Differences in glycemic trends due to reconstruction methods after proximal gastrectomy from the perspective of continuous glucose-monitoring.

PURPOSE: In recent years, clinicians have focused on the importance of preventing hypoglycemia. We evaluated the impact of different reconstruction procedures after proximal gastrectomy on glycemic variability in non-diabetic patients with gastric cancer. METHODS: This prospective observational study was conducted between April 2020 and March 2023. Flash continuous glucose-monitoring, a novel method for assessing glycemic control, was used to evaluate the glycemic profiles after gastrectomy. A flash continuous glucose-monitoring sensor was placed subcutaneously at the time of discharge, and glucose trends were evaluated for 2 weeks. RESULTS: The anastomotic methods for proximal gastrectomy were esophagogastrostomy in 10 patients and double-tract reconstruction in 10 patients. The time below this range (glucose levels < 70 mg/dL) was significantly higher in the double-tract reconstruction group than in the esophagogastrostomy group (p = 0.049). A higher nocturnal time below this range was significantly correlated with an older age and double-tract reconstruction (p = 0.025 and p = 0.025, respectively). CONCLUSION: These findings provide new insights into reconstruction methods after proximal gastrectomy by assessing postoperative hypoglycemia in non-diabetic patients with gastric cancer.

Molecular Changes in Cells of Patients with Type 2 Diabetes Mellitus Depending on Changes in Glycemia Level in the Context of Lifestyle-An Overview of the Latest Scientific Discoveries.

Diabetes mellitus is a significant health problem for medicine and economics. In 80-90% of cases, it is type 2 diabetes (T2DM). An essential aspect for people with T2DM is to control blood glucose levels and avoid significant deviations. Modifiable and non-modifiable factors influence the incidence of hyperglycemia and, sometimes, hypoglycemia. The lifestyle modifiable factors are body mass, smoking, physical activity, and diet. These affect the level of glycemia and impact molecular changes. Molecular changes affect the cell's primary function, and understanding them will improve our understanding of T2DM. These changes may become a therapeutic target for future therapy of type 2 diabetes, contributing to increasing the effectiveness of treatment. In addition, the influence of external factors (e.g., activity, diet) on each domain of molecular characterization has gained importance towards a better understanding of their role in prevention. In the current review, we aimed to collect scientific reports on the latest research about modifiable factors connected with the style of life which affect the glycemic level in the context of molecular discoveries.

Dynamics of glucose levels after Billroth I versus Roux-en-Y reconstruction in patients who undergo distal gastrectomy.

PURPOSE: Recent studies have highlighted the importance of understanding trends in blood glucose levels. We examined the differences in blood glucose fluctuations according to the reconstruction method used after distal gastrectomy (DG) in patients with non-diabetic gastric cancer (GC). METHODS: Sixty-one patients who underwent DG followed by either Billroth 1 (B1) or Roux-en-Y (R-Y) reconstruction were enrolled in this study. We used flash continuous glucose monitoring (CGM), a new technique for assessing glycemic control, to document the post-gastrectomy glycemic profile. Immediately before discharge, a CGM sensor was placed subcutaneously to evaluate blood glucose trends for 2 weeks. RESULTS: The coefficient of variation of glucose levels was significantly higher in the Roux-en-Y (R-Y) group than in the Billroth I (B-I) group (p = 0.0260). The time below range (TBR, glucose levels of < 70 mg/dL) was also significantly higher in the R-Y group (p = 0.0115). Logistic regression analysis revealed that preoperative casual glucose levels of < 100 mg/dL and R-Y reconstruction were independently correlated with risk factors for a postoperative nocturnal TBR of > 30% (p = 0.006 and 0.042, respectively). CONCLUSION: Our findings provide new insights into the post-DG reconstruction method selected for patients with non-diabetic gastric cancer by assessing postoperative blood glucose fluctuations using flash CGM.

Glucose Fluctuations Promote Aortic Fibrosis through the ROS/p38 MAPK/Runx2 Signaling Pathway.

AIM: Glucose fluctuations may be responsible for, or further the onset of arterial hypertension, but the exact mechanisms remain unclear. The purpose of this study was to investigate the mechanisms behind and related to aortic fibrosis and aortic stiffening induced by glucose fluctuations. METHODS: Sprague-Dawley rats were injected with streptozotocin (STZ) and randomly divided into three treatment groups: controlled STZ-induced diabetes (C-STZ); uncontrolled STZ-induced diabetes (U-STZ); and STZ-induced diabetes with glucose fluctuations (STZ-GF). After 3 weeks, rat blood pressure (BP) was tested, and aortic fibrosis was detected by using the Masson trichrome staining technique. Levels of p38 mitogen-activated protein kinase (p38 MAPK), runt-related transcription factor 2 (Runx2), collagen type 1 (collagen I), and NADPH oxidases were determined by Western blot.Rat vascular smooth muscle cells in vitro were used to explore underlying mechanisms. RESULTS: The systolic BP of diabetic rats in the C-STZ, U-STZ, and STZ-GF groups was 127.67 ± 6.53, 150.03 ± 5.24, and 171.63 ± 3.53 mm Hg, respectively (p< 0.05). The mean BP of diabetic rats in the three groups was 91.20 ± 10.07, 117.29 ± 4.28, and 140.58 ± 2.14 mm Hg, respectively (p< 0.05). The diastolic BP of diabetic rats in the three groups was 73.20 ± 12.63, 101.93 ± 5.79, and 125.37 ± 4.62 mm Hg, respectively (p< 0.05). The ratios of fibrosis areas in the aortas of the three groups were 11.85 ± 1.23, 29.00 ± 0.87, and 48.36 ± 0.55, respectively (p< 0.05). The expressions of p38 MAPK, Runx2, and collagen I were significantly increased in the STZ-GF group. In vitro, applications of inhibitors of reactive oxygen species (ROS) and p38 MAPK successfully reversed glucose fluctuations that would have possibly induced aortic fibrosis. CONCLUSIONS: Blood glucose fluctuations aggravate aortic fibrosis via affecting the ROS/p38 MAPK /Runx2 signaling pathway.

Impact of CD14++CD16+ monocytes on plaque vulnerability in diabetic and non-diabetic patients with asymptomatic coronary artery disease: a cross-sectional study.

BACKGROUND: Previously, we have reported that daily glucose fluctuations could affect coronary plaque vulnerability, but the underlying mechanisms remained unclear. This study sought to investigate the impact of CD14++CD16+ monocytes on plaque vulnerability, as assessed by virtual histology intravascular ultrasound (VH-IVUS), as well as their relationship to fluctuating glucose levels in patients with asymptomatic coronary artery disease (CAD). METHODS: Fifty-one patients with asymptomatic CAD, who were undergoing lipid-lowering therapy and underwent VH-IVUS evaluation for angiographically mild to moderate lesions, were enrolled in the study. Standard VH-IVUS parameters, including the percentage volume of the necrotic core (%NC) within the plaque and the presence of a virtual histology thin-cap fibroatheroma (VH-TCFA), were then evaluated. Additionally, monocyte subsets were assessed by flow cytometry, and daily glucose fluctuations were analyzed by measuring the mean amplitude of glycemic excursion (MAGE). RESULTS: Among 82 plaques from 22 diabetes mellitus (DM) patients and 29 non-DM patients, 15 VH-TCFAs were identified. CD14++CD16+ monocyte counts significantly correlated with both  %NC and the presence of VH-TCFA (%NC: r = 0.339, p = 0.002; VH-TCFA: p = 0.003). Multivariate logistic regression analysis revealed that CD14++CD16+ monocyte counts were independently associated with VH-TCFA (odds ratio = 1.029, p = 0.004). Furthermore, CD14++CD16+ monocyte counts were significantly correlated with the MAGE score in the non-DM patients (r = 0.544, p = 0.005). CONCLUSIONS: CD14++CD16+ monocyte levels are associated with coronary plaque vulnerability and can serve as a biomarker for VH-TCFA in patients with CAD undergoing lipid-lowering therapy. In patients without DM, glucose fluctuations may alter the balance of monocyte subsets. Trial registration UMIN Registry number: UMIN000021228.

Postprandial Glucose Surges after Extremely Low Carbohydrate Diet in Healthy Adults.

Carbohydrate-restricted diets are prevalent not only in obese people but also in the general population to maintain appropriate body weight. Here, we report that extreme carbohydrate restriction for one day affects the subsequent blood glucose levels in healthy adults. Ten subjects (median age 30.5 years, BMI 21.1 kg/m2, and HbA1c 5.5%), wearing with a continuous glucose monitoring device, were given isoenergetic test meals for 4 consecutive days. On day 1, day 2 (D2), and day 4 (D4), they consumed normal-carbohydrate (63-66% carbohydrate) diet, while on day 3, they took low-carbohydrate/high-fat (5% carbohydrate) diet. The daily energy intake was 2,200 kcal for males and 1,700 kcal for females. On D2 and D4, we calculated the mean 24-hr blood glucose level (MEAN/24h) and its standard deviation (SD/24h), the area under the curve (AUC) for glucose over 140 mg/dL within 4 hours after each meal (AUC/4h/140), the mean amplitude of the glycemic excursions (MAGE), the incremental AUC of 24-hr blood glucose level above the mean plus one standard deviation (iAUC/MEAN+SD). Indexes for glucose fluctuation on D4 were significantly greater than those on D2 (SD/24h; p = 0.009, MAGE; p = 0.013, AUC/4h/140 after breakfast and dinner; p = 0.006 and 0.005, and iAUC/MEAN+SD; p = 0.007). The value of MEAN/24h and AUC/4h/140 after lunch on D4 were greater than those on D2, but those differences were not statistically significant. In conclusion, consumption of low-carbohydrate/high-fat diet appears to cause higher postprandial blood glucose on subsequent normal-carbohydrate diet particularly after breakfast and dinner in healthy adults.

miR-1273g-3p participates in acute glucose fluctuation-induced autophagy, dysfunction, and proliferation attenuation in human umbilical vein endothelial cells.

Acute glucose fluctuations (AGF) often cause high mortality among critically ill patients, but the mechanisms induced by AGF are not clear. Recent studies suggest that endothelial dysfunction is a key factor that leads to high mortality among critically ill patients. Our goal is to evaluate the phenomenon and mechanisms of endothelial dysfunction induced by AGF. In this study, the functions of human umbilical vein endothelial cells (HUVECs) were compared after treatment with sustained high glucose (SHG), AGF in two groups (AGF1 fluctuations between 5 and 16 mM and AGF2 fluctuations between 5 and 25 mM), and normal glucose levels as a control group (CTR). The medium of the groups was changed every 4 h. The influence of AGF on wound healing was also tested on C57BL/6 mice. The results show that cell proliferation, angiogenesis, and migration functions were injured in the SHG and both AGF groups. AGF2 group shows the worse condition in vitro. In vivo, the wound healing was delayed after the AGF treatment. Furthermore, the markers of apoptosis and autophagy were analyzed. We observed that the autophagy changed in all treatment groups, but apoptosis showed no change. To get to know the mechanism of dysfunction and autophagy, we performed the microRNA chip assay and real-time PCR and found miR-1273g-3p remarkably changed in AGF2 group. After the mimic and inhibitor of miR-1273g-3p were transfected during the AGF2 treatment, we found that the dysfunction and autophagy were partially enhanced by miR-1273g-3p mimic and reversed by miR-1273g-3p inhibitor in AGF2 group. Thus, we conclude that AGF can induce more dysfunction and autophagy, and miR-1273g-3p is also an important factor that leads to the injury.

The strong relation between post-hemodialysis blood methylglyoxal levels and post-hemodialysis blood glucose concentration rise.

BACKGROUND: Hemodialysis is known to decrease blood glucose concentration (BGC), insulin, and methylglyoxal levels. However, the effects of decreases in these factors on the increase in post-hemodialysis BGC remain unknown. This study identifies the effects of hemodialysis-induced changes in concentrations of these elements on post-hemodialysis BGC. METHODS: Study subjects included seventeen insulin-treated diabetes patients receiving hemodialysis. The fluctuations in BGC on hemodialysis-treatment days and non-hemodialysis-treatment days were evaluated using a continuous glucose monitoring system. BGC was evaluated before breakfast, before starting hemodialysis, at the end of hemodialysis, 1 h post-hemodialysis (lunch), and 6 h post-hemodialysis (dinner). BGC, insulin, and methylglyoxal levels were measured at the start and end of hemodialysis. This study also evaluated the changes in the concentrations of glucose and insulin in the arterial line and the venous line during hemodialysis. RESULTS: Hemodialysis decreases BGC, insulin, and methylglyoxal levels. Concentrations of glucose and insulin in the arterial line gradually decreased during dialysis, while concentrations in the venous line approached their original concentrations in the dialysis solution. BGC rose sharply after eating lunch 1 h post-hemodialysis. The blood glucose, insulin, and methylglyoxal concentrations at the end of hemodialysis were associated with the M values and the mean amplitude of glycemic excursion values between before lunch and dinner. In particular, methylglyoxal concentration at the end of hemodialysis was strongly related to the post-hemodialysis increase in BGC. CONCLUSION: Hemodialysis-induced decreases in methylglyoxal concentrations and methylglyoxal concentration at the end of hemodialysis influence post-hemodialysis fluctuations in BGC.

Glucose fluctuations aggravate myocardial fibrosis via activating the CaMKII/Stat3 signaling in type 2 diabtetes.

BACKGROUND: Glucose fluctuations (GF) are a risk factor for cardiovascular complications associated with type 2 diabetes. However, there is a lack of adequate research on the effect of GF on myocardial fibrosis and the underlying mechanisms in type 2 diabetes. This study aimed to investigate the impact of glucose fluctuations on myocardial fibrosis and explore the potential mechanisms in type 2 diabetes. METHODS: Sprague Dawley (SD) rats were randomly divided into three groups: the control (Con) group, the type 2 diabetic (DM) group and the glucose fluctuations (GF) group. The type 2 diabetic rat model was established using a high-fat diet combined with low-dose streptozotocin injection and the GF model was induced by using staggered glucose and insulin injections daily. After eight weeks, echocardiography was used to assess the cardiac function of the three groups. Hematoxylin-eosin and Masson staining were utilized to evaluate the degree of pathological damage and fibrosis. Meanwhile, a neonatal rat cardiac fibroblast model with GF was established. Western and immunofluorescence were used to find the specific mechanism of myocardial fibrosis caused by GF. RESULTS: Compared with rats in the Con and the DM group, cardiac function in the GF group showed significant impairments. Additionally, the results showed that GF aggravated myocardial fibrosis in vitro and in vivo. Moreover, Ca2+/calmodulin­dependent protein kinase II (CaMKII) was activated by phosphorylation, prompting an increase in phosphorylation of signal transducer and activator of transcription 3 (Stat3) and induced nuclear translocation. Pretreatment with KN-93 (a CaMKII inhibitor) blocked GF-induced Stat3 activation and significantly suppressed myocardial fibrosis. CONCLUSIONS: Glucose fluctuations exacerbate myocardial fibrosis by triggering the CaMKII/Stat3 pathway in type 2 diabetes.

Effects of mulberry twig alkaloids(Sangzhi alkaloids) and metformin on blood glucose fluctuations in combination with premixed insulin-treated patients with type 2 diabetes.

Introduction: We aimed to evaluated the effect of premixed insulin (Ins), premixed insulin combined with metformin (Ins+Met) or mulberry twig alkaloids(Ins+SZ-A) on blood glucose fluctuations in patients with type 2 diabetes (T2DM) using continuous glucose monitors (CGM). Methods: Thirty patients with T2DM and poor blood glucose control using drugs were evaluated for eligibility during the screening period. Subsequently, their original hypoglycemic drugs were discontinued during the lead-in period, and after receiving Ins intensive treatment for 2 weeks, they were randomly assigned to receive either Ins, Ins+Met, or Ins+SZ-A treatment for the following 12 weeks. The main efficacy endpoint comprised changes in their CGM indicators changes (mean blood glucose level [MBG], standard deviation of blood glucose [SDBG], mean amplitude of glycemic excursions [MAGE], postprandial glucose excursions [PPGE], the largest amplitude of glycemic excursions [LAGE], mean of daily difference [MODD], time in range between 3.9-10.0 mmol/L [TIR] and area under the curve for each meal [AUCpp]) during the screening, lead-in, and after 12-week treatment period. Changes in glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), 1-h postprandial blood glucose (1h-PBG), 2-h postprandial blood glucose (2h-PBG), fasting blood lipids and postprandial blood lipids were also measured at baseline and after 12 weeks of treatment. Results: The CGM indicators of the three groups during the lead-in period all showed significant improvements compared to the screening period (P<0.05). Compared with those in the lead-in period, all of the CGM indicators improved in the the Ins+Met and Ins+SZ-A groups after 12 weeks of treatment (P<0.05), except for MODD. After 12-week treatment, compared with the Ins group, Ins+Met and Ins+SZ-A groups showed improved MBG, SDBG, TIR, breakfast AUCpp,lunch AUCpp, HbA1c, FBG, 1h-PBG, fasting blood lipid and postprandial blood lipid indicators (P<0.05). Further, the LAGE, PPGE, MAGE, dinner AUCpp and 2h-PBG levels of the Ins+SZ-A group were significantly lower than those of the Ins+Met and Ins groups (P<0.05). Conclusion: Our findings highlight the efficacy of combination therapy (Ins+SZ-A or Ins+Met) in improving blood glucose fluctuations, as well as blood glucose and lipid levels. Ins+SZ-A reduces postprandial blood glucose fluctuations more than Ins+Met and Ins groups. Trial registration number: ISRCTN20835488.

Relationship between Short- and Mid-Term Glucose Variability and Blood Pressure Profile Parameters: A Scoping Review.

Background. Increased variability of glucose (GV) and blood pressure (BPV) is linked to a higher risk of macro- and microvascular complications and other hard endpoints. This scoping review aims to summarize the existing evidence regarding the association between the parameters of the blood pressure (BP) profile, especially BPV, with indices of short- and mid-term GV. Methods. A literature search was conducted in the MEDLINE/PubMed, Cochrane, Embase, Web of Science, and Wiley Online Library databases. Results. The main findings of this review are as follows: (i) 13 studies were included, mainly with small sample sizes; (ii) there was a considerable degree of heterogeneity in the characteristics of the study participants (age range, individuals with normoglycemia, type 1 or 2 diabetes, normal BP, or hypertension), as well as in the methodologies (mainly in terms of the duration of the data collection period) and variability indices examined (mean amplitude of glycemic excursions and coefficient of glucose variation most frequently reported); and (iii) the results were heterogeneous regarding the association between GV and the parameters of the BP profile. Conclusions. There is a significant lack of evidence on the association between GV and BPV. Future research implementing a standardized methodology should focus on the determinants, association, and clinical relevance of GV and BPV.

Sex-Specific Associations Between Low Muscle Mass and Glucose Fluctuations in Patients With Type 2 Diabetes Mellitus.

Objective: Studies have shown that sex differences in lean mass, concentrations of sex hormones, and lifestyles influence cle health and glucose metabolism. We evaluated the sex-specific association between low muscle mass and glucose fluctuations in hospitalized patients with type 2 diabetes mellitus (T2DM) receiving continuous subcutaneous insulin infusion (CSII) therapy. Methods: A total of 1084 participants were included. Body composition was determined by dual-energy X-ray absorptiometry. Intraday blood glucose fluctuation was estimated by the Largest amplitude of glycemic excursions (LAGE) and standard deviation of blood glucose (SDBG). Results: The prevalence of low muscle mass was higher in males than in females (p<0.001). There was a significant sex-specific interaction between the status of low muscle mass and glucose fluctuations (LAGE and SDBG) (p for interaction=0.025 and 0.036 for SDBG and LAGE, respectively). Among males, low muscle mass was significantly associated with a higher LAGE and SDBG (difference in LAGE: 2.26 [95% CI: 1.01 to 3.51], p < 0.001; difference in SDBG: 0.45 [95% CI: 0.25 to 0.65], p < 0.001) after adjustment for HbA1c, diabetes duration, hyperlipidemia, diabetic peripheral neuropathy, diabetic nephropathy, and cardiovascular disease. These associations remained significant after further adjustment for age and C-peptide. Among females, low muscle mass was not associated with LAGE or SDBG after adjustment for all covariates. Conclusion: The prevalence of low muscle mass was higher in males than in females. Low muscle mass was significantly associated with higher LAGE and SDBG among males, but not females.

Effect of short-term acute moderate-intensity resistance exercise on blood glucose in older patients with type 2 diabetes mellitus and sarcopenia.

AIM: To investigate the effects of short-term acute moderate-intensity resistance exercise on blood glucose in older patients with type 2 diabetes mellitus and sarcopenia using ambulatory glucose monitoring technology. METHODS: This is a prospective intervention of an own-controlled before-and-after cohort study. A total of 24 older type 2 diabetes mellitus patients who met the enrollment criteria were selected, including 12 cases in the sarcopenia and 12 in the non-sarcopenia groups. First, they wore ambulatory glucose monitoring devices (Medtronic, Ipro2) and retained baseline data. Then they wore Ipro2 again and carried out two sessions of resistance exercise on alternate days. Blood glucose level, blood glucose fluctuation, and time in target range on the contrast and exercise days were compared and analyzed in both groups. RESULTS: The area under the curve of glucose level across 24 h and the mean blood glucose post exercise decreased (P < 0.05) in the sarcopenia group. On the exercise day, the coefficient of variation of glucose, the largest amplitude of glycemic excursions, amplitude of postprandial glucose excursions and low blood glucose index decreased, whereas the time in target range increased (P < 0.05). CONCLUSIONS: Short-term acute moderate-intensity resistance exercise is an effective and safe exercise modality, which can reduce blood glucose levels, blood glucose fluctuations and the risk of hypoglycemia, as well as improve the time in target range for older patients with type 2 diabetes mellitus and sarcopenia. Geriatr Gerontol Int 2022; 22: 653-659.

[Impact of physical activity on glycemic variability in people with diabetes mellitus type 2]. / Impacto de la actividad física en la variabilidad glucémica en personas con diabetes mellitus tipo 2.

One of the main roles of the prescription of physical activity for people with type 2 diabetes is to reduce hyperglycemia. The beneficial effect of physical training on glycemic levels is considered as the sum of the effects of each exercise session. A better understanding of acute responses to exercise, through short-term glycemic variability, could explain the differences in the results of distinct training protocols. The objective of this study was to analyze the scientific information on different exercise protocols and their association with short-term glycemic variability in patients with type 2 diabetes. A systematic review of studies published in English and Spanish was carried out. The databases used were PubMed, Cochrane, ScienceDirect, and Medline. Only studies conducted in adults (older than 18 years) were included. A total of 36 studies were identified, which were analyzed and completed using the Covidence® platform. The final analysis included 10 articles with 296 patients. The 10 included articles were divided according to the type of intervention protocol used: group 1, acute exercise, and group 2, training. Significant differences were found in glycemic variability in 71.4% of the articles in group 1 and in 100% of the articles included in group 2. Positive effects of acute exercise and physical training on short-term glycemic variability were demonstrated. The findings were more pronounced in the intervention protocols than in physical training.

Blood glucose fluctuations detected by continuous glucose monitoring system in gout patients with normal glucose tolerance and the effect of urate-lowering therapy.

AIM: The aim of this study was to investigate whether there are blood glucose fluctuations in gout patients with hyperuricemia and normal glucose tolerance, and the effect of urate-lowering therapy on blood glucose fluctuations. METHODS: Thirty patients with newly diagnosed gout, hyperuricemia and normal glucose tolerance were enrolled in our study. Continuous glucose monitoring system (CGMS) was used to detect the blood glucose fluctuations of these gout patients. Changes in blood glucose fluctuations after allopurinol therapy were also evaluated. RESULTS: Compared with the reference values of blood glucose fluctuation parameters in China, gout patients had greater glycemic fluctuations including higher mean amplitude of glucose excursions (MAGE) (4.65 vs 1.94 mmol/L, P < .001), higher largest amplitude of blood glucose excursions (LAGE) (4.99 vs 3.72 mmol/L, P < .001) and higher standard deviations of blood glucose (SDBG) (1.36 vs 0.79 mmol/L, P < .001). MAGE was significantly correlated with uric acid (ß = .007, P = .024) and HOMA-insulin resistance (IR) (ß = .508, P = .03). Allopurinol treatment significantly reduced MAGE (4.16 vs 4.65 mmol/L, P < .001), SDBG (0.99 vs 1.36 mmol/L, P < .001) and HOMA-IR (2.26 vs 3.01, P < .001) in gout patients. CONCLUSION: Blood glucose fluctuation increased even in the stage of normal glucose tolerance among gout patients. Blood glucose fluctuations in gout patients were associated with the level of serum uric acid and allopurinol could decrease blood glucose fluctuation as well as IR.

Repetitive Intermittent Hyperglycemia Drives the M1 Polarization and Inflammatory Responses in THP-1 Macrophages Through the Mechanism Involving the TLR4-IRF5 Pathway.

Repetitive intermittent hyperglycemia (RIH) is an independent risk factor for complications associated with type-2 diabetes (T2D). Glucose fluctuations commonly occur in T2D patients with poor glycemic control or following intensive therapy. Reducing blood glucose as well as glucose fluctuations is critical to the control of T2D and its macro-/microvascular complications. The interferon regulatory factor (IRF)-5 located downstream of the nutrient sensor toll-like receptor (TLR)-4, is emerging as a key metabolic regulator. It remains unclear how glucose fluctuations may alter the IRF5/TLR4 expression and inflammatory responses in monocytes/macrophages. To investigate this, first, we determined IRF5 gene expression by real-time qRT-PCR in the white adipose tissue samples from 39 T2D and 48 nondiabetic individuals. Next, we cultured THP-1 macrophages in hypo- and hyperglycemic conditions and compared, at the protein and transcription levels, the expressions of IRF5, TLR4, and M1/M2 polarization profile and inflammatory markers against control (normoglycemia). Protein expression was assessed using flow cytometry, ELISA, Western blotting, and/or confocal microscopy. IRF5 silencing was achieved by small interfering RNA (siRNA) transfection. The data show that adipose IRF5 gene expression was higher in T2D than nondiabetic counterparts (P = 0.006), which correlated with glycated hemoglobin (HbA1c) (r = 0.47/P < 0.001), homeostatic model assessment of insulin resistance (HOMA-IR) (r = 0.23/P = 0.03), tumor necrosis factor (TNF)-α (r = 0.56/P < 0.0001), interleukin (IL)-1ß (r = 0.40/P = 0.0009), and C-C motif chemokine receptor (CCR)-2 (r = 0.49/P < 0.001) expression. IRF5 expression in macrophages was induced/upregulated (P < 0.05) by hypoglycemia (3 mM/L), persistent hyperglycemia (15 mM/L-25 mM/L), and RIH/glucose fluctuations (3-15 mM/L) as compared to normoglycemia (5 mM/L). RIH/glucose fluctuations also induced M1 polarization and an inflammatory profile (CD11c, IL-1ß, TNF-α, IL-6, and monocyte chemoattractant protein (MCP)-1) in macrophages. RIH/glucose fluctuations also drove the expression of matrix metalloproteinase (MMP)-9 (P < 0.001), which is a known marker for cardiovascular complication in T2D patients. Notably, all these changes were counteracted by IRF5 silencing in macrophages. In conclusion, RIH/glucose fluctuations promote the M1 polarization and inflammatory responses in macrophages via the mechanism involving TLR4-IRF5 pathway, which may have significance for metabolic inflammation.

Association of Glucose Fluctuations with Sarcopenia in Older Adults with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus accelerates loss of muscle mass and strength. Patients with Alzheimer's disease (AD) also show these conditions, even in the early stages of AD. The mechanism linking glucose management with these muscle changes has not been elucidated but has implications for clarifying these associations and developing preventive strategies to maintain functional capacity. This study included 69 type 2 diabetes patients with a diagnosis of cognitive impairment (n = 32) and patients with normal cognition (n = 37). We investigated the prevalence of sarcopenia in diabetes patients with and without cognitive impairment and examined the association of glucose alterations with sarcopenia. Daily glucose levels were evaluated using self-monitoring of blood glucose, and we focused on the effects of glucose fluctuations, postprandial hyperglycemia, and the frequency of hypoglycemia on sarcopenia. Diabetes patients with cognitive impairment displayed a high prevalence of sarcopenia, and glucose fluctuations were independently associated with sarcopenia, even after adjusting for glycated hemoglobin A1c (HbA1c) levels and associated factors. In particular, glucose fluctuations were significantly associated with a low muscle mass, low grip strength, and slow walking speed. Our observation suggests the importance of glucose management by considering glucose fluctuations to prevent the development of disability.

Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications.

Accumulating evidence indicates the occurrence and development of diabetic complications relates to not only constant high plasma glucose, but also glucose fluctuations which affect various kinds of molecular mechanisms in various target cells and tissues. In this review, we detail reactive oxygen species and their potentially damaging effects upon glucose fluctuations and resultant downstream regulation of protein signaling pathways, including protein kinase C, protein kinase B, nuclear factor-κB, and the mitogen-activated protein kinase signaling pathway. A deeper understanding of glucose-fluctuation-related molecular mechanisms in the development of diabetic complications may enable more potential target therapies in future.

Glucose Variations and Activity Are Strongly Coupled in Sleep and Wake in Young Adults With Type 1 Diabetes.

BACKGROUND: Glucose variations are common throughout sleep and wakefulness in people with type 1 diabetes mellitus (T1DM). The objective of this investigation was to characterize the time-varying coupling between glucose and unstructured physical activity over a 60-hr period in young adults with T1DM. The hypothesis was that coupling would differ during sleep versus wakefulness and would exhibit circadian variations. METHOD: Young adults with T1DM treated with an insulin pump participated in the study. Glucose variations were monitored with a continuous glucose monitoring system, and activity was assessed using an activity-monitoring band worn on the nondominant wrist. Simultaneous glucose and physical activity data across a continuous 60-hr period were used for analysis. Wavelet coherence analysis was employed to quantify the coupling between physical activity and glucose. Cosinor analysis was used to assess whether glucose/activity coherence exhibited significant circadian variations. RESULTS: Participants comprised 23 adults, aged 18-30 years, with T1DM. Coherence analysis demonstrated substantial coupling between physical activity and glucose variations during both wakefulness and sleep. For rapid (10-30 min) fluctuations, mean coherence was higher during sleep than wakefulness ( F = 10.86, p = .003). Rapid glucose variations consistently led to changes in activity ( p = .001) during sleep but not during wake. Cosinor analysis revealed significant circadian modulation of glucose/activity coupling, especially for fluctuation periods 2-4 hr. CONCLUSIONS: Unstructured physical activity and glucose variations demonstrated strong time- and frequency-dependent coupling over a 60-hr period in young adults with T1DM, with sleep/wake differences and circadian modulation evident in this relationship.