Dysfunction In Type 2 Diabetes Mellitus Research Articles

Mitochondrial Dysfunction as a Factor of Energy Metabolism Disorders in Type 2 Diabetes Mellitus.

The pathogenesis of type 2 diabetes mellitus (T2DM) is based on the development of insulin resistance, which is a disruption to the ability of the tissues to bind to insulin, leading to a general metabolic disorder. Mitochondria are the main participants in cellular energy metabolism, meaning their dysfunction is associated with the development of insulin resistance in T2DM. Mitochondrial function is affected by insulin resistance in various tissues, including skeletal muscle and the liver, which greatly influence glucose homeostasis throughout the body. This review studies mitochondrial dysfunction in T2DM and its impact on disease progression. In addition, it considers the causes underlying the development of mitochondrial dysfunction in T2DM, including mutations in the mitochondrial genome, mitochondrial DNA methylation, and other epigenetic influences, as well as the impact of impaired mitochondrial membrane potential. New therapeutic strategies for diabetes that have been developed to target the mitochondria will also be presented.

Empagliflozin ameliorates vascular calcification in diabetic mice through inhibiting Bhlhe40-dependent NLRP3 inflammasome activation.

Type 2 diabetes mellitus (T2DM) patients exhibit greater susceptibility to vascular calcification (VC), which has a higher risk of death and disability. However, there is no specific drug for VC therapy. NLRP3 inflammasome activation as a hallmark event of medial calcification leads to arterial stiffness, causing vasoconstrictive dysfunction in T2DM. Empagliflozin (EMPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), restrains hyperglycemia with definite cardiovascular benefits. Given the anti-inflammatory activity of EMPA, herein we investigated whether EMPA protected against VC in the aorta of T2DM mice by inhibiting NLRP3 inflammasome activation. Since db/db mice receiving a normal diet developed VC at the age of about 20 weeks, we administered EMPA (5, 10, 20 mg·kg-1·d-1, i.g) to 8 week-old db/db mice for 12 weeks. We showed that EMPA intervention dose-dependently ameliorated the calcium deposition, accompanied by reduced expression of RUNX2 and BMP2 proteins in the aortas. We found that EMPA (10 mg·kg-1·d-1 for 6 weeks) also protected against VC in vitamin D3-overloaded mice, suggesting the protective effects independent of metabolism. We showed that EMPA (10 mg·kg-1·d-1) inhibited the abnormal activation of NLRP3 inflammasome in aortic smooth muscle layer of db/db mice. Knockout (KO) of NLRP3 significantly alleviated VC in STZ-induced diabetic mice. The protective effects of EMPA were verified in high glucose (HG)-treated mouse aortic smooth muscle cells (MOVASs). In HG-treated NLRP3 KO MOVASs, EMPA (1 μM) did not cause further improvement. Bioinformatics and Western blot analysis revealed that EMPA significantly increased the expression levels of basic helix-loop-helix family transcription factor e40 (Bhlhe40) in HG-treated MOVASs, which served as a negative transcription factor directly binding to the promotor of Nlrp3. We conclude that EMPA ameliorates VC by inhibiting Bhlhe40-dpendent NLRP3 inflammasome activation. These results might provide potential significance for EMPA in VC therapy of T2DM patients.

Spontaneous baroreflex sensitivity is attenuated in male UCD-type 2 diabetes mellitus rats: A link between metabolic and autonomic dysfunction.

Patients with type 2 diabetes mellitus (T2DM) have impaired arterial baroreflex function, which may be linked to the co-existence of obesity. However, the role of obesity and its related metabolic impairments on baroreflex dysfunction in T2DM is unknown. This study aimed to investigate the role of visceral fat and adiponectin, the most abundant cytokine produced by adipocytes, on baroreflex dysfunction in T2DM rats. Experiments were performed in adult male UCD-T2DM rats assigned to the following experimental groups (n=6 in each): prediabetic (Pre), diabetes-onset (T0), 4weeks after onset (T4), and 12weeks after onset (T12). Age-matched healthy Sprague-Dawley rats were used as controls. Rats were anesthetized and blood pressure was directly measured on a beat-to-beat basis to assess spontaneous baroreflex sensitivity (BRS) using the sequence technique. Dual-energy X-ray absorptiometry (DEXA) was used to assess body composition. Data are presented as mean±SD. BRS was significantly lower in T2DM rats compared with controls at T0 (T2D: 3.7±3.2ms/mmHg vs Healthy: 16.1±8.4ms/mmHg; P=0.01), but not at T12 (T2D: 13.4±8.1ms/mmHg vs Healthy: 9.2±6.0ms/mmHg; P=0.16). T2DM rats had higher visceral fat mass, adiponectin, and insulin concentrations compared with control rats (all P<0.01). Changes in adiponectin and insulin concentrations over the measured time-points mirrored one another and were opposite those of the BRS in T2DM rats. These findings demonstrate that obesity-related metabolic impairments may contribute to an attenuated spontaneous BRS in T2DM, suggesting a link between metabolic and autonomic dysfunction.

Pattern of Thyroid Dysfunction in Type II Diabetes Mellitus Patients in a Tertiary Care Center: A Cross-Sectional Study

Background: Early identification and intervention of thyroid dysfunction which occurs in association with type-II diabetes mellitus may significantly reduce the risk of adverse cerebrovascular and cardiovascular events in such patients. Hence, this study analyzed the pattern of thyroid dysfunction in T2DM (Type 2 Diabetes mellitus) patients. Methods: The present cross-sectional study was done on 250 T2DM patients, who visited the department of General Medicine in a tertiary care teaching center. Medical history was recorded and venous blood samples were collected for investigations (HbA1C (Hemoglobin A1C), FBS (Fasting blood sugar), PPBS (Postprandial blood sugar), TSH (Thyroid stimulating hormone), T4 (Tetraiodothyronine), anti-TPO (Thyroid peroxidase), and fasting lipid profile). Thyroid dysfunction in patients with T2DM was considered as the primary outcome variable. P value &lt;0.05 was considered statistically significant. Data were analyzed using coGuide software, V.1.03. Results: Females (55.6%) outnumbered males (44.4%) in this study. The prevalence of thyroid dysfunction in our study was 23.6% (95%CI 0.184 to 0.293). Subclinical hypothyroidism was found in 67.79% (95%CI 0.543 to 0.793) participants, overt hypothyroidism in 27.11% (95%CI 0.163 to 0.402), and hyperthyroidism in 5.10% (95%CI 0.010 to 0.141). Females (84.6%) had significantly higher prevalence of anti-TPO positivity compared to males (15.4%)(p=0.013). Conclusions: Findings of this study showed that T2DM patients have higher prevalence of thyroid dysfunction with predominance of subclinical hypothyroidism. Hence, this study emphasizes the importance of annual investigation of TSH levels in all the patients with T2DM. Keywords: Autoimmune Diseases, Hyperthyroidism, Hypothyroidism, Thyroid­Stimulating Hormone, Type II Diabetes Mellitus

Abstract P3149: Effect Of SGLT2 Inhibitors On Atrial Fibrillation Susceptibility In Diabetic Mice

Background: Diabetes mellitus (DM) and heart failure (HF) are independent risk factors for atrial fibrillation (AF), the commonest clinical arrhythmia. A new class of drugs - sodium glucose cotransporter 2 inhibitors (SGLT2i) have beneficial effect in DM and HF and are now part of the guideline directed therapy for HF. However, conflicting evidence exists regarding their role and effect on cardiac arrhythmias including AF independent of their effect on HF and their exact mechanism(s) of action on the heart. Objective: Here we tested the effect of two commonly used SGLT2i on AF susceptibility in a type 2 DM (T2D) mouse model. Methods and Results: We used a T2D mouse model (high fat diet + low dose streptozocin) and a cohort of T2D mice were treated with SGLT2i - Empagliflozin (30mg/kg/d) or Dapagliflozin (5mg/kg/d) for 10 weeks in drinking water. We performed invasive electrophysiologic studies (EPS) to assess AF susceptibility by a rapid atrial burst pacing protocol in male mice aged 5 months at the time of EPS. T2D mice had increased AF susceptibility compared with non-diabetic littermate controls (normal chow diet + citrate buffer) [78% (14/18) vs. 28% (5/18), p &lt; 0.01]. T2D mice treated with Empagliflozin were protected from increased AF susceptibility (22% (3/18) [p &lt; 0.01]) while T2D mice treated with Dapagliflozin were not protected from increased AF susceptibility (58% (11/19) [p = 0.29]). Both Empagliflozin and Dapagliflozin treated T2D mice had normalization of their blood glucose levels to comparable levels with the non-diabetic control mice. T2D mice had mild LV dysfunction compared with non-diabetic controls (EF - 66% vs 81%, p &lt; 0.01) and treatment with either Empagliflozin or Dapagliflozin attenuated the degree of LV dysfunction (EF - 71% in both groups). Conclusion: Taken together, our data support the concept that SGLT2i decrease AF susceptibility in hyperglycemia primed AF, in addition to attenuating LV dysfunction in T2D. However, the effect on AF was only observed with Empagliflozin but not Dapagliflozin treatment independent of their effect on hyperglycemia and LV dysfunction. Further investigations are necessary to determine if there is a class effect of SGLT2i on AF susceptibility and the specific mechanisms of action modulating this effect.

Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes.

Sphingolipids are important biological mediators both in health and disease. We investigated the vascular effects of enhanced sphingomyelinase (SMase) activity in a mouse model of type 2 diabetes mellitus (T2DM) to gain an understanding of the signaling pathways involved. Myography was used to measure changes in the tone of the thoracic aorta after administration of 0.2 U/mL neutral SMase in the presence or absence of the thromboxane prostanoid (TP) receptor antagonist SQ 29,548 and the nitric oxide synthase (NOS) inhibitor L-NAME. In precontracted aortic segments of non-diabetic mice, SMase induced transient contraction and subsequent weak relaxation, whereas vessels of diabetic (Leprdb/Leprdb, referred to as db/db) mice showed marked relaxation. In the presence of the TP receptor antagonist, SMase induced enhanced relaxation in both groups, which was 3-fold stronger in the vessels of db/db mice as compared to controls and could not be abolished by ceramidase or sphingosine-kinase inhibitors. Co-administration of the NOS inhibitor L-NAME abolished vasorelaxation in both groups. Our results indicate dual vasoactive effects of SMase: TP-mediated vasoconstriction and NO-mediated vasorelaxation. Surprisingly, in spite of the general endothelial dysfunction in T2DM, the endothelial NOS-mediated vasorelaxant effect of SMase was markedly enhanced.

Feasibility and Acceptability of a Cognitive Training Study in Individuals with Type 2 Diabetes Mellitus

Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk of cognitive dysfunction. Growing evidence supports the use of cognitive training to target cognitive dysfunction in T2DM, but only limited evidence exists surrounding its feasibility and acceptability. The primary aim of this research is to determine the feasibility and acceptability of a cognitive training study in T2DM. Adults diagnosed with T2DM were randomly allocated to either a 6-week cognitive training group or a usual care control group. Feasibility outcomes (recruitment, adherence, retention, motivation, data collection, and intervention design) were evaluated using a traffic light progression criterion. Qualitative interviews were conducted to explore study acceptability. Cognition was measured at baseline and post-intervention. Forty-one participants completed the study (age 66 ± 9.8 years; HbA1c 54.0 ± 13.3 mmol.mol). Feasibility was shown in the adherence, retention, and motivation of participants, whilst minor amendments were proposed to the study design, recruitment, and data collection. Participants described cognitive training as highly enjoyable, with study components broadly reported as acceptable. Data signalled improvements in cognition, with large improvements observed in executive function. This study provides evidence for the potential feasibility, acceptability, and efficacy for cognitive training in T2DM. Recommendations for future studies are provided.

MP74-03 LONG-TERM ADMINISTRATION OF A PDE-5 INHIBITOR PREVENTS THE DEVELOPMENT OF BLADDER EPITHELIAL ATP INCREASE AND DECREASED DETRUSOR CONTRACTILITY IN TYPE 2 DIABETIC RATS

You have accessJournal of UrologyCME1 Apr 2023MP74-03 LONG-TERM ADMINISTRATION OF A PDE-5 INHIBITOR PREVENTS THE DEVELOPMENT OF BLADDER EPITHELIAL ATP INCREASE AND DECREASED DETRUSOR CONTRACTILITY IN TYPE 2 DIABETIC RATS Kabuto Takafumi, So Inamura, Hisato Kobayashi, Xinmin Zha, Keiko Nagase, Minekatsu Taga, Masaya Seki, Nobuki Tanaka, Yoshinaga Okumura, Osamu Yokoyama, and Naoki Tearada Kabuto TakafumiKabuto Takafumi More articles by this author , So InamuraSo Inamura More articles by this author , Hisato KobayashiHisato Kobayashi More articles by this author , Xinmin ZhaXinmin Zha More articles by this author , Keiko NagaseKeiko Nagase More articles by this author , Minekatsu TagaMinekatsu Taga More articles by this author , Masaya SekiMasaya Seki More articles by this author , Nobuki TanakaNobuki Tanaka More articles by this author , Yoshinaga OkumuraYoshinaga Okumura More articles by this author , Osamu YokoyamaOsamu Yokoyama More articles by this author , and Naoki TearadaNaoki Tearada More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003348.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We examined a series of pathological conditions of bladder wall in a type 2 diabetes mellitus (T2DM) model (Otsuka Long-Evans Tokushima Fatty [OLEFT] rats) and evaluated the effects of a long-term administration of the PDE-5 inhibitor tadalafil (TA) on these conditions. METHODS: Male OLETF and Long-Evans Tokushima Otsuka (LETO) rats were used as T2DM and control groups, respectively. TA was orally administered for 12 weeks (wks) from the age of 36 wks. Bladder blood flow and ATP, prostaglandin E2 (PGE2), and nerve growth factor (NGF) released from the bladder epithelium were measured at 36 and 48 wks of age. Vesicular nucleotide transporter (VNUT), hypoxia-inducible factor-1 alpha (HIF-1α), 8-hydroxy-2′-deoxyguanosine (HIF-1α), the oxidative stress marker 8-OHdG, and the mRNA and protein of pro-inflammatory cytokines and growth factors in the bladder wall were measured by RT-PCRs and ELISAs. Bladder strip contractions to KCl and carbachol were monitored in the OLETF rat bladder. RESULTS: The bladder blood flow in the OLETF rats was decreased at 48 wks compared to 36 wks. TA increased the bladder blood flow. Epithelial ATP was significantly increased in OLETF compared to LETO and decreased by TA in both LETO and OLETF. The bladder VNUT expression was significantly elevated in OLETF versus LETO at 36 wks; it was further enhanced at 48 wks, but a significant decrease occurred with TA in both rat strains. HIF-1α and 8-OHdG of OLETF were upregulated at 48 wks and decreased by TA. In OLETF, the expressions of IL-6, IL-8, bFGF, TNF-α, TGF-β, IGF-1, and IGF1R were increased at 48 wks versus 36 wks. TA decreased IL-6, TNF-α, IGF-1 and IGF1R. In OLETF, the contractile response of bladder strips to KCl and carbachol decreased at 48 wks versus 36 wks, but it recovered after TA administration. CONCLUSIONS: These data suggest that impaired bladder blood flow resulted in increased expressions of HIF-1α, 8-OhdG, and various pro-inflammatory cytokines and growth factors In T2DM. As a result, the bladder epithelial ATP release was enhanced, possibly via VNUT upregulation. A long-term administration of a PDE-5 inhibitor could prevent the development of storage and voiding dysfunction associated with T2DM. This study is the first to suggest that epithelium-derived ATP may be involved in urine storage dysfunction in T2DM and tadalafil inhibits ATP release and improves bladder contraction. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1069 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kabuto Takafumi More articles by this author So Inamura More articles by this author Hisato Kobayashi More articles by this author Xinmin Zha More articles by this author Keiko Nagase More articles by this author Minekatsu Taga More articles by this author Masaya Seki More articles by this author Nobuki Tanaka More articles by this author Yoshinaga Okumura More articles by this author Osamu Yokoyama More articles by this author Naoki Tearada More articles by this author Expand All Advertisement PDF downloadLoading ...

N6-methylation of RNA-bound adenosine regulator HNRNPC promotes vascular endothelial dysfunction in type 2 diabetes mellitus by activating the PSEN1-mediated Notch pathway

AimThe regulatory mechanism of m6A regulators in vascular endothelial function of type 2 diabetes mellitus (T2DM) remains largely unknown. We addressed this issue based on the data retrieved Gene Expression Omnibus (GEO) database and experimental validations. MethodsExpression of m6A methylation regulators was evaluated in T2DM samples of GSE76894 dataset and GSE156341 dataset. Further analysis of candidate m6A methylation regulators was conducted in the thoracic aorta of db/db mice and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs). Ectopic expression and depletion experiments were conducted to detect effects of m6A methylation regulators on vascular endothelial function in T2DM. ResultsIt emerged that three m6A methylation regulators (HNRNPC, RBM15B, and ZC3H13) were highly expressed in T2DM, which were related to vascular EC function, showing diagnostic values for T2DM. HNRNPC expression in the thoracic aorta of db/db mice was higher than that in heterozygous db mice, and HNRNPC expression in HG-induced HUVECs was upregulated when compared with normal glucose-exposed HUVECs. Furthermore, HNRNPC activated PSEN1-dependent Notch pathway to induce eNOS inactivation and NO production decrease, thereby causing vascular endothelial dysfunction in T2DM. ConclusionsHNRNPC impaired vascular endothelial function to enhance the development of vascular complications in T2DM through PSEN1-mediated Notch signaling pathway.

Alterations of Spontaneous Cortical and Subcortical Activity in Type 2 Diabetes Mellitus with and without Depression

Introduction: Type 2 diabetes mellitus (T2DM) patients with depression have a higher risk of complications and mortality than T2DM without depression. However, the exact neuropathophysiological mechanism remains unclear. Consequently, the current study aimed to investigate the alteration of cortical and subcortical spontaneous neural activity in T2DM patients with and without depression. Methods: The demographic data, clinical variables, neuropsychological tests, and functional and anatomical magnetic resonance imaging of depressed T2DM (n = 47) of non-depressed T2DM (n = 59) and healthy controls (n = 41) were collected and evaluated. The correlation analysis, stepwise multiple linear regression, and receiver operating characteristic curve were performed for further analysis. Results: Abnormal neural activities in the bilateral posterior cingulate cortex (PCC) and hippocampus were observed in depressed and non-depressed T2DM and the right putamen of the depressed T2DM. Interestingly, the subcortical degree centrality (DC) of the right hippocampus and putamen were higher in depressed than non-depressed T2DM. Furthermore, the cortical amplitude of low-frequency fluctuation (ALFF) in PCC, subcortical DC in the putamen of depressed T2DM, and hippocampus of non-depressed T2DM was correlated with cognitive scores. In contrast, the cortical fractional ALFF in PCC of non-depressed T2DM was correlated with depression scores. Conclusions: The abnormalities of spontaneous cortical activity in PCC and subcortical activity in the hippocampus might represent the neurobiological feature of cerebral dysfunction in T2DM. Notably, the altered subcortical activity in the right putamen might mainly associate with negative emotion in T2DM, which could be a promising biomarker for recognizing early cerebral dysfunction in depressed T2DM. This study provided a novel insight into the neuropathophysiological mechanism of brain dysfunction in T2DM with and without depression.

Role of chitotriosidase as inflammatory marker of endothelial dysfunction in type-2 diabetes mellitus

Role of chitotriosidase as inflammatory marker of endothelial dysfunction in type-2 diabetes mellitus

Quantitative Assessment of Pancreatic Fat by Quantitative CT in Type 2 Diabetes Mellitus.

To characterize the pancreatic fat deposition (PFD) in patients with type 2 diabetes mellitus (T2DM) by quantitative computed tomography (QCT) and investigate the relationship between PFD and clinical metabolic parameters and islet function. A total of 150 patients with T2DM and 93 age-matched healthy subjects underwent QCT to quantify PFD were included. PFD and various biochemical parameters were correlated by statistical methods and multiple stepwise linear regression modeling. PFD measured by QCT in the T2DM group was statistically higher than that in the healthy control group, and the pancreatic CT value was statistically lower than that in the control group. The QCT measured PFD was negatively correlated with the pancreatic CT values (P < 0.001), and positively correlated with triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), visceral fat area (VAT) and insulin resistance index (HOMA-IR) (P < 0.05) in the T2DM patients. Multiple stepwise linear regression analysis identified PFD as the dependent variable factor for T2DM. This study suggests QCT as a reliable technique in measuring PFD in T2DM. High PFD is positively correlated with the degree of insulin resistance and may play an important role in islet cell dysfunction in T2DM.

Cdc42 upregulation under high glucose induces podocyte apoptosis and impairs β-cell insulin secretion.

ObjectivesThe progressive impairment of β-cell function results in prolonged deterioration in patients with type 2 diabetes mellitus (T2DM). Interestingly, the finding on pancreatitis secondary to renal injury suggests that potential communication exists between kidney and pancreas. Therefore, we aimed to investigate cell division cycle 42 (Cdc42)-mediated podocyte apoptosis and its effect on insulin secretion in islet β-cells.MethodsType 2 diabetic nephropathy mouse models were established to identify the expression of Cdc42 in podocytes by immunohistochemistry. An in vitro co-culture of mouse podocyte MPC5 and β-TC6 cells was preliminarily established. Subsequently, podocyte apoptosis induced by high glucose and Cdc42 was detected by TUNEL staining and western blotting. In addition, the JNK pathway was examined to determine the mechanism of apoptosis in MPC5 cells. Finally, insulin secretion and expression in β-TC6 cells as well as malondialdehyde (MDA) and superoxide dismutase (SOD) levels in both cell types were examined after the regulation of Cdc42 in MPC5 cells.ResultsCdc42 was highly expressed in the podocytes of diabetic nephropathy mice. Exposure to 25 mM glucose for 48 h induced a significant upregulation of Cdc42, Bax, and cleaved caspase-3 as well as a decreased Bcl-2 expression. In addition, marked apoptosis of MPC5 cells was observed compared to normal glucose treatment. After transfection with Cdc42 plasmid, apoptosis of MPC5 cells was enhanced with an increased expression of p-JNK, whereas inhibition of Cdc42 significantly alleviated podocyte apoptosis accompanied by a downregulation of p-JNK. The glucose-stimulated insulin secretion level of β-TC6 cells decreased after the upregulation of Cdc42 in MPC5 cells. Immunofluorescence staining for insulin showed that co-culture with MPC5 cells carrying the Cdc42 plasmid significantly reduced insulin expression, whereas inhibition of Cdc42 in MPC5 cells alleviated the above-mentioned abnormality of β-TC6 cells. The expression of Cdc42 and p-p38 in β-TC6 cells increased following the upregulation of Cdc42 in MPC5 cells; this was concurrent with augmented MDA levels and decreased SOD activity. The opposite result was observed for Cdc42 knockdown in MPC5 cells.ConclusionsCdc42 in podocytes plays a crucial role in insulin secretion by β-cells, which may provide a new therapeutic target to prevent the vicious cycle of β-cell dysfunction in T2DM.

Functional near-infrared spectroscopy of prefrontal cortex during memory encoding and recall in elderly with type 2 diabetes mellitus.

Low-frequency Fahræus-Lindqvist-driven oscillations in the small vessels are crucial because oscillations in small vessels support nutrient supply. Understanding of this is critical in type 2 diabetes mellitus (T2DM) to develop therapeutic measures in order to prevent Alzheimer's Disease Related Dementias. Indeed, vascular factors are known to contribute to cerebrovascular disease as well as mild cognitive impairment and dementia, which are predicted to affect 152 million people by 2050 (Alzheimer's Disease International London, UK, 2019). In this clinical study, we performed functional near-infrared spectroscopy (fNIRS) of the forehead to investigate the effect of the Mini-Cog with three-item recall test on the prefrontal cortex (PFC) activation and the relative oscillatory power in the 0.01-0.02-Hz (FahræΣus-Lindqvist effect) and 0.021-0.052 Hz (smooth muscle autonomic innervation) frequency bands in elderly (60 years and older) T2DM and age-matched controls. We found a significant (p<0.01) difference in the PFC activation between elderly subjects with T2DM and age-matched elderly controls. Moreover, power spectral density (PSD) analysis revealed a significantly lower relative power in 0.021-0.052 Hz (smooth muscle autonomic innervation) frequency band in elderly subjects with T2DM during the Mini-Cog three-item recall test. Furthermore, a drop in the oscillatory power in the 0.01-0.02 Hz frequency band during Mini-Cog three-item recall test was found more pronounced in the elderly subjects with T2DM. Therefore, our study highlighted portable brain imaging to capture cerebrovascular reactivity to cognitive load that may provide a biomarker of cerebrovascular dysfunction in T2DM. Clinical Relevance-Our study establishes forehead portable brain imaging under cognitive load for monitoring cerebrovascular function in T2DM.

Monocyte to High-Density Lipoprotein Cholesterol Ratio Is Associated with Subclinical Left Cardiac Remodeling and Dysfunction in Type 2 Diabetes Mellitus

Chronic inflammation is involved in the development of heart failure (HF) in type 2 diabetes mellitus (T2DM). However, reliable and easily accessible biomarker of subclinical left cardiac remodeling and dysfunction remains a challenge.Overall, 1020 patients with T2DM without overt HF were enrolled from May 2019 to April 2020. Monocyte to high-density lipoprotein ratio (MHR) was calculated by blood monocyte count divided by high-density lipoprotein cholesterol. Left cardiac structure and function were assessed using transthoracic echocardiography. Univariate and multivariate linear regression analyses were used to estimate the association of MHR (Lg transferred) with echocardiographic parameters. We found that septal wall thickness (SWT), left ventricular internal end-diastole dimension (LVIDd), and left ventricular mass index (LVMI) raised with increasing MHR (P = 0.002 for SWT, P < 0.001 for LVIDd, and P = 0.001 for LVMI). Declined trends were shown in ejection fraction (EF) (P = 0.016), E velocity (P = 0.037), E/A ratio (P = 0.009), and tissue Doppler e' (P < 0.001), and elevating trend was observed in E/e' (P < 0.001). In multivariate regression analysis, MHR (Lg transferred) was positively associated with LVIDd (β = 0.031; P = 0.016), LVMI (β = 0.073; P = 0.014), and E/e' (β = 0.331; P < 0.001), whereas it was negatively associated with EF (β = -0.086; P = 0.007), E/A (β = -0.072; P = 0.009), and e' (β = -0.332; P < 0.001).MHR could be a practical biomarker for indicating subclinical cardiac remodeling and dysfunction in T2DM, due to low cost and easy availability.

Taste dysfunction in type 2 diabetes mellitus patients with autonomic neuropathy and its relation with HbA1C level and disease duration

Background: Type 2 diabetes mellitus (T2DM) is a multifactorial, complex disease associated with chronic hyperglycemia, resulting from the interplay of genetic, environmental, and epigenetic factors. T2DM can causes various disabling complications. Diabetic autonomic neuropathy (DAN) is one of the common complications in diabetes. The taste threshold affected by various factors such as age, ethnic backgrounds, drugs, local and systemic diseases, consumption of alcohol, smoking, and tobacco chewing.Method: The present study is undertaken with the objectives to compare the taste dysfunction of four primary sensations in Type 2 DM with autonomic neuropathy and its relation with glycemic control. The 60 patients of T2DM with autonomic neuropathy and 60 healthy controls were taken for the study. Autonomic neuropathy was assessed clinically. Chemical taste test using four solutions of basic tastes (sweet, sour, salty, bitter) were done.Results: Taste dysfunction for sweet was significant in T2DM with uncontrolled hyperglycemia. The taste dysfunction in T2DM patients was not related to gender, disease duration, and type of treatment taken. The study found a significant correlation between taste dysfunction, HbA1C level and blood sugar fasting level in T2DM patients.Conclusions: The taste dysfunction was mainly for sweet. Sour and bitter did not show any difference in case groups compared to controls.

IGF-1 ameliorates streptozotocin-induced pancreatic β cell dysfunction and apoptosis via activating IRS1/PI3K/Akt/FOXO1 pathway.

Type 2 diabetes mellitus (T2DM) is an endocrine disorder with pancreatic β cell dysfunction and/or reduced insulin sensitivity. IGF-1 is critically involved in pancreatic β cell growth, differentiation, and insulin secretion. Insulin-mediated IRS1/PI3K/Akt/FOXO1 signaling has been proved to be closely associated with pancreatic β cell function, hepatic glucose metabolism, and the development of T2DM. This present work was designed to demonstrate the protective role of IGF-1 against pancreatic β cell dysfunction and to probe into the underlying mechanisms. Herein, cell viability, cell apoptosis, insulin secretion, oxidative stress, and glycolysis in STZ-treated INS-1 cells were measured, so as to determine the biological function of IGF-1 against pancreatic β cell dysfunction in T2DM. Additionally, whether IGF-1 could activate IRS1/PI3K/Akt/FOXO1 signaling pathway to manipulate the progression of T2DM was also investigated. It was discovered that IGF-1 treatment enhanced the viability and suppressed the apoptosis of STZ-treated INS-1 cells. Besides, IGF-1 treatment augmented insulin secretion of INS-1 cells in response to STZ. Moreover, IGF-1 exerted protective role against oxidative damage and displayed inhibitory effect on glycolysis in STZ-treated INS-1 cells. Mechanistically, IGF-1 treatment markedly boosted the activation of IRS1/PI3K/Akt/FOXO1 pathway. Furthermore, treatment with AG1024 (an inhibitor of IGF-1R) partially abolished the actions of IGF-1 on cell viability, cell apoptosis, insulin secretion, oxidative stress, and glycolysis in STZ-treated INS-1 cells. To conclude, IGF-1 could improve the viability and inhibit the apoptosis of STZ-treated pancreatic β cells, induce insulin secretion, alleviate oxidative damage, as well as arrest glycolysis by activating IRS1/PI3K/Akt/FOXO1 pathway.

Huang-Lian-Jie-Du decoction attenuates cognitive dysfunction of rats with type 2 diabetes by regulating autophagy and NLRP3 inflammasome activation

Ethnopharmacological relevanceHuang-Lian-Jie-Du decoction (HLJDD) is a traditional Chinese formula that is efficacious in treating diabetes mellitus, Alzheimer's disease, and diabetic encephalopathy; the underlying mechanisms of HLJDD in diabetes-associated cognitive dysfunction remain unclear. Aim of the studyThis study investigated the neuroprotective effects of HLJDD on cognitive function, and the possible underlying mechanisms in type 2 diabetes mellitus (T2DM) in a rat model of cognitive impairment. Materials and methodsTwelve active ingredients in HLJDD were detected using high-performance liquid chromatography analysis. An animal model of cognitive dysfunction in T2DM was induced via a high-sugar and high-fat diet combined with a low dose of streptozotocin. Sprague-Dawley rats were randomly divided into six groups: control, T2DM, metformin (0.34 g/kg/day), and HLJDD groups (3, 1.5, and 0.75 g/kg/day). All treatments were intragastrically administrated for nine continuous weeks after the development of T2DM. Body weight, food and water intake, fasting blood glucose, insulin sensitivity, and blood lipid levels were measured. Spatial learning and memory of the rats were assessed using the Morris water maze test. Hematoxylin and eosin and Nissl staining were performed to evaluate neuronal morphology and vitality. Glutathione, malondialdehyde, and superoxide dismutase levels were measured to determine the level of oxidative stress in the hippocampus. Transmission electron microscopy was performed to observe the synaptic morphology and structure of hippocampal neurons. IL-1β levels in the hippocampus and cerebrospinal fluid were determined. The protein expression of NLRP3, cleaved caspase-1, mature IL-1β, ATG7, P62, LC3, and brain-derived neurotrophic factor (BDNF) was determined using western blotting and immunofluorescence analysis. ResultsHLJDD attenuated cognitive dysfunction in rats with T2DM as shown by the decreased escape latency, increased times crossing the platform and time spent in the target quadrant in the Morris water maze test (P < 0.05), improvement in hippocampal histopathological changes, and an elevated level of cell vitality. HLJDD treatment also reduced blood glucose and lipid levels, ameliorated oxidative stress, and downregulated IL-1β expression in the hippocampus and cerebrospinal fluid (P < 0.05). Moreover, HLJDD enhanced BDNF, ATG7, and LC3 protein expression and significantly inhibited the expression of P62, NLRP3, cleaved caspase-1, and mature IL-1β in the hippocampal CA1 region (P < 0.05). Immunofluorescence results further confirmed that the fluorescence intensity of NLRP3 and P62 in the hippocampus decreased after HLJDD intervention (P < 0.05). ConclusionsHLJDD ameliorated cognitive dysfunction in T2DM rats. The neuroprotective effect is exerted via the modulation of glucose and lipid metabolism, upregulation of autophagy, and inhibition of NLRP3 inflammasome signaling pathway.

Heart Rate Variability measured during rest and after orthostatic challenge to detect autonomic dysfunction in Type 2 Diabetes Mellitus using the Classification and Regression Tree model.

According to the World Health Organization, one in ten adults will have Type 2 Diabetes Mellitus (T2DM) in the next few years. Autonomic dysfunction is one of the significant complications of T2DM. Autonomic dysfunction is usually assessed by standard Ewing's test and resting Heart Rate Variability (HRV) indices. Resting HRV has limited use in screening due to its large intra and inter-individual variations. Therefore, a combined approach of resting and orthostatic challenge HRV measurement with a machine learning technique was used in the present study. A total of 213 subjects of both genders between 20 to 70 years of age participated in this study from March 2018 to December 2019 at Smt. Kashibai Navale Medical College and General Hospital (SKNMCGH) in Pune, India. The volunteers were categorized according to their glycemic status as control (n= 51 Euglycemic) and T2DM (n= 162). The short-term ECG signal in the resting and after an orthostatic challenge was recorded. The HRV indices were extracted from the ECG signal as per HRV-Taskforce guidelines. We observed a significant difference in time, frequency, and non-linear resting HRV indices between the control and T2DM groups. A blunted autonomic response to an orthostatic challenge quantified by percentage difference was observed in T2DM compared to the control group. HRV patterns during rest and the orthostatic challenge were extracted by various machine learning algorithms. The Classification and Regression Tree (CART) model has shown better performance among all the machine learning algorithms. It has shown an accuracy of 84.04%, the sensitivity of 89.51%, a specificity of 66.67%, with an Area Under Receiver Operating Characteristic Curve (AUC) of 0.78 compared to resting HRV alone with 75.12% accuracy, 86.42% sensitivity, 39.22% specificity, with an AUC of 0.63 for differentiating autonomic dysfunction in non-diabetic control and T2DM. It was possible to develop a Classification and Regression Tree (CART) model to detect autonomic dysfunction. The technique of percentage difference between resting and orthostatic challenge HRV indicates the blunted autonomic response. The developed CART model can differentiate the autonomic dysfunction using both resting and orthostatic challenge HRV data compared to only resting HRV data in T2DM. Thus, monitoring HRV parameters using the CART model during rest and after orthostatic challenge may be a better alternative to detect autonomic dysfunction in T2DM as against only resting HRV.

A systematic review on the prevalence and management of subclinical hypothyroidism in patients with Type 2 Diabetes Mellitus

Background: Subclinical hypothyroidism (SCH) remains one of the most common biochemical manifestations of thyroid dysfunction.1 Similarly, type 2 diabetes mellitus (T2DM) is considered the most common metabolic disorder in clinical practice.2Methods: This is a systematic review to ascertain the prevalence and optimum management approach for thyroid dysfunction in patients with T2DM. We conducted a search on PubMed and Google scholar (Figure 1) for articles published between 2010-2020 using the following keywords: subclinical hypothyroidism, type 2 diabetes mellitus, thyroid diseases, diabetic retinopathy, diabetic nephropathy, and diabetic complications. Results: The prevalence of SCH in T2DM patients ranges from 7.8% to 23 % (average around 13.4%). In comparison, the prevalence of SCH in the general population ranges from 6% to 10%. SCH has a higher prevalence in females, older age &gt;60 years old, long duration of T2DM, positive thyroid autoantibodies, glycated hemoglobin (Hba1c) 8%, and obese patients (risk factors).3 The prevalence of SCH in patients with diabetic retinopathy (DR) ranges from 17.3% to 43.3%. Also, the prevalence of SCH among patients with diabetic nephropathy (DN) ranges from 18.1% to 36%. Screening for thyroid dysfunction in T2DM at diagnosis is recommended and justified (Table 1). If patients with SCH have a risk of cardiovascular disease (CVD), DR, DN, symptomatic, presence of goiter, pregnant women, and continuous sustained increases of thyroid-stimulating hormone (TSH) on follow-up, it is recommended to start low dose levothyroxine which improves morbidity. Conclusion: The prevalence of SCH is relatively high in T2DM patients. This supports routine screening of such patients for thyroid dysfunction especially in patients with risk factors and diabetic complications (DR, DN), and consideration of thyroxine replacement wherever warranted although more evidence from randomized controlled trials is needed to explore the possible causal relationships.