PSEUDO-ETIOLATION IN LIGHT proteins reduce greening by binding GLK transcription factors.

Knocking out genes encoding proteins that downregulate the accumulation of pigments may lead to increases in crop quality and yield. PSEUDO-ETIOLATION IN LIGHT 1 (PEL1) downregulates the accumulation of carotenoids in carrot and chlorophyll in Arabidopsis and rice and may inhibit GOLDEN 2-LIKE (GLK) transcription factors. PEL1 belongs to a previously unstudied gene family found only in plants. We used CRISPR/Cas9 technology to knock out each member of the 4-member PEL gene family and both GLK genes in Arabidopsis. In pel mutants, chlorophyll levels were elevated in seedlings; after flowering, chloroplasts increased in size, and anthocyanin levels increased. Although the chlorophyll-deficient phenotype of glk1 glk2 was epistatic to pel1 pel2 pel3 pel4 in most of our experiments, glk1 glk2 was not epistatic to pel1 pel2 pel3 pel4 for the accumulation of anthocyanins in most of our experiments. The pel alleles attenuated growth, altered the accumulation of nutrients in seeds, disrupted an abscisic acid-inducible inhibition of seedling growth response that promotes drought tolerance, and affected the expression of genes associated with diverse biological functions, such as stress responses, cell wall metabolism hormone responses, signaling, growth, and the accumulation of phenylpropanoids and pigments. We found that PEL proteins specifically bind 6 transcription factors that influence the accumulation of anthocyanins, GLK2, and the carboxy termini of GLK1 and Arabidopsis thaliana myeloblastosis oncogene homolog 4 (AtMYB4). Our data indicate that the PEL proteins influence the accumulation of chlorophyll and many other processes, possibly by inhibiting GLK transcription factors and via other mechanisms, and that multiple mechanisms downregulate chlorophyll content.

Perilipin 2 Protects against Lipotoxicity-Induced Islet Fibrosis by Inducing Islet Stellate Cell Activation Phenotype Changes.

Aims: We explored whether and how perilipin 2 (Plin2) protected islets against lipotoxicity-induced islet dysfunction by regulating islet stellate cells (ISCs) activation. Methods: Six-week-old male rats were given a high-fat diet or a control diet for 28 weeks. Glucose metabolic phenotypes were assessed using glucose/insulin tolerance tests, masson, and immunohistochemical staining. ISCs activation levels were assessed from rats and palmitic acid- (PA-) treated cultured ISCs by immunofluorescence, Oil red O staining, electron microscopy, quantitative PCR, and western blotting. Changes in ISCs phenotype of activation degree and its underlying mechanisms were assessed by target gene lentiviral infection, high-performance liquid chromatography (HPLC), and western blotting. Results: Obese rats showed glucose intolerance, decreased endocrine hormone profiles, and elevated expression of α-smooth muscle actin (α-SMA), a polygonal appearance without cytoplasmic lipid droplets of ISCs in rats and isolated islets. PA-treated cultured ISCs exhibited faster proliferation and migration abilities with the induction of mRNA levels of lipid metabolism proteins, especially Plin2. The overexpression of Plin2 resulted in ISCs "re-quiescent" phenotypes associated with inhibition of the Smad3-TGF-ß signaling pathways. Conclusions: Our observations suggest a protective role of Plin2 in weakening ISCs activation. It may serve as a novel therapeutic target for preventing islet fibrosis for T2DM.

Comparative Evaluation of Chiglitazar and Sitagliptin on the Levels of Retinol-Binding Protein 4 and Its Correlation With Insulin Resistance in Patients With Type 2 Diabetes.

Aims: We evaluated the efficacy and significant changes in the levels of retinol-binding protein 4 (RBP-4) and insulin resistance in patients with type 2 diabetes mellitus (T2DM) treated with chiglitazar versus sitagliptin. Methods: Eighty-one T2DM patients with haemoglobin A1c (HbA1c) level of 7.5%-10.0% were selected. Based on the study criteria, patients were randomly assigned to receive chiglitazar (32 mg), chiglitazar (48 mg), or sitagliptin (100 mg) orally for 24 weeks. Sociodemographic and anthropometric characteristics, lipid profiles, glucose profiles, and serum RBP-4 levels were determined at baseline and at the end of the therapy. Results: After treatment for 24 weeks, significant changes in fasting blood glucose (FBG), fasting insulin (Fins), 2 h-blood glucose (2h-BG), the score values of insulin resistance/insulin secretion/ß cell function (HOMA-IR, HOMA-IS, and HOMA-ß), triglyceride (TG), free fatty acid (FFA), high-density lipoprotein cholesterol (HDL-C), and RBP-4 levels were detected in patients with chiglitazar administration and sitagliptin administration. Changes in RBP-4 levels were positively correlated with changes in HOMA-IR and 2 h-BG in linear regression. Conclusions: Chiglitazar showed a greater improvement in parameters of diabetes than sitagliptin, and changes in serum RBP-4 levels were associated with changes in insulin-sensitizing parameters. Clinical Trial Registration: ClinicalTrials.gov, CT.gov identifier: NCT02173457.

Serum ErbB2 concentration positively correlated to the glycemic variations in newly diagnosed Type 2 diabetic patients.

Evidences indicate that elevated levels of circulating ErbB2 are closely associated with increased incidence of diabetes. However, the relationship between ErbB2 concentration and glycemic variations (GV) in type 2 diabetic (T2D) patients remains elucidated. The aim of this study was to assess whether there is an association between serum ErbB2 concentration and GV in newly diagnosed T2D patients. This was a three-center, and observational study. Between April 2019 and July 2019, a total of 106 newly diagnosed T2D patients were recruited. All recruited subjects were admitted as inpatients and received anti-diabetes agents free during the study period. At baseline, fasting serum was collected for ErbB2 measurement and all recruited patients were subjected a prospective CGM for at least 3 days. The primary endpoint was the relationships between ErbB2 concentrations and GV in T2D patients. Data of a total of 95 subjects who met the inclusion criteria were analyzed at the endpoint. Subjects were divided into quartiles according to their serum ErbB2 concentrations. We observed that subjects with an elevated level of ErbB2 had a higher value of GV in terms of mean amplitude of glucose excursion (MAGE), standard deviation of mean glucose (SDMG), and the coefficient of variation (CV%) than those with lower levels (all P < 0.05). Multiple linear regression analyzes after adjusting for confounder factors indicate that serum ErbB2 levels were significantly positively correlated with the MAGE (ß = 0.664, t = 7.218, P < 0.01), SD (ß = 0.469, t = 5.125, P < 0.01) and CV% (ß = 0.337, t = 4.442, P < 0.01), respectively. Our data indicated that diabetic patients with higher ErbB2 concentrations may have large GV, which is an independent risk factor for microvascular and macrovascular complications.

Effects of Dapagliflozin Adjunct to Insulin on Glycemic Variations in Patients with Newly Diagnosed Type 2 Diabetes: A Randomized, Controlled, Open-Labeled Trial.

BACKGROUND: This study is aimed at investigating whether dapagliflozin adjunct to insulin therapy further improves glycemic control compared to insulin therapy alone in patients with newly diagnosed type 2 diabetes (T2D). METHODS: This single-centre, randomized, controlled, open-labeled trial recruited newly diagnosed T2D patients. Subjects were randomized 1 : 1 to the dapagliflozin add-on to continuous subcutaneous insulin infusion (CSII) group (DAPA) or the CSII therapy group for 5 weeks. Standard meal tests were performed 3 times at days -3, 7, and 35 for glucose, C-peptide, and insulin level determination. Two-time continuous glucose monitoring (CGM) was performed at baseline and at the end of the study. The primary endpoint was the difference in the mean amplitude of glycemic excursions (MAGEs) between the groups. RESULTS: A total of 66 subjects completed the study, with 34 and 32 patients in the DAPA and CSII groups, respectively. Patients in the DAPA group exhibited significant decreases in MAGE levels at the endpoint. We also observed that patients in the DAPA group had a lower homoeostasis model assessment insulin resistance (HOMA-IR) and a higher homoeostasis model assessment B (HOMA-B) value at 1 week and 5 weeks compared to those with insulin therapy, respectively. In addition, our data showed that patients in the DAPA group showed a significantly lower insulin dose (0.07 U/kg) and weighed less than those in the CSII group. CONCLUSION: Our data indicate that dapagliflozin adjunct to insulin is a safe and effective therapy for improving glycemic variations, insulin sensitivity, and weight loss in newly diagnosed T2D patients.

Fasting Glucose of 6.1 mmol/L as a Possible Optimal Target for Type 2 Diabetic Patients with Insulin Glargine: A Randomized Clinical Trial.

To observe whether different insulin glargine titration algorithms based on fasting blood glucose (FBG) levels lead to different glycaemic variations (GVs) in type 2 diabetes (T2D) patients, a prospective, randomized, single-centre, comparative, three-arm parallel-group, open-label, treat-to-target, 24-week study was performed. A total of 71 uncontrolled T2D patients were recruited and randomized 1 : 3 : 3 into Groups 1, 2, and 3 (insulin titration goals of FBG ≤ 5.6, ≤6.1, and ≤7.0) for this study. The initiated insulin glargine dose was recommended at 0.2 U/kg/day and was then titrated following the FBG target. Patients were subjected to two 3-day continuous glucose monitoring (CGM) at baseline and the endpoint, wherein the CGM data were analysed, and the study's primary endpoint was the difference in 24 hrs mean amplitude of glycaemic excursion (MAGE) among the three groups. We observed that patients in the three groups had similar MAGE levels at the endpoint; however, Group 2 achieved a significant decrease in the MAGE level from baseline to the endpoint as compared to Groups 1 and 3 (all p < 0.05). We also observed that these patients had significant glycated haemoglobin A1c (HbA1c) value improvements as compared to the other two groups (all p < 0.05). Therefore, choosing an FBG level of 6.1 mmol/L as an insulin titration target provided significant GVs and HbA1c value improvements in T2D patients. Moreover, our data indicated that an FBG of 6.1 mmol/L could possibly be an insulin glargine titration target in T2D patients.

Vitamin A and Its Multi-Effects on Pancreas: Recent Advances and Prospects.

Vitamin A (VA), which is stored in several forms in most tissues, is required to maintain metabolite homeostasis and other processes, including the visual cycle, energy balance, epithelial cell integrity, and infection resistance. In recent years, VA molecules, also known as retinoids, have been extensively explored and used in the treatment of skin disorders and immune-related tumors. To date, several observational and interventional studies have explored the relationship between VA status and the pathogenesis of diabetes. In particular, VA micronutrients have been shown to regulate pancreatic development, ß-cell function, pancreatic innate immune responses, and pancreatic stellate cells phenotypes through multiple mechanisms. However, there are still many problems to be proven or resolved. In this review, we summarize and discuss recent and available evidence on VA biological metabolism in the pancreas. Analysis of the effects of VA on metabolism in the pancreas will contribute to our understanding of the supportive physiological roles of VA in pancreas protection.

Rapid Changes in Serum Testosterone in Men With Newly Diagnosed Type 2 Diabetes With Intensive Insulin and Metformin.

OBJECTIVE: To investigate the effect of metformin on testosterone levels in men with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Seventy men with newly diagnosed drug-naive T2DM and HbA1c >9.0% (75 mmol/mol) were treated with intensive insulin pump therapy for 5 days to achieve glucose normalization. They were randomized to control (continued on intensive insulin only) and metformin (plus metformin) groups (1:1) for 1 month. Testosterone was measured at baseline, randomization, and after 1-month treatment. RESULTS: Total, free, and bioavailable testosterone increased significantly within 5 days (all P < 0.001). After 1 month, compared with the control group, the metformin group had lower total (12.7 vs. 15.3 nmol/L), free (0.20 vs. 0.24 nmol/L), and bioavailable (4.56 vs. 5.31 nmol/L) testosterone (all P < 0.05). CONCLUSIONS: In men with T2DM, 1-month oral metformin may decrease serum testosterone levels independent of blood glucose control. The effects of long-term metformin on testosterone in men need further study.

Men with Latent Autoimmune Diabetes and Type 2 Diabetes May Have Different Change Patterns in Free Testosterone.

OBJECTIVE: Type 2 diabetic (T2D) male patients with low total testosterone (TT) levels are at an increasing risk of all-cause mortality. However, the levels of TT in male patients with latent autoimmune diabetes in adults (LADA) remain largely unknown. Research Design and Methods. This was a single-center, open, observational study. The inclusion criteria were male patients who were diagnosed with LADA, and sex, body mass index, C-peptide, and glycated hemoglobin (HbA1c) levels matched with those of T2D patients. Islet function/sensitivity and sex hormone concentrations were determined at baseline and 1-year follow-up. The primary endpoint was the changes in androgen levels from baseline to 1-year follow-up in patients with LADA. RESULTS: Our data showed that TT and Bio-T levels remained unchanged, while FT levels significantly decreased from baseline to 1-year follow-up in patients with T2D. However, TT, Bio-T, and FT concentrations dramatically increased in the LADA group from baseline to 1-year follow-up. Furthermore, a Spearman analysis showed that changes of TT, FT, and Bio-T levels from baseline to endpoint were significantly negatively correlated with Δ homeostasis model assessment-2 IR (ΔHOMA2-IR), respectively. CONCLUSIONS: The FT change patterns in patients with LADA may differ from those in patients with T2D. Our data also indicated the significant negative correlation between insulin sensitivity and changes of TT, FT, and Bio-T levels along with the diabetic duration in patients with T2D and LADA.

Relationship Between Estimated Glycosylated Hemoglobin Using Flash Glucose Monitoring and Actual Measured Glycosylated Hemoglobin in a Chinese Population.

INTRODUCTION: The aim of this study was to investigate the relationship between actual measured glycated hemoglobin (HbA1c) and estimated glycated hemoglobin (EA1c) in the flash glucose monitoring (FGM) system in Chinese patients with type 2 diabetes. METHODS: This study was conducted in Nanjing First Hospital. Each patient used FGM twice in a 3-month period (during the first 14 days immediately after baseline and during a second 14-day period from days 76 to 90 after baseline). HbA1c measurements were made using a high-performance liquid chromatography assay before the start of the first FGM period (baseline) and at the end of the second FGM period. RESULTS: A total of 74 patients (35 men; mean age ± standard deviation [SD] 67.6 ± 5.2 years) were enrolled in the study. The mean (± SD) duration of diabetes was 11.9 ± 7.8 months. The first and second HbA1c measurements were both higher than the EA1c (both p < 0.001). Mean glucose (MG) gradually decreased over time and was the lowest on day 14. Linear regression showed that only HbA1c at baseline affected the gap between HbA1c and EA1c (ß = 0.319, p = 0.01) when the educational level, age, gender, duration of diabetes, body mass index, HbA1c at baseline, and number of scans daily were included as independent variables. The best model for calculating EA1c was EA1c% = MG mmol/L × 0.669 - 0.213 × 8th MG + 3.351 when MG > 9.7 mmol/L, and EA1c % = (MG mmol/L + 2.590)/1.590 when MG ≤ 9.7 mmol/L. The correlation coefficient for EA1c and HbA1c in this model (model 7) is higher than that reported the original model in the FGM system 1 (0.955 vs. 0.822, respectively; p < 0.001). CONCLUSIONS: The EA1c used by FreeStyle Libre™ is lower than the actual measured HbA1c. Improvement in the glucose levels during FGM in these patients may contribute to the lowering of EA1c. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov, number NCT03785301.

Sexual Differences in response to Mid- or Low-Premixed Insulin Analogue in Patients with Type 2 Diabetes.

OBJECTIVE: To observe whether there are sexual-related differences in response to mid- or low-premixed insulin in type 2 diabetic patients. METHODS: This was an analysis of CGM data of a previous study. After screening, patients with longstanding T2D receive a 7-day continuous subcutaneous insulin infusion (CSII) therapy, and then subjects were randomly assigned 1 : 1 into two groups receiving Novo Mix 30 or Humalog Mix 50 regimen for a 2-day phage, followed by a 4-day cross-over period. A 4-day continuous glucose monitoring (CGM) was performed during the cross-over period. The primary endpoint was the differences in glycemic control between male and female patients receiving mid- or low-premixed insulin therapy. RESULTS: A total of 102 patients (52 men and 50 women) completed the study. Our data showed that male patients had significant decrease in mean glucose levels monitored by CGM after three meals during Humalog Mix 50 treatment period compared to those received Novo Mix 30 regimen (0900: 11.0 ± 2.5 vs. 12.2 ± 2.8, 1000: 9.9 ± 2.9 vs. 11.3 ± 3.1, 1200: 8.0 ± 1.9 vs. 9.1 ± 2.5, 1400: 9.2 ± 2.3 vs. 10.3 ± 2.5, and 2000: 7.3 ± 2.1 vs. 8.2 ± 2.4 mmol/L, p < 0.05, respectively). In addition, male patients receiving Novo Mix 30 experienced a significantly increased hypoglycemic duration compared to those of receiving Humalog Mix 50 (0 (0, 4.8) vs. 0 (0, 0), p < 0.05, respectively). In addition, male patients receiving Novo Mix 30 experienced a significantly increased hypoglycemic duration compared to those of receiving Humalog Mix 50 (0 (0, 4.8) vs. 0 (0, 0). CONCLUSION: Our data indicate that male patients with T2D receiving mid-premixed insulin analogue regimen may have a potential benefit of improvement in glycemic control compared to female patients. This trial is registered with ClinicalTrials.gov ChiCTR-IPR-15007340.

Contributions of Fasting and Postprandial Glucose Concentrations to Haemoglobin A1c in Drug-Naïve Mal-Glucose Metabolism in Chinese Population Using Continuous Glucose Monitoring System.

AIM: To clarify the contributions of fasting glucose (FG) and postprandial glucose (PG) to HbA1c in drug-naïve patients with type 2 diabetes (T2D) and impaired glucose tolerate (IGT)/impaired fasting glucose (IFG). METHODS: Continuous glucose monitoring (CGM) was performed in 305 drug-naïve Chinese patients with T2D or IGT/IFG. The incremental area under the curve (AUC) above a glucose value of 6.1 mmol/L or FG glucose levels were calculated to evaluate the contributions of PG or FG to HbA1c values. RESULTS: According to quintiles of HbA1c, T2D patients were divided into five groups (group 1 to 5), and patients with IGT/IFG were assigned into group 0. PG was the predominant contributor in the lower groups with HbA1c 4.9∼6.0% and 6.1∼7.8%. The relative contributions of FG and PG to HbA1c had no significance in the middle groups of HbA1c (7.9∼8.7% and 8.8∼9.5%). FG contributed significantly more than PG in the higher groups of HbA1c (9.6∼10.9% and 11.0∼14.6%). Regression analyses indicate that the contributions of FG and PG were equal (both 50%) when the level of HbA1c was 8.5%. CONCLUSIONS: In drug-naïve patients with T2D or IGT/IFG, PG contributed more in patients with HbA1c < 8.5%, whereas FG became the predominant contributor in the poorly controlled patients with HbA1c ≥ 8.5%. These results may help the health-care provider set appropriate plasma glucose testing goals with the expectation of achieving specific HbA1c values.

Lipotoxicity reduces ß cell survival through islet stellate cell activation regulated by lipid metabolism-related molecules.

BACKGROUND: Islet stellate cells (ISCs) activation is mainly associated with islet fibrosis, which contributes to the progression of type 2 diabetes. However, the molecular mechanism underlying this process is not fully understood. METHODS: In order to investigate this process the current study examined ectopic fat accumulation in rats with high-fat diet (HFD) induced obesity. Levels of lipotoxicity-induced ISC activation and islet function were assessed via intraperitoneal glucose and insulin tolerance tests, and immunohistochemistry. The expression of lipid metabolism- and ISC activation-related markers was evaluated in cultured ISCs treated with palmitic acid (PA) using quantitative PCR and western blotting. We also overexpressed sterol regulatory element-binding protein (SREBP)-1c in ISCs by lentiviral transduction, and assessed the effects on insulin release in co-cultures with isolated rat islets. RESULTS: HFD increased body weight and ectopic fat accumulation in pancreatic islets. Lipotoxicity caused progressive glucose intolerance and insulin resistance, upregulated α-smooth muscle actin, and stimulated the secretion of extracellular matrix. Lipotoxicity reduced the expression of lipid metabolism-related molecules in ISCs treated with PA, especially SREBP-1c. Overexpression of SREBP-1c in ISCs improved islet viability and insulin secretion in co-cultures. CONCLUCIONS: These results indicate that lipotoxicity-induced ISC activation alters islet function via regulation of lipid metabolism, suggesting that therapeutic strategies targeting activated ISC may be an effective treatment for prevention of ISC activation-associated islet dysfunction.

Lipoprotein-associated phospholipase A2 is a risk factor for diabetic kidney disease.

AIMS: This study aimed to determine the association between lipoprotein-associated phospholipase A2 (Lp-PLA2), a marker for inflammation in the vessel wall and independently associated with atherosclerosis, and the incidence of diabetic kidney disease (DKD) in patients with type 2 diabetes (T2D). METHODS: A total of 1452 patients were enrolled in this retrospective cross­sectional study. We recruited patients with T2D who were tested for glycated hemoglobin, fasting and 2 h post-meal serum C-peptide, blood lipid profile, 24 h urine albumin excretion rate (UAER), blood creatine, blood albumin, uric acid, and Lp-PLA2. RESULTS: Among the patients with T2D, 40.3% were diagnosed with DKD and the correlation between DKD and Lp-PLA2 was the most significant one compared to other diabetic complications (odds ratio = 1.651, P < 0.001). Plasma Lp-PLA2 level in patients with DKD was significantly higher and increased Lp-PLA2 level was independently associated with the incidence of DKD after adjustment for age, gender, duration of diabetes, glycated hemoglobin, body mass index, blood lipids, blood pressure, presence of coronary heart disease and carotid plaque, and use of statins (odds ratio = 1.545, P = 0.013). Lp-PLA2 was found to be positively correlated with UAER (r = 0.123, P < 0.001) and negatively correlated with estimated glomerular filtration rate (eGFR) (r = -0.71, P = 0.009). CONCLUSIONS: Increased plasma level of Lp-PLA2 is associated with incidence and development of DKD in patients with T2D. Lp-PLA2 should be considered as a biomarker for early detection and follow-up of DKD. TRIAL REGISTRATION: clinicaltrials.gov, No. NCT03362112, Registered 30 November 2017, retrospectively registered.

Association of high circulating testosterone with increased glycaemic variability in type 2 diabetes: A cross-sectional study in China.

BACKGROUND: Testosterone affects insulin resistance, but the effect of testosterone treatment on type 2 diabetes (T2D) remains controversial. We aimed to investigate the association between circulating total testosterone (TT) and glycaemic variability using continuous glucose monitoring (CGM) in patients with T2D. METHODS: A total of 248 men with T2D were enrolled in the study. Clinical characteristics and plasma for glycated haemoglobin (HbA1c) and C-peptide assessment were collected. TT was measured using a chemiluminescent immunometric assay. All patients were subjected to a 3-day CGM before making adjustments for hypoglycaemic therapy. RESULTS: TT positively correlated with the standard deviation of mean blood glucose (SDBG) (P < 0.05), especially in older patients. Linear regression analysis showed that SDBG was associated with HbA1c (ß = 0.354, P < 0.001) and TT (ß = 0.164, P = 0.008) after adjusting for age, duration of diabetes, body mass index, fasting/postprandial C-peptide, and use of different hypoglycaemic drugs. The cut-off value of TT for predicting glycaemic variability was 14.76 mmol/L according to receiver operating characteristic (ROC) analysis. SDBG, the coefficient of variation, the incremental area under the curve of glucose (AUC) > 10 mmol/L, and AUC night were increased in the group with TT > 14.76 nmol/L (P < 0.01 for all variables). Body mass index and fasting/postprandial C-peptide were lower in the group with TT > 14.76 nmol/L than in the group with TT ≤ 14.76 nmol/L (P < 0.05). CONCLUSIONS: Circulating TT levels should be assessed in patients with T2D in addition to HbA1c for predicting glycaemic variability. More frequent blood glucose monitoring or CGM is suggested for patients with T2D and high testosterone levels. CLINICAL TRIALS REGISTRATION: NCT03519529, ClinicalTrials.gov.

Glycemic variation in uncontrolled Graves' disease patients with normal glucose metabolism: Assessment by continuous glucose monitoring.

PURPOSE: To observe the glycemic variation (GV) in uncontrolled Graves' disease (GD) patients with normal glucose metabolism measured by continuous glucose monitoring (CGM). METHODS: This was a single-center, open-label, observational study. From January 2017 to October 2017, 20 GD patients with normal glucose metabolism and 24 healthy control subjects were recruited. Serum samples were obtained at 0, 30, and 120 min after oral glucose loading for glucose, insulin, and C-peptide level measurements. Fasting plasma fasting free triiodothyronine (FT3), free thyroxin (FT4), and thyroid stimulating hormone concentrations were also detected. All participants were subjected to a 3-day CGM after baseline data were collected. The primary endpoint was the difference in the mean amplitude of the glycemic excursions between the two groups. RESULTS: Compared with the healthy subjects, the GD patients had higher mean amplitude of glycemic excursions (MAGE) (P < 0.01). Multiple linear stepwise regression analysis showed that FT4 level was an independent factor for the MAGE. Interestingly, the GD patients had a significant prolongation in the time to peak glucose, especially after breakfast (P < 0.01), and the elevation in the incremental area under the curve of glucose after breakfast till 4 hours later. CONCLUSIONS: Uncontrolled GD patients with normal glucose metabolism had a greater GV, and the FT4 level may contributed to the increased GV.

A Single-Blinded Trial Using Resting-State Functional Magnetic Resonance Imaging of Brain Activity in Patients with Type 2 Diabetes and Painful Neuropathy.

About two-thirds of patients with painful diabetic neuropathy (PDN) suffer from anxiety and/or depression disorders. However, the pathogenesis of PDN is unclear, in particular with respect to the mechanism associated with the central nervous system. We used the neuroimaging techniques of fraction amplitude of low-frequency fluctuation (fALFF) and regional homogeneity of resting-state functional magnetic resonance imaging (fMRI) to explore the brain activity in patients with PDN. The symptoms, signs and mental conditions of 19 patients with PDN and of 18 patients with non-pain neuropathy were assessed separately and compared. Blood oxygenation level-dependent resting-state fMRI scans of the brain were performed in all 37 patients with neuropathy and in 15 gender- and age-matched healthy controls. Our data showed that patients with PDN had increased insulin resistance (p = 0.03), increased depression (p = 0.02) and increased anxiety (p < 0.001) compared with the controls and that all of these conditions were associated with abnormal spontaneous activities in several regions of the brain, including the somatosensory, cognitive and emotional regions. The duration of diabetes, level of glycated hemoglobin, homeostasis model assessment of insulin resistance and estimated glomerular filtration rate were significantly correlated to abnormal spontaneous activity in patients' brains. These results lead to the conclusion that patients with PDN have abnormal brain activity, indicating that the central nervous system may contribute to painful diabetic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03700502.

Twenty Minute Moderate-Intensity Post-Dinner Exercise Reduces the Postprandial Glucose Response in Chinese Patients with Type 2 Diabetes.

BACKGROUND Postprandial hyperglycemia and glycemic fluctuations are significant cardiovascular disease risk factors for patients with type 2 diabetes. We investigated the effects of a single session of post-dinner moderate-intensity exercise on the postprandial glycemic response compared with a non-exercise condition in a study population of Chinese patients with type 2 diabetes. MATERIAL AND METHODS This randomized crossover self-controlled pilot study involved 29 patients with type 2 diabetes who participated in post-dinner exercise days using non-exercise days as a control. The interstitial glucose level was monitored using a continuous glucose monitoring system, with a standardized diet and medication. For the non-exercise control days, patients pursued normal daily activities but refrained from unusual strenuous physical activity. On the exercise days, participants walked on a treadmill for 20 minutes after dinner, with a heart rate reserve of 40%. RESULTS Post-dinner moderate-intensity exercise reduced the 2-hour postprandial glucose spike, mean glucose level, and peak glucose level compared to the control condition. The cumulative glucose total area under the curve during 1-hour post-exercise was lower with exercise than under the control condition. The 12-hour standard deviation of blood glucose and the coefficient variation of glucose were significantly lower in the with exercise day compared to the control day, although the 12-hour mean amplitude of glycemic fluctuations did not reach statistical significance. No nocturnal hypoglycemia subsequently occurred on the exercise day. CONCLUSIONS A short session of moderate-intensity post-dinner exercise can improve postprandial hyperglycemia and glycemic excursions in Chinese patients with type 2 diabetes, with no potential hypoglycemia risk at a later period.

Insulin Injection Technique is Associated with Glycemic Variability in Patients with Type 2 Diabetes.

INTRODUCTION: Patients with type 2 diabetes (T2D) receiving premixed insulin often fail to achieve optimal glycemic control. The insulin injection technique (IT) itself may be one of the factors affecting glycemic variability (GV). The aim of this study was to assess the relationship between GV and IT in patients with T2D using premixed insulin. METHODS: This was a single center, cross-sectional, and self-controlled trial. Patients with T2D using premixed insulin were enrolled as inpatients. The 4-day study consisted of a 2-day patient insulin injection period (days 0 and 1) and a 2-day specialist nurse insulin injection period (days 2 and 3). Patient insulin IT were assessed on day 1 by two independent nurses using a skill-related scale consisting of 15 items, with a maximum score for each item of 2 and a total optimum score of 30. All patients underwent 96-h continuous glucose monitoring (CGM) during the 4-day study, and CGM data collected on days 1 and 3 were recorded and analyzed. The primary outcome was the relationship between the insulin IT score and the 24-h mean amplitude glycemic excursion (MAGE) during the patient injection period. RESULTS: A total of 52 inpatients with T2D who used premixed insulin were recruited and completed the study. The mean total insulin IT score of these patients was considerably lower than the optimum score (17.0 ± 4.4 vs. 30). Our CGM data showed that the MAGE was significantly higher during the patient injection period than during the nurse injection period (P < 0.05). Multiple linear stepwise regression analysis showed that the patient IT score was negatively correlated to the MAGE (P < 0.05). The patient IT score was also negatively correlated to glycated hemoglobin (HbA1c; P < 0.05). CONCLUSIONS: A poorer insulin IT may negatively affect GV and HbA1c control in patients with T2D using premixed insulin. Our data indicate that the insulin IT is important for short- and long-term glycemic control. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identification number: NCT03513055.

Male Patients with Longstanding Type 2 Diabetes Have a Higher Incidence of Hypoglycemia Compared with Female Patients.

INTRODUCTION: To explore whether there was a gender difference in the risk of hypoglycemia during intensive insulin therapy in patients with longstanding type 2 diabetes (T2D). This was a post hoc analysis of a single-center, open-label and prospective trial. METHODS: All subjects were admitted as inpatients, underwent a standard bread meal test at baseline and received a 7-day continuous subcutaneous insulin infusion (CSII) therapy for achieving glycemic control. Patients then were randomized 1:1 to two groups receiving (1) 4 days of Novo Mix 30 followed by 2 days of Humalog Mix 50; (2) 4 days of Humalog Mix 50 followed by 2 days of Novo Mix 30. All patients were subjected to 4-day retrospective continuous glucose monitoring (CGM) during the last 4 days in this study. The primary outcome was the incidences of hypoglycemia monitored by CGM at the end point. RESULTS: A total of 102 patients met the inclusion criteria and completed the study. Our data revealed that 29 patients (28%) experienced hypoglycemia as detected by CGM at the end point. Binary logistic stepwise regression analysis showed that only gender significantly correlated with hypoglycemia (B = 1.17, p = 0.017). Importantly, male patients had a significantly higher incidence of hypoglycemia than female patients (male = 20/52, female = 9/50, p = 0.022), although male patients required significantly lower insulin doses to maintain glycemic control than female patient (p = 0.00). CONCLUSION: Male patients with longstanding T2D had a higher incidence of hypoglycemia than female patients during intensive insulin therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, ChiCTR-IPR-15007340.