Diabetes mellitus is seventh-leading cause of death in the United States, and has a substantial economic burden, contributing $237 billion in direct medical costs. The incidence rate of type 2 diabetes (T2DM) is expected to continue to increase, disproportionally impacting vulnerable groups. The increasing prevalence and disproportionate burden emphasize the need for health systems to effectively integrate and implement large- and small-scale, culturally tailored nurse-led diabetes prevention programs (DPP) and diabetes self-management education programs (DSME). This two-stage analysis uses a health system approach to provide a synopsis of evidence-based nurse-led DPP and DSME implementation across various health system settings. Using the results from an integrative review, a health system focused framework was developed and applied to two case studies highlighting specific aspects of how successful large- and small-scale nurse-led interventions are integrated into health systems across varying vulnerable populations specifically Veterans, Asian Americans and Haitians. Case study results use examples to show large-scale implementation of DSME across the federal Veterans Health Administration (VHA) improves diabetes self-management and access for Veterans and smaller-scale DPP and DSME programs within community health centers targeting vulnerable populations impact health literacy and diabetes self-management. These examples demonstrate key steps toward improving access and outcomes for diabetes management and the critical role of nurse-led diabetes interventions as a priority across the health system and the importance of financial and organizational support for DPP and DSME programs to overcome access barriers to improve diabetes interventions and management.

There is a lack of knowledge on the changes in peripheral nerve function in people with well-controlled, recently diagnosed type 2 diabetes compared with those with normal glucose tolerance (NGT). In this study, we aimed to investigate the natural course of the function of lower extremity small and large nerve fibers in people with NGT and its decline in those with well-controlled type 2 diabetes.

This prospective observational study assessed changes in nerve function in participants of the German Diabetes Study with recently diagnosed (≤1 year) type 2 diabetes and age-matched and sex-matched individuals with NGT after 5 years and in a larger group of participants with type 2 diabetes after 5 and 10 years. Reference tests of lower extremity peripheral nerve function included peroneal motor nerve conduction velocity (MNCV) and sural sensory nerve conduction velocity (SNCV), sural sensory nerve action potential (SNAP), malleolar vibration perception threshold (VPT), and thermal detection thresholds (TDTs). Data were analyzed using multiple linear or logistic regression analyses.

At baseline, all 5 nerve function measures showed impairment in the 52 individuals in the diabetes group (33% female, median age 51.7 years) compared with the 52 individuals in the matched NGT group (33% female, median age 51.4 years). After 5 years, 2 nerve indices declined in the diabetes group (peroneal MNCV and VPT) and 3 in the NGT group (peroneal MNCV, VPT, and TDT for cold), with similar 5-year declines observed in both groups after adjustment for baseline values and pairwise matching. In addition, the Neuropathy Disability Score increased in the NGT group but not in the diabetes group. Comparable patterns of decline after 5 and 10 years were found in the larger diabetes cohort of 141 individuals (39% female, median baseline age 53.6 years). The observed 10-year prevalence of abnormal NCVs closely matched estimates based on natural aging-related decline (14.2% vs 12.8% for peroneal MNCV and 30.2% vs 31.0% for sural SNCV).

These findings suggest that nerve function deterioration in well-controlled type 2 diabetes is primarily influenced by nerve function status at diagnosis and physiologic aging, rather than diabetes-related progression.

Covering: 2015 to 2025Chemical crosstalk is universal to all life, niche-specific, and essential to thrive. This crosstalk is mediated by a large diversity of molecules, including metal ions, small molecules, polysaccharides, nucleic acids, lipids, and proteins. Among these, specialized small molecules referred to as natural products (NPs) play an important role in microbe-drug/environment interactions, microbe-microbe, and microbe-host interactions. Microbial communication using NPs allows microbes to sense quorum, form biofilms, eliminate competition, establish symbiosis, evade immune attack, and respond to stress. In most cases, the elucidation of small molecule mediators and effectors of microbe-host interactions presents a major challenge due to the relatively low abundance of microbial metabolites in a milieu of host, microbe, and environmental metabolites. Advances in analytical instrumentation, such as mass spectrometers, and both experimental as well as computational methods to analyze data, coupled with the use of model organisms, have enabled fundamental discoveries of mechanisms of small molecule-mediated host-microbe interactions. The focus of this review is to detail the approaches applied in the last decade to disentangle microbiome-derived NPs in human and murine model systems. Select recent findings from diverse biological ecosystems are discussed to inform relevant parallels and potential strategies for research in human health.

Achieving optimal glycemic control for persons with diabetes remains difficult. Real-world continuous glucose monitoring (CGM) data can illuminate previously underrecognized glycemic fluctuations. We aimed to characterize glucose trajectories in individuals with Type 1 and Type 2 diabetes, and to examine how baseline glycemic control, CGM usage frequency, and regional differences shape these patterns.

We linked Dexcom CGM data (2015-2020) with Veterans Health Administration electronic health records, identifying 892 Type 1 and 1716 Type 2 diabetes patients. Analyses focused on the first three years of CGM use, encompassing over 2.1 million glucose readings. We explored temporal trends in average daily glucose and time-in-range values.

Both Type 1 and Type 2 cohorts exhibited a gradual rise in mean daily glucose over time, although higher CGM usage frequency was associated with lower overall glucose or attenuated increases. Notable weekly patterns emerged: Sundays consistently showed the highest glucose values, whereas Wednesdays tended to have the lowest. Seasonally, glycemic control deteriorated from October to February and rebounded from April to August, with more pronounced fluctuations in the Northeast compared to the Southwest U.S.

Our findings underscore the importance of recognizing day-of-week and seasonal glycemic variations in diabetes management. Tailoring interventions to account for these real-world fluctuations may enhance patient engagement, optimize glycemic control, and ultimately improve health outcomes.

This study aimed to examine the associations between visit-to-visit variability in fasting plasma glucose (FPG) and HbA1c with echocardiographic variables in patients with type 2 diabetes using epidemiologic and Mendelian randomization (MR) methods.

From January 2001 to December 2020, 2,326 (1,233 men and 1,093 women) subjects with type 2 diabetes who underwent echocardiography assessment were enrolled in the diabetes care management program of a medical center in Taiwan. The echocardiographic variables included those for cardiac structural, cardiac systolic, and diastolic function. Variability in FPG and HbA1c within one-year prior echocardiographic measurements was calculated using coefficient of variation (CV). A two-stage multivariable regression analysis was used to assess the causal relationship among FPG-CV, HbA1c-CV, and echocardiographic variables using 22 SNPs for FPG and 14 SNPs for HbA1c as instrumental variables.

A total of 2,326 participants were included, with a mean age of 64.5 years and 53.0% were men. Epidemiologic and MR analyses show the significant associations between left atrium diameter (LAD), left ventricular systolic diameter (LVSd), left ventricular mass (LVM), left ventricular ejection fraction (LVEF), E, and E/e' ratio with FPG variability. Significant associations between HbA1c variability and echocardiographic variables including LAD, E/e', and deceleration time identified in the epidemiologic approach became non-significant in the MR analysis when controlling for covariates.

Our epidemiologic and MR studies demonstrated that visit-to-visit variability of FPG in patients with type 2 diabetes was independently associated with the left cardiac structure as well as systolic and diastolic function.

The metabolic disorder diabetes mellitus occurs when there is an inadequate level of insulin or excessive insulin resistance. There has been evidence that this pathogenesis has been approached via a different strategy. It activates homeostatic glucose and improves peripheral glucose utilization by targeting the PPAR-γ. In this regard, the present study aims to investigate 2-thioxothiazolidin-4-one derivatives (D1-15) as PPAR-γ regulators by computational approach followed by evaluation of physicochemical properties and ADMET profiles. The protein target PPAR-γ (PDB ID: 3DZY) was docked against 2-thioxothiazolidin-4-one derivatives using the glide suite. The results indicate the high binding affinity of compounds D7, D11 (-6.509 and -7.276 kcal/mol) and they were compared against standard drug rosiglitazone (-7.289 kcal/mol). MD simulation studies were also carried out at 150 ns to identify the key interactions in protein-ligand complexes in a dynamic environment not only to confirm our findings but to validate them as well. The findings indicated that certain designed compounds, namely D7 and D11, exhibited notable activity against PPAR-γ inhibitors, as evidenced by their favorable glide scores. The chosen derivatives of 2-thioxothiazolidin-4-one appear to hold promise as potential sources for advancing the development of antidiabetic agents targeting the PPAR-γ enzyme.

An elderly man with type 2 diabetes on two times per day biphasic insulin presented after a fall in the toilet, preceded by reduced intake and transient loss of consciousness. Paramedics found profound hypoglycaemia (capillary blood glucose (BG) - 0.9 mmol/L) and administered intravenous glucose, raising BG to 7.2 mmol/L. In the emergency department, he experienced recurrent hypoglycaemia (BG 1.8 and 2.6 mmol/L). ECG revealed T-wave abnormalities and QT prolongation, raising concerns for myocardial ischaemia or arrhythmia. Troponin was mildly elevated (14 ng/L), but he remained haemodynamically stable (pulse 52, BP 120/56, RR 16, SpO₂ 99%). Glycated haemoglobin (HbA1c) was 73 mmol/mol, potassium 3.2 mmol/L with normal renal function. CT of the head was unremarkable. Following glucose correction, ECG abnormalities resolved and there were no further indications of acute coronary syndrome (ACS) or arrhythmia. His insulin regimen was changed to insulin glargine 10 units daily, with continued metformin. This case underscores the critical need to recognise hypoglycaemia-induced ECG changes, preventing misdiagnosis and unnecessary cardiac interventions.

Diabetes is a widespread disease associated with long-term complications. Treatment of diabetes alleviates these complications but cause an increased risk of recurrent hypoglycemia (RH). Hypoglycemia exposure increases the risk of cardiovascular events by an unknown mechanism. Since the effect of mild/moderate hypoglycemia on thrombosis is unknown, we studied the effect of RH exposure on platelet function and thrombosis in insulin-treated diabetic (ITD) rats.

ITD rats were randomized to either control or hypoglycemia groups. First, we determined the minimum duration and frequency of RH exposure that increases the risk of thrombosis and the time window after a single hypoglycemic episode (SH)/RH exposure with increased risk of thrombosis in male ITD rats. Next, we confirmed whether RH exposure increases the risk of thrombosis in female ITD rats. Subsequently, we evaluated the impact of RH exposure on platelet susceptibility to aggregation and platelet gene expression.

One hour hypoglycemia increased the clot weight and the effect of SH and RH on thrombosis lasted for at least 1 and 7 days post-exposure, respectively. A minimum frequency of twice-a-week hypoglycemia exposure for 6 weeks increased the risk of thrombosis in male ITD rats. Increased susceptibility of platelet activation was observed in RH-exposed male ITD rats. Lastly, we identified RH-induced alterations in the platelet transcriptome in male ITD rats. We also confirmed that RH exposure increases the risk of thrombosis in female rats.

Understanding the mechanism of RH-induced platelet activation and thrombosis may help limit thrombotic complications in diabetes.

Diabetes is a complex metabolic disorder affecting over 37 million people in the United States. Without proper management, diabetes can lead to a myriad of complications, including cardiovascular disease, kidney failure, and vision loss. Obesity is a major contributor to type 2 diabetes, but genetic and physiological factors make weight loss difficult, necessitating medication management for both conditions. Government-approved weight loss medications, including glucagon-like peptide-1 agonists and amylin analogs, have proven to be effective for both conditions. However, intensive glycemic control involving antidiabetic medications, while beneficial for reducing diabetic complications, can often precipitate hypoglycemic events, which are characterized by cardiac arrhythmias, coma, confusion, and even mortality. A new drug under investigation, CagriSema, combines cagrilintide, an amylin analog, with semaglutide, a glucagon-like peptide-1 agonist. This drug is being marketed as a safe and potentially superior medication to lower both Hemoglobin A1c and body weight. In this article, the pathophysiology, current guidelines, and management of diabetes will be reviewed, with an emphasis on the clinical evidence for tight glucose control and avoiding hypoglycemic events. Following this, an overview of recent trials on antidiabetic medications, including those involving CagriSema, will be presented, along with prospects for future trials in this promising area of research.

Aims: In subjects with type 2 diabetes (DM), poor glycemic control, and advanced chronic kidney disease (CKD), the kidney benefit of the reduction of glycated hemoglobin (HbA1c) is not well established. Methods: In a retrospective cohort, we included patients with DM, CKD grade 3b-5, and HbA1c > 9% to evaluate the risk of developing major adverse kidney events (MAKE) defined as the start of kidney replacement therapy (KRT), ≥ 25% or ≥ 40% decline in the glomerular filtration rate (eGFR) from baseline, and death; patients were divided according to the HbA1c levels at the end of the follow-up into the following groups: > 75 mmol/mol (≥ 9.0%), 74-64 mmol/mol (8.9%-8.0%), 64-53 mmol/mol (7.9%-7.0%), and < 52 mmol/mol (< 7.0%). We described their characteristics and analyzed their risks, adjusting for confounding variables. Results: From 2015 to 2023, 111 patients were included. In 46 patients (41.4%), the HbA1c at the end of follow-up (60 months) was still > 75 mmol/mol (≥ 9%), and each patient had a mean of 4.9 HbA1c measurements. The mean age was 59 years, and 46% were male; the baseline eGFR was 25 mL/min/1.73 m2. MAKE occurred in 67% of cases. In a multivariate analysis, the risk of MAKE was not associated with the HbA1c groups, nor was it associated with any of the MAKE components individually, nor in certain subgroups. When evaluating the magnitude of percentage changes in HbA1 with the initiation of KRT, we did not find any association. Conclusions: With advanced CKD and poor glycemic control, changes in HbA1c during long follow-up are not associated with MAKE or its individual components.

Cardiovascular disease is the most common complication and cause of death in people with diabetes. Hypoglycaemia is independently associated with the development of cardiovascular complications, including death. The aim of this study was to assess changes in cardiac function and workload during acute hypoglycaemia in people with and without diabetes and to explore the role of diabetes type, magnitude of the adrenaline response, and other phenotypic traits.

We enrolled people with type 1 diabetes (n = 24), people with insulin-treated type 2 diabetes (n = 15) and controls without diabetes (n = 24). All participants underwent a hyperinsulinaemic-normoglycaemic-(5.3 ± 0.3 mmol/L)-hypoglycaemic (2.8 ± 0.1 mmol/L)-glucose clamp. Cardiac function was assessed by echocardiography, with left ventricular ejection fraction (LVEF) as the primary endpoint.

During hypoglycaemia, LVEF increased significantly in all groups compared to baseline (6.2 ± 5.2%, p < 0.05), but the increase was significantly lower in type 1 diabetes compared to controls without diabetes (5.8 ± 3.4% vs. 9.4 ± 5.0%, p = 0.03, 95% CI difference: -5.0, -0.3). In people with type 1 diabetes, ΔLVEF was inversely associated with diabetes duration (β: -0.16, 95% CI: -0.24, -0.53, p = 0.001) and recent exposure to hypoglycaemia (β: -0.30, 95% CI: -0.53, -0.07, p = 0.015). Hypoglycaemia also increased global longitudinal strain (GLS) in controls without diabetes (p < 0.05), but this did not occur in the two diabetes subgroups (p > 0.10).

Hypoglycaemia increased LVEF in all groups, but the increase diminished with longer disease duration and prior exposure to hypoglycaemia in type 1 diabetes, suggesting adaptation to recurrent hypoglycaemia. The increment in GLS observed in controls was blunted in people with diabetes. More research is needed to determine the clinical relevance of these findings.

Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.

We investigated the association between younger-onset type 2 diabetes, duration of diabetes, and cancer risk based on data from the Da Qing Diabetes Prevention Outcome Study (DQDPOS).

The analysis recruited 620 younger-onset (age≤50 years) and 649 older-onset (age>50 years) patients with type 2 diabetes, and 310 younger non-diabetes controls (age≤50 years). Multiple regression analysis was used to test the influence of younger-onset diabetes and duration of diabetes on the long-term risk of cancer.

The annual incidence of all cancer among the non-diabetes, younger-, and older-onset type 2 diabetes was significantly different (3.7, 5.5, and 4.0/1000 person-years, respectively). The standard Cox analysis revealed that the patients with younger-onset diabetes had a significantly higher risk of cancer than those with older-onset diabetes (hazard ratio [HR]:1.81; 95% confidence interval [CI]:1.20-2.73) and younger non-diabetic controls (HR:2.43; 95% CI:1.34-4.41) after adjustment for diabetes duration and other confounders. Stepwise general linear regression model analysis revealed that a longer diabetes-free time was associated with longer lifetime cancer-free years (partial R2 = 0.36, p < 0.001), in addition to the non-modifiable predictor duration of diabetes.

Younger-onset type 2 diabetes was significantly associated with an increased risk of cancer beyond the influence of diabetes duration.

To evaluate the effect of impaired fasting glucose (IFG) and various anti-diabetic agents on the risk of incident major cardiovascular events (MACE) in patients with inflammatory arthritis (IA) including rheumatoid arthritis (RA) and psoriatic arthritis (PsA).

This was a population-based retrospective cohort study. Patient identification and data retrieval were conducted using a big data platform (The Hospital Authority Data Collaboration Lab) in Hong Kong. Patients with IA were recruited from Jan 2006 to Dec 2015 and followed up until the end of 2018. Time-dependent Cox proportional hazards regression models were used to analyze the association between fasting glucose (FG) levels and anti-diabetic drug use with MACE in IA patients.

A total of 13,905 patients (12,233 RA and 1,672 PsA) were included. 934 patients (6.7%) developed the first MACE after a total of 119,571 patient-years of follow-up. More patients in the MACE group had IFG (FG 5.6-6.9 mmol/l) (19.4% vs. 15.2%, p < 0.001) and FG ≥ 7 mmol/l (17.6% vs. 8.1%, p < 0.001) at baseline. In the subgroup of patients who were not taking any anti-diabetic medications, a prediabetic state was found to be independently associated with a higher risk of MACE (HR 2.43, 95%CI 1.97-2.99 in CRP model and HR 2.54, 95%CI 1.50-7.71 in ESR model). On the other hand, in patients with diabetes, sulfonylurea use increased the risk of MACE development by 55% (HR 1.55, 95%CI 1.14-2.09) after adjusting for other covariates.

In a large cohort of patients with IA, IFG and sulfonylureas use were found to be independently associated with an increased risk of incident MACE.

Obesity is associated with both high and low levels of hypoglycemia, and impairment of counterregulatory hormones may predispose individuals to hypoglycemia. This study aimed to explore differences in the responsiveness of insulin counterregulatory hormones to hypoglycemia between men with or without obesity who have been newly diagnosed with type 2 diabetes mellitus (T2DM). This study enrolled 25 men newly diagnosed with T2DM who were hospitalized in the Department of Endocrinology and Metabolism between January 2022 and December 2022. All participants were treated with intensive insulin pump therapy to achieve glycemic control within one week, then a hyperinsulinemic-hypoglycemic clamp was used to evaluate insulin counter-regulatory hormones for hypoglycemia. Based on the body mass index, 10 and 15 patients were included in the obese and nonobese groups, respectively. During the hyperinsulinemic-hypoglycemic clamp test, the obese group showed a significant lower multiple of adrenocorticotropic hormone elevation than the nonobese group (P = 0.040). Regarding the proportion of hormone response multiples reaching the target, those who reached the reaction multiple were lower in the obese group than those in the non-obese group, although the differences were not statistically significant (all P > 0.05). The responses of insulin counterregulatory hormones to hypoglycemia in men with obesity and newly diagnosed T2DM were significantly lower than those in men with T2DM but without obesity.

Despite the recognition by key guidelines that achieving early glycaemic control has important benefits in individuals with type 2 diabetes (T2D) and that addressing excess adiposity is one of the central components of comprehensive person-centred T2D care, a substantial proportion of individuals with T2D do not meet their metabolic treatment goals. Prior treatment paradigms were limited by important treatment-associated risks such as hypoglycaemia and body weight gain. Therefore, a more conservative, sequential approach to treatment was typically utilized. One potential consequence of this approach has been a missed opportunity to achieve a 'legacy effect', where early treatment to reach glycaemic targets is associated with enduring long-term benefits in T2D. Additionally, while previous treatment approaches have addressed core defects in T2D, including insulin resistance and β-cell function decline, they have been unable to address one of the underlying causal abnormalities-excess adiposity. Here, we review currently available evidence for the beneficial long-term effects of early glycaemic control and management of body weight in people with T2D and discuss potential next steps.

Reduction of major atherosclerotic cardiovascular events (MACE) has not been consistent among different glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to assess the association between the magnitude of glycemic control, body weight loss, and reductions in systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) achieved through GLP-1 RA therapy and MACE.

Electronic databases (MEDLINE, CENTRAL, SCOPUS) were searched through March 2023. Studies were eligible if they were cardiovascular outcome trials (CVOTs) comparing GLP-1 RAs versus placebo in T2DM patients. The outcome of interest was 3-point MACE - cardiovascular death, myocardial infarction, or stroke. Random-effects meta-regression analyses evaluated the associations between reductions of HbA1c, body weight, SBP and LDL-C and reduction of MACE.

Overall, 8 CVOTs were included (60079 patients, 30693 with GLP-1 RAs). Reductions of HbA1C were associated with the reduction of 3P-MACE (Log RR -0.290 [95% CI -0.515;-0.064], p = 0.012), with an estimated RR reduction of 25% for each 1% absolute reduction in HbA1C levels. Body weight loss was associated with the reduction of 3P-MACE (Log RR -0.068 [95% CI -0.135;-0.001], p = 0.047), with an estimated RR reduction of 7% for each 1 kg reduction in body weight. Reductions of SBP (Log RR -0.058 [95% CI -0.192;0.076], p = 0.396) and LDL-C (Log RR -0.602 [95% CI -4.157;2.953], p = 0.740) were not associated with the reduction of 3P-MACE.

In T2DM patients, more potent GLP-1 RAs in reducing HbA1c and body weight were associated with greater reductions of MACE.

Diabetic cardiomyopathy (DC) is a serious complication of diabetes, characterized by myocardial fibrosis, hypertrophy, oxidative stress, and inflammation. Perillaldehyde (PAE), a natural monoterpene, has shown potential in mitigating cardiac damage.

This study aims to elucidate the molecular mechanism of the protective effect of PAE on the DC and the interaction between DC pathogenesis.

Network pharmacology and molecular docking were used to identify PARP1 as a core target for PAE in DC. Animal experiments involved intervening DC mice with PAE and assessing cardiac function, oxidative stress, and apoptosis. In vitro, high glucose-induced H9c2 cells were used to validate PAE's effects on cell viability and protein expression.

The results showed that PAE improved the general condition of DC mice, reduced cardiac injury and cardiac insufficiency, decreased myocardial mitochondrial damage, and reduced apoptosis. In addition, PAE upregulated the expression of Bcl-2, downregulated Bax protein expression, inhibited Caspase-3 activity, and inhibited the expression of PARP1, TRPM2, CaN, and CaMKII proteins in DC mice and high glucose-induced H9c2 cells.

Mechanically, this study clarified that PAE's inhibition of the PARP1-TRPM2-CaMKII/CaN pathway reduces calcium-activated mitochondrial damage, apoptosis, and oxidative stress in diabetic cardiomyopathy. This discovery provides an innovative therapeutic strategy for DC and an experimental foundation for PAE's drug development, with significant practical implications.

Zhigancao Decoction (ZGCD) is derived from "Treatise on Febrile Diseases" and is traditionally prescribed for treating a variety of cardiovascular conditions. As of now, there are no data to support its use as a treatment for diabetic cardiomyopathy (DCM) and the mechanism behind the effect is unclear as well. In the present study, clinical evidence for the efficacy of ZGCD in patients with DCM was examined using a meta-analysis and its underlying anti-DCM molecular mechanisms were explored via network pharmacology.

The current study utilized an extensive search strategy encompassing various domestic and foreign databases databases to retrieve pertinent articles published up to June 2024. In light of this, a thorough evaluation of the benefits and safety of Zhigancao decoction (ZGCD) was conducted in this study using RevMan and Stata. Subsequently, a number of active compounds and target genes for ZGCD were gathered from the TCMSP and BATMAN-TCM databases, while the main targets for DCM were obtained from databases such as GenCards, OMIM, TTD, and DrugBank. To select core genes, protein-protein interaction networks were generated using the STRING platform, and enrichment analyses were completed using the Metascape platform.

Meta-analysis results were ultimately derived from 9 studies involving 661 patients in total. In comparison with WM therapy alone, the pooled results showed that ZGCD significantly enhanced overall effectiveness. Additionally, the utilization of ZGCD was leading to a reduction in LVEDV, LVESV and LVDD, also a greater increase in LVEF. Meanwhile, the utilization of ZGCD during intervention was more effective in reducing SBP, and DBP. In addition, the ZGCD showed potential in reducing the occurrence of adverse events. In the context of network pharmacology, five constituents of ZGCD-namely lysine, quercetin, gamma-aminobutyric acid, stigmasterol, and beta-sitosterol-are posited to exert anti-diabetic cardiomyopathy (anti-DCM) effects through interactions with the molecular targets ASS1, SERPINE1, CACNA2D1, AVP, APOB, ICAM1, EGFR, TNNC1, F2, F10, IGF1, TNNI2, CAV1, INSR, and INS. The primary mechanisms by which ZGCD may achieve its anti-DCM effects are likely mediated via the AGEs/RAGE signaling pathway, as well as through pathways related to lipid metabolism and atherosclerosis.

In comparison to WM therapy alone, ZGCD demonstrates greater efficacy and safety in the management of DCM. ZGCD not only significantly reduces blood pressure, but also enhances cardiac function while producing fewer adverse effects. The therapeutic effects of ZGCD on DCM can likely be ascribed to its capacity to modulate the AGEs-RAGE signaling pathway, as well as its efficacy in enhancing lipid metabolism and mitigating atherosclerosis.

identifier (INPLASY202430133).

This expert consensus reviews the reality of primary care clinical management of people with type 2 diabetes (T2D) on non-intensive insulin therapy, with an emphasis on the use of continuous glucose monitoring (CGM) technology for effective care in this participant group. Here, we identify key unmet needs for skills and systems development within this frontline healthcare setting, along with major challenges and opportunities associated with managing these changes effectively.

The authors participated in two primary care consensus panels held on 28 November 2023 and on 21 May 2024. The focus for these expert panels was to understand the unmet needs within primary care to manage adults with T2D treated with non-intensive insulin therapy and incorporating the use of CGM systems. A Delphi Survey was undertaken among a wider group of Primary Care Diabetes Technology Network members in the United Kingdom, to understand prevalent attitudes to management of adults with T2D on insulin and using CGM in primary care. Based on these activities, a series of consensus statements were tested in a second Delphi Survey.

The activities described, involving primary care healthcare professionals (HCPs) with expertise in diabetes management, identified a series of training and educational needs within UK general practice that are central to skills development for the care of adults with T2D on insulin therapy and the application of CGM technology. Potential barriers to effective primary care management of people with T2D using CGM devices were identified. Areas of concern included confidence in national and local guidelines for the management of T2D using CGM systems, lack of experience on the part both of HCPs and people with T2D, clinical workflows and systems, as well as inbuilt resistance to change among primary care teams. However, the expert group were clear that the goal of providing care for people with T2D on non-intensive insulin therapy using CGM technology as standard of care could be met (94.3%, n = 33). This will deliver clinical benefits for people with T2D, and improvements to clinical workflows in primary care. Cost-savings to the health service were also identified as an outcome.

The need to adapt to the management of people with T2D on insulin therapy puts significant pressure on current workflows and skills for primary care teams. Steps in overcoming these immediate pressures, to ensure effective clinical management of people with T2D, are discussed, along with a series of consensus statements that identify the key areas of change to manage. Ultimately, the great majority of expert primary care HCPs were confident or very confident that using CGM technology will become the standard of care for people with T2D treated with insulin in primary care.

Skeletal muscle is the key target of insulin action. Therefore, a reduction in skeletal muscle mass may trigger insulin resistance, a mechanism of diabetes. Creatinine is the only metabolite of creatine phosphate in the skeletal muscle. Exploring the association between serum creatinine level and T2DM is helpful for the early identification and prevention of T2DM.

Five electronic databases, PubMed, Scopus, Web of Science, Embase, and Epistemonikos, were searched for relevant articles published up to June 2024. Cohort studies and case-control studies were evaluated using the Joanna Briggs Institute (JBI) checklist. The random-effects model calculated the pooled risk ratio and 95% confidence intervals (CIs) based on a heterogeneity test (I2 statistics). Egger's test was used to evaluate publication bias.

The pooled RR of diabetes type 2 for the lowest versus the highest serum creatinine was 1.39 (95% CI: 1.17-1.64); I2 = 90.1%; p = 0.002. We found a non-linear association between low serum creatinine level and T2DM risk (pNonlinearity = 0.02), and a decrease of each 0.1 mg/dL serum creatinine increases 1% risk of T2DM [RR = 1.49 (95% CI: 1.17-2.82), I2 = 0%, p = 0.999].

This meta-analysis offers evidence of the negative relationship between serum creatinine levels and the risk of developing T2DM in a linear dose-response pattern.

Vascular endothelium is integral to the regulation of vascular homeostasis and maintenance of normal arterial function in healthy individuals. Endothelial dysfunction is a significant contributor to the advancement of atherosclerosis, which can precipitate cardiovascular complications. A notable correlation exists between diabetes and endothelial dysfunction, wherein chronic hyperglycemia and acute fluctuations in glucose levels exacerbate oxidative stress. This results in diminished nitric oxide synthesis and heightened production of endothelin-1, ultimately leading to endothelial impairment. In clinical settings, it is imperative to implement appropriate therapeutic strategies aimed at enhancing endothelial function to prevent and manage diabetes-associated vascular complications. Various antidiabetic agents, including insulin, GLP-1 receptor agonists, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, thiazolidinediones (TZDs), and metformin, are effective in mitigating blood glucose variability and improving insulin sensitivity by lowering postprandial glucose levels. Additionally, traditional Chinese medicinal compounds, such as turmeric extract, resveratrol, matrine alkaloids, tanshinone, puerarin, tanshinol, paeonol, astragaloside, berberine, and quercetin, exhibit hypoglycemic properties and enhance vascular function through diverse mechanisms. Consequently, larger randomized controlled trials involving both pharmacological and herbal interventions are essential to elucidate their impact on endothelial dysfunction in patients with diabetes. This article aims to explore a comprehensive approach to the treatment of diabetic endothelial dysfunction based on an understanding of its pathophysiology.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) enhance cardiovascular outcomes in individuals with type 2 diabetes mellitus (T2DM). Whether such effects also occur in T2DM patients with atrial fibrillation (AF) remains unknown. We aimed to investigate SGLT2i use on cardiovascular outcomes in patients with concomitant AF and T2DM.

Patients with both AF and T2DM were identified from TriNetX, an international electronic medical record. Participants were divided into 2 groups according to their use of SGLT2i, at a 1:1 distribution through propensity score matching (PSM). The hazard ratio (HR) for clinical outcomes was determined using multivariate Cox hazards regression model.

We studied 339 792 patients with AF and T2DM, with 32 945 (9.70%) SGLT2i users. Following PSM, 17 011 patients aged 68.4 ± 7.9 years were included in each group. After a 3-year follow-up, patients treated with SGLT2i showed significantly reduced risks of stroke (adjusted HR: 0.830, P < .001), dementia (adjusted HR: 0.662, P < .001), long-standing persistent AF (adjusted HR: 0.917, P < .001), heart failure (adjusted HR: 0.833, P < .001), and all-cause mortality (adjusted HR: 0.532, P < .001).

The use of SGLT2i was associated with reduced risks of stroke, dementia, long-standing persistent AF, heart failure, and mortality in patients with both AF and T2DM. SGLT2i may be considered as a potential first-line therapy for this population.

Complications of diabetes mellitus have significant impacts on morbidity, mortality, quality of life, and health costs for individuals. Setting and achieving glycemic targets to prevent these complications is a top priority when managing diabetes. However, patients often already have complications when diagnosed with diabetes mellitus. Therefore, methods to prevent disease progression become a crucial component of diabetes management. The purpose of this article is to review glycemic targets and methods of screening and managing diabetes-related complications.

A PubMed review of the literature pertaining to diabetes mellitus, glycemic targets, microvascular complications, and macrovascular complications was conducted. We reviewed articles published between 1993 and 2024. Guidelines published by nationally recognized organizations in the fields of diabetes, nephrology, and cardiology were referenced. Public health statistics obtained by the Center for Disease Control and Prevention and the National Kidney Foundation were used.

Achieving glycemic targets and screening for diabetes-related complications at appropriate intervals remains the key factor for early detection and intervention. An algorithmic approach to glycemic management based on individual risk factors is beneficial in choosing pharmacotherapy.

The consequences of diabetes-related complications can be detrimental. However, achieving and maintaining glycemic targets combined with diligent screening, reduction of risk factors, and prompt treatment can halt disease progression.

Elderly individuals are susceptible to the accrual of White Matter Lesions (WMLs), a subcategory of cerebral small-vessel disease. WMLs are strongly linked to an increased risk of strokes, intracerebral hemorrhages, and dementia. While the relationship between blood glucose levels and the development of WMLs has been investigated in previous studies, the findings remain inconsistent. Some evidence suggests that glucose dysregulation, including both hypo- and hyperglycemia, may contribute to WML formation through mechanisms such as endothelial dysfunction and chronic inflammation. However, other studies report no significant correlation. This inconsistency underscores the need for further investigation.

In this investigation, the primary data were derived from a predictive mathematical model designed to estimate WMLs based on parameters obtained from routine medical examinations, with head MRI scans serving as the reference standard for WML diagnosis and quantification. We leveraged multivariable logistic regression analysis to scrutinize the relationship between blood glucose concentrations and WMLs. Additionally, we employed a restricted cubic spline regression model to investigate a potential non-linear relationship between these variables.

There were 1904 participants who underwent medical check-ups which included a head MRI. Generally, the relationship between blood glucose levels and white matter lesions followed an asymmetric U-shaped curve (P for non-linearity = 0.004). A consistent finding was that compared to the individuals in the 2nd and 3rd quartiles (95 to 107 mg/dl), the 1st quartile (OR, 1.71; 95% CI: 1.26-2.30) and 4th quartile (OR, 1.57; 95%CI: 1.12-2.20) had white matter lesions were significantly higher.

An asymmetric U-shaped relationship exists between blood glucose and WMLs, with the lowest risk occurring at 95-107 mg/dl. Management of blood glucose can help prevent the occurrence and development of WMLs. However, the study's cross-sectional design limits causal inference, and the reliance on pre-existing data constrained the availability of variables.

Diet rich in chicken protein has gained a widespread popularity for its profound effect on weight loss and glycemic control; however, its long-term effect on cardiovascular health and the underlying mechanisms remains obscure. Here, we demonstrated that higher intake of chicken protein was an independent risk factor for sub-clinical atherosclerosis. Adherence to high chicken protein diet (HCD) alleviated excessive weight gain and glycemic control regardless of the presence of gut microbiota in apolipoprotein E-deficient mice. In contrast, long-term HCD administration enhanced intestinal cholesterol absorption and accelerated atherosclerotic plaque formation in a gut microbiota-dependent manner. Integrative analysis of 16S rDNA sequencing and metabolomics profiling identified 3-Methyl-L-histidine (3-MH), resulting from an enrichment of Lachnospiraceae, as the key microbial effector to the atherogenic effect of HCD. Mechanistically, 3-MH facilitated the binding of hepatocyte nuclear factor 1A (HNF1A) to the promoter of NPC1-like intracellular cholesterol transporter 1 (NPC1L1), whereas inhibition of HNF1A-NPC1L1 axis abolished the atherogenic effect of 3-MH. Our findings uncovered a novel link between microbiota-derived 3-MH and disturbed cholesterol homeostasis, which ultimately accelerated atherosclerosis, and argued against the recommendation of HCD as weight loss regimens considering its adverse role in vascular health.

Diabetes increases ischemic heart injury via incompletely understood mechanisms. We recently reported that diabetic adipocytes-derived small extracellular vesicles (sEV) exacerbate myocardial reperfusion (MI/R) injury by promoting cardiomyocyte apoptosis. Combining in vitro mechanistic investigation and in vivo proof-concept demonstration, we determined the underlying molecular mechanism responsible for diabetic sEV-induced cardiomyocyte apoptosis after MI/R.

Adult mice were fed a high-fat diet (HFD) for 12 weeks. sEV were isolated from plasma or epididymal adipose tissue. HFD significantly increased the number and size of plasma- and adipocyte-derived sEV. Intramyocardial injection of an equal number of diabetic plasma sEV in nondiabetic hearts significantly increased cardiac apoptosis and exacerbated MI/R-induced cardiac dysfunction. Diabetic plasma sEV significantly activated cardiac caspase 9 but not caspase 8, suggesting that diabetic sEV induces cardiac apoptosis via the mitochondrial pathway. These pathologic alterations were phenotyped by intramyocardial injection of sEV isolated from diabetic adipocytes or HGHL-challenged 3T3L1 adipocytes. To obtain direct evidence that diabetic sEV promotes cardiomyocyte apoptotic cell death, isolated neonatal rat ventricular cardiomyocytes (NRVMs) were treated with sEV and subjected to simulated ischemia/reperfusion (SI/R). Treatment of cardiomyocytes with sEV from diabetic plasma, diabetic adipocytes, or HGHL-challenged 3T3L1 adipocytes significantly enhanced SI/R-induced apoptosis and reduced cell viability. These pathologic effects were replicated by a miR-130b-3p (a molecule increased dramatically in diabetic sEV) mimic and blocked by a miRb-130b-3p inhibitor. Molecular studies identified PGC-1α (i.e. PGC-1α1/-a) as the direct downstream target of miR-130b-3p, whose downregulation causes mitochondrial dysfunction and apoptosis. Finally, treatment with diabetic adipocyte-derived sEV or a miR-130b-3p mimic significantly enhanced mitochondrial reactive oxygen species (ROS) production in SI/R cardiomyocytes. Conversely, treatment with a miR-130b-3p inhibitor or overexpression of PGC-1α extremely attenuated diabetic sEV-induced ROS production.

We obtained the first evidence that diabetic sEV promotes oxidative stress and mitochondrial-mediated cardiomyocyte apoptotic cell death, exacerbating MI/R injury. These pathological phenotypes were mediated by miR-130b-3p-induced suppression of PGC-1α expression and subsequent mitochondrial ROS production. Targeting miR-130b-3p mediated cardiomyocyte apoptosis may be a novel strategy for attenuating diabetic exacerbation of MI/R injury.

In this cross-sectional analysis, we explored how fluctuations in glycemic levels impact executive functions and psychosocial outcomes in patients with type 2 diabetes mellitus (T2DM). The goal was to understand the relationship between glycemic control and both neuropsychological and psychosocial health. We stratified participants into well-controlled and poorly controlled groups based on glycated hemoglobin (HbA1c) levels and variability, including a healthy control group for comparison. The study consisted of neuropsychological tests and psychosocial assessments. Results indicated that the poorly controlled T2DM group experienced significant executive dysfunction and scored lower on the Tower of London, Wisconsin Card Sorting, and Digit Span Tests, reflecting a broader impact on quality of life and resilience. These findings support the importance of maintaining stable glycemic levels for better executive and psychosocial outcomes and highlight the need for regular neuropsychological and psychosocial assessments in diabetes care.

Diabetes mellitus is a metabolic syndrome that has grown globally to become a significant public health challenge. Hypothesizing that the plasma membrane protein, transient receptor potential ankyrin-1, is a pivotal target in insulin resistance, we investigated the mechanism of action of cinnamaldehyde (CIN), an electrophilic TRPA1 agonist, in skeletal muscle, a primary insulin target. Specifically, we evaluated the effect of CIN on insulin resistance, hepatic glycogen accumulation and muscle and adipose tissue glucose uptake. Furthermore, the in vitro role of CIN in glucose uptake and intracellular signaling was determined in insulin-resistant rats whose calcium influx was analyzed. Moreover, the serum lipid profile was assessed following short-term CIN treatment in rats, and lipid tolerance was analyzed. The effects of CIN on insulin resistance were mediated by TRPA1, with downstream signaling involving the activation of PI3-K, MAPK, PKC, as well as extracellular calcium and calcium release from intracellular stores. Additionally, cytoskeleton integrity was required for the complete action of CIN on glucose uptake in muscle. CIN also ameliorated the serum lipid profile and improved triglyceride tolerance following acute vivo exposure.

The hybrid closed-loop (HCL) system, Medtronic MiniMed™ 770G, has been available for use by Japanese individuals with type 1 diabetes mellitus since 2021. The aim of this study was to evaluate the effect of its use on glycemic variability and quality of life (QOL) in this population. This multicenter, open-label, prospective observational study included 14 Japanese individuals with type 1 diabetes mellitus treated with MiniMed™ 640G. Participants who switched to the 770G system were evaluated for time in range (TIR) and other glycemic outcomes at baseline and at 3 and 12 months post-transition. QOL was assessed using the Diabetes Therapy-Related QOL (DTR-QOL) scale. The mean baseline glycated hemoglobin was 7.52 ± 1.05%, and body mass index (BMI) was 21.78 ± 3.07 kg/m2. By study completion, individuals used the HCL system approximately 80% of the time in a day. TIR showed improvement, with an increased achievement ratio of TIR > 70% at 12 months. Hypoglycemia occurrence was minimal at 12 months. In addition, all-time sensor glucose measurements decreased after 12 months, and there were no significant changes in BMI or daily insulin dose. DTR-QOL scores did not significantly differ, possibly owing to increased total alarms and sensor calibration times. Transitioning to the Medtronic MiniMed™ 770G system led to an improved achievement ratio of TIR > 70% and reduced hyperglycemia at 12 months. However, no significant change in QOL was observed, probably because of the increased number of total alarms.

The online version contains supplementary material available at 10.1007/s13340-024-00778-7.

An aging population combined with a rapidly increasing prevalence of diabetes foreshadows a global epidemic of cardiovascular and kidney disease that threatens to halt improvements in life and health-span and will have particularly severe consequences in older adults. The management of diabetes has been transformed with the recent development of newer anti-hyperglycemic agents that have demonstrated superior efficacy. However, the utility of these drugs extends beyond glycemic control to benefits for managing obesity, cardiovascular disease (CVD), chronic kidney disease, and heart failure. Numerous cardiovascular and kidney outcomes trials of these drugs have played an instrumental role in shaping current guidelines for the management of diabetes and CVD. Older adults with diabetes are diverse in terms of their comorbidities, diabetic complications, and cognitive and functional status. Therefore, there is an unmet need for personalized management of diabetes and CVD in this population. In this review, we provide an overview of the epidemiological burden and management of diabetes and CVD in older adults. We then focus on randomized cardiovascular and kidney outcome trials with anti-hyperglycemic agents to propose an evidence-based approach to the management of diabetes in older adults with high risk of cardiovascular and kidney disease.

Newer incretin-based therapies for type 2 diabetes (T2D) have the potential to substantially reduce glycated hemoglobin (HbA1c) and weight with a low associated risk of hypoglycemia. This study aimed to assess the percentage of participants randomized to tirzepatide or comparator who achieved the composite endpoint of HbA1c ≤ 6.5% and weight reduction ≥ 10% without hypoglycemia across prespecified baseline characteristics: T2D duration (≤ 5, > 5-10, or > 10 years), sex, HbA1c (≤ 8.5% or > 8.5%), age (< 65 or ≥ 65 years), and body mass index (< 30, 30 to < 35, or ≥ 35 kg/m2).

This post hoc analysis of SURPASS-1 through -5 evaluated adult study participants with T2D treated with tirzepatide 5, 10, or 15 mg versus placebo or active comparator. Missing HbA1c and weight values were imputed from mixed models for repeated measures. Logistic regression was used to compare tirzepatide versus comparators for the percentage of participants reaching the composite endpoint.

Across subgroups, the composite endpoint was achieved by a median of approximately 30%, 45%, and 54% of participants who received tirzepatide 5, 10, and 15 mg, respectively; this was consistent across baseline subgroups, except that a greater percentage of women than men achieved the composite endpoint. The most common treatment-emergent adverse events were gastrointestinal in nature.

In this post hoc analysis, tirzepatide achieved the composite outcome of glycemic control and weight loss with no hypoglycemia, irrespective of baseline characteristics. This may help clinicians as they select suitable treatment in diverse populations.

ClinicalTrials.gov: NCT03954834, NCT03987919, NCT03882970. NCT03730662, and NCT04039503.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Stroke triggers are factors that may precipitate a stroke within a given time interval and can predict the timing of a stroke. While hypoglycemia has been established as a risk factor for cardiovascular events such as acute ischemic stroke (AIS), there is limited research demonstrating hypoglycemic events as stroke triggers. We hypothesize an association between hypoglycemic events and the occurrence of stroke among patients with diabetes.

We used Medicare inpatient, outpatient, emergency department, and subacute nursing facility data sets from January 1, 2016, to December 31, 2019, and validated using International Classification of Diseases, Tenth Revision, Clinical Modification codes to identify conditions. We used a case-crossover study design, testing whether exposure to a hypoglycemia encounter within progressively longer case periods (up to 30 days before index AIS) was associated with the subsequent occurrence of AIS, compared with control periods of equal length exactly 1 year before the case period. We used conditional logistical regression models to estimate odds ratios and 95% CIs.

There were 237 667 index admissions with AIS and diabetes during the study period. There were increased odds of AIS following an encounter with hypoglycemia. The risk was the highest immediately on the first day following the hypoglycemia encounter (odds ratio, 3.694 [95% CI, 2.694-5.065]; P<0.0001) and gradually became lower as the case-control period lengthened. At a 30-day case-control interval, the risk was lowest but still significant (odds ratio, 2.345 [95% CI, 2.179-2.523]; P<0.0001).

We found that hypoglycemic events in patients with diabetes are associated with a more than 3-fold greater risk of AIS in the first day but can trigger AIS in the 30 days following the event. More research is needed to assess the link between the severity of hypoglycemia and stroke occurrence, as well as the severity of the stroke. These results, if confirmed in other studies, emphasize the importance of avoiding hypoglycemic events in patients with diabetes.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Patients with type 1 diabetes mellitus (T1DM) experience multiple episodes of hypoglycemia, resulting in dysfunctional counter-regulatory responses with time. The recent experimental study by Jin et al explored the role of intestinal glucagon-like peptide-1 (GLP-1) in impaired counter-regulatory responses to hypoglycemia. They identified intestinal GLP-1 along with GLP-1 receptor (GLP-1R) as the new key players linked with impaired counter-regulatory responses to hypoglycemia in type 1 diabetic mice. They also demonstrated that excessive expression of GLP-1 and GLP-1R was associated with attenuated sympathoadrenal responses and decreased glucagon secretion. The study has enormous clinical relevance as defective counter regulation and hypoglycemia unawareness negatively impacts the intensive glycemic management approach in this group of patients. However, the physiological processes must be validated in dedicated human studies to comprehensively understand the pathophysiology of this complex relationship, and to clarify the true extent of impaired hypoglycemia counter regulation by intestinal GLP-1. For now, following the results of the index study and other similar studies, GLP-1 analogues usage in T1DM must be carefully monitored, as there is an inherent risk of worsening the already impaired counter-regulatory responses in these patients. Further studies in the future could identify other key players involved in this clinically relevant interaction.

Type 2 diabetes is associated with cardiovascular disease, possibly due to impaired vascular fibrous repair. Yet, the mechanisms are elusive. Here, we investigate alterations in the fibrous repair processes in type 2 diabetes atherosclerotic plaque extracellular matrix by combining multi-omics from the human Carotid Plaque Imaging Project cohort and functional studies. Plaques from type 2 diabetes patients have less collagen. Interestingly, lower levels of transforming growth factor-ß distinguish type 2 diabetes plaques and, in these patients, lower levels of fibrous repair markers are associated with cardiovascular events. Transforming growth factor-ß2 originates mostly from contractile vascular smooth muscle cells that interact with synthetic vascular smooth muscle cells in the cap, leading to collagen formation and vascular smooth muscle cell differentiation. This is regulated by free transforming growth factor-ß2 which is affected by hyperglycemia. Our findings underscore the importance of transforming growth factor-ß2-driven fibrous repair in type 2 diabetes as an area for future therapeutic strategies.

Linggui-Zhugan (LGZG) comprises four herbs and is a classic formula in traditional Chinese medicine. There is strong clinical evidence of its pleiotropic effects in the prevention of diabetes and its related complications. Although several classes of drugs are currently available for clinical management of diabetic kidney disease (DKD), tight glycemic and/or hypertension control may not prevent disease progression. This study evaluated the therapeutic effect of the ethnopharmacological agent LGZG on DKD.

This study aimed to investigate the effects of LGZG formula with standard quality control on experimental DKD and its related metabolic disorders in animal model. Meanwhile, the present study aimed to investigate regulatory effects of LGZG on renal proteinase 3 (PR3) to reveal mechanisms underlying renoprotective benefits of LGZG.

LGZG decoction was fingerprinted by high-performance liquid chromatography for quality control. An experimental model of DKD was induced in C57 BL/6J mice by a combination of high-fat diet feeding, uninephrectomy, and intraperitoneal injection of streptozocin. The LGZG decoction was administrated by daily oral gavage.

Treatment with LGZG formula significantly attenuated DKD-like traits (including severe albuminuria, mesangial matrix expansion, and podocyte loss) and metabolic dysfunction (disordered body composition and dyslipidemia) in mice. RNA sequencing data revealed a close association of LGZG treatment with marked modulation of signaling pathways related to podocyte injury and cell apoptosis. Mechanistically, LGZG suppressed the DKD-triggered increase in renal PR3 and podocyte apoptosis. In-vitro incubation of mouse immortalized podocytes with LGZG-medicated serum attenuated PR3-mediated apoptosis.

Our data demonstrated that the LGZG formula protected against DKD in mice and was closely associated with its inhibitory effects on PR3-mediated podocyte apoptosis.