Type 2 Diabetes Comorbidities Research Articles

Household economic burden of type-2 diabetes and hypertension comorbidity care in urban-poor Ghana: a mixed methods study

BackgroundNon-communicable diseases (NCDs) predispose households to exorbitant healthcare expenditures in health systems where there is no access to effective financial protection for healthcare. This study assessed the economic burden associated with the rising burden of type-2 diabetes (T2D) and hypertension comorbidity management, and its implications for healthcare seeking in urban Accra.MethodsA convergent parallel mixed-methods study design was used. Quantitative sociodemographic and cost data were collected through survey from a random community-based sample of 120 adults aged 25 years and older and living with comorbid T2D and hypertension in Ga Mashie, Accra, Ghana in November and December 2022. The monthly economic cost of T2D and hypertension comorbidity care was estimated using a descriptive cost-of-illness analysis technique from the perspective of patients. Thirteen focus group discussions (FGDs) were conducted among community members with and without comorbid T2D and hypertension. The FGDs were analysed using deductive and inductive thematic approaches. Findings from the survey and qualitative study were integrated in the discussion.ResultsOut of a total of 120 respondents who self-reported comorbid T2D and hypertension, 23 (19.2%) provided complete healthcare cost data. The direct cost of managing T2D and hypertension comorbidity constituted almost 94% of the monthly economic cost of care, and the median direct cost of care was US$19.30 (IQR:10.55–118.88). Almost a quarter of the respondents pay for their healthcare through co-payment and insurance jointly, and 42.9% pay out-of-pocket (OOP). Patients with lower socioeconomic status incurred a higher direct cost burden compared to those in the higher socioeconomic bracket. The implications of the high economic burden resulting from self-funding of healthcare were found from the qualitative study to be: 1) poor access to quality healthcare; (2) poor medication adherence; (3) aggravated direct non-medical and indirect cost; and (4) psychosocial support to help cope with the cost burden.ConclusionThe economic burden associated with healthcare in instances of comorbid T2D and hypertension can significantly impact household budget and cause financial difficulty or impoverishment. Policies targeted at effectively managing NCDs should focus on strengthening a comprehensive and reliable National Health Insurance Scheme coverage for care of chronic conditions.

Posttraumatic Stress Disorder and Type 2 Diabetes Outcomes in Veterans

Posttraumatic stress disorder (PTSD) symptom reduction is linked with lower risk of incident type 2 diabetes (T2D), but little is known about the association between PTSD and comorbid T2D outcomes. Whether PTSD is a modifiable risk factor for adverse T2D outcomes is unknown. To determine whether patients with PTSD who improved and no longer met diagnostic criteria for PTSD had a lower risk of adverse T2D outcomes compared with patients with persistent PTSD. This retrospective cohort study used deidentified data from US Veterans Health Administration (VHA) historical medical records (from October 1, 2011, to September 30, 2022) to create a cohort of patients aged 18 to 80 years with comorbid PTSD and T2D. Data analysis was performed from March 1 to June 1, 2024. Diagnoses of PTSD and T2D. The main outcomes were insulin initiation, poor glycemic control, any microvascular complication, and all-cause mortality. Improvement of PTSD was defined as no longer meeting PTSD diagnostic criteria, per a PTSD Checklist score of less than 33. Entropy balancing controlled for confounding. Survival and competing risk models estimated the association between meeting PTSD criteria and T2D outcomes. Subgroup analyses examined variation by age, sex, race, PTSD severity, and comorbid depression status. The study cohort included 10 002 veterans. More than half of patients (65.3%) were aged older than 50 years and most (87.2%) were men. Patients identified as Black (31.6%), White (62.7%), or other race (5.7%). Before controlling for confounding with entropy balancing, patients who no longer met PTSD diagnostic criteria had similar incidence rates for starting insulin (22.4 vs 24.4 per 1000 person-years), poor glycemic control (137.1 vs 133.7 per 1000 person-years), any microvascular complication (108.4 vs 104.8 per 1000 person-years), and all-cause mortality (11.2 vs 11.0 per 1000 person-years) compared with patients with persistent PTSD. After controlling for confounding, no longer meeting PTSD criteria was associated with a lower risk of microvascular complications (hazard ratio [HR], 0.92 [95% CI, 0.85-0.99]). Among veterans aged 18 to 49 years, no longer meeting PTSD criteria was associated with a lower risk of insulin initiation (HR, 0.69 [95% CI, 0.53-0.88]) and all-cause mortality (HR, 0.39 [95% CI, 0.19-0.83]). Among patients without depression, no longer meeting PTSD criteria was associated with a lower risk of insulin initiation (HR, 0.73 [95% CI, 0.55-0.97]). The findings of this cohort study of patients with comorbid PTSD and T2D suggest that PTSD is a modifiable risk factor associated with a modest reduction in microvascular complications. Further research is needed to determine whether findings are similar in non-VHA health care settings.

Weight loss treatment for COVID-19 in patients with NCDs: a pilot prospective clinical trial

COVID-19 comorbid with noncommunicable chronic diseases (NCDs) complicates the diagnosis, treatment, and prognosis, and increases the mortality rate. The aim is to evaluate the effects of a restricted diet on clinical/laboratory inflammation and metabolic profile, reactive oxygen species (ROS), and body composition in patients with COVID-19 comorbid with NCDs. We conducted a 6-week open, pilot prospective controlled clinical trial. The study included 70 adult patients with COVID-19 comorbid with type 2 diabetes (T2D), hypertension, or nonalcoholic steatohepatitis (NASH). Interventions: a restricted diet including calorie restriction, hot water drinking, walking, and sexual self-restraint. Primary endpoints: COVID-19 diagnosis by detecting SARS-CoV-2 genome by RT-PCR; weight loss in Main group; body temperature; C-reactive protein. Secondary endpoints: the number of white blood cells; erythrocyte sedimentation rate; adverse effects during treatment; fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), systolic/diastolic blood pressure (BP); blood lipids; ALT/AST, chest CT-scan. In Main group, patients with overweight lost weight from baseline (− 12.4%; P < 0.0001); 2.9% in Main group and 7.2% in Controls were positive for COVID-19 (RR: 0.41, CI: 0.04–4.31; P = 0.22) on the 14th day of treatment. Body temperature and C-reactive protein decreased significantly in Main group compared to Controls on day 14th of treatment (P < 0.025). Systolic/diastolic BP normalized (P < 0.025), glucose/lipids metabolism (P < 0.025); ALT/AST normalized (P < 0.025), platelets increased from baseline (P < 0.025), chest CT (P < 0.025) in Main group at 14 day of treatment. The previous antidiabetic, antihypertensive, anti-inflammatory, hepatoprotective, and other symptomatic medications were adequately decreased to completely stop during the weight loss treatment. Thus, the fast weight loss treatment may be beneficial for the COVID-19 patients with comorbid T2D, hypertension, and NASH over traditional medical treatment because, it improved clinical and laboratory/instrumental data on inflammation; glucose/lipid metabolism, systolic/diastolic BPs, and NASH biochemical outcomes, reactive oxygen species; and allowed patients to stop taking medications.Trial Registration: ClinicalTrials.gov NCT05635539 (02/12/2022): https://clinicaltrials.gov/ct2/show/NCT05635539?term=NCT05635539&draw=2&rank=1.

Diabetes-related risk factors and survival among individuals with type 2 diabetes and breast, lung, colorectal, or prostate cancer

Premature death in diabetes is increasingly caused by cancer. The objectives were to estimate the excess mortality when individuals with type 2 diabetes(T2D) were diagnosed with cancer, and to examine the impact of modifiable diabetes-related risk factors. This longitudinal nationwide cohort study included individuals with T2D registered in the Swedish National Diabetes Register between 1998–2019. Poisson models were used to estimate mortality as a function of time-updated risk-factors, adjusted for sex, age, diabetes duration, marital status, country of birth, BMI, blood pressure, lipids, albuminuria, smoking, and physical activity. We included 690,539 individuals with T2D and during 4,787,326 person-years of follow-up 179,627 individuals died. Overall, the all-cause mortality rate ratio was 3.75 [95%confidence interval(CI):3.69–3.81] for individuals with T2D and cancer compared to those remaining free of cancer. The most marked risk factors associated to mortality among individuals with T2D and cancer were low physical activity, 1.59 (1.57–1.61) and smoking, 2.15 (2.08–2.22), whereas HbA1c, lipids, hypertension, and BMI had no/weak associations with survival. In a future with more patients with comorbid T2D and cancer diagnoses, these results suggest that smoking and physical activity might be the two most salient modifiable risk factors for mortality in people with type 2 diabetes and cancer.

Glucagonlike peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors in ischemic strokes with diabetes 2.

Cardiovascular outcome trials demonstrate that glucagonlike peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events in patients with type 2 diabetes (T2D), whereas dipeptidyl peptidase-4 inhibitors (DPP-4is) have not shown cardiovascular benefits. We compared acute ischemic stroke (AIS) with T2D treated with either a GLP-1RA or DPP-4i prior to the index stroke. This national cohort study included AIS patients with T2D from 2017 to 2020 in Denmark who were users of a GLP-1RA or DPP-4i. To be categorized as a user, we required at least 12 months of exposure and no concurrent treatment with another newer glucose-lowering medication during the last 3 months prior to the index stroke. GLP-1RA users were compared to users of DPP-4i while adjusting for the calendar year of index stroke, age, sex, comorbidity, and socioeconomic factors. The study included 1567 AIS events with T2D; 593 were users of GLP-1RA and 974 of DPP-4i. The absolute risk of a very severe stroke was 2.4% (95% confidence interval [CI] = 1.2-3.7) in GLP-1RA users and 6.1% (95% CI = 4.6-7.7) in DPP-4i users. The corresponding adjusted risk ratio (aRR) of GLP-1RA versus DPP-4i was 0.49 (95% CI = 0.24-1.00). The aRRs of 30-day and 365-day mortality were 0.55 (95% CI = 0.32-0.94) and 0.72 (95% CI = 0.53-0.98), respectively. The risk of a very severe stroke as well as the 30-day and 365-day poststroke mortality rates were lower among the AIS patients with comorbid T2D receiving GLP-1RA prior to the index stroke compared to those receiving DPP-4i. Hence, GLP-1RA may improve stroke outcomes in comparison with DPP-4i.

Effect of astaxanthin in type-2 diabetes -induced APPxhQC transgenic and NTG mice

ObjectivesAggregation and misfolding of amyloid beta (Aβ) and tau proteins, suggested to arise from post-translational modification processes, are thought to be the main cause of Alzheimer's disease (AD). Additionally, a plethora of evidence exists that links metabolic dysfunctions such as obesity, type 2 diabetes (T2D), and dyslipidemia to the pathogenesis of AD. We thus investigated the combinatory effect of T2D and human glutaminyl cyclase activity (pyroglutamylation), on the pathology of AD and whether astaxanthin (ASX) treatment ameliorates accompanying pathophysiological manifestations. MethodsMale transgenic AD mice, APPxhQC, expressing human APP751 with the Swedish and the London mutation and human glutaminyl cyclase (hQC) enzyme and their non-transgenic (NTG) littermates were used. Both APPxhQC and NTG mice were allocated to 3 groups, control, T2D-control, and T2D-ASX. Mice were fed control or high fat diet ± ASX for 13 weeks starting at an age of 11–12 months. High fat diet fed mice were further treated with streptozocin for T2D induction. Effects of genotype, T2D induction, and ASX treatment were evaluated by analysing glycemic readouts, lipid concentration, Aβ deposition, hippocampus-dependent cognitive function and nutrient sensing using immunosorbent assay, ELISA-based assays, western blotting, immunofluorescence staining, and behavioral testing via Morris water maze (MWM), respectively. ResultsAPPxhQC mice presented a higher glucose sensitivity compared to NTG mice. T2D-induced brain dysfunction was more severe in NTG compared to the APPxhQC mice. T2D induction impaired memory functions while increasing hepatic LC3B, ABCA1, and p65 levels in NTG mice. T2D induction resulted in a progressive shift of Aβ from the soluble to insoluble form in APPxhQC mice. ASX treatment reversed T2D-induced memory dysfunction in NTG mice and in parallel increased hepatic pAKT while decreasing p65 and increasing cerebral p-S6rp and p65 levels. ASX treatment reduced soluble Aβ38 and Aβ40 and insoluble Aβ40 levels in T2D-induced APPxhQC mice. ConclusionsWe demonstrate that T2D induction in APPxhQC mice poses additional risk for AD pathology as seen by increased Aβ deposition. Although ASX treatment reduced Aβ expression in T2D-induced APPxhQC mice and rescued T2D-induced memory impairment in NTG mice, ASX treatment alone may not be effective in cases of T2D comorbidity and AD.

Type 2 diabetes mellitus in patients with ischemic stroke - A nationwide study.

Type 2 diabetes (T2D) is a risk factor for ischemic stroke (IS) and associated with an adverse prognosis. Both stroke and diabetes care has evolved substantially during the last decade. This study aimed to determine the prevalence of T2D among IS patients along with time trends in the risk profile, use of glucose-lowering medications, quality-of-care and clinical outcomes, including stroke severity; length-of-stay; mortality, readmission and recurrent stroke in a large national cohort. Registry-based cohort study including all IS events in Denmark from 2004 to 2020. IS with co-morbid T2D were compared to IS without diabetes while adjusting for age, sex, stroke severity, co-morbidity and socio-economic factors. The study included 169,262 IS events; 24,479 with co-morbid T2D. The prevalence of T2D in IS increased from 12.0% (2004-2006) to 17.0% (2019-2020). The adjusted absolute 30-day mortality risk in IS with T2D decreased from 9.9% (2004-2006) to 7.8% (2019-2020). The corresponding adjusted risk ratios (aRR) were 1.22 95% confidence interval (1.09-1.37) and 1.29 (1.11-1.50), respectively. The aRR of 365-day mortality was in 2004-2006: 1.20 (1.12-1.29) and in 2019-2020: 1.34 (1.22-1.47). The 30- and 365-day readmissions rates were also consistently higher in IS with T2D. The prevalence of T2D in IS increased over time. The 30- and 365-day mortality rates decreased over the time-period but were consistently higher in IS with co-morbid T2D. Readmissions were also higher in IS with T2D. This highlights an urgent need for strategies to further improve the prognosis in IS patients with co-morbid T2D.

Aggravated Systemic Inflammation and Atherogenicity in African Patients Living With Type 2 Diabetes and Hypertension Comorbidity.

To explore routinely measured markers of systemic inflammation in hypertension (HTN) and type 2 diabetes (T2D) comorbidity, and their association with atherogenicity. This study included a total of 70 patients with T2D which were categorised into 2 groups, that is with T2D and with HTN comorbidity (T2D + HTN) (n = 35/group). All measured laboratory parameters were determined using standardised methods. The neutrophil/lymphocyte ratio (NLR) was elevated in patients with T2D + HTN when compared to those with T2D (P = .0494). This was also the case with C-reactive protein (CRP) levels (P < .0001) and systemic immune-inflammation (SII) index (P = .0298). Notably, the majority of patients with T2D + HTN [63% (n = 22)] were classified as having an intermediate or high atherogenic index of plasma (AIP). The correlation analysis of systemic inflammation showed significant associations between CRP and age (r = .24, P = .0477); CRP and red blood cell count (r = -.4, P = .0455), and SII and systolic blood pressure (SBP) (r = .33, P = .0056). However, there was no association between inflammatory profiles and lipograms (P > .05). We further assessed predictors for an elevated AIP using mutivariable regression model adjusted for age, SBP, CRP and SII. Only NLR was a significant predictor of AIP (β = .287, SE: 0.1, P = .0046). HTN comorbidity in T2D is associated with exacerbated levels of inflammation and atherogenicity. NLR is a significant independent risk factor for increased atherogenicity in patients with T2D. Therefore, the use of therapeutic strategies that target and alleviate inflammation in patients with T2D and HTN comorbidity is imperative in reducing the initiating and progression of cardiovascular events (CVEs).

LD block disorder-specific pleiotropic roles of novel CRHR1 in type 2 diabetes and depression disorder comorbidity

AbstractMajor depressive disorder (MDD) and type 2 diabetes (T2D) are complex disorders whose comorbidity can be due to hypercortisolism and may be explained by dysfunction of the corticotropin-releasing hormone receptor 1 (CRHR1) and cortisol feedback within the hypothalamic–pituitary–adrenal axis (HPA axis). To investigate the role of the CRHR1 gene in familial T2D, MDD, and MDD-T2D comorbidity, we tested 152 CRHR1 single-nucleotide-polymorphisms (SNPs), via 2-point parametric linkage and linkage disequilibrium (LD; i.e., association) analyses using 4 models, in 212 peninsular families with T2D and MDD. We detected linkage/LD/association to/with MDD and T2D with 122 (116 novel) SNPs. MDD and T2D had 4 and 3 disorder-specific novel risk LD blocks, respectively, whose risk variants reciprocally confirm one another. Comorbidity was conferred by 3 novel independent SNPs. In silico analyses reported novel functional changes, including the binding site of glucocorticoid receptor-alpha [GR-α] on CRHR1 for transcription regulation. This is the first report of CRHR1 pleiotropic linkage/LD/association with peninsular familial MDD and T2D. CRHR1 contribution to MDD is stronger than to T2D and may antecede T2D onset. Our findings suggest a new molecular-based clinical entity of MDD-T2D and should be replicated in other ethnic groups.

Glucose dysregulation promotes oncogenesis in human bladder cancer by regulating autophagy and YAP1/TAZ expression.

Glucose dysregulation is strongly correlated with cancer development, and cancer is prevalent in patients with Type 2 diabetes (T2D). We aimed to elucidate the mechanism underlying autophagy in response to glucose dysregulation in human bladder cancer (BC). 220 BC patients were included in this retrospective study. The expression of YAP1, TAZ and AMPK, EMT-associated markers, and autophagy marker proteins was analysed by immunohistochemistry, western blotting, and quantitative real-time PCR (qPCR). Further, T24 and UMUC-3 BC cells were cultured in media with different glucose concentrations, and the expression of YAP1, TAZ, AMPK and EMT-associated markers, and autophagy marker proteins was analysed by western blotting and qPCR. Autophagy was observed by immunofluorescence and electron microscopy. BC cell viability was tested using MTT assays. A xenograft nude mouse model of diabetes was used to evaluate tumour growth, metastasis and survival. A poorer pathologic grade and tumour-node-metastasis stage were observed in patients with BC with comorbid T2D than in others with BC. YAP1 and TAZ were upregulated in BC samples from patients with T2D. Mechanistically, high glucose (HG) promoted BC progression both in vitro and in vivo and inhibited autophagy. Specifically, various autophagy marker proteins and AMPK were negatively regulated under HG conditions and correlated with YAP1 and TAZ expression. These results demonstrate that HG inhibits autophagy and promotes cancer development in BC. YAP1/TAZ/AMPK signalling plays a crucial role in regulating glucose dysregulation during autophagy. Targeting these effectors exhibits therapeutic significance and can serve as prognostic markers in BC patients with T2D.

Neutrophil gelatinase-associated lipocalin: function, specificity, role in the diagnosis of renal dysfunction in hypertensive patients with concomitant type 2 diabetes and obesity

Background. Neutrophil gelatinase-associated lipocalin (NGAL) belongs to the superfamily of lipocalins whose main function is the binding and transportation of hydrophobic molecules, si­derophores, as the most important ligands of NGAL. The diagnostic significance of NGAL as a marker of renal dysfunction, as well as its prognostic value in terms of the further prognosis of the course of renal pathology has now been confirmed. The purpose of the study: to determine the role of NGAL in the development of renal dysfunction in hypertensive patients with comorbid type 2 diabetes (T2D) and obesity. Materials and methods. One hundred and eleven patients with hypertension (50 men, 61 women) aged 54.37 ± 1.18 years and 20 controls were examined. During the examination, they were divi­ded into 4 groups depending on the presence of comorbid pathology: hypertension — the first group (n = 22); hypertension combined with obesity — the second group (n = 30); hypertension combined with T2D — the third group (n = 31); hypertension, T2D and obesity — the fourth group (n = 28). In all patients, body weight and height were measured, body mass index was calculated, levels of glycated hemoglobin, lipid metabolism, systolic and diastolic blood pressure were measured. The content of NGAL in blood serum was evaluated by the enzyme-linked immunosorbent assay. Results. The level of NGAL in all patients included in the study was significantly higher compared to the control group (p &lt; 0.01). However, it was highest in comorbidity of hypertension, T2D and obesity, which, in turn, indicates a high risk of interstitial fibrosis in these patients. A significant correlation was found between the level of NGAL and the concentration of cardiotrophin (p &lt; 0.032), catestatin (p &lt; 0.001), β2-microglobulin (p &lt; 0.001), cystatin (p &lt; 0.021), atherogenic coefficient (p &lt; 0.011), NT-proBNP (p &lt; 0.014), vitamin D (p &lt; 0.004). The obtained data demonstrate the significant role of NGAL in the development of early cardiovascular and renal complications in our patients. Conclusions. A significant increase in the level of NGAL was found in patients with hypertension, hypertension with T2D, hypertension with obesity, hypertension with T2DM and obesity compared to healthy individuals (p &lt; 0.01). A significant correlation of the NGAL level with the serum concentration of cardiotrophin, catestatin, cystatin C, β2-microglobulin, atherogenic coefficient, NT-proBNP, and vitamin D in the exami­ned patients was proved.

Association of GLP-1 Receptor Agonists with Chronic Obstructive Pulmonary Disease Exacerbations among Patients with Type 2 Diabetes.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D) have worse clinical outcomes compared with patients without metabolic dysregulation. GLP-1 (glucagon-like peptide 1) receptor agonists (GLP-1RAs) reduce asthma exacerbation risk and improve FVC in patients with COPD. Objectives: To determine whether GLP-1RA use is associated with reduced COPD exacerbation rates, and severe and moderate exacerbation risk, compared with other T2D therapies. Methods: A retrospective, observational, electronic health records-based study was conducted using an active comparator, new-user design of 1,642 patients with COPD in a U.S. health system from 2012 to 2022. The COPD cohort was identified using a previously validated machine learning algorithm that includes a natural language processing tool. Exposures were defined as prescriptions for GLP-1RAs (reference group), DPP-4 (dipeptidyl peptidase 4) inhibitors (DPP-4is), SGLT2 (sodium-glucose cotransporter 2) inhibitors, or sulfonylureas. Measurements and Main Results: Unadjusted COPD exacerbation counts were lower in GLP-1RA users. Adjusted exacerbation rates were significantly higher in DPP-4i (incidence rate ratio, 1.48 [95% confidence interval, 1.08-2.04]; P = 0.02) and sulfonylurea (incidence rate ratio, 2.09 [95% confidence interval, 1.62-2.69]; P < 0.0001) users compared with GLP-1RA users. GLP-1RA use was also associated with significantly reduced risk of severe exacerbations compared with DPP-4i and sulfonylurea use, and of moderate exacerbations compared with sulfonylurea use. After adjustment for clinical covariates, moderate exacerbation risk was also lower in GLP-1RA users compared with DPP-4i users. No statistically significant difference in exacerbation outcomes was seen between GLP-1RA and SGLT2 inhibitor users. Conclusions: Prospective studies of COPD exacerbations in patients with comorbid T2D are warranted. Additional research may elucidate the mechanisms underlying these observed associations with T2D medications.

Socioeconomic inequalities in type 2 diabetes comorbidities in different population subgroups: trend analyses using German health insurance data

While socioeconomic inequalities in the prevalence and management of type 2 diabetes (T2D) are well established, little is known about whether inequalities exist in the prevalence and the temporal development of T2D comorbidities. Previous research points towards expansion of morbidity in T2D as depicted mainly by a rising trend of T2D comorbidities. Against this background, and using German claims data, this study aims to examine whether socioeconomic status (SES) inequalities exist in the rates and the temporal development of T2D comorbidities. Since previous research indicates varying risk levels for T2D prevalence in the population subgroups: working individuals, nonworking spouses and pensioners, the analyses are stratified by these three population subgroups. The study is done on a large population of statutory insured individuals with T2D in three time-periods between 2005 and 2017. Predicted probabilities of three comorbidity groups and the number of comorbidities were estimated using logistic and ordinal regression analyses among different income, education and occupation groups. Interaction analyses were applied to examine whether potential SES inequalities changed over time. The study showed that neither the cross-sectional existence, nor the temporal development of T2D comorbidities differed significantly among SES groups, ruling out SES inequalities in the prevalence and the temporal development of T2D comorbidities in Germany. In men and women of all examined population subgroups, predicted probabilities for less severe cardiovascular (CVD) comorbidities, other vascular diseases and the number of comorbidities per individual rose significantly over time regardless of SES, but little if any change took place for more severe CVD comorbidities. Another important finding is that the population subgroup of nonworking spouses had markedly higher predicted probabilities for most of the examined outcomes compared to working individuals. The study indicates that the expansion of morbidity in T2D in Germany does not appear to be SES-dependent, and applies equally to different population subgroups. Yet, the study highlights that nonworking spouses are a susceptible population subgroup that needs to be focused upon when planning and implementing T2D management interventions.

UPS of the CNS: Longitudinal profiling of mitochondrial DNA in neuronal‐enriched packages from plasma of individuals with cognitive decline

AbstractBackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder that disproportionately burdens Mexican Americans (MAs) due to a combination of population‐specific environmental exposures and genetic risk factors. In addition to AD, MAs have a higher prevalence of metabolic comorbidities such as type 2 diabetes (T2D) that have been implicated in accelerated age‐related cognitive impairment. Tissue‐specific mitochondrial dysfunction and oxidative stress are early and prominent features of both AD and T2D that propagate systemic inflammation as these diseases progress. Despite the shared pathophysiology, we do not fully understand the underlying molecular mechanisms linking cognitive decline and metabolic stress, especially in understudied minority populations. Mitochondrial dysfunction may serve as the biological basis of the AD health disparity in MAs who experience earlier onset of symptoms and have an overrepresentation of T2D compared to non‐Hispanic whites (NHWs). This project aims to study T2D‐related risk for cognitive impairment by assessing the packages that neurons secrete to communicate with cells in the periphery. These neuronal‐enriched exosomes (NEEs) can cross the blood‐brain barrier and are thus capable of mediating systemic inflammation in response to CNS‐sourced stress through their mitochondrial DNA (mtDNA) cargo. We hypothesize that plasma NEE mtDNA load will reflect cognitive status and T2D comorbidity over time.MethodsExosomes of neuronal origin were enriched via CD171‐based immunocapture in longitudinal plasma samples (two timepoints, 5 years apart) from 348 Texas Alzheimer’s Research and Care Consortium (TARCC) participants stratified by race/ethnicity (MA/NHW), cognitive status (AD/MCI/NC), and T2D comorbidity (+/‐). The success of NEE isolation was assessed using nanoparticle tracking analysis (NTA) and immunoblotting against CD171 and CD81 (canonical exosome surface marker). Following extraction of total DNA from NEEs, absolute mtDNA load and deletion ratio were estimated using a real‐time qPCR assay targeting sites within the minor (D‐loop) and major (ND4) arcs.ResultsHerein, we demonstrate the ability to isolate NEEs from plasma and quantify their mtDNA cargo. Resultant values were analyzed for longitudinal differences and correlation with disease status based on various neuropsychological measures.ConclusionAs the first effort to assess mtDNA in NEEs, this project provides novel insight into how T2D confers risk for AD across different populations over time.

Impacts of physical activity and particulate air pollution on the onset, progression and mortality for the comorbidity of type 2 diabetes and mood disorders

ObjectiveThe co-occurrence of type 2 diabetes (T2D) and mood disorders (depression or anxiety) is an exceedingly common comorbidity with poor prognosis. We aimed to explore the effects of physical activity (PA), fine particulate matter (PM2.5) air pollution or their interactions on the initiation, progression and subsequent mortality of this comorbidity. MethodsThe prospective analysis was based on 336,545 participants in UK Biobank. Multi-state models were applied to capture potential impacts in all transition phases simultaneously along the natural history of the comorbidity. ResultsPA [walking (4th vs 1st quantile), moderate (4th vs 1st quantile) and vigorous activities (yes vs no)] protected against incident T2D and comorbid mood disorders afterwards, incident mood disorders, and all-cause mortality from baseline health and T2D, with the risk reductions ranging from 9 % to 23 %. Moderate and vigorous activities further prevented T2D development or mortality among depressive/anxious population. PM2.5 was associated with higher risks of developing incident mood disorders [Hazard ratio (HR) per interquartile range increase = 1.03], as well as of developing incident T2D (HR = 1.04) and further transition to comorbid mood disorders (HR = 1.10). The impacts of PA and PM2.5 were stronger during transitions to comorbidities than the occurrence of first diseases. The benefits of PA remained across all PM2.5 levels. ConclusionsPhysical inactivity and PM2.5 could accelerate the initiation and progression of the comorbidity of T2D and mood disorders. PA and reducing pollution exposure may be included in health promotion strategies to decrease the comorbidity burden.

Hypericin as a potential drug for treating Alzheimer's disease and type 2 diabetes with a view to drug repositioning.

Alzheimer's disease (AD) and type 2 diabetes (T2D) are two of the most common diseases in elderly population and they have a high rate of comorbidity. Study has revealed that T2D is a major risk factor of AD, and thus exploring therapeutic approaches that can target both diseases has drawn much interest in recent years. In this study, we tried to explore drugs that could be potentially used to prevent or treat both AD and T2D via a drug repositioning approach. We first searched the known drugs that may be effective to T2D treatment based on the network distance between the T2D-associated genes and drugs deposited in the DrugBank database. Then, via molecular docking, we further screened these drugs by examining their interaction with islet amyloid polypeptide (IAPP) and Aβ42 peptide, the key components involved in the pathogenesis of T2D or AD. Finally, the binding between the selected drug candidates and the target proteins was verified by molecular dynamics (MD) simulation; and the potential function of the drug candidates and the corresponding targets were analyzed. From multiple resources, 734 T2D-associated genes were collected, and a list of 1109 drug candidates for T2D was obtained. We found that hypericin had the lowest binding energy and the most stable interaction with either IAPP or Aβ42 peptide. In addition, we also found that the target genes regulated by hypericin were differentially expressed in the tissues related to the two diseases. Our results show that hypericin may be able to bind with IAPP and Aβ42 stably and prevent their accumulation, and thus could be a promising drug candidate for treating the comorbidity of AD and T2D.

Novel implication of the prolactin (PRL) gene in the comorbidity of type 2 diabetes and depression.

The prolactin (PRL) system plays important behavioral, social, and metabolic roles, such as mediating social bonding and insulin secretion. Inherited dysfunction of the PRL pathway-related genes is associated with psychopathology and insulin resistance. We have previously suggested that the PRL system might be implicated in the comorbidity of psychiatric (depression) and type 2 diabetes (T2D) owing to the pleiotropy of PRL pathway-related genes. To our knowledge, no PRL variants have so far been reported in patients with either major depressive disorder (MDD) and/or T2D. In this study, we analyzed 6 variants within the PRL gene and tested them for the presence of parametric linkage and/or linkage disequilibrium (LD, i.e., linkage and association) with familial MDD, T2D, and their comorbidity. We found, for the first time, that the PRL gene and its novel risk variants are linked to and in LD (i.e., linkage and association) with familial MDD, T2D, and MDD-T2D comorbidity. PRL might play a key role in mental-metabolic comorbidity and can be considered a novel gene in MDD and T2D.

Evaluation of some immune and inflammatory responses in diabetes and HIV co-morbidity.

Co-existence of diabetes in the HIV infected reportedly further complicates the attendant impairment of immunity and increases susceptibility to opportunistic infections. This study aimed to evaluate some immune and inflammatory parameters in HIV and type 2 diabetes (T2D) co-morbidity: Immunoglobulin M and G (IgM and IgG), Interleukin-6, CD4+ T-cells and C-reactive protein. The study involved 200 subjects grouped according to their HIV and diabetes status: Group 1 'Diabetic HIV seropositive' (n=40), Group 2 'Non diabetic HIV seropositive'(n=60), Group 3 'Diabetic HIV seronegative'(n=50), and Group 4 'Control non diabetic HIV seronegative'(n=50). Blood samples were collected for testing. CRP levels were significantly elevated in diabetes and HIV co-morbidity compared to other groups. IL-6 levels were significantly higher in diabetics with or without HIV infection. In addition, IL-6 was significantly elevated in individuals with poor glycemic control (HbA1c > 9.0%) compared to those with good glycemic control. IgG and IgM levels in diabetic HIV seropositive subjects were highest compared with other groups. The increased IL-6, CRP, IgG, IgM and decreased CD4+ T cell counts observed in co-morbidity suggest that HIV and T2D co-morbidity exacerbate the immune and inflammatory impairment observed in either disease entity.

Comparison of Glucose Control Profile in Patients With Depression and Type 2 Diabetes Receiving Bupropion or Venlafaxine: A Randomized Controlled Clinical Trial

Background and Objective This study aims to compare the effects of bupropion and venlafaxine on glucose control of patients with depression and type 2 diabetes (T2D). Materials &amp; Methods TThis randomized controlled trial was carried out in endocrinology clinic affiliated to Babol University of Medical Sciences on adult patients with comorbid T2D and depression in two groups. The first group (n=19) received venlafaxine 37.5-150 mg daily, while the second group (n=16) was treated with bupropion 75-300 mg per day. The primary outcomes were the severity of depressive symptoms and the glucose control profile. Depressive symptoms were assessed with the Beck depression inventory (BDI). Data was analyzed in SPSS software, version 17 package. P&lt;0.05 was considered as statically significant. Results A significant decrease in depressive symptoms for both groups was reported, but the difference between the two groups was not statistically significant (P=0.342). Venlafaxine caused a significant increase in HbA1c from 7.64 to 8.03 (P=0.04), while bupropion caused a decrease in HbA1c from 7.35 to 7.23 (P=0.06). These changes were significantly different between the two groups (P=0.028). Conclusion Venlafaxine can reduce depression, but it is not suggested as a proper drug for treating depression in people with T2D. However, bupropion seems to be a good choice due to its positive effect on depressive symptoms and glycemic control in patients with comorbid T2D and depression.

Identification of shared genetic architecture between non-alcoholic fatty liver disease and type 2 diabetes: A genome-wide analysis.

The incidence of complications of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) has been increasing. In order to identify the shared genetic architecture of the two disease phenotypes of NAFLD and T2D, a European population-based GWAS summary and a cross-trait meta-analysis was used to identify significant shared genes for NAFLD and T2D. The enrichment of shared genes was then determined through the use of functional enrichment analysis to investigate the relationship between genes and phenotypes. Additionally, differential gene expression analysis was performed, significant differentially expressed genes in NAFLD and T2D were identified, genes that overlapped between those that were differentially expressed and cross-trait results were reported, and enrichment analysis was performed on the core genes that had been obtained in this way. Finally, the application of a bidirectional Mendelian randomization (MR) approach determined the causal link between NAFLD and T2D. A total of 115 genes were discovered to be shared between NAFLD and T2D in the GWAS analysis. The enrichment analysis of these genes showed that some were involved in the processes such as the decomposition and metabolism of lipids, phospholipids, and glycerophospholipids. Additionally, through the use of differential gene expression analysis, 15 core genes were confirmed to be linked to both T2D and NAFLD. They were correlated with carcinoma cells and inflammation. Furthermore, the bidirectional MR identified a positive causal relationship between NAFLD and T2D. Our study determined the genetic structure shared between NAFLD and T2D, offering a new reference for the genetic pathogenesis and mechanism of NAFLD and T2D comorbidities.