Association of blood groups/Rh and diabetes mellitus in Karachi city, Pakistan / Associação de grupos sanguíneos/Rh e diabetes mellitus na cidade de Karchi, Paquistão

Abstract The main purpose of this study was to find out a possible association between ABO blood groups or Rh and diabetes mellitus (DM) in the local population of eight (8) different towns of Karachi, Pakistan. For this purpose a survey was carried out in Karachi to have a practical observation of these towns during the period of 9 months from June 2019 to Feb. 2020. Out of eighteen (18) towns of Karachi, samples (N= 584) were collected from only eight (8) Towns of Karachi and gave a code-number to each town. Diabetic group sample was (n1=432) & pre-diabetes sample was (n2 =152). A standard Abbot Company Glucometer for Random Blood Sugar (RBS) and Fasting Blood Sugar (FBS) tests, standard blood anti sera were used for ABO/Rh blood type. Health assessment techniques were performed ethically by taking informed consent from all registered subjects. Finally data was analyzed by SPSS version 20.0. In our current study, the comparison of ABO blood groups frequencies between diabetic and pre-diabetic individuals were carried out. The percentage values of blood Group-B as given as: (32% in DM vs. 31% in pre-diabetics), followed by blood Group-O as: (18% in DM vs. 11% in pre-diabetics). Contrary to Group-"B" & "O", blood Group-A and Group-AB were distribution percentage higher pre-diabetic as compared to DM patients, as given as: Group-A (32% in pre-diabetics vs. 26% in DM) & Group-AB (26% in pre-diabetics vs. 24% in diabetic's patients). In addition, percentage distribution of Rh system was also calculated, in which Rh+ve Group was high and more common in DM patients as compared to pre-diabetics; numerically given as: Rh+ve Group (80% in DM vs. 72% in pre-diabetics). Different views and dimensions of the research topic were studied through literature support, some have found no any association and some established a positive association still some were not clear in making a solid conclusion. It is concluded that DM has a positive correlation with ABO blood groups, and people with Group-B have increased susceptibility to DM disease.

Resumo O objetivo principal deste estudo foi descobrir uma possível associação entre grupos sanguíneos ABO ou Rh e diabetes mellitus (DM) na população local de oito (8) diferentes cidades de Karachi, Paquistão. Para tanto, foi realizado um levantamento em Karachi para observação prática dessas cidades durante o período de 9 meses de junho de 2019 a fevereiro de 2020.De dezoito (18) cidades de Karachi, as amostras (N = 584) foram coletadas de apenas oito (8) cidades de Karachi e deram um número-código para cada cidade. A amostra do grupo de diabéticos foi (n1 = 432) e a amostra de pré-diabetes foi (n2 = 152). Um glicômetro padrão da Abbot Company para testes de açúcar no sangue aleatório (RBS) e açúcar no sangue em jejum (FBS), antissoros de sangue padrão foram usados ​​para o tipo de sangue ABO / Rh. As técnicas de avaliação de saúde foram realizadas de forma ética, tomando o consentimento informado de todos os indivíduos registrados. Finalmente, os dados foram analisados ​​pelo SPSS versão 20.0.No presente estudo, foi realizada a comparação das frequências dos grupos sanguíneos ABO entre diabéticos e pré-diabéticos. Os valores percentuais do sangue do Grupo-B são dados como: (32% em DM vs. 31% em pré-diabéticos), seguido pelo sangue do Grupo-O como: (18% em DM vs. 11% em pré-diabéticos). Ao contrário dos Grupos "B" e "O", sangue do Grupo-A e Grupo-AB tiveram distribuição percentual maior de pré-diabéticos em comparação com pacientes com DM, dado como: Grupo-A (32% em pré-diabéticos vs. 26% em DM) e Grupo AB (26% em pré-diabéticos vs. 24% em pacientes diabéticos). Além disso, também foi calculada a distribuição percentual do sistema Rh, no qual o Grupo Rh + ve foi elevado e mais comum em pacientes com DM em comparação aos pré-diabéticos; dados numericamente como: Grupo Rh + ve (80% em DM vs. 72% em pré-diabéticos). Diferentes visões e dimensões do tema de pesquisa foram estudadas com o suporte da literatura, alguns não encontraram nenhuma associação e alguns estabeleceram uma associação positiva, embora alguns não estivessem claros em fazer uma conclusão sólida. Conclui-se que o DM tem correlação positiva com os grupos sanguíneos ABO, e as pessoas com o Grupo B têm maior suscetibilidade à doença DM.

Antidiabetic and hepato-renal protective effects of medicinal plants in STZ induced diabetic rats / Efeitos antidiabéticos e hepatorrenais de plantas medicinais em ratos diabéticos induzidos por STZ

The antidiabetic and hepato-renal protective effects of Citrullus colocynthis and Momordica charantia ethanol extracts were investigated in streptozotocin (STZ) induced diabetic male albino rats. Diabetic rats were treated with C. colocynthis, M. charantia or C. colocynthis + M. charantia mixed extract at a dose of 250 mg /kg body weight per oral per day for 21 days. The mean body weight of all the diabetic rat groups on day 1 of treatment (day 10 of diabetes) was significantly lower than the normal control rat group (P<0.05). The blood glucose level of all the diabetic rat groups on day 1 of treatment (day 10 of diabetes) was significantly (P<0.05) higher (> 200 mg/dl) than the normal control rat group (95.5 ± 2.7). At the end of treatment (day 21), the diabetic rats treated with plant extracts showed significant increase (P<0.05) in body weight and significant (P<0.05) reduction in blood glucose level when compared to diabetic control animals. Significant increase (< 0.05) was observed in the serum bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), urea and creatinine levels of diabetic control rat group. The serum levels of these liver and kidney-related parameters of diabetic rats treated with plant extract were significantly lower when compared to diabetic control rat group (p < 0.05). Photomicrographs of liver and kidney microsections from diabetic rats treated with these plant extracts showed amelioration in the hepato-renal histoarchitectures. It was concluded that the C. colocynthis and M. charantia methanol extracts are antidiabetic and hepato-renal protective in STZ induced diabetic male rats. Treatment of the diabetic rats with C. colocynthis + M. charantia mixed extract is more effective in the amelioration of diabetes and hepato-renal injuries in STZ induced diabetic male rats.

Os efeitos protetores antidiabéticos e hepatorrenais dos extratos etanólicos de Citrullus colocynthis e Momordica charantia foram investigados em ratos albinos machos diabéticos induzidos por estreptozotocina (STZ). Ratos diabéticos foram tratados com extrato misto de C. colocynthis, M. charantia ou C. colocynthis + M. charantia na dose de 250 mg/kg de peso corporal por via oral por dia durante 21 dias. O peso corporal médio de todos os grupos de ratos diabéticos no dia 1 de tratamento (dia 10 de diabetes) foi significativamente menor do que o grupo de ratos controle normal (P < 0,05). O nível de glicose no sangue de todos os grupos de ratos diabéticos no dia 1 de tratamento (dia 10 de diabetes) foi significativamente (P < 0,05) maior (> 200 mg/dl) do que o grupo de ratos controle normal (95,5 ± 2,7). Ao final do tratamento (dia 21), os ratos diabéticos tratados com extratos vegetais apresentaram aumento significativo (P < 0,05) no peso corporal e redução significativa (P < 0,05) na glicemia quando comparados aos animais controle diabéticos. Aumento significativo (< 0,05) foi observado nos níveis séricos de bilirrubina, alanina transaminase (ALT), aspartato transaminase (AST), fosfatase alcalina (ALP), ureia e creatinina do grupo controle diabético. Os níveis séricos desses parâmetros hepáticos e renais de ratos diabéticos tratados com extrato vegetal foram significativamente menores quando comparados ao grupo controle de ratos diabéticos (p < 0,05). Fotomicrografias de microseções de fígado e rim de ratos diabéticos tratados com esses extratos vegetais mostraram melhora nas histoarquiteturas hepatorrenais. Concluiu-se que os extratos metanólicos de C. colocynthis e M. charantia são antidiabéticos e hepatorrenais protetores em ratos machos diabéticos induzidos por STZ. O tratamento de ratos diabéticos com extrato misto de C. colocynthis + M. charantia é mais eficaz na melhora do diabetes e lesões hepatorrenais em ratos machos diabéticos induzidos por STZ.

Synthesis and evaluation of 2-phenylamino-1, 4-naphthoquinones derivatives as potential hypoglycaemic agents / Síntese e avaliação de derivados de 2-fenilamino-1, 4-naftoquinonas como potenciais agentes hipoglicemiantes

Due to the severe side effects revealed by most of the currently used antidiabetic medicines, search for finding new and safe drugs to manage diabetes is continued. Naphthoquinones possessing strong antioxidant properties have been employed as candidates for diabetes therapy. Present study is aimed at finding the antioxidant and hypoglycaemic potential of some novel derivatives of 2-phenylamino-1,4-naphthoquinones (PAN) including chloro, nitro, methyl and bromo (5a-d) derivatives synthesized by single pot experiment. Product crystals were purified by TLC and characterized by FT-IR. The antioxidant potential of the compounds was assayed through DPPH radical scavenging and reducing power activities noted as UV-vis. absorbance. The DPPH assay has showed the powerful antioxidant activity of nitro and bromo derivatives, while the nitro derivative showed the significant reduction potential towards FRAP assay. Hypoglycaemic potential of the compounds was studied in rat animal model. All synthesized compounds revealed better hypoglycaemic activity; however, the chloro-derivative exhibited the more potent hypoglycaemic activity showing about 43% reduction in the mean blood glucose levels of the treated animals. As the bioreduction of naphthoquinones may be influenced by changing its redox properties, it has been noticed that the e-donating resonance effect (+R) of 'chloro' group has shown the significant effects on biological activity through stabalization of its imine form which limits the potential of generation of free radicals during bioreduction of quinones and thus has been proposed as the reason of its hypoglycaemic activity. Future studies employing the properties of e-donating groups of PAN may optimize the drug-receptor interaction for better drug designing and drug development strategies against diabetes and also for the clinical trials.

Em razão dos graves efeitos colaterais causados pela maioria dos medicamentos antidiabéticos atualmente utilizados, continua a busca por novos medicamentos seguros para o controle do diabetes. As naftoquinonas, que possuem fortes propriedades antioxidantes, têm sido empregadas como candidatas à terapia do diabetes. O presente estudo visa encontrar o potencial antioxidante e hipoglicemiante de alguns novos derivados de 2-fenilamino-1,4-naftoquinonas (PAN), incluindo derivados de cloro, nitro, metil e bromo (5a-d) sintetizados por experimento em pote único. Os cristais do produto foram purificados por TLC e caracterizados por FT-IR. O potencial antioxidante dos compostos foi testado por meio de atividades de sequestro de radicais DPPH e redução de energia observada como absorção no UV-vis. O ensaio DPPH mostrou a poderosa atividade antioxidante dos derivados nitro e bromo, enquanto o derivado nitro mostrou o potencial de redução significativo para o ensaio FRAP. O potencial hipoglicêmico dos compostos foi estudado em modelo animal de rato. Todos os compostos sintetizados revelaram melhor atividade hipoglicemiante; no entanto, o derivado cloro apresentou atividade hipoglicêmica mais potente, com redução de 43% nos níveis médios de glicose no sangue dos animais tratados. Como a biorredução de naftoquinonas pode ser influenciada pela alteração de suas propriedades redox, notou-se que o efeito da doação eletrônica por ressonância (+R) do grupo "cloro" tem sido significativo na atividade biológica por meio da estabilização de sua forma imina, que limita o potencial de geração de radicais livres durante a biorredução de quinonas, e, portanto, tem sido proposto como a razão de sua atividade hipoglicemiante. Estudos futuros empregando as propriedades de grupos de doação eletrônica de PAN podem otimizar a interação droga-receptor para melhor planejamento de medicamentos e estratégias de desenvolvimento de medicamentos contra o diabetes e também para os ensaios clínicos.

Ginsenoside Rg3 has effects comparable to those of ginsenoside re on diabetic kidney disease prevention in db/db mice by regulating inflammation, fibrosis and PPARγ.

Ginsenoside Rg3 (Rg3) is an adjuvant antitumor drug, while ginsenoside Re (Re) is an adjuvant antidiabetic drug. Our previous studies demonstrated that Rg3 and Re both have hepatoprotective effects in db/db mice. The present study aimed to observe the renoprotective effects of Rg3 on db/db mice, with Re as the control. The db/db mice were randomly assigned to receive daily oral treatment with Rg3, Re or vehicle for 8 weeks. Body weight and blood glucose were examined weekly. Blood lipids, creatinine, and BUN were examined by biochemical assay. Hematoxylin and eosin and Masson staining were used for pathological examination. The expression of peroxisome proliferator­activated receptor gamma (PPARγ) and inflammation and fibrosis biomarkers was examined by immunohistochemical and reverse transcription­quantitative PCR. Although neither had a significant effect on body weight, blood glucose or lipids, Rg3 and Re were both able to decrease the creatinine and blood urea nitrogen levels of db/db mice to levels similar to those of wild type mice and inhibit pathological changes. The expression of PPARγ was upregulated and biomarkers of inflammation and fibrosis were downregulated by Rg3 and Re. The results showed that the potential of Rg3 as a preventive treatment of diabetic kidney disease was similar to that of Re.

Factors associated with severity and anatomical distribution of diabetic foot ulcer in Uganda: a multicenter cross-sectional study.

BACKGROUND: Diabetic foot ulcer (DFU) is a devastating complication of diabetes mellitus (DM) that is associated with increased mortality, morbidity, amputation rate and economic burden. This study aimed at identifying the anatomical distribution and factors associated with severity of DFU in Uganda. METHODOLOGY: This was a multicenter cross-sectional study conducted in seven selected referral hospitals in Uganda. A total of 117 patients with DFU were enrolled in this study between November 2021 and January 2022. Descriptive analysis and modified Poisson regression analysis were performed at 95% confidence interval; factors with p-value < 0.2 at bivariate analysis were considered for multivariate analysis. RESULTS: The right foot was affected in 47.9% (n = 56) of patients, 44.4% (n = 52) had the DFU on the plantar region of the foot and 47.9% (n = 56) had an ulcer of > 5 cm in diameter. The majority (50.4%, n = 59) of patients had one ulcer. 59.8% (n = 69) had severe DFU, 61.5% (n = 72) were female and 76.9% had uncontrolled blood sugar. The mean age in years was 57.5 (standard deviation 15.2 years). Primary (p = 0.011) and secondary (p < 0.001) school educational levels, moderate (p = 0.003) and severe visual loss (p = 0.011), 2 ulcers on one foot (p = 0.011), and eating vegetables regularly were protective against developing severe DFU (p = 0.03). Severity of DFU was 3.4 and 2.7 times more prevalent in patients with mild and moderate neuropathies (p < 0.01), respectively. Also, severity was 1.5 and 2.5 higher in patients with DFU of 5-10 cm (p = 0.047) and in those with > 10 cm diameter (p = 0.002), respectively. CONCLUSION: Most DFU were located on the right foot and on the plantar region of the foot. The anatomical location was not associated with DFU severity. Neuropathies and ulcers of > 5 cm diameter were associated with severe DFU but primary and secondary school education level and eating vegetables were protective. Early management of the precipitating factors is important to reduce the burden of DFU.

Placental Mesenchymal Stem Cells Alleviate Podocyte Injury in Diabetic Kidney Disease by Modulating Mitophagy via the SIRT1-PGC-1alpha-TFAM Pathway.

The use of mesenchymal stem cells (MSCs) has become a new strategy for treating diabetic kidney disease (DKD). However, the role of placenta derived mesenchymal stem cells (P-MSCs) in DKD remains unclear. This study aims to investigate the therapeutic application and molecular mechanism of P-MSCs on DKD from the perspective of podocyte injury and PINK1/Parkin-mediated mitophagy at the animal, cellular, and molecular levels. Western blotting, reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to detect the expression of podocyte injury-related markers and mitophagy-related markers, SIRT1, PGC-1α, and TFAM. Knockdown, overexpression, and rescue experiments were performed to verify the underlying mechanism of P-MSCs in DKD. Mitochondrial function was detected by flow cytometry. The structure of autophagosomes and mitochondria were observed by electron microscopy. Furthermore, we constructed a streptozotocin-induced DKD rat model and injected P-MSCs into DKD rats. Results showed that as compared with the control group, exposing podocytes to high-glucose conditions aggravated podocyte injury, represented by a decreased expression of Podocin along with increased expression of Desmin, and inhibited PINK1/Parkin-mediated mitophagy, manifested as a decreased expression of Beclin1, the LC3II/LC3I ratio, Parkin, and PINK1 associated with an increased expression of P62. Importantly, these indicators were reversed by P-MSCs. In addition, P-MSCs protected the structure and function of autophagosomes and mitochondria. P-MSCs increased mitochondrial membrane potential and ATP content and decreased the accumulation of reactive oxygen species. Mechanistically, P-MSCs alleviated podocyte injury and mitophagy inhibition by enhancing the expression of the SIRT1-PGC-1α-TFAM pathway. Finally, we injected P-MSCs into streptozotocin-induced DKD rats. The results revealed that the application of P-MSCs largely reversed the markers related to podocyte injury and mitophagy and significantly increased the expression of SIRT1, PGC-1α, and TFAM compared with the DKD group. In conclusion, P-MSCs ameliorated podocyte injury and PINK1/Parkin-mediated mitophagy inhibition in DKD by activating the SIRT1-PGC-1α-TFAM pathway.

CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes.

In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on diabetic cardiomyopathy (DCM), as the spontaneous cardiac dysfunction, cardiac cell hypertrophy, and cardiac fibrosis occurred in DICAR deficiency (DICAR+/-) mice, whereas the DCM was alleviated in DICAR-overexpressed DICARTg mice. At the cellular level, we found that overexpression of DICAR inhibited, but knockdown of DICAR enhanced the diabetic cardiomyocyte pyroptosis. At the molecular level, we identified that DICAR-VCP-Med12 degradation could be the underlying molecular mechanism in DICAR-mediated effects. The synthesized DICAR junction part (DICAR-JP) exhibited a similar effect to the entire DICAR. In addition, the expression of DICAR in circulating blood cells and plasma from diabetic patients was lower than that from health controls, which was consistent with the decreased DICAR expression in diabetic hearts. DICAR and the synthesized DICAR-JP may be drug candidates for DCM.

E2F2 Promotes Wound Healing of Diabetic Foot Ulcer by Regulating CDCA7L Transcription.

OBJECTIVE: The E2F2 transcription factor can accelerate cell proliferation and wound healing. However, its mechanism of action in a diabetic foot ulcer (DFU) remains unclear. Therefore, this study explores the influence of E2F2 on wound healing in DFU by examining cell division cycle-associated 7-like (CDCA7L) expression. METHODS: CDCA7L and E2F2 expression in DFU tissues were analyzed with databases. CDCA7L and E2F2 expression were altered in human umbilical vein endothelial cells (HUVECs) and spontaneously transformed human keratinocyte cell culture (HaCaT) cells. Cell viability, migration, colony formation, and angiogenesis were evaluated. Binding of E2F2 to the CDCA7L promoter was examined. Subsequently, a diabetes mellitus (DM) mouse model was established and treated with full-thickness excision followed by CDCA7L overexpression. Wound healing in these mice was observed and recorded, and vascular endothelial growth factor receptor 2 (VEGFR2) and hematopoietic progenitor cell antigen CD34 (CD34) expression were determined. E2F2 and CDCA7L expression levels in cells and mice were evaluated. The expression of growth factors was tested. RESULTS: CDCA7L expression was downregulated in DFU tissues and wound tissues from DM mice. Mechanistically, E2F2 bound to the CDCA7L promoter to upregulate CDCA7L expression. E2F2 overexpression enhanced viability, migration, and growth factor expression in HaCaT cells and HUVECs, and augmented HUVEC angiogenesis and HaCaT cell proliferation, which was nullified by silencing CDCA7L. In DM mice, CDCA7L overexpression facilitated wound healing and elevated the expression level of growth factors. CONCLUSIONS: E2F2 facilitated cell proliferation and migration and fostered wound healing in DFU cells through binding to the CDCA7L promoter.

Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.

BACKGROUND: Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD). Recently, genome-wide association studies (GWAS) identified several single nucleotide polymorphism (SNP) significantly correlated with DM. The study aimed to explore the relationships of the top significant DM SNPs with carotid atherosclerosis (CA). METHODS: We used a case-control design and randomly selected 309 cases and 439 controls with and without, respectively, carotid plaque (CP) from a community-based cohort. Eight recent GWAS on DM in East Asians reported hundreds of SNPs with genome-wide significance. The study used the top significant DM SNPs, with a p-value < 10-16, as the candidate genetic markers of CA. The independent effects of these DM SNPs on CA were assessed by multivariable logistic regression analyses to control the effects of conventional cardio-metabolic risk factors. RESULTS: Multivariable analyses showed that, 9 SNPs, including rs4712524, rs1150777, rs10842993, rs2858980, rs9583907, rs1077476, rs7180016, rs4383154, and rs9937354, showed promising associations with the presence of carotid plaque (CP). Among them, rs9937354, rs10842993, rs7180016, and rs4383154 showed significantly independent effects. The means (SD) of the 9-locus genetic risk score (9-GRS) of CP-positive and -negative subjects were 9.19 (1.53) and 8.62 (1.63), respectively (p < 0.001). The corresponding values of 4-locus GRS (4-GRS) were 4.02 (0.81) and. 3.78 (0.92), respectively (p < 0.001). The multivariable-adjusted odds ratio of having CP for per 1.0 increase in 9-GRS and 4-GRS were 1.30 (95% CI 1.18-1.44; p = 4.7 × 10-7) and 1.47 (95% CI 1.74-9.40; p = 6.1 × 10-5), respectively. The means of multi-locus GRSs of DM patients were similar to those of CP-positive subjects and higher than those of CP-negative or DM-negative subjects. CONCLUSIONS: We identified 9 DM SNPs showing promising associations with CP. The multi-locus GRSs may be used as biomarkers for the identification and prediction of high-risks subjects for atherosclerosis and atherosclerotic diseases. Future studies on these specific SNPs and their associated genes may provide valuable information for the preventions of DM and atherosclerosis.

Identification of biomarkers and prediction of upstream miRNAs in diabetic nephropathy.

Objective: To explore biomarkers of diabetic nephropathy (DN) and predict upstream miRNAs. Methods: The data sets GSE142025 and GSE96804 were obtained from Gene Expression Omnibus database. Subsequently, common differentially expressed genes (DEGs) of renal tissue in DN and control group were identified and protein-protein interaction network (PPI) was constructed. Hub genes were screened from in DEGs and made an investigation on functional enrichment and pathway research. Finally, the target gene was selected for further study. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficiency of target gene and predicted its upstream miRNAs. Results: 130 common DEGs were obtained through analysis, and 10 Hub genes were further identified. The function of Hub genes was mainly related to extracellular matrix (ECM), collagen fibrous tissue, transforming growth factor (TGF) -ß, advanced glycosylation end product (AGE) -receptor (RAGE) and so on. Research showed that the expression level of Hub genes in DN group was significantly higher than that in control group. (all P<0.05). The target gene matrix metalloproteinase 2 (MMP2) was selected for further study, and it was found to be related to the fibrosis process and the genes regulating fibrosis. Meanwhile, ROC curve analysis showed that MMP2 had a good predictive value for DN. miRNA prediction suggested that miR-106b-5p and miR-93-5p could regulate the expression of MMP2. Conclusion: MMP2 can be used as a biomarker for DN to participate in the pathogenesis of fibrosis, and miR-106b-5p and miR-93-5p may regulate the expression of MMP2 as upstream signals.

Daytime and scheduled surgery for major dysvascular lower extremity amputation.

INTRODUCTION: Patients undergoing a major dysvascular lower extremity amputation (LEA) often have a poor outcome with a high risk of complications and mortality despite improvements in care and perioperative programmes. We evaluated whether scheduled surgery would reduce the failure rate in patients with a major LEA. METHODS: A total of 328 consecutive patients undergoing a major LEA from 2016 to 2019 were enrolled at a single centre. Early failure was defined as re-amputation or revision within 30 days of the index amputation. In 2018, a new regime comprising two scheduled surgery days was implemented. The risk of failure comparing the two cohorts (2016-2017, n = 165 versus 2018-2019, n = 163) was calculated for amputation on scheduled versus non-scheduled days and for other potentially influencing factors. RESULTS: The median (25-75% quartiles) age of all patients was 74 (66-83) years, 91% had an American Society of Anesthesiologists (ASA) grade ≥ 3 and 92% had atherosclerosis or diabetes mellitus. The index amputee levels were 36% below-knee, 60% transfemoral and 4% bilateral transfemoral. In the intervention cohort, 59% were amputated on the scheduled days versus 36% in the control group (p less-than 0.001). Correspondingly, more patients (72.4% versus 57.6%, p = 0.005) were amputated during daytime and the 30-day failure rate was reduced to 11.0% (n = 18) versus 16.4% (n = 27) (p = 0.2). Risk of failure on scheduled days in the intervention group was 8.3% versus 14.9% on any other day (p = 0.2). Correspondingly, daytime surgery reduced the risk of failure (6.8% versus 22.2%, p = 0.005). CONCLUSION: Daytime and scheduled surgery for major LEA may possibly reduce early risk of failure. FUNDING: none. TRIAL REGISTRATION: not relevant.

Prognostic implications of stress hyperglycemia ratio in patients with myocardial infarction with nonobstructive coronary arteries.

BACKGROUND: The role of stress hyperglycemia in acute myocardial infarction (AMI) has long been emphasized. Recently, the stress hyperglycemia ratio (SHR), a novel index reflecting an acute glycemia rise, has shown a good predictive value in AMI. However, its prognostic power in myocardial infarction with nonobstructive coronary arteries (MINOCA) remains unclear. METHODS: In a prospective cohort of 1179 patients with MINOCA, relationships between SHR levels and outcomes were analyzed. SHR was defined as acute-to-chronic glycemic ratio using admission blood glucose (ABG) and glycated hemoglobin. The primary endpoint was defined as major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, stroke, revascularization, and hospitalization for unstable angina or heart failure. Survival analyses and receiver-operating characteristic (ROC) curve analyses were performed. RESULTS: Over the median follow-up of 3.5 years, the incidence of MACE markedly increased with higher SHR tertile levels (8.1%, 14.0%, 20.5%; p < 0.001). At multivariable Cox analysis, elevated SHR was independently associated with an increased risk of MACE (HR 2.30, 95% CI: 1.21-4.38, p = 0.011). Patients with rising tertiles of SHR also had a significantly higher risk of MACE (tertile 1 as reference; tertile 2: HR 1.77, 95% CI: 1.14-2.73, p = 0.010; tertile 3: HR 2.64, 95% CI: 1.75-3.98, p < 0.001). SHR remained a robust predictor of MACE in patients with and without diabetes; whereas ABG was no longer associated with the MACE risk in diabetic patients. SHR showed an area under the curve of 0.63 for MACE prediction. By incorporating SHR to TIMI risk score, the combined model further improved the discrimination for MACE. CONCLUSIONS: The SHR independently confers the cardiovascular risk after MINOCA, and may serve as a better predictor than glycemia at admission alone, particularly in those with diabetes.KEY MESSAGESStress hyperglycemia ratio (SHR) is independently associated with the prognosis in a distinct population with myocardial infarction with nonobstructive coronary arteries (MINOCA).SHR is a better predictor of prognosis than admission glycemia alone, especially in diabetic patients with MINOCA.SHR may serve as a prognostic marker for risk stratification as well as a potential target for tailored glucose-lowering treatment in MINOCA.

Causal associations between site-specific cancer and diabetes risk: A two-sample Mendelian randomization study.

Background: Both cancer and diabetes are complex chronic diseases that have high economic costs for society. The co-occurrence of these two diseases in people is already well known. The causal effects of diabetes on the development of several malignancies have been established, but the reverse causation of these two diseases (e.g., what type of cancer can cause T2D) has been less investigated. Methods: Multiple Mendelian randomization (MR) methods, such as the inverse-variance weighted (IVW) method, weighted median method, MR-Egger, and MR pleiotropy residual sum and outlier test, were performed to evaluate the causal association of overall and eight site-specific cancers with diabetes risk using genome-wide association study summary data from different consortia, such as Finngen and UK biobank. Results: A suggestive level of evidence was observed for the causal association between lymphoid leukaemia and diabetes by using the IVW method in MR analyses (P = 0.033), indicating that lymphoid leukaemia increased diabetes risk with an odds ratio of 1.008 (95% confidence interval, 1.001-1.014). Sensitivity analyses using MR-Egger and weighted median methods showed consistent direction of the association compared with the IVW method. Overall and seven other site-specific cancers under investigation (i.e., multiple myeloma, non-Hodgkin lymphoma, and cancer of bladder, brain, stomach, lung, and pancreas) were not causally associated with diabetes risk. Conclusions: The causal relationship between lymphoid leukaemia and diabetes risk points to the necessity of diabetes prevention amongst leukaemia survivors as a strategy for ameliorating the associated disease burden.

Improving outcomes in co-morbid diabetes and COVID-19: A quasi-experimental study.

BACKGROUND: High-risk people living with diabetes (PLWD) have increased risk for morbidity and mortality. During the first coronavirus disease 2019 (COVID-19) wave in 2020 in Cape Town, South Africa, high-risk PLWD with COVID-19 were fast-tracked into a field hospital and managed aggressively. This study evaluated the effects of this intervention by assessing the impact of this intervention on clinical outcomes in this cohort. METHODS: A retrospective quasi-experimental study design compared patients admitted pre- and post-intervention. RESULTS: A total of 183 participants were enrolled, with the two groups having similar demographic and clinical pre-Covid-19 baselines. Glucose control on admission was better in the experimental group (8.1% vs 9.3% [p = 0.013]). The experimental group needed less oxygen (p  0.001), fewer antibiotics (p  0.001) and fewer steroids (p = 0.003), while the control group had a higher incidence of acute kidney injury during admission (p = 0.046). The median glucose control was better in the experimental group (8.3 vs 10.0; p = 0.006). The two groups had similar clinical outcomes for discharge home (94% vs 89%), escalation in care (2% vs 3%) and inpatient death (4% vs 8%). CONCLUSION: This study demonstrated that a risk-based approach to high-risk PLWD with COVID-19 may yield good clinical outcomes while making financial savings and preventing emotional distress.Contribution: We propose a risk-based approach to guide clinical management of high risk patients, which departs significantly from the current disease-based model. More research using randomised control trial methodology should explore this hypothesis.

Dietary advanced glycation end products (dAGEs): An insight between modern diet and health.

Advanced glycation end products (AGEs) are formed by a series of chemical reactions of amino acids, peptides, proteins, and ketones at normal temperature or heated non-enzymatic conditions. A large amount of AGEs derived from Maillard Reaction (MR) during the process of food heat-processing. After oral intake, dietary AGEs are converted into biological AGEs through digestion and absorption, and accumulated in almost all organs. The safety and health risk of dietary AGEs have attracted wide attention. Increasing evidence have shown that uptake of dietary AGEs is closely related to the occurrence of many chronic diseases, such as diabetes, chronic kidney disease, osteoporosis, and Alzheimer's disease. This review summarized the most updated information of production, bio-transport in vivo, detection technologies, and physiological toxicity of dietary AGEs, and also discussed approaches to inhibit dietary AGEs generation. Impressively, the future opportunities and challenges on the detection, toxicity, and inhibition of dietary AGEs are raised.

High triglyceride-glucose index is associated with poor cardiovascular outcomes in Chinese acute coronary syndrome patients without diabetes mellitus who underwent emergency percutaneous coronary intervention with drug-eluting stents.

Background: Previous research has supported the association between the triglyceride-glucose index (TyG index) and the incidence and prognosis of cardiovascular disease. However, the association between the TyG index and the prognosis of patients with acute coronary syndrome (ACS) without diabetes mellitus (DM) who underwent emergency percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) has not been thoroughly investigated, and these patients may easily be neglected. Therefore, this study aimed to investigate the association between the TyG index and major adverse cardiovascular and cerebrovascular events (MACCEs) in Chinese ACS patients without DM who underwent emergency PCI with DES. Methods: The total number of ACS patients without DM who underwent emergency PCI with DES for this study was 1650. Ln [fasting triglycerides (mg/dL) ×fasting plasma glucose (mg/dL)/2] is the formula used to calculate the TyG index. According to the TyG index, we classified the patients into two groups. The frequency of the following endpoint events was calculated and compared between the two groups: all-cause death, non-fatal myocardial infarction (MI), non-fatal ischemia stroke, ischemia-driven revascularization and cardiac rehospitalization. Results: After a median of 47 months of follow-up [47 (40, 54)], 437 (26.5%) endpoint events were recorded in total. The TyG index was further demonstrated to be independent of MACCE by multivariable Cox regression analysis (hazard ratio [HR], 1.493; 95% confidence interval [CI], 1.230-1.812; p<0.001). The TyG index≥7.08 group had a considerably greater incidence of MACCE (30.3% vs. 22.7% in the TyG index<7.08 group, p<0.001), cardiac death (4.0% vs. 2.3% in the TyG index<7.08 group, p=0.047), and ischemia-driven revascularization (5.7% vs. 3.6% in the TyG index<7.08 group, p=0.046) than the TyG index<7.08 group. Between the two groups, there was no discernible difference in all-cause death (5.6% vs. 3.8% in the TyG index<7.08 group, p=0.080), non-fatal MI (1.0% vs. 0.2% in the TyG index<7.08 group, p=0.057), non-fatal ischemic stroke (1.6% vs. 1.0% in the TyG index<7.08 group, p=0.272), and cardiac rehospitalization (16.5% vs. 14.1% in the TyG index<7.08 group, p=0.171). Conclusion: For ACS patients without DM who received emergency PCI with DES, the TyG index might be an independent predictor of MACCE.

DNA methylation profiling reveals novel pathway implicated in cardiovascular diseases of diabetes.

Objective: Epigenetics was reported to mediate the effects of environmental risk factors on disease pathogenesis. We intend to unleash the role of DNA methylation modification in the pathological process of cardiovascular diseases in diabetes. Methods: We screened differentially methylated genes by methylated DNA immunoprecipitation chip (MeDIP-chip) among the enrolled participants. In addition, methylation-specific PCR (MSP) and gene expression validation in peripheral blood of participants were utilized to validate the DNA microarray findings. Results: Several aberrantly methylated genes have been explored, including phospholipase C beta 1 (PLCB1), cam kinase I delta (CAMK1D), and dopamine receptor D5 (DRD5), which participated in the calcium signaling pathway. Meanwhile, vascular endothelial growth factor B (VEGFB), placental growth factor (PLGF), fatty acid transport protein 3 (FATP3), coagulation factor II, thrombin receptor (F2R), and fatty acid transport protein 4 (FATP4) which participated in vascular endothelial growth factor receptor (VEGFR) signaling pathway were also found. After MSP and gene expression validation in peripheral blood of participants, PLCB1, PLGF, FATP4, and VEGFB were corroborated. Conclusion: This study revealed that the hypomethylation of VEGFB, PLGF, PLCB1, and FATP4 might be the potential biomarkers. Besides, VEGFR signaling pathway regulated by DNA methylation might play a role in the cardiovascular diseases' pathogenesis of diabetes.

Serum glycoprotein non-metastatic melanoma protein B (GPNMB) level as a potential biomarker for diabetes mellitus-related cataract: A cross-sectional study.

Background: Diabetes mellitus (DM), a metabolic disease that has attracted significant research and clinical attention over the years, can affect the eye structure and induce cataract in patients diagnosed with DM. Recent studies have indicated the relationship between glycoprotein non-metastatic melanoma protein B (GPNMB) and DM and DM-related renal dysfunction. However, the role of circulating GPNMB in DM-associated cataract is still unknown. In this study, we explored the potential of serum GPNMB as a biomarker for DM and DM-associated cataract. Methods: A total of 406 subjects were enrolled, including 60 and 346 subjects with and without DM, respectively. The presence of cataract was evaluated and serum GPNMB levels were measured using a commercial enzyme-linked immunosorbent assay kit. Results: Serum GPNMB levels were higher in diabetic individuals and subjects with cataract than in those without DM or cataract. Subjects in the highest GPNMB tertile group were more likely to have metabolic disorder, cataract, and DM. Analysis performed in subjects with DM elucidated the correlation between serum GPNMB levels and cataract. Receiver operating characteristic (ROC) curve analysis also indicated that GPNMB could be used to diagnose DM and cataract. Multivariable logistic regression analysis illustrated that GPNMB levels were independently associated with DM and cataract. DM was also found to be an independent risk factor for cataract. Further surveys revealed the combination of serum GPNMB levels and presence of DM was associated with a more precise identification of cataract than either factor alone. Conclusions: Increased circulating GPNMB levels are associated with DM and cataract and can be used as a biomarker of DM-associated cataract.

Non-dipping blood pressure pattern is associated with higher risk of new-onset diabetes in hypertensive patients with obstructive sleep apnea: UROSAH data.

Objective: Impairment of circadian blood pressure (BP) patterns has been associated with cardiovascular risks and events in individuals with hypertension and in general populations, which are more likely to be found in obstructive sleep apnea (OSA). The aim of this study was to investigate the association of non-dipping BP pattern with new-onset diabetes in hypertensive patients with OSA, based on Urumqi Research on Sleep Apnea and Hypertension (UROSAH) data. Materials and methods: This retrospective cohort study included 1841 hypertensive patients at least 18 years of age, who were diagnosed with OSA without baseline diabetes and had adequate ambulatory blood pressure monitoring (ABPM) data at enrollment. The exposure of interest for the present study was the circadian BP patterns, including non-dipping and dipping BP pattern, and the study outcome was defined as the time from baseline to new-onset diabetes. The associations between circadian BP patterns and new-onset diabetes were assessed using Cox proportional hazard models. Results: Among 1841 participants (mean age: 48.8 ± 10.5 years, 69.1% male), during the total follow-up of 12172 person-years with a median follow-up of 6.9 (inter quartile range: 6.0-8.0) years, 217 participants developed new-onset diabetes with an incidence rate of 17.8 per 1000 person-years. The proportion of non-dippers and dippers at enrollment in this cohort was 58.8% and 41.2%, respectively. Non-dippers were associated with higher risk of new-onset diabetes compared with dippers (full adjusted hazard ratio [HR]=1.53, 95% confidence interval [CI]: 1.14-2.06, P=0.005). Multiple subgroup and sensitivity analyses yielded similar results. We further explored the association of systolic and diastolic BP patterns with new-onset diabetes separately, and found that diastolic BP non-dippers were associated with higher risk of new-onset diabetes (full adjusted HR=1.54, 95% CI: 1.12-2.10, P=0.008), whereas for systolic BP non-dippers, the association was nonsignificant after adjusted the confounding covariates (full adjusted HR=1.35, 95% CI: 0.98-1.86, P=0.070). Conclusions: Non-dipping BP pattern is associated with an approximately 1.5-fold higher risk of new-onset diabetes in hypertensive patients with OSA, suggesting that non-dipping BP pattern may be an important clinical implication for the early prevention of diabetes in hypertensive patients with OSA.