EDITORIAL: ADVANCES IN DIABETES AND HYPERTENSION RESEARCH

Christiano Argano^1*Rosario Scaglione²

• ¹Dipartimento di Medicina Interna, ARNAS Ospedali Civico Di Cristina Benfratelli, Palermo, Italy
• ²2. Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties. [PROMISE], University of Palermo, Palermo, Italy

Diabetes and hypertension represent an outstanding burden on health care systems [1]. In 2024, 589 million adults (aged 20-79), equal to 1 in 9 subjects, were living with diabetes worldwide. This number is predicted to rise to 853 million by 2050 [2]. Diabetes and its comorbidities often lead to increased use of primary care and hospital services [3], representing a major cause of death and resulting in an estimated $1.015 trillion in global health expenditures in 2024 [2].On the other hand, the number of individuals with hypertension doubled between 1990 and 2019, rising from 650 million to 1.3 billion [4]. Hypertension can lead to stroke, heart attack, heart failure, kidney damage, and other diseases [5]. It is worth to outline that only 21% of people with hypertension have it under control, and cardiovascular protection remains to date one of the most important goals of antihypertensive treatment [6].It is well known that diabetes and hypertension are closely linked conditions that share common risk factors like obesity, insulin resistance, and inflammation, often occurring together [7]. Hyperglycaemia can damage blood vessels and kidneys, which elevates blood pressure, while hypertension itself can increase the risk of developing diabetes [7]. These comorbidities significantly increase the risk of cardio and cerebrovascular and kidney diseases, requiring integrated management that includes lifestyle changes and medications and a holistic approach for patient care [8].In this regard, this research topic aimed to provide insight into various aspects of the relationship between diabetes and hypertension presenting novelties on the potential pathological mechanism underlying these relationships Overall, 3 meta-analysis, 2 prospective studies, 8 studies focused on different aspects of diabetes and 8 others focused on the diabetes-hypertension association have been published.In the research topic, Ming Wang et al. analyzed proteomic data using two-dimensional gel electrophoresis and electrospray-quadrupole time-of-flight MS/MS in 80 obese patients, 76 patients with newly diagnosed type 2 diabetes mellitus (T2DM) combined with obesity, and 73 healthy controls, in light of several studies indicating the need to identify increasingly reliable serum markers for the diagnosis and progression of diabetes. Several proteins were found to be differentially expressed, with α2-macroglobulin (α2-MG) showing significant upregulation in the obesity and T2DM+obesity groups and higher α2-MG levels in the obesity and T2DM+obesity groups than in the control group. These data suggest that α2-MG levels are highly sensitive and specific for predicting obesity and T2DM, indicating its potential as a T2DM diagnostic biomarker.Miaomiao Peng et al. evaluated the association between ALDH2 and diabetes risk by analyzing data from 4,535 participants in the China Cardiometabolic Disease and Cancer Cohort Study, considering studies that have linked genetic variations, such as the ALDH2 rs671 genotype variant, to an increased risk of developing diabetes in Asians [9]. Among male participants, the ALDH2 rs671 GA/AA genotype was associated with a lower diabetes risk compared to the GG genotype after adjusting for alcohol consumption and other potential confounders. Subgroup analyses revealed that this protective effect was most pronounced in individuals with a BMI < 24. Abdominal adiposity accounted for 30.4% of the ALDH2-diabetes association, and BMI mediated 18.9% of this relationship; however, alcohol consumption showed no significant mediating effect (p = 0.56). These findings revealed that East Asian men with the ALDH2 GG genotype had an increased risk of diabetes compared to those with the GA/AA genotype, particularly among individuals with a BMI < 24. Thus, individuals with the GG genotype, even with normal BMI, might benefit from exercise and dietary intervention able to reduce waist circumference.In light of data implicating adropin, a newly identified peptide hormone expressed in the liver, brain and kidney, in processes such as lipid metabolism and inflammation involved in the development of diabetic nephropathy, I-Wen Chen et al. measured serum adropin levels in eighteen patients with early chronic kidney disease (CKD) and forty patients with advanced CKD. Nine subjects without diabetes were studied as a control group. Subjects with T2DM had significantly higher adropin levels than controls. T2DM patients with advanced CKD had higher adropin levels than those with early CKD. Among T2DM patients, subjects who experienced CKD progression had higher adropin levels than those without. Thus, adropin predicts CKD progression in T2DM patients with 86% sensitivity and 70% specificity at 6872.24 pg/ml cutoff value.The association with CKD progression was still significant after adjusting for age, gender and body mass index.These findings suggest that serum adropin might be applied as a potential biomarker for predicting CKD progression in subjects with T2D.Tong Feng et al examined the association between sleep-disordered breathing (SDB) and the risk of metabolic syndrome (MetS) among various gender-age groups and symptom subtypes, identified the nocturnal hypoxia parameter that best reflects this relationship, and assessed the connection between sleep variables and MetS. Combining these parameters into a sleep quality score may improve predictions of health outcomes. Participants were monitored using the Type IV sleep monitoring device and completed structured questionnaires.The severity of SDB was independently associated with an increased risk of MetS, particularly in males under 60 and females aged 60 and above. A total of 1,483 SDB patients were included into four distinct clusters: Cluster 1 included the pure insomnia group with fewer daytime symptoms; Cluster 2 consisted of the minimally symptomatic group; Cluster 3 comprised the insomnia group with multiple daytime symptoms; and Cluster 4 encompassed the group with upper airway symptoms and sleepiness. Among the SDB subtypes, there was no significant difference in the prevalence of metabolic syndrome. However, the pure insomnia group had the highest prevalence of hypertension.These findings suggest the relevant role of gender, age differences, and sleep symptom subtypes when evaluating SDB and MetS. This approach would indicate that, early identification, and consideration of different subtypes are necessary to optimize treatment in these subjects. Chinese exercises (TCEs) on glycemic control, lipid profile, and weight management in prediabetic subjects. This marks the first time HIIT and TCEs have been included in such an assessment. A total of 74 studies involving 5,683 participants were included. Results showed that HIIT was the most effective for reducing haemoglobin A1c [Surface Under the Cumulative Ranking (SUCRA) 84.3%], and increasing high-density lipoprotein (SUCRA 87.3%). AT+RT was most effective in reducing total cholesterol (SUCRA 98.3%), TG (SUCRA 99.9%), low-density lipoprotein (SUCRA 82.2%), and body mass index (SUCRA 66.4%). TCEs showed the most significant improvements in reducing 2hPG (SUCRA 83.5%), body weight (SUCRA 79.1%), and waist circumference (SUCRA 84.6%). These results might indicate that various exercise interventions significantly improved glycemic and lipid profiles in prediabetic patients and that HIIT and AT+RT were found to be the most effective interventions. These findings provide the latest evidence to support exercise interventions for managing prediabetes.Haoyi Yang et.al studied the effects of SY-009, a novel SGLT1 inhibitor, on plasma metabolomics in patients with T2DM and the potential metabolic regulatory mechanism involved. A total of 50 participants with T2DM were enrolled and randomly assigned to the 0.5 mg BID, 1 mg BID, 2 mg BID, 1 mg QD, and 2 mg QD dose groups, with a 4:1 random allocation within each group to receive either the SY-009 capsule or placebo. SY-009 caused a series of postprandial plasma metabolite changes in patients with T2DM, especially significant changes in the bile acid profile, which provides a new perspective on the mechanism by which SY-009 lowers blood glucose.Mei Xue et.al performed a meta-analysis to obtain a comprehensive overview of the differences between once-weekly basal insulin (including icodec and basal insulin Fc) and once-daily basal insulin (including glargine and degludec) in patients with T1DM e T2DM.Currently, novel basal insulin analogs have been utilized for once-weekly subcutaneous administration able to improve treatment acceptance and adherence. Icodec and basal insulin Fc [14,15,16] are the two most advanced once-weekly basal insulins for the treatment of patients with T1DM e T2DM. The Authors evaluated a total of 12 studies, comprising 5,895 patients, with 3,104 (52.7%) using once-weekly insulin and 2,791 (47.3%) using once-daily insulin. In the pooled data, glycated hemoglobin changes from baseline to the end-of-trial demonstrated significantly good glycemic control in the once-weekly insulin group, especially in insulin-naïve T2DM patients or patients using icodec. Once-weekly insulin was correlated with a higher risk of level 1 hypoglycemia. There was no significant difference in fasting plasma glucose, time in range, and level 2 or 3 hypoglycemic events.These data indicate that once-weekly basal insulin is safe and effective in a slight decrease of HbA1c with similar levels of 2 and 3 grade of hypoglycemic events compared to once-daily insulin, although the risk of level 1 hypoglycemia and weight gain was increased.Yaning Chen et.al retrospectively analyzed the data on clinical presentations, laboratory, and cranial CT and MRI of six patients with diabetic striatopathy (DS), a rare disorder with clinical manifestations of hemichorea, non-ketotic hyperglycemia, and high signal on MRI or high density on CT scan in basal ganglia, typically associated with poor glycemic control, to raise awareness amongst physicians about this rare neurological manifestation, often overlooked, in patients with diabetes.All six patients complained of involuntary unilateral movements, which primarily affected the arm and leg.Bilateral caudate nucleus hyperdensities were shown on the CT examination in Case 3, while the other 5 patients, unilateral caudate nucleus hyperdensity was shown. In addition, five patients (except Case 5) underwent MRI, all showing hypersignal lesions on the T1-weighted images. A low signal in the right basal ganglia was shown on MRI susceptibility-weighted imaging sequences in Case 6. All six patients exhibited carotid artery or cerebral artery stenosis. Following strict blood glucose control and symptomatic management, the symptoms of chorea improved significantly in all patients, and repeat images indicated that the lesions gradually disappeared. In conclusion, DS may occur in patients with ketotic hyperglycemia. Typical movement disorders do not always coincide with typical imaging. The Authors speculate that poor vascular conditions and marked hyperglycemia combine to promote the development of DS. It is recommended to test blood glucose levels at the time of diagnosis with hemichorea.Enhui Zu et.al analyzed the mediating role of the atherogenic index of plasma (AIP), a novel biomarker, [17], in the relationship between multiple obesity indices (BMI, WHR, WHtR, and BAI) and the prevalence of diabetes in hypertensive subjects. This cross-sectional study from the China Multi-Ethnicity Cohort study suggested that obesity indices were significantly higher in diabetic patients compared to those without. Moreover, logistic regression analysis suggested that higher quartiles of obesity indices were associated with an increased risk of diabetes whether in crude or adjusted models (p < 0.05). Mediation analysis revealed that the association between obesity and the risk of diabetes, mediated by BMI, WHR, waist-to-height ratio (WHtR), and body adiposity index (BAI), through the AIP was 17.2%, 15.3%, 15.8%, and 19.2%, respectively. These data are consistent with the indication that AIP significantly mediates the association between each of the four obesity indices and diabetes prevalence in hypertensive patients. to high-density lipoprotein cholesterol ratio (NHHR) and the risk of diabetes and prediabetes among adults with hypertension. NHHR is an emerging composite lipid marker that offers superior predictive value for cardiovascular disease, metabolic syndrome, fatty liver, and certain renal diseases.In this cross-sectional survey, 10,250 hypertensive patients, including 2,198 with diabetes and 4,138 with prediabetes, were screened from National Health and Nutrition Examination Survey (NHANES)-collected data during 2009-2018.The fully adjusted model indicated each unit increase in NHHR was associated with a 21% higher risk of diabetes/prediabetes. In patients with hypertension, the NHHR was positively correlated with the prevalence of diabetes and prediabetes, with a nonlinear trend in the fitted curve (nonlinearity, P=0.007). These data indicate that NHHR is positively and non-linearly correlated with diabetes/prediabetes in patients with hypertension, particularly among women. This may support the use of NHHR as a valuable tool to identify patients at high risk for these conditions. The lipid accumulation product (LAP) [18], may be considered a more accurate indicator of metabolic risk associated with visceral obesity and excessive lipid accumulation. The Chinese Visceral Adiposity Index (CVAI) [19], has been reported as a surrogate biomarker for assessing visceral fat accumulation. In view of this, the Authors analyzed the role on T2DM of the associations of WC, BMI, LAP, CVAI, and triglycerideglucose (TyG) index.A total of 1,965 hypertensive subjects aged 45 years and older were included in the cross-sectional analysis, and 1,576 hypertensive subjects without T2DM for the cohort analysis. The risk of T2DM increased significantly with higher quartiles of WC, BMI, LAP, CVAI, and TyG (all P-trend < 0.001).In the cohort study, Cox regression model showed that WC, BMI, LAP, CVAI and TyG were associated with a higher risk of incident T2DM. ROC analysis revealed that TyG had the strongest area under the curve.These data indicate that higher levels of WC, BMI, LAP, CVAI, and TyG are associated with a higher risk of developing incident T2DM in Chinese elderly hypertensive patients, and TyG might be the most effective predictive indicator. sectional study from the on-going REACTION study in China and meta-analysis of epidemiological studies.A total of 4,177 participants aged 58.62 ± 8.40 years were included. TyG was significantly associated with higher odds of hypertension, and the association is present both in isolated systolic hypertension and in systolic-diastolic hypertension but not in isolated diastolic hypertension. Moreover, data from meta-analysis of 34 relevant studies were included. A positive association between the TyG index and hypertension was revealed in the meta-analysis of cohort studies and cross-sectional studies. These data indicated that higher TyG index were significantly associated with a higher risk of clinical hypertension, which may provide new insights into the clinical management of hypertension.Lingli Zhao et. in their prospective study utilized data from the Bogalusa Heart Study [20] to try to explain the relationship between changes in the TyG index during childhood and pre-Hypertension adulthood based on a positive correlation between the TyG index and blood pressure, indicating that a high TyG index is related to a greater risk of developing pre-hypertension and hypertension. Data on triglycerides, fasting glucose, and low-density lipoprotein cholesterol were collected from cross-sectional examinations of participants during childhood. Blood pressure in adulthood was subdivided into normotensive and prehypertensive groups. Logistic regression was employed to evaluate the relationship between the TyG index in childhood and pre-Hypertension in adulthood.A total of 1,222 participants were included in the study, of whom 258 presented with pre-hypertension in adulthood. A significant association between an increase in TyG index in childhood and pre-hypertension in adulthood, stratified by race and gender was found. Each unit increase in the TyG index was associated with a 70% increased likelihood of pre-HTN among American Caucasian participants and a 90% increased likelihood among male participants, independent of potential confounders. This suggests that a high TyG index may be a robust predictor of pre-HTN events in these groups. Accordingly, the monitoring of TyG index may help in screening subjects at higher risk of pre-hypertension. and hypertension disorders of pregnancy (HDP) to explain the adverse birth outcomes often presenting in these women. The data were from the Zhoushan Maternal and Child Health Hospital electronic medical recorder system (EMRS). 13645 pregnant women were included. GDM+HDP was significantly associated with a higher risk of composite adverse neonatal outcomes, including preterm birth, placenta previa, and/or neonatal jaundice, a higher risk of small for gestational age and large for gestational age compared with the normal group. In addition, HDP diagnosed in the 21-27th week comorbid with GDM had the lowest gestational age at delivery (P=0.0002) and birth weight (P=0.0138). Moreover, combined hyperglycemia comorbid with HDP had the strongest association with reduced gestational age (β= -0.83, P=0.0021).These results suggest that pregnant women suffering from both GDM and HDP had a higher risk of adverse neonatal outcomes. Accordingly, the prevent and treatment of GDM and HDP, especially their comorbidity, have to be strongest developed in pregnant women.Yuking Yang et.al reported that time systolic blood pressure in target range (SBP-TTR) is a new metric for evaluating blood pressure control, which refers to the proportion of time that SBP remains within the target range [21]. This index has been reported as an independent risk factor for stroke and it would be particularly useful in monitoring all those conditions in which a controlled reduction in pressure is necessary.The Authors included 28,591 participants with and without diabetes [mean age, 57.5 years; 83.8% men; 23.2% with diabetes] from the Kailuan Study. After a median of 8.7 years follow-up, 2,206 stroke cases occurred. Among subjects with diabetes, those with SBP-TTR 75%-100% had a lower risk of stroke compared to those with SBP-TTR 0%-25%. Among subjects without diabetes, those with SBP-TTR 50%-75% had a significantly lower risk of stroke. A significant interaction between diabetes status and SBP-TTR was found. These results are consistent with the indication that higher SBP-TTR was associated with a reduced risk of stroke among subjects with or without diabetes. This finding emphasizes the importance of maintaining blood pressure within the target range to mitigate stroke risk. This requires strong blood pressure control in diabetic patients.Zeyang Zhen et.al. evaluated the role of human urinary kallidinogenase (HUK) [22,23] in reducing the incidence of progressive ischemic stroke (PIS) in patients with acute ischemic stroke (AIS) above all in a subgroup with vascular pathology and thrombolytic treatment. 916 patients with AIS were included. The patients were divided into two groups based on whether they received HUK treatment in addition to standard care or standard care alone. In addition, subgroup analyses were conducted based on stroke subtype (TOAST classification), thrombolysis treatment, and infarction location. HUK treatment significantly reduced the incidence of PIS (p < 0.001), with the most notable effects in patients with large-artery atherosclerosis and small-artery occlusion, those not undergoing intravenous thrombolysis, and those with anterior circulation infarctions. Conversely, no significant reduction was noted in patients with cardioembolic stroke. These promising data indicate that HUK treatment appears to be an effective strategy for reducing the risk of PIS in patients with AIS, particularly in those at higher risk owing to specific vascular pathologies. These findings support the use of HUK in clinical practice to improve the outcomes of patients with stroke.Taken together, the studies published in this Research Topic increase the reader's understanding of the interactions between diabetes and hypertension, update their knowledge, particularly concerning new pathophysiological aspects, and identify novel biomarkers that can be used to explore the increased cardiometabolic and cerebrovascular risk in clinical practice.