Efficacy of Self-Review of Lifestyle Behaviors with Once-Weekly Glycated Albumin Measurement in People with Type 2 Diabetes: A Randomized Pilot Study.

INTRODUCTION: Lifestyle management, including appropriate modifications of nutrition, exercise, and medication behaviors, is essential for optimal glycemic control. The absence of appropriate monitoring methods to validate the lifestyle change may hinder the modification and continuation of behaviors. In this study, we evaluated whether once-weekly glycated albumin (GA) measurement received via a smartphone application could improve glycemia management in patients with type 2 diabetes mellitus by supporting self-review and modification of lifestyle behaviors. METHODS: This open-label, randomized controlled, single-center study in Japan with an 8-week intervention period was conducted in individuals with type 2 diabetes mellitus and HbA1c levels between 7.0 and 9.0% (53‒75 mmol/mol). The intervention was once-weekly home monitoring of GA with a daily self-review of lifestyle behaviors using a smartphone application, in addition to conventional treatment. RESULTS: A total of 98 participants (72.0% males; age 63.2 ± 11.4 years; HbA1c 7.39 ± 0.39% [57.3 ± 4.3 mmol/mol]) were randomly assigned to the intervention or control group. Significant decreases of the GA and HbA1c levels from the baseline to the last observation day were observed in the intervention group (- 1.71 ± 1.37% [- 39.1 ± 31.3 mmol/mol] and - 0.32 ± 0.32% [- 3.5 ± 3.5 mmol/mol], respectively). Significant decreases of the body weight, waist circumference, and caloric expenditure (p < 0.0001 and p = 0.0003, p = 0.0346, respectively), but not of the caloric intake (p = 0.678), were also observed in the intervention group as compared with the control group. CONCLUSIONS: Self-review of lifestyle behaviors in combination with once-weekly GA home testing received via a smartphone application might potentially benefit glycemic management in people with type 2 diabetes mellitus. TRIAL REGISTRATION: jRCTs042220048.

Overexpression of UBE2E2 in Mouse Pancreatic ß-Cells Leads to Glucose Intolerance via Reduction of ß-Cell Mass.

Genome-wide association studies have identified several gene polymorphisms, including UBE2E2, associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Here, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in noncoding regions was associated with upregulation of UBE2E2 mRNA in the human pancreas. Although glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic ß-cell-specific UBE2E2-transgenic (TG) mice exhibited reduced insulin secretion and decreased ß-cell mass. In TG mice, suppressed proliferation of ß-cells before the weaning period and while receiving a high-fat diet was accompanied by elevated gene expression levels of p21, resulting in decreased postnatal ß-cell mass expansion and compensatory ß-cell hyperplasia, respectively. In TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in ß-cells play an important role in regulating glucose homeostasis and ß-cell mass.

Bi-weekly Glycated Albumin Measurement was Useful to Encourage Behavioral Changes in People with Type 2 Diabetes Mellitus.

INTRODUCTION: Hemoglobin A1c (HbA1c), representing the average blood glucose over 1-2 months, is the most commonly used glycemic marker in people with diabetes. Glycated albumin (GA) reflects the average blood glucose over the most recent 1-2 weeks. We considered whether the faster response of GA compared with HbA1c could make people with diabetes realize their glycemic control intuitively and effectively. METHODS: We randomized 61 people with diabetes into the control and intervention groups. Blood samples were collected from both every fortnight over an 8-week period (five times; visit 1-5). Only the intervention group was notified of the GA levels on the same day. At the beginning and end of the study, International Physical Activity Questionnaire and Eating Behavior Questionnaire assessments, and body composition measurements were conducted. RESULTS: The body weight change was significantly lower in the intervention group at visit 2 and visit 5. The percent body fat change was lower, while the percent skeletal muscle mass change at visit 5 was higher in the intervention group. Increasing GA trend was observed in the control group, but not in the intervention group. The fasting plasma glucose and HbA1c changes at visit 5 were similar in the two groups. Physical activity level change tended to be higher in the intervention group. The YN Eating Behavior Questionnaire score changes were similar in the two groups. CONCLUSION: Bi-weekly GA measurement over an 8-week period in people with type 2 diabetes induced behavioral changes. Development of this method is expected to improve diabetes management. TRIAL REGISTRATION: UMIN000037795.

Impact of the COVID-19 pandemic on the glycemic control in people with diabetes mellitus: A retrospective cohort study.

AIM: To investigate the impact of the COVID-19 pandemic and its preventive measures on the glycemic and lipid control in people with diabetes mellitus (DM). MATERIALS AND METHODS: We conducted this retrospective cohort study from April 2019 to March 2021; we termed the period from April 2019 to March 2020 as the pre-COVID-19 period, and the period from April 2020 to March 2021 as the COVID-19 period, and divided each of these two periods into four quarters. RESULTS: In the 1st quarter of the COVID period, when the Japanese government declared the first public health emergency, 3,465 people with diabetes mellitus were receiving treatment, which was 10.4% lower than that in the pre-COVID period. The annual mean HbA1c level was significantly elevated in the COVID-19 period. The annual mean total cholesterol (TC) and triglyceride (TG) levels were also significantly higher in the COVID-19 period. Although there were no significant differences in the glycemic control or annual medication between the two periods in people with type 1 diabetes mellitus, the annual mean HbA1c, TC, and TG levels were significantly higher in the COVID-19 period in people with type 2 diabetes mellitus. Furthermore, a significant increase in the percentage of prescriptions for glinides, biguanides, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists for people with type 2 diabetes mellitus was observed in the COVID period. CONCLUSIONS: It appears from our study that COVID-19 and its preventive measures had a negative impact on the glycemic and lipid control in people with diabetes mellitus.

Development of a high-performance liquid chromatographic glycated albumin assay using finger-prick blood samples.

BACKGROUND: Home blood glucose monitoring can be effective for the self-management of diabetic patients. Hemoglobin A1c (HbA1c) is a widely used marker that reflects the average blood glucose within 1-2 months but does not sensitively respond to behavioral changes. Self-monitoring of blood glucose, continuous glucose monitoring, and flush glucose monitoring are sensitive; however, the cost and invasiveness of these tests prevent their widespread use. We focused on glycated albumin (GA), which reflects the average blood glucose levels over 1-2 weeks, and established a GA measurement method for self-sampling, finger-prick blood, which may be submitted for testing through postal service to receive weekly results. METHODS: A high-performance liquid chromatography assay was established to measure GA levels in finger-prick blood samples from 103 diabetic patients and the results were compared with venous blood measurements using an enzymatic method. Furthermore, conditions for sending blood samples by mail were evaluated. Under these conditions, samples from 27 healthy and 32 patient volunteers sent through postal service were compared with samples stored in the laboratory. RESULTS: GA levels were measured in samples containing > 20 µg albumin, which resulted in a CV less than 0.3%. The correlation between the GA levels of finger-prick blood measured using HPLC and the GA levels of venous blood measured using the enzymatic method was R2 = 0.988 with the slope âˆ¼ 1.0, suggesting that the two were nearly equivalent. GA levels were stable for four days at 30 °C and two days at 37 °C. Mail-delivered samples exhibited a high correlation with samples that were not sent (R2 > 0.99). CONCLUSIONS: We established a method to measure GA levels in self-sampled, finger-prick blood sent through postal service in Japan. The method is applicable for weekly feedback of GA levels, which is potentially useful for motivating behavioral changes. In addition to markers such as HbA1c and blood glucose, GA can be used as a marker for assessing dietary and physical activities. This study highlighted the importance of GA monitoring by developing a suitable measurement method for weekly monitoring of GA levels.

Associations of sleep quality with the skeletal muscle strength in patients with type 2 diabetes with poor glycemic control.

AIMS/INTRODUCTION: Patients with type 2 diabetes mellitus are reported to be at a high risk for sarcopenia, and are known to have a poorer sleep quality. However, the association between sleep quality and skeletal muscle in patients with type 2 diabetes mellitus is not yet precisely understood. MATERIALS AND METHODS: A total of 110 inpatients with type 2 diabetes mellitus aged 40-90 years were enrolled. The sleep quality was assessed using the Pittsburgh sleep quality index (PSQI). Skeletal muscle mass was measured using bioelectrical impedance analysis. Muscle strength was evaluated by measuring the grip strength. We also performed dietary surveys and measurements of the plasma amino acid levels. RESULTS: A high total score on the PSQI was significantly associated with reduced muscle strength, and the association persisted even after adjustments for confounders. On the other hand, adjusted analysis did not reveal any significant associations between the PSQI total score and the skeletal muscle mass. In regard to the associations with subscores of the PSQI, the scores for sleep latency, sleep efficiency, and daytime dysfunction were significantly negatively associated with the muscle strength. Although poor sleep quality was associated with a high confectionery intake and low plasma arginine, citrulline, and ornithine levels, neither confectionery intake levels nor the plasma levels of these amino acids was associated with the muscle strength. CONCLUSIONS: Our study revealed a significant association between the sleep quality and muscle strength in patients with type 2 diabetes mellitus. These results suggest that poor sleep quality is an important risk factor for sarcopenia in patients with type 2 diabetes mellitus.

Evaluation of glycated albumin levels in tears and saliva as a marker in patients with diabetes mellitus.

AIMS: Glycated albumin (GA) is a biomarker, whose level reflects glycemic control status over the previous 2 weeks. To develop a non-invasive method for evaluating glycemic control in people with diabetes mellitus, we investigated the measurement of GA levels in tears and saliva, which could be collected noninvasively. METHODS: Tear and saliva samples were collected from 48 participants with diabetes mellitus. The GA levels in the tear and saliva specimens were measured by Liquid Chromatography-Mass Spectrometry (LC-MS/MS). RESULTS: GA levels in both tear and saliva samples were significantly correlated with the GA levels in the blood (P < 0.001). Multiple regression analysis revealed that these correlations were maintained even after adjustments for the BMI, age, and nephropathy stage (P < 0.001). CONCLUSION: GA levels in tear and saliva specimens, as diabetes-related biomarkers, can be measured non-invasively. Since this measurement can be performed noninvasively and not as frequently as compared with the more invasive finger prick method, it is expected to reduce the burden on people with diabetes in terms of both the invasiveness and cost-effectiveness. In the future, we would like to verify the effect of regular GA measurement on the glycemic control while considering the clinical cost-effectiveness.

Impact of the COVID-19 pandemic on the glycemic control, eating habits, and body compositions of people with diabetes mellitus: A retrospective longitudinal observational study.

AIMS/INTRODUCTION: To evaluate the impact of the COVID-19 pandemic on the glycemic control, eating habits, and body composition of people with diabetes mellitus; to identify the determinants of worsening glycemic control in people with diabetes mellitus. MATERIALS AND METHODS: This retrospective, longitudinal observational study was performed in outpatients with diabetes mellitus who visited our hospital between April 2019 and March 2020 (pre-COVID-19 period) and continued for follow up from April 2020 to March 2021 (COVID-19 period). We compared the glycemic control, nutritional intakes, and body composition of people with diabetes mellitus between the two periods. The changes in the HbA1c values (ΔHbA1c) and other study variables were compared between the two periods. Logistic regression analysis was performed to identify the factors associated with the increase of HbA1c levels. RESULTS: A significant increase of HbA1c was observed during the COVID-19 period. The percent fat mass (FM) also increased, while the percent skeletal muscle mass (SMM) decreased during the COVID-19 period. After adjustments for age and sex, the ΔBMI (OR:2.33), ΔFM (OR:1.45), and ΔSMM (OR:0.51) were identified as being associated with elevated levels of HbA1c. CONCLUSIONS: The COVID-19 pandemic had a negative impact on the glycemic control and body composition of people with diabetes mellitus. The increased body weight and FM and decreased SMM observed during the pandemic were associated with poor glycemic control in people with diabetes mellitus.

Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus.

Insulin receptor substrate-1 (Irs1) is one of the major substrates for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor tyrosine kinases. Systemic Irs1-deficient mice show growth retardation, with resistance to insulin and IGF-1, although the underlying mechanisms remain poorly understood. For this study, we generated mice with brain-specific deletion of Irs1 (NIrs1KO mice). The NIrs1KO mice exhibited lower body weights, shorter bodies and bone lengths, and decreased bone density. Moreover, the NIrs1KO mice exhibited increased insulin sensitivity and glucose utilization in the skeletal muscle. Although the ability of the pituitary to secrete growth hormone (GH) remained intact, the amount of hypothalamic growth hormone-releasing hormone (GHRH) was significantly decreased and, accordingly, the pituitary GH mRNA expression levels were impaired in these mice. Plasma GH and IGF-1 levels were also lower in the NIrs1KO mice. The expression levels of GHRH protein in the median eminence, where Irs1 antibody staining is observed, were markedly decreased in the NIrs1KO mice. In vitro, neurite elongation after IGF-1 stimulation was significantly impaired by Irs1 downregulation in the cultured N-38 hypothalamic neurons. In conclusion, brain Irs1 plays important roles in the regulation of neurite outgrowth of GHRH neurons, somatic growth, and glucose homeostasis.

Association between tear and blood glucose concentrations: Random intercept model adjusted with confounders in tear samples negative for occult blood.

AIMS/INTRODUCTION: To prevent diabetic complications, strict glucose control and frequent monitoring of blood glucose levels with invasive methods are necessary. We considered the monitoring of tear glucose levels might be a possible method for non-invasive glucose monitoring. To develop tear glucose monitoring for clinical application, we investigated the precise correlation between the blood and tear glucose concentrations. MATERIALS AND METHODS: A total of 10 participants and 20 participants with diabetes were admitted, and blood and tear samples were collected. Before statistical analysis, we eliminated tear samples contaminated with blood. We observed the daily blood and tear glucose dynamics, and carried out a random intercept model analysis to examine the association between the blood and tear glucose concentrations. RESULTS: Tear occult blood tests showed that the tear glucose concentrations and their variation increased in both participants with and without diabetes as contamination of blood increased. In both participants with and without diabetes, fluctuations of the plasma glucose concentrations were observed depending on the timing of collection of the samples, and the dynamics of the tear glucose concentrations paralleled those of the plasma glucose concentrations. The random intercept model analysis showed a significant association between the plasma and tear glucose concentrations in participants with diabetes (P < 0.001). This association still existed even after adjusting for the glycated hemoglobin levels and the prandial state (P < 0.001). CONCLUSIONS: It is important to eliminate the tear samples contaminated with blood. Tear glucose monitoring might be a reliable and non-invasive substitute method for monitoring the blood glucose concentrations for diabetes patients, irrespective of glycated hemoglobin levels and timing of sample collection.

Role of insulin receptor substrates in the progression of hepatocellular carcinoma.

Several cellular signaling pathways, including insulin/IGF signaling, are known to be activated in hepatocellular carcinoma (HCC). Here, we investigated the roles of insulin receptor substrate (Irs) 1 and Irs2, both of which are the major molecules to be responsible for transducing insulin/IGF signaling in the liver, in the development of HCC by inducing chemical carcinogenesis using diethylnitrosamine (DEN) in mice. The Irs1 mRNA and protein expressions were upregulated in the tumors, along with enhanced insulin signaling. Liver-specific Irs1-knockout (LIrs1KO) mice exhibited suppression of DEN-induced HCC development, accompanied by reduced cancer cell proliferative activity and reduced activation of Akt. Gene expression analyses revealed that the tumors in the DEN-treated LIrs1KO mice showed modest metabolic alterations during hepatocarcinogenesis as well as decreased inflammation and invasion potentials. On the other hand, liver-specific Irs2-knockout (LIrs2KO) mice showed a similar pattern of HCC development to the DEN-treated control wild-type mice. Based on the knowledge that Wnt/ß-catenin signaling is activated in HCC, we focused on Wnt/ß-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes, associated with insulin-stimulated Akt activation. These data suggest that upregulated Irs1 by Wnt/ß-catenin signaling plays a crucial role in the progression of HCC.

Injury mortality and accessibility to emergency care in Japan: an observational epidemiological study.

BACKGROUND: Unintentional injury is a major cause of death across the globe. The accessibility to emergency medical services may affect the rate of preventable trauma deaths. The purpose of this study was to analyze the accessibility to emergency medical hospitals in municipalities in Japan and to clarify whether accessibility was associated with the mortality rate attributed to unintentional injuries. METHODS: An observational epidemiological study was conducted in all 1,742 municipalities in Japan. Measurements assessed were population size, accessibility to emergency hospitals, and mortality rates attributed to unintentional injuries. Accessibility of each municipality to their nearest emergency hospital was calculated with a computer simulation using a geographic information system. After calculating demographic statistics and the Gini coefficient of accessibility, multivariate analyses were used to examine the correlation between accessibility time and mortality. Municipalities were divided into six groups according to accessibility time, and we then performed a correlation analysis between accessibility time and mortality using analysis of covariance. RESULTS: The median time of accessibility to emergency hospitals was 34.5 minutes. The Gini coefficient of accessibility time was 0.410. A total of 385 municipalities (23.4%) had an accessibility time of over 60 minutes. Accessibility was significantly related to mortality (beta coefficient =0.006; P<0.001). The mortality rate in municipalities with an accessibility time of <15 minutes was lower than that in all other groups. The mortality rate in municipalities with an accessibility time of 15-30 minutes was lower than that in municipalities with an accessibility time of >30 minutes, and the mortality rate in municipalities with an accessibility time of 30-45 minutes was lower than that in municipalities with an accessibility time of 60-90 minutes (P<0.001). CONCLUSION: The geographical disparities for emergency care accessibility were related to the rate of death by unintentional injury. Improving accessibility to emergency hospitals could help decrease the mortality rate of preventable trauma. Meanwhile, our findings suggest the need for substantially shorter accessibility times to emergency care facilities in many municipalities in Japan.

Fish oil promotes macrophage reverse cholesterol transport in mice.

OBJECTIVE: Fish oil (FO), and specifically omega 3 fatty acids, has favorable effects on cardiovascular outcomes. The aim of this study was to investigate the effects of FO on the process of macrophage reverse cholesterol transport (RCT) in an in vivo mouse model. METHODS AND RESULTS: C57BL/6J mice were fed a FO diet, whereas control mice were fed diets containing alternative sources of fats, soybean oil (SO), and coconut oil (CO) for 4 weeks. Macrophage RCT was assessed by injecting [(3)H]cholesterol-labeled J774 macrophages intraperitoneally into mice. After 48 hours, tissues were harvested and feces were collected. An increase in the excretion of macrophage-derived [(3)H]-tracer recovered in fecal neutral sterols for FO-fed mice was observed (273% versus SO and 182% versus CO). FO also decreased [(3)H]-tracer in hepatic cholesteryl ester compared to SO and CO by 76% and 56%, respectively. To specifically determine the effect of FO on the fate of HDL-derived cholesterol, mice fed FO or SO diets were injected with HDL labeled with [(3)H]cholesteryl oleate, and the disappearance of [(3)H]-tracer from blood and its excretion in feces was measured. There was no significant difference in the fractional catabolic rate of [(3)H]cholesteryl oleate-HDL between the 2 groups. However, there was a 242% increase in the excretion of HDL-derived [(3)H]-tracer recovered in fecal neutral sterols in FO-fed mice, concordant with significantly increased expression of hepatic Abcg5 and Abcg8 mRNA. CONCLUSIONS: As measured by this tracer-based assay, FO promoted reverse cholesterol transport, primarily by enhancement of the hepatic excretion of macrophage-derived and HDL-derived cholesterol.