A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin.

AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.

Cancer Risk in Graves Disease with Radioactive 131I Treatment: A Nationwide Cohort Study.

Radioactive 131I (RAI) therapy has potential effects for the treatment of Graves disease (GD). However, whether RAI therapy for GD increases cancer risk remains controversial in medicine and public health. We aimed to investigate whether the risk of cancer increases in patients with GD receiving RAI therapy compared with those who did not. Methods: We used the Korean National Health Insurance Service's National Health Information Database from 2004 to 2020 and defined GD as prescribing antithyroid drugs, RAI, or thyroidectomy as a treatment for GD (International Classification of Diseases, 10th revision, E05 group). We investigated the hazard ratios (HRs) of overall and site-specific cancers associated with RAI in patients with GD. Subsequent cancer was defined as a primary malignancy treated at least 1 y after RAI therapy. Results: In total, 10,737 patients with GD who received RAI therapy (7,193 women, 67.0%; mean age, 43.7 ± 13.4 y) were matched to 53,003 patients with GD who had never received RAI treatment (35,471 women, 66.9%; mean age, 43.8 ± 13.2 y) in a 1:4-5 ratio by age, sex, and health checkup data. The median follow-up duration was 8.7 y (interquartile range, 5.2-12.1 y), and the median cumulative RAI dose was 555 MBq (interquartile range, 370-630 MBq) in the RAI therapy group. During 2004-2020, the overall subsequent cancer rates were 5.66 and 5.84 per 1,000 person-years in the RAI and non-RAI groups, respectively, with an unadjusted HR of 0.97 (95% CI, 0.88-1.06); this remained at 0.96 (95% CI, 0.83-1.10) after adjustment for multiple clinical confounding factors. For cancer subtypes, the risk of leukemia was significantly increased, with an HR of 2.39 (95% CI, 1.17-4.91). However, a loss of statistical significance was observed after adjusting for confounding factors, which may be attributed to the limited number of absolute events. Moreover, cancer-specific mortality was not different between the RAI and the non-RAI groups, with an adjusted HR of 0.99 (95% CI, 0.66-1.47). Conclusion: This study identified that the overall cancer risk in patients with GD who received RAI therapy compared with those who did not was not significant in Korea. Further long-term studies are needed to determine the risks and advantages of RAI therapy in patients with GD.

2023 Diabetic Kidney Disease Fact Sheet in Korea.

BACKGRUOUND: To investigate the prevalence, incidence, comorbidities, and management status of diabetic kidney disease (DKD) and diabetes-related end-stage kidney disease (ESKD) in South Korea. METHODS: We used the Korea National Health and Nutrition Examination Survey data (2019 to 2021, n=2,665) for the evaluation of prevalence, comorbidities, control rate of glycemia and comorbidities in DKD, and the Korean Health Insurance Service-customized database (2008 to 2019, n=3,950,857) for the evaluation of trends in the incidence and prevalence rate of diabetes-related ESKD, renin-angiotensin system (RAS) blockers and sodium glucose cotransporter 2 (SGLT2) inhibitors use for DKD, and the risk of atherosclerotic cardiovascular disease (ASCVD) and mortality according to DKD stages. DKD was defined as albuminuria or low estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 in patients with diabetes mellitus. RESULTS: The prevalence of DKD was 25.4% (albuminuria, 22.0%; low eGFR, 6.73%) in patients with diabetes mellitus aged ≥30 years. Patients with DKD had a higher rate of comorbidities, including hypertension, dyslipidemia, and central obesity; however, their control rates were lower than those without DKD. Prescription rate of SGLT2 inhibitors with reduced eGFR increased steadily, reaching 5.94% in 2019. Approximately 70% of DKD patients were treated with RAS blockers. The prevalence rate of diabetesrelated ESKD has been steadily increasing, with a higher rate in older adults. ASCVD and mortality were significantly associated with an in increase in DKD stage. CONCLUSION: DKD is prevalent among Korean patients with diabetes and is an independent risk factor for cardiovascular morbidity and mortality, which requiring intensive management of diabetes and comorbidities. The prevalence of diabetes-related ESKD has been increasing, especially in the older adults, during past decade.

Attention to Innate Circadian Rhythm and the Impact of Its Disruption on Diabetes.

Novel strategies are required to reduce the risk of developing diabetes and/or clinical outcomes and complications of diabetes. In this regard, the role of the circadian system may be a potential candidate for the prevention of diabetes. We reviewed evidence from animal, clinical, and epidemiological studies linking the circadian system to various aspects of the pathophysiology and clinical outcomes of diabetes. The circadian clock governs genetic, metabolic, hormonal, and behavioral signals in anticipation of cyclic 24-hour events through interactions between a "central clock" in the suprachiasmatic nucleus and "peripheral clocks" in the whole body. Currently, circadian rhythmicity in humans can be subjectively or objectively assessed by measuring melatonin and glucocorticoid levels, core body temperature, peripheral blood, oral mucosa, hair follicles, rest-activity cycles, sleep diaries, and circadian chronotypes. In this review, we summarized various circadian misalignments, such as altered light-dark, sleep-wake, rest-activity, fasting-feeding, shift work, evening chronotype, and social jetlag, as well as mutations in clock genes that could contribute to the development of diabetes and poor glycemic status in patients with diabetes. Targeting critical components of the circadian system could deliver potential candidates for the treatment and prevention of type 2 diabetes mellitus in the future.

Gender differences in association between expiratory dynamic airway collapse and severity of obstructive sleep apnea.

OBJECTIVES: Repetitive unbalances and tensions generated by inspiratory efforts against an obstructive upper airway during sleep predispose the development of expiratory central airway collapse. In addition, structures of the upper airway between men and women have differences and could be the reasons for differences in obstructive sleep apnea (OSA) prevalence between genders. The present study aimed to evaluate the association between parameters of expiratory dynamic tracheal collapse measured using chest multidetector CT and objectively measured OSA severity between men and women. MATERIALS AND METHODS: A total of 901 participants who underwent chest CT and overnight in-home polysomnography from the Korean Genome and Epidemiology Study were cross-sectionally analyzed (women: 46.2%). The participants were divided into three groups based on OSA severity by apnea-hypopnea index (AHI). Multivariate linear regression analysis was performed to determine the effects of central airway collapse after adjustment for cardiovascular-related covariates. RESULTS: In a multivariate analysis, percentages of expiratory lumen structure reductions involving area, diameter, and perimeter were associated with AHI (all p values < 0.05) and with OSA severity (moderate-to-severe OSA than no OSA: ß = 3.30%, p = 0.03; ß = 2.05%, p = 0.02; ß = 1.97%, p = 0.02, respectively) in women, whereas men had only a greater percentage of expiratory wall thickness reduction in moderate-to-severe OSA than no OSA (ß = 0.72%, p = 0.003). In addition, women with both mild OSA and moderate-to-severe OSA had higher expiratory tracheal collapse than men without OSA, and a moderate effect of sex was observed (p for interaction = 0.007). CONCLUSION: The expiratory dynamic tracheal collapse was independently associated with severity of OSA in women than in men. CLINICAL RELEVANCE STATEMENT: Differences of pharyngeal structures and inherent features of airways by genders may affect the dissimilarities in vulnerability to sleep apnea between men and women. KEY POINTS: • The expiratory dynamic tracheal collapse was independently associated with severity of OSA in women than in men. • Women with over mild OSA had higher expiratory tracheal collapse than men without OSA, and moderate effect of sex was observed. • Structural differences of airway may affect differences in susceptibility of sleep apnea between genders.

2023 Clinical Practice Guidelines for Diabetes Mellitus of the Korean Diabetes Association.

In May 2023, the Committee of Clinical Practice Guidelines of the Korean Diabetes Association published the revised clinical practice guidelines for Korean adults with diabetes and prediabetes. We incorporated the latest clinical research findings through a comprehensive systematic literature review and applied them in a manner suitable for the Korean population. These guidelines are designed for all healthcare providers nationwide, including physicians, diabetes experts, and certified diabetes educators who manage patients with diabetes or individuals at risk of developing diabetes. Based on recent changes in international guidelines and the results of a Korean epidemiological study, the recommended age for diabetes screening has been lowered. In collaboration with the relevant Korean medical societies, recently revised guidelines for managing hypertension and dyslipidemia in patients with diabetes have been incorporated into this guideline. An abridgment containing practical information on patient education and systematic management in the clinic was published separately.

Additive impact of diabetes and sarcopenia on all-cause and cardiovascular mortality: A longitudinal nationwide population-based study.

OBJECTIVE: Diabetes mellitus (DM) and sarcopenia (SP) are growing public health concerns in an aging society, which share common pathophysiological mechanisms and are associated with serious health consequences. We investigated the impact of DM and SP on all-cause and cardiovascular mortalities in a longitudinal nationwide population-based study. METHODS: The study analyzed data from the Korea National Health and Nutrition Examination Survey conducted between 2008 and 2011, including information on appendicular skeletal muscle mass data. Mortality data up to December 2020 were retrieved from the National Death Registry. RESULTS: Among the 17,920 participants, 14,737 (82.2 %) had neither DM nor SP (DM-/SP-), 1349 (7.5 %) had only DM (DM+/SP-), 1425 (8.0 %) had only SP (DM-/SP+), and 409 (2.3 %) had both DM and SP (DM+/SP+). Compared to the DM-/SP- group, the DM-/SP+ and DM+/SP+ groups demonstrated increased all-cause mortality with adjusted hazard ratios (HRs) of 1.47 (95 % confidence interval [CI]: 1.14-1.89) and 1.85 (95 % CI: 1.28-2.69), respectively, while the DM+/SP- group did not (HR 1.29, 95 % CI: 0.97-1.74). The DM+/SP+ group demonstrated the highest risk of overall mortality (p-for-trend <0.001). Compared to the DM-/SP- group, only the DM+/SP+ group demonstrated increased cardiovascular mortality with HRs of 2.10 (95 % CI: 1.11-4.00) while the DM+/SP- (HR 1.35, 95 % CI: 0.79-2.30) and DM-/SP+ (HR 1.42, 95 % CI: 0.84-2.43) groups did not. CONCLUSIONS: The coexistence of DM and SP additively increased the risk of all-cause and cardiovascular mortality. Individuals with either disease may require more careful management to prevent the development of the other disease to reduce mortality.

Clinical and Lifestyle Determinants of Continuous Glucose Monitoring Metrics in Insulin-Treated Patients with Type 2 Diabetes Mellitus.

BACKGRUOUND: There was limited evidence to evaluate the association between lifestyle habits and continuous glucose monitoring (CGM) metrics. Thus, we aimed to depict the behavioral and metabolic determinants of CGM metrics in insulin-treated patients with type 2 diabetes mellitus (T2DM). METHODS: This is a prospective observational study. We analyzed data from 122 insulin-treated patients with T2DM. Participants wore Dexcom G6 and Fitbit, and diet information was identified for 10 days. Multivariate-adjusted logistic regression analysis was performed for the simultaneous achievement of CGM-based targets, defined by the percentage of time in terms of hyper, hypoglycemia and glycemic variability (GV). Intake of macronutrients and fiber, step counts, sleep, postprandial C-peptide-to-glucose ratio (PCGR), information about glucose lowering medications and metabolic factors were added to the analyses. Additionally, we evaluated the impact of the distribution of energy and macronutrient during a day, and snack consumption on CGM metrics. RESULTS: Logistic regression analysis revealed that female, participants with high PCGR, low glycosylated hemoglobin (HbA1c) and daytime step count had a higher probability of achieving all targets based on CGM (odds ratios [95% confidence intervals] which were 0.24 [0.09 to 0.65], 1.34 [1.03 to 1.25], 0.95 [0.9 to 0.99], and 1.15 [1.03 to 1.29], respectively). And participants who ate snacks showed a shorter period of hyperglycemia and less GV compared to those without. CONCLUSION: We confirmed that residual insulin secretion, daytime step count, HbA1c, and women were the most relevant determinants of adequate glycemic control in insulin-treated patients with T2DM. In addition, individuals with snack consumption were exposed to lower times of hyperglycemia and GV.

Diabetes Mellitus in the Elderly Adults in Korea: Based on Data from the Korea National Health and Nutrition Examination Survey 2019 to 2020.

BACKGRUOUND: We evaluated the prevalence and management of diabetes mellitus (DM) in elderly Korean patients based on data from the Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: A total of 3,068 adults aged 65 years and older (19.8% of total population) were analyzed using KNHANES from 2019 to 2020. Prevalence, awareness, treatment, and control rates, and comorbidities were analyzed. Lifestyle behaviors and energy intake were also measured. RESULTS: The prevalence of DM and prediabetes was 29.6% and 50.5%, respectively. The awareness, treatment and control rates were 76.4%, 73.3%, and 28.3%, respectively. The control rate was 77.0% if A1C <7.5% criteria was used. The mean A1C value of individuals with known DM was 7.1%, and 14.5% of the known DM patients had A1C ≥8.0%. Abdominal obesity, hypertension, and hypercholesterolemia were combined with DM in 63.9%, 71.7%, and 70.7%, respectively, and the rate of integrated management was 36.0% (A1C <7.5% criteria). A total of 40.1% of those with DM walked regularly. The percentage of energy intake from carbohydrates was higher in those with DM than in those without DM (P=0.044), while those of fat (P=0.003) and protein (P=0.025) were lower in those with DM than in those without DM in women. CONCLUSION: In 2019 to 2020, three of 10 adults aged 65 years and older in Korea had DM, and approximately 70% of them had comorbidities. A strategy for more individualized comprehensive care for the elderly patients with DM is urgently needed.

Effects of dapagliflozin compared with glimepiride on body composition in Asian patients with type 2 diabetes inadequately controlled with metformin: The BEYOND study.

AIMS: To evaluate the effect of dapagliflozin on body composition such as total body fat (BF) mass, abdominal visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) areas compared with glimepiride in Korean patients with type 2 diabetes. MATERIALS AND METHODS: This was a 52-week, multicentre, randomized, parallel-group, open-label, Phase IV (NCT02564926) study. Patients with inadequate glycaemic control (glycated haemoglobin ≥7.0% and <10.0%) on metformin monotherapy (≥1000 mg/day) were randomized 1:1 to receive dapagliflozin 10 mg/day or glimepiride 1-2 mg/day for 12 months as an add-on to metformin. Baseline and end of study body composition evaluations included dual-energy X-ray absorptiometry and abdominal computed tomography scans. RESULTS: Of 124 enrolled patients from 14 centres, 121 received study treatment (dapagliflozin: 60; glimepiride: 61) and 106 (85.5%) completed the study. Over 52 weeks, the dapagliflozin group showed the following differences versus the glimepiride group: -2.59 kg BF mass, -1.94% BF%, -17.55 cm2 VAT area, -18.39 cm2 SAT area, -0.46% glycated haemoglobin, -18.25 mg/dl fasting blood glucose, -3.7 kg weight, -2.21 cm waist circumference, -1.37 kg/m2 body mass index, -6.81 mmHg systolic blood pressure and +657.71 ng/ml in adiponectin; all were statistically significant. Both groups had similar incidences of adverse events; however, hypoglycaemic events were mainly (12 of 15) reported in the glimepiride group. CONCLUSION: Dapagliflozin reduced total BF mass, abdominal VAT and SAT areas, and showed better glycaemic control than glimepiride. Being safe and well-tolerated, dapagliflozin appears to be a more favourable alternative to sulphonylureas as add-on therapy after metformin monotherapy failure in Korean patients with type 2 diabetes.

Association of blood pressure measurements in sitting, supine, and standing positions with the 10-year risk of mortality in Korean adults.

OBJECTIVES: This prospective cohort study investigated the association between blood pressure (BP) as measured in different body postures and all-cause and cardiovascular (CV) mortality risk. METHODS: This population-based investigation included 8,901 Korean adults in 2001 and 2002. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured sequentially in the sitting, supine, and standing positions and classified into 4 categories: 1) normal, SBP <120 mmHg and DBP <80 mmHg; 2) high normal/prehypertension, SBP 120-129 mmHg and DBP <80 mmHg/SBP 130-139 mmHg or DBP 80-89 mmHg; 3) grade 1 hypertension (HTN), with SBP 140-159 mmHg or DBP 90-99 mmHg; and 4) grade 2 HTN, SBP ≥160 mmHg or DBP ≥100 mmHg. The date and cause of individual deaths were confirmed in the death record data compiled until 2013. Data were analyzed using Cox proportional hazard regression. RESULTS: Significant associations were found between the BP categories and all-cause mortality, but only when BPs were measured in the supine position. The multivariate hazard ratios (95% confidence intervals) were 1.36 (1.06-1.75) and 1.59 (1.06-2.39) for grade 1 and grade 2 HTN, respectively, compared with the normal category. The associations between the BP categories and CV mortality were significant regardless of body posture among participants ≥65 years, whereas they were significant for supine BP measurements only in those <65 years. CONCLUSIONS: BP measured in the supine position predicted all-cause mortality and CV mortality better than BP measured in other postures.

Renal Protection of Mineralocorticoid Receptor Antagonist, Finerenone, in Diabetic Kidney Disease.

Chronic kidney disease (CKD) is the most common cause of end-stage renal disease in patients with type 2 diabetes mellitus (T2DM). CKD increases the risk of cardiovascular diseases; therefore, its prevention and treatment are important. The prevention of diabetic kidney disease (DKD) can be achieved through intensive glycemic control and blood pressure management. Additionally, DKD treatment aims to reduce albuminuria and improve kidney function. In patients with T2DM, renin-angiotensin-aldosterone system inhibitors, sodium glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can delay the progression of DKD. Hence, there is a need for novel treatments that can effectively suppress DKD progression. Finerenone is a first-in-class nonsteroidal mineralocorticoid receptor antagonist with clinically proven efficacy in improving albuminuria, estimated glomerular filtration rate, and risk of cardiovascular events in early and advanced DKD. Therefore, finerenone is a promising treatment option to delay DKD progression. This article reviews the mechanism of renal effects and major clinical outcomes of finerenone in DKD.

Efficacy and safety of enavogliflozin versus dapagliflozin added to metformin plus gemigliptin treatment in patients with type 2 diabetes: A double-blind, randomized, comparator-active study: ENHANCE-D study.

AIMS: This study evaluated the efficacy and safety of enavogliflozin, a novel sodium-glucose cotransporter 2 inhibitor, versus dapagliflozin in Korean patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and gemigliptin. METHODS: In this multicenter, double-blind, randomized study, patients with inadequate response to metformin (≥ 1000 mg/day) plus gemigliptin (50 mg/day) were randomized to receive enavogliflozin 0.3 mg/day (n = 134) or dapagliflozin 10 mg/day (n = 136) in addition to the metformin plus gemigliptin therapy. The primary endpoint was change in HbA1c from baseline to week 24. RESULTS: Both treatments significantly reduced HbA1c at week 24 (-0.92% in enavogliflozin group, -0.86% in dapagliflozin group). The enavogliflozin and dapagliflozin groups did not differ in terms of changes in HbA1c (between-group difference: -0.06%, 95% confidence interval [CI]: -0.19, 0.06) and fasting plasma glucose (between-group difference: -3.49 mg/dl [-8.08;1.10]). An increase in urine glucose-creatinine ratio was significantly greater in the enavogliflozin group than in the dapagliflozin group (60.2 g/g versus 43.5 g/g, P < 0.0001). The incidence of treatment-emergent adverse events was similar between the groups (21.64% versus 23.53%). CONCLUSIONS: Enavogliflozin, added to metformin plus gemigliptin, was well tolerated and as effective as dapagliflozin in the treatment of patients with T2DM.

Sleep Duration and the Risk of Type 2 Diabetes: A Community-Based Cohort Study with a 16-Year Follow-up.

BACKGRUOUND: We aimed to investigate the moderating effects of obesity, age, and sex on the association between sleep duration and the development of diabetes in Asians. METHODS: We analyzed data from a cohort of the Korean Genome and Epidemiology Study conducted from 2001 to 2020. After excluding shift workers and those with diabetes at baseline, 7,407 participants were stratified into three groups according to sleep duration: ≤5 hours/night, >5 to 7 hours/night (reference), and >7 hours/night. The Cox proportional hazards analyses were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes mellitus (T2DM). Subgroup analyses were performed according to obesity, age, and sex. RESULTS: During 16 years of follow-up, 2,024 cases of T2DM were identified. Individuals who slept ≤5 h/night had a higher risk of incident diabetes than the reference group (HR, 1.17; 95% CI, 1.02 to 1.33). The subgroup analysis observed a valid interaction with sleep duration only for obesity. A higher risk of T2DM was observed in the ≤5 hours/night group in non-obese individuals, men, and those aged <60 years, and in the >7 hours/night group in obese individuals (HRs were 1.34 [95% CI, 1.11 to 1.61], 1.22 [95% CI, 1 to 1.49], and 1.18 [95% CI, 1.01 to 1.39], respectively). CONCLUSION: This study confirmed the effect of sleep deprivation on the risk of T2DM throughout the 16-year follow-up period. This impact was confined to non-obese or young individuals and men. We observed a significant interaction between sleep duration and obesity.

Safety and Effectiveness of Empagliflozin in Korean Patients with Type 2 Diabetes Mellitus: Results from a Nationwide Post-Marketing Surveillance.

BACKGROUND: To evaluate the safety and effectiveness of empagliflozin in routine clinical settings, we collected and assessed the clinical profiles of Korean patients with type 2 diabetes mellitus. METHODS: This was a post-marketing surveillance study of empagliflozin 10 and 25 mg. Information on adverse events and adverse drug reactions (ADRs) was collected as safety data sets. Available effectiveness outcomes, including glycosylated hemoglobin (HbA1c) level, fasting plasma glucose, body weight, and blood pressure, were assessed. RESULTS: The incidence rate of ADRs was 5.14% in the safety dataset (n=3,231). Pollakiuria, pruritis genital, and weight loss were the most common ADRs. ADRs of special interest accounted for only 1.18%, and there were no serious events that led to mortality or hospitalization. In the effectiveness data set (n=2,567), empagliflozin significantly reduced the mean HbA1c level and body weight during the study period by -0.68%±1.39% and -1.91±3.37 kg (both P<0.0001), respectively. In addition, shorter disease duration, absence of dyslipidemia, and higher baseline HbA1c levels were identified as the clinical features characteristic of a "responder" to empagliflozin therapy. CONCLUSION: Empagliflozin is a safe and potent glucose-lowering drug in routine use among Korean patients with type 2 diabetes mellitus. It is expected to have better glycemic efficacy in Korean patients with poorly controlled type 2 diabetes mellitus.

Association of long-term hyperglycaemia and insulin resistance with brain atrophy and cognitive decline: A longitudinal cohort study.

AIM: To investigate the longitudinal changes in brain volume and cognitive function associated with diabetes at midlife, and to examine whether long-term hyperglycaemia, insulin resistance or secretory function is associated with brain atrophy and cognitive decline. MATERIALS AND METHODS: We used data from 2377 participants with both baseline and 4-year follow-up brain magnetic resonance images and neuropsychological measures from the Ansan cohort of the Korean Genome Epidemiology Study. Time-weighted mean glycaemic values were calculated using all measurements over an average duration of 10.6 years from cohort initiation to baseline visits. RESULTS: Type 2 diabetes was associated with greater white matter volume reduction (adjusted volume difference = -1.96 ml, 95% CI: -3.73, -0.18) and executive function decline (adjusted Z score difference = -0.14, 95% CI: -0.23, -0.05) during the follow-up period of 4.2 years. Decline of verbal and visual memory or verbal fluency was not associated with diabetes. Greater executive function decline was associated with higher time-weighted mean HbA1c level over the preceding 10.6 years (P < .001), but not with insulin resistance markers in the diabetes group. Participants with diabetes, whose time-weighted average HbA1c level was maintained above 6.5% over the previous decade, showed greater decline in executive function and global cognition than the normal glucose group. CONCLUSIONS: Long-term hyperglycaemia was a major independent factor associated with rapid cognitive decline in middle-aged adults with diabetes. Maintaining ideal glucose levels in diabetes at midlife might prevent later rapid cognitive decline.

Associations between Body Mass Index, Waist Circumference, and Myocardial Infarction in Older Adults Aged over 75 Years: A Population-Based Cohort Study.

Background and Objectives: Body mass index (BMI) is widely used as a standard screening method for obesity and an indicator of related diseases. However, its inability to distinguish between lean body mass and body fat limits its utility. This limitation may be more prominent in older populations, wherein age-related sarcopenia and increased visceral fat due to the redistribution of adipose tissue may preclude a precise estimation of obesity. Many studies suggest that waist circumference (WC) is more strongly related to obesity-related diseases. There are also different opinions on whether the obesity paradox is real or a result of confusing interpretations. This study seeks to determine the association between myocardial infarction (MI), BMI, and WC in older adults and to determine if BMI and WC can reliably predict the risk of cardiovascular disease. Materials and Methods: We conducted a cohort study of older Korean adults aged over 75 years registered in the National Health Insurance System Senior database. Results: The results from the analysis using model 5, which was adjusted for each study variable, showed that the lower the BMI, the higher the hazard ratio (HR) of MI and vice versa. On the other hand, groups with lower than normal WC showed lower HR; even if it was higher, the difference was not statistically significant. Those with abdominal obesity tended to have an increased HR of MI. Conclusions: This study found that HR for MI has a negative relationship with BMI, whereas it has a positive relationship with WC. Furthermore, WC is a more appropriate indicator for predicting the risk of MI in the older population.

Night blood pressure variability, brain atrophy, and cognitive decline.

Background: Although blood pressure variability (BPV) has emerged as a novel risk factor for Alzheimer's disease, few studies have examined the effects of night BPV on brain structure and function. This study investigated the association of night BPV with brain atrophy and cognitive function changes. Methods: The analysis included 1,398 participants with valid ambulatory blood pressure (BP) monitoring at baseline and both baseline and 4-year follow-up brain magnetic resonance images who were recruited from the Korean Genome and Epidemiology Study. Participants underwent a comprehensive neuropsychological test battery. BPV was derived from ambulatory BP monitoring and calculated as a standard deviation (SD) of 24-h and daytime and nighttime BP. Results: During the median follow-up of 4.3 years, increased SD of night systolic or diastolic BP was an indicator of total brain volume reduction, while daytime BPV or night average BP was not associated with total brain volume changes. High SD of night systolic BP was associated with reduced gray matter (GM) volume, independent of average night BP, and use of antihypertensive drugs. It also was associated with a reduction of temporal GM volume, mostly driven by atrophy in the left entorhinal cortex and the right fusiform gyrus. In cognitive performance, high variability of night systolic BP was associated with a decrease in visual delayed recall memory and verbal fluency for the category. Conclusion: Increased night BPV, rather than night mean BP, was associated with reduced brain volume and cognitive decline. High night BPV could be an independent predictor for rapid brain aging in a middle-aged population.

Renoprotective Mechanism of Sodium-Glucose Cotransporter 2 Inhibitors: Focusing on Renal Hemodynamics.

Diabetic kidney disease (DKD) is a prevalent renal complication of diabetes mellitus that ultimately develops into end-stage kidney disease (ESKD) when not managed appropriately. Substantial risk of ESKD remains even with intensive management of hyperglycemia and risk factors of DKD and timely use of renin-angiotensin-aldosterone inhibitors. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce hyperglycemia primarily by inhibiting glucose and sodium reabsorption in the renal proximal tubule. Currently, their effects expand to prevent or delay cardiovascular and renal adverse events, even in those without diabetes. In dedicated renal outcome trials, SGLT2 inhibitors significantly reduced the risk of composite renal adverse events, including the development of ESKD or renal replacement therapy, which led to the positioning of SGLT2 inhibitors as the mainstay of chronic kidney disease management. Multiple mechanisms of action of SGLT2 inhibitors, including hemodynamic, metabolic, and anti-inflammatory effects, have been proposed. Restoration of tubuloglomerular feedback is a plausible explanation for the alteration in renal hemodynamics induced by SGLT2 inhibition and for the associated renal benefit. This review discusses the clinical rationale and mechanism related to the protection SGLT2 inhibitors exert on the kidney, focusing on renal hemodynamic effects.

Plasma and urinary extracellular vesicle microRNAs and their related pathways in diabetic kidney disease.

To explore extracellular vesicle microRNAs (EV miRNAs) and their target mRNAs in relation to diabetic kidney disease (DKD), we performed paired plasma and urinary EV small RNA sequencing (n = 18) in patients with type 2 diabetes and DKD (n = 5) and healthy subjects (n = 4) and metabolic network analyses using our own miRNA and public mRNA datasets. We found 13 common differentially expressed EV miRNAs in both fluids and 17 target mRNAs, including RRM2, NT5E, and UGDH. Because succinate dehydrogenase B was suggested to interact with proteins encoded by these three genes, we measured urinary succinate and adenosine in a validation study (n = 194). These two urinary metabolite concentrations were associated with DKD progression. In addition, renal expressions of NT5E and UGDH proteins were increased in db/db mice with DKD compared to control mice. In conclusion, we profiled DKD-related EV miRNAs in plasma and urine samples and found their relevant target pathways.