss; whereas patients with high insulin-secreting ability, hyperglucagonemia, and short-duration diabetes may obtain better glycemic control with liraglutide.

[The predictive factors of good glycaemic control in Chinese patients receiving biphasic insulin as part 30: a subgroup analyses from the A1 chieve study].

OBJECTIVE: To identify the baseline factors associated with achievement of glycosylated haemoglobin A1c (HbA1c) < 7.0% in Chinese patients receiving biphasic insulin as part 30 (BIAsp 30), who were previously inadequately controlled with oral anti-diabetic drugs (OADs). METHODS: A1 chieve was a multinational, prospective, open-label, 24-week non-interventional study in patients with type 2 diabetes initiating insulin analogues in 28 countries. The patients were enrolled to take BIAsp 30 according to physician's clinical judgments, who was also responsible for the treatment regimen and dosage adjustment. Primary safety endpoints were the incidence of serious drug adverse reactions (SADRs) including serious hypoglycaemia. Major efficacy endpoints were change in HbA1c, fasting plasma glucose (FPG), 2h post-prandial plasma glucose (2 hPG) from baseline. Relationships between baseline predictive baseline factors and achievement of HbA1c < 7.0% after treatment were examined using multivariate analysis. RESULTS: In China, 4 100 patients initiated BIAsp 30 [54.2% males, age (56.2 ± 13.6) years]. No SADRs were reported. Mean HbA1c was reduced from (9.3 ± 2.1)% to (7.0 ± 1.0)%; FPG was reduced from (10.2 ± 3.3) mmol/L to (6.8 ± 1.3) mmol/L. Changes in 2 hPG after breakfast, lunch and dinner were (-5.6 ± 4.7), (-4.9 ± 4.3) and (-4.2 ± 4.1) mmol/L, respectively (all P < 0.001). The proportion of patients achieving HbA1c < 7.0% increased from 9.7% at baseline to 54.2% at week 24. Multivariate analysis revealed a negative relationship between baseline HbA1c, FPG, 2 hPG and HbA1c < 7.0% after treatment. CONCLUSIONS: In the Chinese subgroup of the A1 chieve study, lower baseline HbA1c, FPG, 2 hPG were predictive factors for achieving HbA1c < 7.0% after 24-week treatment of BIAsp 30, indicating that the earlier initiation of BIAsp 30 in patients poorly controlled with OADs, the more helpful for them to achieve treatment target.

[Association between retinopathy and sleep disorder in patients with type 2 diabetes mellitus].

OBJECTIVE: To explore the association between retinopathy and sleep disorder in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 440 patients with T2DM treated from July 2011 to July 2013 in Metabolic Disease Hospital of Tianjin Medical University were divided into 2 groups according to Pittsburgh Sleep Quality Index: non-sleep disorder group (258 cases) and sleep disorder group (182 cases). Biochemical parameters including hepatorenal function, blood lipids, glycosylated hemoglobin (HbA1c), fructosamine and hemorrheology were detected. Oral glucose tolerance test, insulin releasing test and glucagon releasing test were performed to detect the inteR-group differences of α-cell and ß-cell function after fasting and glucose-load management. The logistic regression analysis was performed to identify the factors relevant to retinopathy. RESULTS: The ratio of retinopathy was 42.9% in sleep disorder group, which was higher compared to those in non-sleep disorder group (32.6%), P=0.027. The levels of fasting plasma glucose, postprandial blood glucose, HbA1c, fructosamine, systolic blood pressure, diastolic blood pressure and the indicators of hemorrheology (plasma viscosity, erythrocyte aggregation index, erythrocyte rigidity index, fibrinogen) were significantly higher in patients with sleep disorder compared to those without sleep disorder, while the erythrocyte defomation index was significantly lower in sleep disorder group (all P<0.05). The levels of glucagon and glucagon/insulin ratio at each time point as well as area under curve of glucagon were significantly higher in sleep disorder group (all P<0.05). The levels of fasting insulin, homeostasis model assessment for insulin resistance index (HOMA-IR) and area under curve of insulin were significantly higher in patients with sleep disorder compared to those without sleep disorder, while insulin sensitivity index was lower in patients with sleep disorder (all P<0.05). Logistic regression analysis showed that retinopathy was positively related to HbA1c (OR: 1.744-3.249), fibrinogen (OR: 1.687-2.998), systolic blood pressure (OR: 1.152-2.013), HOMA-IR (OR: 1.006-1.389) and sleep disorder (OR: 1.144-2.426), and negatively related to insulin sensitivity index (OR: 0.107-0.784) (all P<0.05). CONCLUSION: Sleep disorders may be associated with retinopathy through multiple mechanisms in patients with T2DM.

[Association between sleep disorder and osteoporosis in elderly female patients with type 2 diabetes mellitus].

OBJECTIVE: To explore the association between sleep disorder and osteoporosis in elderly female patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 536 elderly female T2DM patients from July 2011 to July 2014 were divided into two groups of patients without sleep disorder and those with sleep disorder based upon the Pittsburgh Sleep Quality Index. The bone mineral density of femoral neck, Wards triangle, greater trochanter and lumbar spines (L2-L4) were measured by dual-energy X-ray absorptiometry. Biochemical indicators were detected in two groups. Oral glucose tolerance and insulin releasing tests were performed. We compared the differences of bone mineral density and ß-cell function after fasting and glucose-load. The logistic regression analyses were performed between sleep disorder and osteoporosis and other indicators. RESULTS: The levels of high sensitivity C-reactive protein (hs-CRP), HbA1c, cortisol (COR), adrenocorticotropic hormone (ACTH), fasting insulin (FINS) and homeostasis model assessment-estimated insulin resistance (HOMA-IR) were significantly higher in patients with sleep disorder compared to those without sleep disorder [(3.5 ± 1.1) vs (2.6 ± 0.9) mg/L, (8.0 ± 1.9)% vs (7.3 ± 1.6)%, (512 ± 88) vs (436 ± 76) nmol/L, (6.4 ± 2.3) vs (5.1 ± 2.0) pmol/L, (13.4 ± 4.3) vs (12.4 ± 4.0) mU/L, 4.7 ± 0.8 vs 3.8 ± 0.8, all P < 0.05]. Insulin sensitivity index (ISI) was lower in patients with sleep disorder than that in patients without sleep disorder (-4.2 ± 0.5 vs -4.0 ± 0.4, P < 0.05). The bone mineral density of femoral neck, Wards triangle, greater trochanter and lumbar spines (L2-L4) were significantly lower and the prevalence rate of osteoporosis was significantly higher in patients with sleep disorder compared to those in patients without sleep disorder (all P < 0.05). Logistic regression analysis showed that sleep disorder was positively correlated with HOMA-IR, HbA1c, COR and ACTH (all P < 0.05) and negatively with ISI (P < 0.05). Logistic regression analysis showed that osteoporosis was positively correlated with postmenopausal duration, HbA1c, COR, ACTH and sleep disorder (all P < 0.05) and negatively with ISI (P < 0.05). CONCLUSION: Sleep disorder causes osteoporosis through various mechanisms in elderly female T2DM patients. Improving sleep disorder may help to reduce the prevalence of osteoporosis.

[Association between sleep disorders and dawn phenomenon in patients with type 2 diabetes mellitus].

OBJECTIVE: To explore the association between sleep disorders and dawn phenomenon in patients with type 2 diabetes mellitus (T2DM). METHODS: From July 2011 to July 2014 at Metabolic Disease Hospital, Tianjin Medical University, 316 T2DM patients on continuous glucose monitoring were divided into two groups according to the Pittsburgh Sleep Quality Index, i.e. those without sleep disorders (n = 186) and those with sleep disorders (n = 130). Biochemical parameters including hepatorenal functions, blood lipids, glycosylated hemoglobin (HbA1c) and fructosamine were detected. Oral glucose tolerance test, insulin releasing test and glucagon releasing test were performed to detect the inter-group differences of glucose concentration and α-cell and ß-cell functions after fasting and glucose loading. And the correlation and regression analyses were performed between sleep disorders and other parameters. RESULTS: The level of HbA1c, fructosamine, increment of fasting glucose and nocturnal nadir glucose, glucose increment before and after breakfast, 24 h mean glucose, fasting insulin, homeostasis model assessment of insulin resistance index (HOMA-IR) and area under curve of insulin were significantly higher in patients with sleep disorders than those without sleep disorders (8.2% ± 2.0% vs 7.4% ± 1.7%, (0.33 ± 0.10) vs (0.29 ± 0.07) mmol/L, (1.511 ± 0.294) vs (0.889 ± 0.233) mmol/L, (2.144 ± 0.400) vs (1.522 ± 0.378) mmol/L, (9.917 ± 1.800) vs (8.694 ± 1.622) mmol/L, (13.49 ± 4.68) vs (12.16 ± 4.56) mU/L, 4.98 ± 0.90 vs 3.82 ± 0.82, (8.47 ± 0.59) vs (8.25 ± 0.54), all P < 0.05). Insulin sensitivity index was lower in patients with sleep disorders than that in those without sleep disorders (-4.28 ± 0.62 vs -4.03 ± 0.52, P < 0.05). The level of glucagon at each timepoint and area-under-curve of glucagon were significantly higher in patients with sleep disorders than those without sleep disorders. The levels of 0, 30, 180 min glucagon/insulin ratio and glucagon/glucose ratio were significantly higher in patients with sleep disorders (all P < 0.05). Sleep disorder was positively correlated with HOMA-IR, glucagon/insulin ratio, increment of fasting glucose and nocturnal nadir glucose and dawn phenomenon (all P < 0.05). Yet there was a negative correlation with insulin sensitivity index (P < 0.05). CONCLUSIONS: Sleep disorders are associated with dawn phenomenon. And improving sleep disorder helps to improve the dawn phenomenon and optimize overall glycemic control.

Amide proton transfer weighted contrast has diagnostic capacity in detecting diabetic foot: an MRI-based case-control study.

Objective: To evaluate the role of foot muscle amide proton transfer weighted (APTw) contrast and tissue rest perfusion in quantifying diabetic foot (DF) infection and its correlation with blood parameters. Materials and methods: With approval from an ethical review board, this study included 40 diabetes mellitus (DM) patients with DF and 31 DM patients without DF or other lower extremity arterial disease. All subjects underwent MRI, which included foot sagittal APTw and coronal arterial spin labeling (ASL) imaging. The normalized MTRasym (3.5 ppm) and the ratio of blood flow (rBF) in rest status of the affected side lesions to the non-affected contralateral side were determined. The inter-group differences of these variables were evaluated. Furthermore, the association between normalized MTRasym (3.5 ppm), rBF, and blood parameters [fasting blood glucose (FBG), glycosylated hemoglobin content, C-reactive protein, neutrophil percentage, and white blood cell count] was explored. Using an ROC curve, the diagnostic capacity of normalized MTRasym (3.5 ppm), BF, and blood biochemical markers in differentiating with or without DF in DM was assessed. Results: In the DF group, MTRasym (3.5 ppm) and BF in lesion and normalized MTRasym (3.5 ppm) were higher than those in the control group (p < 0.05). In addition, correlations were identified between normalized MTRasym (3.5 ppm) and blood parameters, such as C-reactive protein, glycosylated hemoglobin content, FBG, neutrophil ratio, and white blood cell (p < 0.001). Meanwhile, association between BF in lesion and blood parameters, such as C-reactive protein, neutrophil percentage, and FBG (p < 0.01). AUC of normalized MTRasym (3.5 ppm) in identifying with/without DF in patients with DM is 0.986 (95% CI, 0.918-1.00) with the sensitivity of 97.22% and the specificity of 100%. Conclusion: Normalized MTRasym (3.5 ppm) and the BF in lesion may be treated as a safer and more convenient new indicator to evaluate the tissue infection without using a contrast agent, which may be useful in monitoring and preoperatively assessing DF patients with renal insufficiency.

Effects of 24-week treatment with acarbose on glucagon-like peptide 1 in newly diagnosed type 2 diabetic patients: a preliminary report.

BACKGROUND: Treatment with the alpha-glucosidase inhibitor (AGI) acarbose is associated with a significant reduction the risk of cardiovascular events. However, the underlying mechanisms of this effect are unclear. AGIs were recently suggested to participate in stimulating glucagon-like peptide 1 (GLP-1) secretion. We therefore examined the effects of a 24-week treatment of acarbose on endogenous GLP-1, nitric oxide (NO) levels, nitric oxide synthase (NOS) activity, and carotid intima-media thickness (CIMT) in newly diagnosed patients with type 2 diabetes (T2D). METHODS: Blood was drawn from 24 subjects (14 male, 10 female, age: 50.7 ± 7.36 years, BMI: 26.64 ± 3.38 kg/m2, GHbA1c: 7.00 ± 0.74%) with drug-naïve T2D at 0 and 120 min following a standard mixed meal for the measurements of active GLP-1, NO and NOS. The CIMT was measured prior to and following 24 weeks of acarbose monotherapy (mean dose: 268 mg daily). RESULTS: Following 24 weeks of acarbose treatment, both fasting and postprandial plasma GLP-1 levels were increased. In patients with increased postprandial GLP-1 levels, serum NO levels and NOS activities were also significantly increased and were positively related to GLP-1 levels. Although the CIMT was not significantly altered following treatment with acarbose, a decreased CIMT was negatively correlated with increased GLP-1 levels. CONCLUSIONS: Twenty-four weeks of acarbose monotherapy in newly diagnosed patients with T2D is associated with significantly increased levels of both fasting and postprandial GLP-1 as well as significantly increased NO levels and NOS activity for those patients in whom postprandial GLP-1 levels were increased. Therefore, the benefits of acarbose on cardiovascular risk may be related to its stimulation of GLP-1 secretion.

Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of major depression. Individuals with type 2 diabetes (T2DM) have a high prevalence of major depression and low levels of BDNF. We therefore explored whether the BDNF Val66Met polymorphism is associated with co-morbid depression and whether depression affects the serum levels of BDNF in a Han Chinese subjects with T2DM. METHODS: A Total of 296 T2DM patients and 70 healthy volunteers (Health control, HC group) were recruited in this study. T2DM patients were divided into two subgroups: depressive diabetes group (DDM group, n = 64) and non-depressive diabetes group (NDDM group, n = 232), according to the presence or the absence of depression assessed by Center for Epidemiologic Studies Depression Scale (CES-D) and Patient Health Questionnaire-9 (PHQ-9). Val66Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). Serum BDNF levels were measured by ELISA kit. RESULTS: In this study, 21.6% (64/296) patients with T2DM had depression. The BDNF Val66Met genotype distributions were statistically different among the three groups (χ2 = 7.39, p < 0.05). DDM group carried the highest frequencies of Met allele (53.9%) compared to HC group (39.3%) and NDDM group (38.8%). Subjects with Met/Met had lowest serum BDNF levels (76.59 ± 5.12 pg/ml, F = 7.39, p < 0.05) compared to subjects with Val/Met (79.04 ± 5.19 pg/ml) and Val/Val (83.83 ± 3.97 pg/ml). Within T2DM group, it was also observed that the serum BDNF levels in DDM group were significantly lower than those in NDDM group (76.67 ± 5.35 vs. 79.84 ± 3.97 pg/ml, p < 0.05). In type 2 diabetes subjects, BDNF serum levels were significant correlations with genotypes (r = -0.346, p < 0.01), depression scores (r = -0.486, p < 0.01) and HbA1c (r = -0.168, p < 0.05). After adjustment for gender, HbA1c, BMI and numbers of complications, BDNF Val/Met genotype distributions (OR = 2.105, p < 0.05) and decreased serum BDNF levels (OR = 0.835, p < 0.01) were independently associated with depression in T2DM. CONCLUSIONS: The BDNF Val66Met polymorphism might be implicated in the pathogenesis of depression in T2DM by decreasing serum BDNF levels in Han Chinese Subjects.

Preliminary observational study of metabonomics in patients with early and late-onset type 2 diabetes mellitus based on UPLC-Q-TOF/MS.

Non-targeted metabonomic techniques were used to explore changes in metabolic profiles of patients with early onset and late onset T2DM. Newly diagnosed early onset T2DM (EarT2DM) and late onset T2DM (LatT2DM) patients were recruited, and the matched age, sex, and low-risk population of diabetes mellitus were selected as the control group. 117 adults were recruited in the study, including 21 in EarT2DM group with 25 in corresponding control group (heaCG1), and 48 in LatT2DM group with 23 in corresponding control group (heaCG2). There were 15 relatively distinctive metabolic variants in EarT2DM group and 10 distinctive metabolic variants in LatT2DM group. The same changing pathways mainly involved protein, aminoacyl-tRNA biosynthesis, fatty acid biosynthesis, taurine metabolism, arginine biosynthesis, lysosome and mTOR signaling pathway. The independent disturbed pathways in EarT2DM included branched chain amino acids, alanine, aspartate and glutamate metabolism. The independent disturbed pathways in LatT2DM involved linoleic acid metabolism, biosynthesis of unsaturated fatty acids, arginine, proline metabolism and FoxO signaling pathway. T2DM patients at different diagnosed ages may have different metabolite profiles. These metabolic differences need to be further verified.

Urine Immunoglobin G Greater Than 2.45 mg/L Has a Correlation with the Onset and Progression of Diabetic Kidney Disease: A Retrospective Cohort Study.

AIM: To further assess the correlation between urine immunoglobin G (IgG) greater than 2.45 mg/L and the onset and progression of diabetic kidney disease (DKD). METHODS: One thousand and thirty-five patients with type 2 diabetes mellitus (T2DM) were divided into two groups based on the baseline levels of 24 h urinary albumin excretion (24 h UAE): one group with 24 h UAE < 30 mg/24 h and one with 24 h UAE ≥ 30 mg/24 h. The groups were subdivided using baseline levels of urine IgG (≤2.45 mg/L and >2.45 mg/L; hereafter, the Low and High groups, respectively). We used logistic regression to assess the risk of urine IgG and it exceeding 2.45 mg/L. Kaplan-Meier curves were used to compare the onset and progression time of DKD. The receiver operating characteristic curve was used to test the predictive value of urine IgG exceeding 2.45 mg/L. RESULTS: Urine IgG was an independent risk factor for the onset and progression of DKD. The rate and risk of DKD onset and progression at the end of follow-up increased significantly in the High group. The onset and progression time of DKD was earlier in the High group. Urine IgG exceeding 2.45 mg/L has a certain predictive value for DKD onset. CONCLUSIONS: Urine IgG exceeding 2.45 mg/L has a correlation with the onset and progression of DKD, and it also has a certain predictive value for DKD onset.

Predicting population: development and validation of a new predictive nomogram for evaluating medication nonadherence risk in a type 2 diabetes.

Background: Diabetes mellitus is a growing global health challenge and affects patients of all ages. Treatment aims to keep blood glucose levels close to normal and to prevent or delay complications. However, adherence to antidiabetic medicines is often unsatisfactory. Purpose: Here, we established and internally validated a medication nonadherence risk nomogram for use in Chinese type 2 diabetes mellitus (T2DM) patients. Methods: This cross-sectional study was carried out from July-December 2020 on randomly selected T2DM patients visiting a diabetes clinic and included 753 participants. Adherence was analyzed based on an eight-item Morisky Medication Adherence Scale (MMAS-8). Other data, including patient demographics, treatment, complications, and comorbidities, were also collected on questionnaires. Optimization of feature selection to develop the medication nonadherence risk model was achieved using the least absolute shrinkage and selection operator regression model (LASSO). A prediction model comprising features selected from LASSO model was designed by applying multivariable logistic regression analysis. The decision curve analysis, calibration plot, and C-index were utilized to assess the performance of the model in terms of discrimination, calibration, and clinical usefulness. Bootstrapping validation was applied for internal validation. Results: The prediction nomogram comprised several factors including sex, marital status, education level, employment, distance, self-monitoringofbloodglucose, disease duration, and dosing frequency of daily hypoglycemics (pills, insulin, or glucagon-like peptide-1). The model exhibited good calibration and good discrimination (C-index = 0.79, 95% CI [0.75-0.83]). In the validation samples, a high C-index (0.75) was achieved. Results of the decision curve analysis revealed that the nonadherence nomogram could be applied in clinical practice in cases where the intervention is decided at a nonadherence possibility threshold of 12%. Conclusion: The number of patients who adhere to anti-diabetes therapy was small. Being single male, having no formal education, employed, far from hospital, long disease duration, and taking antidiabetics twice or thrice daily, had significant negative correlation with medication adherence. Thus, strategies for improving adherence are urgently needed.

Hyperinsulinemia impairs the metabolic switch to ketone body utilization in proximal renal tubular epithelial cells under energy crisis via the inhibition of the SIRT3/SMCT1 pathway.

Objective: To investigate the effects and mechanism of hyperinsulinemia on the metabolic switch to ß-hydroxybutyrate (BHB) absorption and utilization under a starvation or hypoxic environment in proximal tubular epithelial cells. Methods: A high-fat diet-induced hyperinsulinemia model in ZDF rats was used to test the expression of key enzymes/proteins of ketone body metabolism in the kidney. Notably, 12-week-old renal tubule SMCT1 specific knockout mice (SMCT1 flox/floxCre+) and control mice (SMCT1 flox/floxCre-) were used to confirm the roles of SMCT1 in kidney protection under starvation. The changes of key enzymes/proteins of energy metabolism, mitochondrial function, and albumin endocytosis in HK2 cells under low glucose/hypoxic environments with or without 50 ng/mL insulin were studied. Silent information regulation 2 homolog 3 (SIRT3) was overexpressed to evaluate the effect of hyperinsulinemia on the metabolic switch to BHB absorption and utilization through the SIRT3/SMCT1 pathway in HK2 cells. Results: In ZDF rats, the expression of HMGCS2 increased, the SMCT1 expression decreased, while SCOT remained unchanged. In renal tubule SMCT1 gene-specific knockout mice, starvation for 48 h induced an increase in the levels of urine retinol-binding protein, N-acetyl-ß-glucosaminidase, and transferrin, which reflected tubular damages. In HK2 cells under an environment of starvation and hypoxia, the levels of key enzymes related to fatty acid oxidation and ketone body metabolism were increased, whereas glucose glycolysis did not change. The addition of 2 mmol/l BHB improved ATP production, mitochondrial biosynthesis, and endocytic albumin function, while cell apoptosis was reduced in HK2 cells. The addition of 50 ng/ml insulin resulted in the decreased expression of SMCT1 along with an impaired mitochondrial function, decreased ATP production, and increased apoptosis. The overexpression of SIRT3 or SMCT1 reversed these alterations induced by a high level of insulin both in low-glucose and hypoxic environments. Conclusions: The increased absorption and utilization of BHB is part of the metabolic flexibility of renal tubular epithelial cells under starvation and hypoxic environments, which exhibits a protective effect on renal tubular epithelial cells by improving the mitochondrial function and cell survival. Moreover, hyperinsulinemia inhibits the absorption of BHB through the inhibition of the SIRT3/SMCT1 pathway.

Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway.

Aim: Patients with diabetic ketosis often exhibit albuminuria. We previously found that acute hyperglycaemia can cause nephrotoxic injury. Here, we explored whether an excessive ketone body level causes kidney injury and the potential underlying mechanism. Methods: Fifty-six type 2 diabetes without ketosis (NDK group), 81 type 2 diabetes with ketosis (DK group), and 38 healthy controls (NC group) were enrolled. Clinical data were collected before and after controlling diabetic ketosis. Beta-hydroxybutyric acid (BOHB), an AKT activator, an AKT inhibitor, or plasmids encoding DAB2 were transformed into human renal proximal tubule epithelial cells (HK-2 cells). Results: The urinary albumin-to-creatinine ratio (ACR), transferrin (TF), immunoglobulin G (IgG), Beta2-microglobulin (ß2-MG), retinol-binding protein (RBP), N-acetyl-beta-glucosaminidase (NAG), and Beta-galactosidase (GAL) were higher in the DK than NC and NDK groups. The proportion of patients with an increased urinary level of TF, IgG, ß2-MG, RBP, NAG, or GAL was higher in the DK group too. After controlling ketosis, urinary microalbumin, TF, IgG, ß2-MG, and RBP decreased significantly. In HK-2 cells, albumin endocytosis and megalin expression decreased with increasing BOHB concentration. Compared with BOHB treatment, BOHB with AKT activator significantly increased the DAB2, megalin levels and albumin endocytosis; the AKT inhibitor treatment exhibited the opposite effects. Compared with BOHB treatment, megalin expression and albumin endocytosis were significantly increased after BOHB with DAB2 overexpression treatment. Conclusions: Patients with diabetic ketosis may suffer from glomerular and tubular injuries that recover after ketosis control. High concentrations of BOHB downregulate megalin expression by inhibiting the AKT/DAB2/megalin signalling pathway and albumin endocytosis in proximal renal tubules.