Estrogen Receptor Is Required for Metformin-Induced Apoptosis in Breast Cancer Cells Under Hyperglycemic Conditions.

Backgrounds: About 25% to 30% of estrogen receptor (ER)-positive breast cancer patients develop resistance to endocrine therapy. Human epidermal growth factor receptor 2 (HER2) has been shown to cooperate with several growth factors that regulate cellular energy metabolism, including the insulin-like growth factor 1 receptor (IGF-1R). Objective: As the first-line therapy for type 2 diabetes mellitus (T2DM) patients, metformin is widely known to inhibit the metabolic reprogramming of cancer cells. This study aims to investigate metformin's efficacy in inhibiting endocrine resistance related to genes regulating energy metabolism in both ER-positive and ER-negative breast cancer cell lines under hyperglycemic conditions. Design and methods: MDA-MB-361 (ER-positive, HER2-positive) and SKBR3 (ER-negative, HER2-positive) cancer cell lines were used to represent ER status. Cell viability and cell survival rate were measured using the colorimetric assay of Cell Counting Kit-8. All mRNA levels were quantified using real-time quantitative polymerase chain reaction preceded by reverse transcription. A P value of <.05 was considered statistically significant. Results: Unlike MDA-MB-361, SKBR3 were found to acquire resistance upon metformin treatment in hyperglycemic conditions. Moreover, the mRNA expression of IGF-1R and its downstream signaling, such as the mammalian target of rapamycin (mTOR), was not affected by metformin. Meanwhile, the mRNA expression level of ribosomal S6 kinase 1 (S6K1) was upregulated, whereas forkhead box O1 (FOXO1) was downregulated after metformin treatment in hyperglycemic conditions. Conclusions: This preliminary study suggests that an alternative pathway of metformin resistance may exist in the absence of ERα. Therefore, relying solely on metformin may be inadequate to inhibit the aggressiveness of breast cancer cells.

Navigating metformin's impact on breast cancer: insights into resistance, alternative pathways, and the crucial role of estrogen receptor under high-glucose conditions Around 25% to 30% of breast cancer patients with estrogen receptor (ER)-positive tumors become resistant to hormone therapy. This study explores whether metformin, a drug commonly used for type 2 diabetes, can counteract this resistance by affecting genes linked to energy metabolism. The research focused on both ER-positive (MDA-MB-361) and ER-negative (SKBR3) breast cancer cell lines under high-glucose conditions. Results showed that although metformin inhibited the growth of ER-positive cells, it surprisingly promoted resistance in ER-negative cells. The expression of insulin-like growth factor 1 receptor (IGF-1R) and its downstream signals like mammalian target of rapamycin (mTOR) remained unaffected by metformin. However, metformin did alter the expression of other genes related to energy metabolism, suggesting that a different resistance pathway might exist in ER-negative cases. In conclusion, this early study implies that relying solely on metformin might not be sufficient to combat the aggressiveness of breast cancer cells, particularly in cases lacking ERα. More research is needed to understand alternative pathways and develop more effective strategies against resistance.

Factors Influencing Hypoglycemia in Type 2 Diabetes Mellitus Outpatients with State Health Insurance at Regional General Hospitals in Jakarta, Indonesia.

BACKGROUND: Hypoglycemia is an acute episode that can lead to death in patients with diabetes mellitus (DM). This condition is preventable with patient education, and identifying factors influencing their occurrence is essential to creating effective and efficient education. It also leads to prevention and control by re-organizing the service system and diabetes policies. This study aimed to determine factors contributing to hypoglycemic episodes in type 2 DM outpatients covered by the state-provided Jaminan Kesehatan Nasional (JKN) health insurance. METHODS: The study used a cross-sectional design and collected data from five regional general hospitals in Jakarta, Indonesia. The outpatients were sampled consecutively from two hospitals in September-November 2021, one in January-March 2022, and two others in April-June 2023. Interviews produced primary data related to experienced hypoglycemic episodes, and medical records provided secondary data on patients' clinical characteristics and treatments. Binary logistic regression analysis was employed to process the contributing factors statistically. RESULTS: From 501 patients who met the inclusion and exclusion criteria, it was found that the prevalence of hypoglycemia was 53.3%. Factors that significantly increased hypoglycemic risk (p < 0.05) were high HbA1C levels (OR 1.9; 95% CI 1.2-2.9), comorbidities (OR 1.6; 95% CI 1.1-2.4), insulin/sulfonylurea therapy (OR 2; 95% CI 1-4), non-smoking habit (OR 2.2; 95% CI 1.3-3.6) and physically active lifestyle (OR 1.8; 95% CI 1.2-2.6). CONCLUSION: The prevalence of hypoglycemia in type 2 diabetes mellitus (DM) outpatients with the state-provided health insurance Jaminan Kesehatan Nasional (JKN) at general hospitals in Jakarta is high. The diabetes self-management education (DSME) services provided by health professionals for these outpatients must be further improved.

Development and validation of cost-effective SYBR Green-based RT-qPCR and its evaluation in a sample pooling strategy for detecting SARS-CoV-2 infection in the Indonesian setting.

A low-cost SYBR Green-based RT-qPCR method to detect SARS-CoV-2 were developed and validated. Primers targeting a conserved and vital region of the N genes of SARS-CoV-2 were designed. In-silico study was performed to analyse the compatibility of the selected primer pair with Indonesian SARS-CoV-2 genome sequences available from the GISAID database. We determined the linearity of our new assay using serial dilution of SARS-CoV-2 RNA from clinical samples with known virus concentration. The assay was then evaluated using clinically relevant samples in comparison to a commercial TaqMan-based test kit. Finally, we applied the assay in sample pooling strategies for SARS-CoV-2 detection. The SYBR Green-based RT-qPCR method was successfully developed with sufficient sensitivity. There is a very low prevalence of genome variation in the selected N primer binding regions, indicating their high conservation. The validation of the assay using clinical samples demonstrated similar performance to the TaqMan method suggesting the SYBR methods is reliable. The pooling strategy by combining 5 RNA samples for SARS-CoV-2 detection using the SYBR RT-qPCR methods is feasible and provides a high diagnostic yield. However, when dealing with samples having a very low viral load, it may increase the risk of missing positive cases.

Platelet Glycoprotein-Ib (GPIb) May Serve as a Bridge between Type 2 Diabetes Mellitus (T2DM) and Atherosclerosis, Making It a Potential Target for Antiplatelet Agents in T2DM Patients.

Type 2 diabetes mellitus (T2DM) is a persistent metabolic condition that contributes to the development of cardiovascular diseases. Numerous studies have provided evidence that individuals with T2DM are at a greater risk of developing cardiovascular diseases, typically two to four times more likely than those without T2DM, mainly due to an increased risk of atherosclerosis. The rupture of an atherosclerotic plaque leading to pathological thrombosis is commonly recognized as a significant factor in advancing cardiovascular diseases caused by TD2M, with platelets inducing the impact of plaque rupture in established atherosclerosis and predisposing to the primary expansion of atherosclerosis. Studies suggest that individuals with T2DM have platelets that display higher baseline activation and reactivity than those without the condition. The expression enhancement of several platelet receptors is known to regulate platelet activation signaling, including platelet glycoprotein-Ib (GPIb). Furthermore, the high expression of platelet GP1b has been reported to increase the risk of platelet adhesion, platelet-leucocyte interaction, and thrombo-inflammatory pathology. However, the study exploring the role of GP1b in promoting platelet activation-induced cardiovascular diseases in T2DM patients is still limited. Therefore, we summarize the important findings regarding pathophysiological continuity between T2DM, platelet GPIb, and atherosclerosis and highlight the potential therapy targeting GPIb as a novel antiplatelet agent for preventing further cardiovascular incidents in TD2M patients.

Evaluation of the Use of Antimicrobial Therapy for Treating Diabetic Foot Infections in an Indonesia Referral Hospital: A Retrospective Cohort Study.

BACKGROUND: Diabetic foot infection (DFI) is a common complication of hyperglycemia and is related to prolongation of hospitalization, mortality, high hospitalization costs and decreased quality of life. Antibiotic therapy is one of the most critical factors in the eradication of infection. This study aims to determine the appropriateness of antibiotic use based on the local and international clinical guidelines and its short-term effect on patients' clinical improvement. MATERIALS AND METHODS: This retrospective cohort study was conducted using secondary data from DFI inpatients from 1 January 2018 to 31 May 2020, from Dr. Cipto Mangunkusumo Hospital (RSCM), the National Referral Hospital of Indonesia. The Gyssens algorithm was used to help assess the appropriateness of antibiotics. All subjects were type 2 Diabetes Mellitus (T2DM) adult patients diagnosed with DFI. The primary outcome was a clinical improvement of infection after 7 - 14 days of antibiotic use. The clinical improvement of infection was defined by a minimum of three of these criteria: reduced or no purulent secretions, no fever, the area around the wound did not feel warm, no or reduced local oedema, no local pain, reduced redness or erythema, and decreased leukocytes count. RESULTS: A total of 113 (63.5%) eligible subjects from a total of 178 were recruited. Among the patients, 51.4% had a duration of T2DM for ≥10 years, 60.2% had uncontrolled hyperglycemia, 94.7% had a history of complications, 22.1% had a history of amputation, and 72.6% had ulcer grade ≥3. Based on the Gyssens algorithm, 54.0% of the subjects were given antibiotics appropriately, while the other 46.0% were not. The proportion of improved patients in the appropriate antibiotics group was higher but not statistically significant than those in the inappropriate group (60.7% vs. 42.3%, P = 0.079). However, the results of the multivariate analysis demonstrated that the appropriate use of antibiotics would increase clinical improvement by 2.6 times, compared to inappropriate use after controlling for the covariates (adjusted odds ratio: 2.616, 95% confidence interval: 1.117 - 6.126, P = 0.027). CONCLUSION: Only half of the patients with DFI received appropriate antibiotics, although an appropriate antibiotics usage was independently associated with better short-term clinical improvement in DFI. This suggests that we should effort to improve appropriateness in antibiotics usage in DFI.

Absence of Association Between Serum Mutant p53 with HbA1c and Insulin in Brain Tumor Patients with Type 2 Diabetes Mellitus.

AIMS: This study aims to determine the prevalence of Type 2 Diabetes Mellitus (T2DM) in primary Brain Tumor (BT) subjects and assess the relationship between serum mutant p53 serum and HbA1c and insulin. BACKGROUND: T2DM is known to increase the risk of various types of cancer, which are thought to be caused by hyperglycemia, hyperinsulinemia, and inflammation. A cohort study that looked at more than 500,000 subjects with DM over 11 years showed an increased risk of different types of cancer, including brain tumors. However, several recent studies have shown the opposite. One of the important pathways in the pathogenesis of brain tumors is the p53 pathway, in which mutations in the TP53 gene can cause brain cell growth abnormalities. OBJECTIVE: The first stage involved taking subject data for the period January 2017-November 2020 from the medical records of the RSUPN Dr. Cipto Mangunkusumo Hospital Indonesia to assess the prevalence of T2DM in BT subjects. The second stage was an observational study with a crosssectional design that collected primary data on subjects (n=86) to assess the relationship between serum mutant p53 serum and HbA1c and insulin. METHODS: The analysis of serum mutant p53 serum and insulin was made using the ELISA method, while measurement of HbA1c was made using the boronate affinity method. RESULT: The results show the prevalence of T2DM in BT subjects at Dr. Cipto Mangunkusumo Hospital Indonesia was relatively low (9%). Serum mutant p53 levels in T2DM (1.53 ng/mL ± 0.60) were significantly higher than in BT+T2DM and BT (P < 0.001). The HbA1c value was significantly lower in BT (5.15% ± 0.44) compared to BT+T2DM and T2DM (P < 0.001), while T2DM insulin levels (39.54 IU/mL ± 19.1) were significantly higher than BT+T2DM and BT (P < 0.001). There was no correlation between serum mutant p53 levels and HbA1c and insulin in the three groups. CONCLUSION: The study concludes that the prevalence of BT with T2DM is relatively low (9%) and that serum levels of mutant p53 in T2DM subjects are higher than in subjects with BT, but there is no correlation between serum mutant p53 levels and HbA1c and insulin values. Further research needs to be conducted by analyzing p53 mutants from other specimens, such as brain tumor tissue.

"Phardiacare" Program for Improved Medication Adherence and Clinical Outcomes of Type 2 Diabetes Mellitus Patients in Community Health Centers.

BACKGROUND: The role of pharmacists in middle-income countries such as Indonesia is still not optimal. In this study, we developed a program called "Phardiacare", a specific pharmacist-led program for Type 2 diabetes mellitus (T2DM) patients. OBJECTIVE: The objective of this study is to assess the effectiveness of the application of the "Phardiacare" program in improving medication adherence and clinical outcomes in T2DM patients. METHODS: The study was quasi-experimental, with a pretest-posttest design, and was conducted prospectively from July to October 2019 at the Matraman and Jatinegara District Health Center, Jakarta, Indonesia. The study comprised 33 T2DM patients in an intervention group (IG) who received the "Phardiacare" program and 33 patients in a control group (CG). Assessment was performed of HbA1c, FBG, LDL, HDL, total cholesterol, triglycerides, and blood pressure. RESULTS: HbA1c after intervention in the IG was lower than that of the CG (p <0.05). Intra-group mean differences showed improvement in the clinical parameters of FBG, triglycerides, and diastolic blood pressure in the IG (p <0.05), but not in the CG. Other clinical parameters did not show significant improvement. The results of the multivariate analysis showed that the "Phardiacare" program had a 16 times greater effect in reducing levels of HbA1c in the IG [95% CI 3.995:67.113, p <0.001] compared to the CG, even after controlling for confounding variables. CONCLUSION: The "Phardiacare" program was effective in improving patient medication adherence by decreasing HbA1c and FBG, but it did not have a significant effect on LDL, HDL, total cholesterol, and systolic blood pressure. Therefore, the implementation of Phardiacare program in the management of chronic diseases, especially T2DM, should be considered.

Low-cost SYBR Green-based RT-qPCR assay for detecting SARS-CoV-2 in an Indonesian setting using WHO-recommended primers.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the ongoing coronavirus disease 2019 (COVID-19) pandemic. For laboratory diagnosis, low-cost detection of SARS-CoV-2 is urgently needed, particularly in developing countries with limited resources. Probe- or TaqMan-based real-time reverse transcription polymerase chain reaction (RT-qPCR) is currently the gold standard for diagnosing infected individuals, as recommended by the World Health Organization (WHO). However, this assay is expensive, making it difficult to use for diagnosis on a large scale. Therefore, in this study, we develop and validate an alternative approach for RT-qPCR diagnosis by employing the DNA intercalating dye SYBR Green. We evaluate and use two WHO-recommended primers, namely CCDC-N and HKU-ORF1b-nsp14. The compatibility of the two primers was tested in silico with Indonesian SARS-CoV-2 genome sequences retrieved from the GISAID database and using bioinformatic tools. Using in vitro-transcribed RNA, optimization, sensitivity, and linearity of the two assays targeting the N and Nsp-14 genes were carried out. For further evaluation, we used clinical samples from patients and performed the SYBR Green-based RT-qPCR assay protocol in parallel with TaqMan-based commercial assay. Our results show that our methodology performs similarly to the broadly used TaqMan-based detection method in terms of specificity and sensitivity and thus offers an alternative assay for the detection of SARS-CoV-2 RNA for diagnostic purposes.

Role of urinary H2O2, 8-iso-PGF2α, and serum oxLDL/ß2GP1 complex in the diabetic kidney disease.

Oxidant species is reported as a major determinant in the pathophysiology of diabetic kidney disease. However, reactive oxygen species (ROS) formation in the initial phase and progressing phase of diabetic kidney disease remains unclear. Therefore, we conducted this study to find out what ROS and their modified product are associated with eGFR in type 2 diabetes mellitus (T2DM) patients. A cross-sectional study was performed on 227 T2DM patients. The study subjects were divided into three groups based on their eGFR stage (Group 1, eGFR > 89 ml/min/1.73 m2; Group 2, eGFR = 60-89 ml/min/1.73 m2; and Group 3, eGFR < 60 ml/min/1.73 m2). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum oxLDL/ß2GPI complex and urinary 8-iso-PGF2α, while ferrous ion oxidation xylenol orange method 1 (FOX-1) was used to measure urinary hydrogen peroxide (H2O2). H2O2 significantly decreased across the groups, whereas OxLDL/ß2GPI complex increased, but not significant, and there was no trend for 8-iso-PGF2α. Consistently, in the total study population, only H2O2 showed correlation with eGFR (r = 0.161, p = 0.015). Multiple linear regression analysis showed that significant factors for increased eGFR were H2O2, diastolic blood pressure, and female. Whereas increased systolic blood pressure and age were significant factors affecting the decrease of eGFR. We also found that urinary H2O2 had correlation with serum oxLDL/ß2GPI complex in total population. This finding could lead to further research on urinary H2O2 for early detection and research on novel therapies of diabetic kidney disease.

A Systematic Review of Randomized Controlled Trials of Antibiotic Use in Diabetic Foot Ulcer Infections: Focus on Clinical Cure.

BACKGROUND: The use of antibiotics in diabetic foot ulcer infections (DFUI) is essential in reducing morbidity. Optimal administration of antibiotics can improve clinical outcomes and reduce the risk of antibiotic resistance. This study aims to review the efficacy, in terms of clinical cure, of various regimens and the duration of antibiotic administration in DFUI patients, based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The efficacy based on microbiological response is also reviewed as the secondary outcome. MATERIALS AND METHODS: We used three databases, namely PubMed, Scopus, and ScienceDirect, to search for randomized controlled trials (RCTs) in patients with DFUI who required antibiotics. RESULTS: A total of 16 studies were included in the systematic review. The study locations and bacterial patterns varied, with the most common pathogen being Staphylococcus aureus. Most studies did not demonstrate a significant difference in clinical cure and pathogen eradication, either in the comparison between systemic and topical antibiotics or in the duration of administration. Some studies had similar characteristics and were analyzed to conclude. These studies showed that ertapenem had comparable efficacy to piperacillin/tazobactam. Similar results were also conducted from studies of piperacillin-tazobactam+amoxicillin-clavulanic acid vs. moxifloxacin. CONCLUSION: Most studies have heterogeneous characteristics, possibly due to differences in research location. Therefore, there is no strong evidence to recommend a specific antibiotic with the highest efficacy. However, since all included studies are RCTs, this review provides a good summary in considering antibiotic choices when treating DFUI patients.

The chemical constituents of Sterculia comosa (wall) Roxb woods for arginase inhibitory, antioxidant activity, and molecular docking against SARS CoV-2 protein.

Flavonoids and phenols have an arginase inhibitory and antioxidant activity. The Sterculia genus has phenols and flavonoids content. This study aimed to investigate the arginase inhibitory and antioxidant activity of the chemical constituent of Sterculia comosa (wall) Roxb and also their binding affinities to arginase. The most active extract was methanol extract. This active extract was determined for its arginase inhibitory and antioxidant activity, determined the total phenols and total flavonoids, and identified chemical compound. The methanol extract has IC50 2.787 µg/ml for arginase inhibitory activity and IC50 4,199 µg/ml for DPPH scavenging activity. The total phenols 723.61 mg GAE/gr, total flavonoids content 28.96 mg QE/gr extract. The chemical constituent: KC4.4.6 ((-)-2-(E)-caffeoyl-D-glyceric acid) and KC4.4.5.1 (trans-isoferulic acid) have an arginase inhibitory activity KC4.4.6: 98,03 µg/ml and KC4.4.5.1: 292,58 µg/ml. Antioxidant activity with DPPH methods KC4.4.6: 48,77 µg/ml and KC4.4.5.1: 88,08 µg/ml. Antioxidant by FRAP methods KC4.4.6: 16,4 FeEAC mol/g and KC4.4.5.1: 15,79 FeEAC mol/g. The isolate trans-isoferulic acid predicted has good interaction to arginase. Isolate KC4.4.6. Predicted has good interaction to PLPro of SARS CoV-2 PLpro. However, both isolates did not show good interaction to 3CLPro, nsp12, and Spike protein of SARS CoV-2.

Comparison of Metformin-sulfonylurea and Metformin-acarbose Combination Therapies on Glycemic Outcomes: A Retrospective Cohort Study.

OBJECTIVE: Pharmacological therapy for type 2 diabetes mellitus features various combinations of treatments, with different therapies providing different levels of effectiveness. In clinical settings, choices are driven by cost, effectiveness, and safety considerations, and these choices are still under question in Indonesia. This study aimed to compare the effectiveness of metformin-sulfonylurea and metformin-acarbose combination therapies on glycemic parameters in patients with type 2 diabetes mellitus. METHODS: This study was carried out at Gatot Soebroto Army Hospital in Jakarta and utilized a retrospective cohort study design. Participants had consumed the same drug without switching for six months and were divided into a metformin-sulfonylurea group (n = 100) and a metformin-acarbose group (n = 100). The effectiveness of treatment was evaluated by considering hemoglobin A1c (HbA1c), two hours postprandial glucose, and fasting blood glucose. RESULTS: After six months' consumption, there were no statistical differences between results for the metformin-sulfonylurea and metformin-acarbose groups in terms of change of HbA1c (p = 0.062), controlled two hours postprandial blood glucose (p = 0.649), and controlled fasting blood glucose (p = 0.282). Regular exercise was the most significant factor for constant/decreased HbA1c, whereas being male and following a diet were the most significant factors for controlled two hours postprandial blood glucose and fasting blood glucose, respectively. CONCLUSION: Based on the analysis performed, there was no significant difference in the effectiveness of six months' consumption of metformin-sulfonylurea and metformin-acarbose on HbA1c, two hours postprandial blood glucose, and fasting blood glucose.

Current updates on protein as biomarkers for diabetic kidney disease: a systematic review.

BACKGROUND: In the past decade, researchers have been focused on discovering protein biomarkers for diabetic kidney disease. This paper aims to search for, analyze, and synthesize current updates regarding the development of these efforts. METHODS: We systematically searched the ScienceDirect, SpringerLink, and PubMed databases for observational studies of protein biomarkers in patients with diabetes mellitus. We included studies published between January 2018 and April 2020, that were based on a population of patients with type-1 or type-2 diabetes mellitus aged ⩾18 years, with an observational design such as cross-sectional, case-control, or cohort studies. The dependent variable of the research results was in the form of protein biomarkers from urine, plasma, or serum. RESULTS: Following the screening process, 20 research articles with available full text met the inclusion criteria. These could be categorized as glomerular biomarkers (ANGPTL4, beta-2 microglobulin, Smad1, and glypican-5); inflammatory biomarkers (MCP-1 and adiponectin); and tubular biomarkers (NGAL, VDBP, megalin, sKlotho, and KIM-1). The development of a panel of biomarkers showed more promising results than those for a single biomarker in diagnosing diabetic kidney disease. CONCLUSION: All the biomarkers discussed in this review showed promising results for predicting diabetic kidney disease because they correlate with albuminuria, eGFR, or both. However, of the 11 protein biomarkers, none have prognostic value beyond albuminuria and eGFR.

Adherence to Treatment and Glycemic Control in Patients with Type 2 Diabetes Mellitus: A 4-Year Follow-up PTM Bogor Cohort Study, Indonesia.

PURPOSE: Large-scale evaluation of the treatment adherence in patients with type 2 diabetes mellitus (DM) in Indonesian is limited. We aim to evaluate the treatment adherence of Indonesian type 2 DM patients using national "big data" and investigate its association with glycemic parameters. PATIENTS AND METHODS: We analyzed baseline and fourth-year data sets from 2011 to 2018 obtained from the Indonesian Ministry of Health Cohort Study of Non-Communicable Disease Risk Factors in Bogor, West Java (the PTM Bogor Cohort Study). This was a retrospective cohort study in which the sample was divided into two groups. One group adhered to treatment from primary health centers and followed the prescribed medicine/treatment regimen (treated group), while the other did not follow the treatment (untreated group). We evaluated changes in fasting blood glucose (FBG) and post-prandial blood glucose (PPBG) by controlling for other variables. RESULTS: From 5690 subjects, 593 were type 2 DM diagnosed and 342 were eligible at the baseline. At 4-year observation, 212 eligible patients remained, consisting of 62 subjects who adhered to treatment, and more than double that number who were untreated (150 subjects). More significant decreases in FBG and PPBG were found in the treated group (FBG 80.6%, PPBG 90.3%) than in the untreated group (FBG 42.0%, PPBG 67.3%). The results of the multivariate analysis showed that after 4 years observation, treated patients have reduced FBG 3.304 times more and PPBG 3.064 times more than untreated patients, with control factors such as decrease in LDL levels and use of oral drugs. CONCLUSION: There were less than half as many treated patients as untreated patients involved in the PTM Bogor Study Group. At the fourth-year follow-up, treated patients experienced three times more significant decreases in FBG and PPBG than those who were untreated, even after being controlled by several confounding factors. Given the importance of these findings, it is suggested that immediate strategic action be taken to improve Indonesian patients' adherence to treatment.

The effect of repeated education using live demonstrations and videos of how to use inhalation drugs on quality of life for COPD patients.

Repeated education regarding the proper use of inhalers can reduce the error rate in inhaler-using patients and improve COPD patients' quality of life. This study investigates the effect of repeated education on the quality of life of COPD patients during the pandemic of COVID-19 from February to June 2020. Repeated education is provided using direct demonstrations to patients through educational media in the form of short videos made by the researchers for each inhaler type. This is a pre-experimental study design which was carried out prospectively at Grha Permata Ibu Hospital, Depok. The quality of life of 22 subjects was examined using the COPD assessment test (CAT) questionnaire. Each patient was given a direct verbal demonstration of the appropriate use of the inhaler. One month later, each patient was provided further education using less than 2 min of video sent to them online via the WhatsApp application. Final quality-of-life examination and assessment of inhaler technique were carried out three months after the initial examination. Assessment of proper inhaler technique was carried out using a specific checklist regarding the use of inhaler translated by the researcher. Before and after delivery of repeated education, the mean CAT score showed a decrease of two points, i.e., 12.8 ± 1.3 and 10.8 ± 2.0, respectively. This indicated that quality of life of the patients had significant improvement. However, as many as 63.6% of patients still made mistakes in using inhaler even though they had been educated. For DPI-type inhalers, mistake mostly happened at step "breath out gently, away from inhaler". For pMDI-type inhalers, mistake mostly happened at step "while holding breath, remove inhaler from mouth". It can be concluded that repeated education regarding proper inhaler technique with direct demonstrations and further maintained by videos can improve the quality of life in COPD patients.

Effect of Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor on Kidney Function and Blood Potassium Level in Indonesian Type 2 Diabetes Mellitus with Hypertension: A Three-Month Cohort Study.

PURPOSE: National formulary restrictions in Indonesia (2019) require estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 to be able to prescribe telmisartan and valsartan and ACE-I intolerance to be able to prescribe irbesartan and candesartan. These restrictions are based on economic considerations and differ from American Diabetes Association (ADA) (2020) guidelines which allow equal use of angiotensin II receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACE-I) without restriction. Since there is a need to evaluate the different effects of ACE-I and ARB in the Indonesian hypertensive type 2 diabetes mellitus (T2DM) population, we compare their effects on urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and blood potassium level. PATIENTS AND METHODS: A prospective cohort study at RSUPN Dr. Cipto Mangunkusumo Hospital was conducted in 123 T2DM patients. We followed the study subjects prospectively for three months using a validated questionnaire, health record, and laboratory data. RESULTS: After 3 months of observation, there were no significant changes, except increased BMI values (p = 0.046) in the ACE-I group, and decreased LDL value (p = 0.016) and HDL value (p = 0.004) in the ARB group. Multivariate analysis showed that the consumption of ACE-I or ARB was not associated with a decrease/constant of UACR or increase potassium level, even after adjusting by confounding variables. Interestingly, we found ARB was more likely to increase eGFR, but the significance was lost once the duration of ACE-I/ARB use was entered into the model. In addition, BMI >25 kg/m2 was a significant factor associated with decreased/constant UACR, maleness was significant for increased eGFR, and declining systolic blood pressure for increase in potassium level. CONCLUSION: ACE-I and ARB have a similar effect on UACR and blood potassium level, but ARB slightly increased eGFR compared to ACE-I within three months of consumption.

The potential of metformin as an antineoplastic in brain tumors: A systematic review.

Brain tumors are challenging to handle and cause severe mortality and morbidity. The primary therapy for brain tumors, a combination of radiotherapy, chemotherapy (i.e temozolomide), and corticosteroids, is considered inadequate to improve patients' clinical conditions and associated with many adverse effects. There is an urgent need for new compounds or repurposing of existing therapies, which could improve brain tumor patients' prognosis. Metformin, commonly used for type 2 diabetes medication, has been examined for its protective action in cancer, reducing cancer risk and cancer-related mortality. However, its effect on cancer is still in rigorous debate. This study examines recent studies on the effects of metformin in primary brain tumor patients through systematic reviews. The literature search was performed on PubMed, ScienceDirect, and SpringerLink databases for articles published between 2013 and 2020. We selected clinical studies comparing the therapeutic outcomes of brain tumor therapy with and without metformin. The clinical benefits of the drug were assessed through the overall survival (OS) and progression-free survival (PFS) of brain tumor patients. Those studies demonstrated that the combination of metformin with temozolomide given post-radiotherapy resulted in better OS and PFS. Nonetheless, the efficacy and safety of metformin need further clinical testing in the wider population.

Comparison of Effects of ACEIs and ARBs on Albuminuria and Hyperkalemia in Indonesian Hypertensive Type 2 Diabetes Mellitus Patients.

PURPOSE: Due to economic consideration, Indonesia's formulary restrictions are at odds with the treatment guidelines of the American Diabetes Association (ADA) and the Eighth Joint National Committee (JNC 8). ADA and JNC 8 equally recommend the prescription of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for hypertensive patients with type 2 diabetes mellitus (T2DM) with overt proteinuria (urine albumin to creatinine ratio (UACR) ≥ 300 mg/g creatinine). However, since 1 April 2018, Indonesian formulary restricted telmisartan and valsartan only for T2DM patients with declined renal function as shown by eGFR value. There is no compelling evidence in favor of ACEI over ARB or vice versa except for data supporting the early use of both drugs in patients with overt proteinuria. However, ARB is a choice if ACEI's side effects, that is, coughing, occurs. Therefore, it necessitates a detailed evaluation of the effects of ACEIs and ARBs on albuminuria and their side effect, hyperkalemia, specific to Indonesian T2DM patients. METHODS: This cross-sectional study involved 134 T2DM patients whose treatment was restricted to either ACEIs (n = 57) or ARBs (n = 77) for at least two months before the study during May-October 2018. Patients with known end-stage renal disease and those receiving dialysis were excluded. UACR and blood potassium levels were compared between the two study groups. Also, the risk factors of albuminuria and hyperkalemia were estimated using multivariate analysis. RESULTS: T2DM patients in the ACEI and ARB groups had similar characteristics except for a higher body mass index (p=0.008), lower glomerular filtration rate (p=0.04), and a longer duration of prior treatment (p < 0.001) in the ARB group. This study showed no differences between the ACEI and ARB groups in the proportion of cases with albuminuria (p=0.97) and hyperkalemia (p=0.86), even after adjustment for confounders. In addition, uncontrolled diastolic blood pressure was a significant factor associated with albuminuria (OR: 4.897, 95% CI: 1.026-23.366; p=0.046), whereas a female was 70.1% less likely to develop hyperkalemia than a male (OR: 0.299, 95% CI: 0.102-0.877; p=0.028). CONCLUSION: This cross-sectional study demonstrated that ACEIs and ARBs have a similar effect on albuminuria and hyperkalemia in Indonesian hypertensive T2DM patients, even after correction for potentially confounding variables.

Sera Anti-P53 Antibody Provides New Information Which Explains the Link Between Diabetes and Cancer.

INTRODUCTION: Abnormalities in glucose metabolism in diabetic patients may lead to an increased risk of certain cancers. Epidemiological studies and meta-analysis have shown that factors such as gender, age, obesity, and insulin resistance are related to cancer incidence. The anti-p53 antibody is a known cancer marker due to tumor-associated p53 accumulation. Many studies have aimed to unravel the link between diabetes and cancer. Here, we aimed to elucidate the impact of diabetes on malignancies by analyzing anti-p53 antibody in sera of type 2 diabetes mellitus (T2DM) patients. MATERIALS AND METHODS: We conducted an observational study with a cross-sectional design. A total of 149 subjects comprised of 78 T2DM patients (32 with cancer risk and 46 subjects without cancer risk), 51 T2DM patients with cancer, and 20 healthy subjects as controls from multisites. The anti-p53 antibody was measured by enzyme-linked immunosorbent assay, while HbA1c was measured using the NGSP standardized method. RESULTS: We observed an 8.3-fold (p<0.05) increase of anti-p53 antibody in the sera of T2DM patients and a 24-fold increase (p<0.001) in T2DM patients with cancer compared to healthy subjects. The anti-p53 antibodies significantly increased almost three times (p<0.05) in T2DM patients with cancer (0.72 U/mL±0.20) compared to T2DM patients (0.25 U/mL±0.05). Meanwhile, this antibody was almost undetectable in healthy subjects as a control group (0.03 U/mL±0.03). The anti-p53 antibody level was higher in T2DM with cancer risk patients. However, we did not find a significant difference for it in T2DM without cancer risk patients (0.19 U/mL±0.03) and T2DM with cancer risk patients (0.29 U/mL±0.08). Multivariate regression analysis showed that T2DM with cancer was the only one independent factor (beta=0.218, p=0.019) that could predict the increase of anti-p53 antibody, controlled by age, gender, BMI, DM duration, and HbA1c. CONCLUSION: Our results showed that anti-p53 antibody almost not detected in healthy subjects, but 8.3-fold increase in the sera of T2DM patients and 24-fold increase in T2DM patients with cancer. Therefore, this biomarker provides new information which explains the link between diabetes and cancer.

Effect of Pharmacist Intervention on Medication Adherence and Clinical Outcomes of Type 2 Diabetes Mellitus Outpatients in Primary Healthcare in Indonesia.

OBJECTIVE: In Indonesia, the role of pharmacists in primary healthcare is still very limited or even absent. This study evaluates the effectiveness of programs delivered for type 2 diabetes mellitus (T2DM) patients by pharmacists in primary healthcare through counseling, short message service (SMS) reminders, and medication booklets. METHODS: A quasi-experimental study with a pretest-posttest design was conducted from April to August 2018 at Merdeka and Dempo primary health-care centers, Palembang, South Sumatra Province, Indonesia. Counseling and medication booklets were distributed three times during the study period, while SMS reminders were sent once a week. Counseling was given for the management of diabetes mellitus (DM), including during the Ramadan fasting period, together with management for acute and chronic complications. The medication adherence level was measured using a medication adherence questionnaire (MAQ) and pill count adherence (PCA). The study sample comprised 80 T2DM patients, who were allocated into either the control group (CG) (n = 40) or intervention group (IG) (n = 40). Clinical outcomes were determined by measuring glycated hemoglobin (HbA1c), blood pressure, and lipid profiles. FINDINGS: After the intervention, the IG showed significant improvements in most parameters, except for high-density lipoprotein cholesterol and systolic and diastolic blood pressure. HbA1c levels were reduced, while MAQ scores and PCA scores were improved. Lipid parameters were significantly reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and triglyceride (TG). Compared with the CG, most parameters were significantly improved in the IG. Pharmacist counseling significantly improved almost all clinical parameters (HbA1c, TC, LDL-c, and TG). Pharmacist counseling was 7.1 times greater in lowering HbA1c compared with no counseling, after adjusted by other variables. The variable that most influenced the lowering of HbA1c was infrequent ("not often") consumption of unhealthy foods (OR 14.9; 95% CI 3.5-63.7). CONCLUSION: The pharmacist primary health-care intervention program implemented in this study significantly improved HbA1c, TC, LDL-c, TG, and medication adherence in outpatients with T2DM.