Diabetes mellitus in breast cancer survivors: metabolic effects of endocrine therapy.

Breast cancer is the most common invasive malignancy in the world, with millions of survivors living today. Type 2 diabetes mellitus (T2DM) is also a globally prevalent disease that is a widely studied risk factor for breast cancer. Most breast tumours express the oestrogen receptor and are treated with systemic therapies designed to disrupt oestrogen-dependent signalling. Since the advent of targeted endocrine therapy six decades ago, the mortality from breast cancer has steadily declined; however, during the past decade, an elevated risk of T2DM after breast cancer treatment has been reported, particularly for those who received endocrine therapy. In this Review, we highlight key events in the history of endocrine therapies, beginning with the development of tamoxifen. We also summarize the sequence of reported adverse metabolic effects, which include dyslipidaemia, hepatic steatosis and impaired glucose tolerance. We discuss the limitations of determining a causal role for breast cancer treatments in T2DM development from epidemiological data and describe informative preclinical studies that suggest complex mechanisms through which endocrine therapy might drive T2DM risk and progression. We also reinforce the life-saving benefits of endocrine therapy and highlight the need for better predictive biomarkers of T2DM risk and preventive strategies for the growing population of breast cancer survivors.

FGF1 supports glycolytic metabolism through the estrogen receptor in endocrine-resistant and obesity-associated breast cancer.

BACKGROUND: Obesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not be the best predictor of breast cancer risk or prognosis on an individual level. Adult weight gain is an independent indicator of breast cancer risk. Our previous work described a murine model of obesity, ER-positive breast cancer, and weight gain and identified fibroblast growth factor receptor (FGFR) as a potential driver of tumor progression. During adipose tissue expansion, the FGF1 ligand is produced by hypertrophic adipocytes as a stimulus to stromal preadipocytes that proliferate and differentiate to provide additional lipid storage capacity. In breast adipose tissue, FGF1 production may stimulate cancer cell proliferation and tumor progression. METHODS: We explored the effects of FGF1 on ER-positive endocrine-sensitive and resistant breast cancer and compared that to the effects of the canonical ER ligand, estradiol. We used untargeted proteomics, specific immunoblot assays, gene expression profiling, and functional metabolic assessments of breast cancer cells. The results were validated in tumors from obese mice and breast cancer datasets from women with obesity. RESULTS: FGF1 stimulated ER phosphorylation independently of estradiol in cells that grow in obese female mice after estrogen deprivation treatment. Phospho- and total proteomic, genomic, and functional analyses of endocrine-sensitive and resistant breast cancer cells show that FGF1 promoted a cellular phenotype characterized by glycolytic metabolism. In endocrine-sensitive but not endocrine-resistant breast cancer cells, mitochondrial metabolism was also regulated by FGF1. Comparison of gene expression profiles indicated that tumors from women with obesity shared hallmarks with endocrine-resistant breast cancer cells. CONCLUSIONS: Collectively, our data suggest that one mechanism by which obesity and weight gain promote breast cancer progression is through estrogen-independent ER activation and cancer cell metabolic reprogramming, partly driven by FGF/FGFR. The first-line treatment for many patients with ER-positive breast cancer is inhibition of estrogen synthesis using aromatase inhibitors. In women with obesity who are experiencing weight gain, locally produced FGF1 may activate ER to promote cancer cell metabolic reprogramming and tumor progression independently of estrogen.

Modeling key enablers influencing FinTechs offering SME credit services: A multi-stakeholder perspective.

The study models inter-relationship among key enablers that influence the growth of FinTechs that offer credit services to small and medium enterprises (SMEs). It focuses on emerging market of India, which is the world's third-largest FinTech centre. It employs Grey DEMATEL method to measure the cause-effect relationship based on the assessment given by FinTech practitioners, experts, policymakers, and investors. The results show that credit demand by SME borrowers, availability of alternate data sources, and Covid-19 are the critical enablers that exercise strong impact on FinTech system. Collaboration between FinTechs and traditional financial institutions, end-to-end financial solutions, and scalability of business operations are recognized as critical dependents that are hugely affected by others. The study recommends policymakers to foster collaborative environment, strengthen digital data landscape, and improve financial literacy to develop FinTech sector. It recommends practitioners to focus on data security and to offer end-to-end financial solutions to its SME borrowers.

Rho Kinase Inhibitors as a Neuroprotective Pharmacological Intervention for the Treatment of Glaucoma.

Glaucoma is a leading cause of irreversible blindness, and its prevalence has led to research into treatment modalities for glaucoma to prevent the progression of the disease. The primary treatment for glaucoma that has been extensively used is ocular hypotensives to reduce raised intraocular pressure. This treatment has its drawbacks due to the existence of other variants of glaucoma, such as normal-tension glaucoma, where the intraocular pressure is measured to be within regular levels. Hence, there is a need for new treatment interventions which can deliver a better prognosis for glaucoma. Neuroprotection is a new concept studied recently, and neuroprotective agents are being developed for glaucoma therapy. Rho kinase inhibitors are one such neuroprotective agent, and the most recent addition to the class of ocular hypotensives, where they function by reducing raised intraocular pressure. Its neuroprotective capabilities, such as cell survival and axon regeneration, are yet to be determined in detail. This literature review article aims to look into the need for new treatments such as neuroprotection to prevent the progression of glaucoma and the efficacy of rho kinase inhibitors in the treatment of glaucoma, with particular emphasis on its neuroprotective abilities. It also aims to identify the limitations that can occur while approaching neuroprotective therapy, as well as how it can enable future treatment modalities. By exploring this field, blindness caused by progressive glaucoma can be halted and managed by glaucoma therapy.

'Digital Wellbeing': The Need of the Hour in Today's Digitalized and Technology Driven World!

The constant contact and usage of technology in today's world have brought about the dire consequences of digital addiction and its effects. This has led to a serious dilemma of management of screentime by an individual. Studies have shown a negative impact of excessive gadget use leading to a decline in performance rates, effect on sleep patterns, and reduction in workplace achievements thereby causing hindrance in unlocking the maximum potential of an individual. This has paved the way for the introduction of a novel concept known as 'Digital well-being' for tackling this underlying issue to bring about screen time reduction as well as to establish an ideal work-life balance. Digital well-being enhances the usage of technology itself to combat increased screen time by using restraints and promotes wellness by enabling productive and healthy lifestyles. In a new era where smartphones and technology have begun to dictate our lives, it is necessary to apply restraints and ensure there is a balance of wellness as well as productivity outflow. Digital well-being can be achieved by interventions that should be administered with the use of apps and healthy practices. The use of new-age apps acts as positive reinforcement and helps in providing a restrictive environment as well as maintains the time invested for useful and productive engagements. There is a lot of research yet to be done regarding this topic empirically regarding its success and this review article aims to approach the effectiveness of digital wellbeing and its applications in combating stress and increasing work performance and preventing digital addiction.

Gender-Based Vegetarian and Nonvegetarian Dietary Impact on Cardiac Autonomic Function of Heart Rate Variability.

Objective: Cardiovascular disease is one among the major mortality threats throughout the world. Autonomic activity of the nervous system can be examined by heart rate variability (HRV) analysis. Association of sympathetic and parasympathetic activities is directly related to HRV modulation. The aim of the study is to determine variations in HRV parameters among adult/adolescent male and female subjects due to vegetarian and nonvegetarian diet.Method: Ninety undergraduate students in each male and female group (N = 180) volunteered for the study. Based upon food habits, male and female subjects were categorized into four groups. Short-term (5-minute) heart rate recordings were measured from the subjects in a seated position before breakfast with minimum of 12 hours' fasting. Two-way analysis of variance was performed among the time and frequency domain variables.Results: Time domain variables are observed as significant (p < 0.05) between vegetarian males and females and also (p < 0.05) between male vegetarian and female nonvegetarians for standard deviation of NN intervals. Frequency domain HRV indices such as low frequency (LF; p = 0.01), high frequency (HF; p = 0.0001), and LF/HF (p < 0.001) resulted between male and female vegetarians. Significance of LF (p = 0.02), HF (p < 0.0001), and LF/HF (p < 0.01) was measured between male vegetarians and female nonvegetarians. LF (p = 0.02), HF (p = 0.04), and LF/HF (p = 0.002) resulted between nonvegetarian males and females. HF (p = 0.05) was enumerated between male vegetarians and nonvegetarians.Conclusions: Significant predominance of sympathetic cardiac activity was observed among male nonvegetarian consumers more than female vegetarians. Analysis demonstrates that the gender-based influence of vegetarian and nonvegetarian diet has significant correlation under HRV measurements.

4,4'-Diisothiocyanatostilbene-2,2'-disulfonate modulates voltage-gated K+ current and influences cell cycle arrest in androgen sensitive and insensitive human prostate cancer cell lines.

The stilbene derivative, 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), an anion channel blocker is used in the present study to evaluate its modulatory effect on voltage-gated K+ current (IK) in human prostate cancer cell lines (LNCaP and PC-3). Voltage-gated K+ (KV) channels in the plasma membrane are critically involved in the proliferation of tumor cells. Therefore, KV channels are considered as a novel potential target for cancer treatment. The results of the present study show that the external perfusion of DIDS activates IK in a concentration-dependent manner, although the known K+ channel blocker TEA failed to block the DIDS activated IK in PC-3 cells. Whereas, in LNCaP cells, the higher concentration of DIDS blocked IK, though this effect was not completely recovered after washout. The difference in function of DIDS might be due to the expression of different Kv channel isoforms in LNCaP and PC-3 cells. Further, the anticancer studies show that treatment of DIDS significantly induced G2/M phase cell cycle arrest and induced moderate and low level of cell death in LNCaP and PC-3 cells respectively. This finding reveals that DIDS modulates IK and exerts cell cycle arrest and cell death in LNCaP and PC-3 cells.

Modulatory Effect of Selected Dietary Phytochemicals on Delayed Rectifier K+ Current in Human Prostate Cancer Cells.

Phytochemicals are ubiquitous in naturally occurring dietary elements that exhibits diverse pharmacological properties over various pathological disorders, including cancer. Voltage gated K+ (KV) channel in the plasma membrane contributes to wide range of cellular processes including cancer progression. Therefore, modulation of KV channel is being considered as a novel potential target for cancer therapy. The whole cell patch clamp technique was used to record the modulatory effect of chrysin, naringenin, caffeic acid, gallic acid, and zingerone on delayed rectifier potassium current (IK) in human prostate cancer cells LNCaP and PC-3. Among the tested compounds, zingerone blocked IK in a concentration-dependent manner in LNCaP cells and estimated the IC50 value of 141 µM and Emax was 81.3%. Further analysis of KV channel activation kinetics showed that zingerone induces a positive shift in the activation curve in LNCaP cells, whereas the inhibitory effect of gallic acid on IK was significantly less potent than the inhibition caused by zingerone. However, chrysin, naringenin, and caffeic acid did not modulate the KV channel conductance in LNCaP or PC-3 cells. Our findings confirmed that not all the tested phytochemicals to be effective modulators of IK and suggested that IK inhibitory effect of zingerone and gallic acid may be responsible for their anticancer effects in prostate cancer cells.

Piperine blocks voltage gated K+ current and inhibits proliferation in androgen sensitive and insensitive human prostate cancer cell lines.

Piperine is an attractive therapeutic alkaloid from black pepper that exhibits a broad spectrum of pharmacological properties over various pathological disorders including cancer. Voltage gated K+ (KV) channels play an important role in regulating cancer cell proliferation and are considered as potential target for cancer treatment. However, the implication of piperine in KV associated anticancer activities on human prostate cancer cells LNCaP and PC-3 remains unrevealed. The electrophysiological and pharmacological data identifies that both androgen sensitive (LNCaP) and insensitive (PC-3) prostate cancer cells typically expressed voltage gated K+ current (IK). This current was significantly blocked by piperine in a concentration-dependent manner with an IC50 value 39.91 µM in LNCaP and 49.45 µM in PC-3 cells. Analysis of voltage-dependence of activation kinetics showed that piperine induces a positive shift in the relative activation curve in both the cells. Piperine also depolarized the resting membrane potential by an average of 10.2 mV and 8.3 mV in LNCaP and PC-3 cells, respectively. The anticancer studies showed that, treatment with piperine concentration dependently induced G1 phase cell cycle arrest and apoptosis in LNCaP and PC-3 cells. These results unravel that the IK inhibition might be responsible for the anticancer effect of piperine on androgen sensitive and insensitive human prostate cancer cells.

Anticancer mechanism of troxerutin via targeting Nrf2 and NF-κB signalling pathways in hepatocarcinoma cell line.

Troxerutin (TX), a bioflavonoid widely present in various fruits and vegetables, has shown to exhibit numerous pharmacological properties including anti-neoplastic and anti-cancer activities. Nrf2 and NF-κB are the key transcription factors that regulate oxidative stress and inflammation, therefore we assessed whether TX modulate these pathways and its downstream proteins in HuH-7 hepatocarcinoma cells. TX induced apoptotic cellular and nuclear changes were examined by fluorescence staining techniques, agarose gel electrophoresis and flow cytometry. Oxidative stress was determined through biochemical analysis of antioxidant enzymes and lipid peroxidation profile. The protein expressions of NF-κB and Nrf2 pathway regulators, cell proliferation markers and apoptotic pathway mediators were evaluated by performing immunoblotting, immunocytochemistry and molecular docking. Our results revealed that TX inhibits the growth of HuH-7 cells in a concentration and time-dependent manner. TX treated HuH-7 cells exhibited increased heme oxygenase (HO)-1 protein expression, augmented nuclear translocation of Nrf2, and reduced oxidative stress. Furthermore, TX suppressed the expression of IKKß which subsequently inhibited the nuclear translocation of NF-κB (p65 subunit), and thus downregulated NF-κB mediated inflammatory responses, proliferation and cell survival. Collectively, our results indicate that TX exerts anti-cancer effect in HuH-7 hepatocarcinoma cells possibly through simultaneous regulation of the molecular signalling pathways, Nrf2 and NF-κB.

Troxerutin subdues hepatic tumorigenesis via disrupting the MDM2-p53 interaction.

Hepatocellular carcinoma (HCC) is the leading cause of cancer death worldwide that lacks proper medical prognosis and treatment. In the present study, the anti-tumoral potential of troxerutin (TX), an ethnomedicine, was examined in relation to its effects on the promoter 2-acetylaminofluorene (2-AAF) in N-nitrosodiethylamine (NDEA) initiated HCC, as compared to its effects on HCC induced by NDEA alone. Liver samples from each experimental group were collected and evaluated for histological, biochemical and cellular characterization. The protein expressions of apoptotic and cell proliferation markers were determined via immunohistochemistry and western blotting. Molecular docking was also performed to delineate the inhibitory mechanism of TX on HCC. The results show that only higher doses of TX showed a significant reduction in the incidence of hepatic nodule formation, and they also counteracted NDEA plus 2-AAF induced alterations in the enzymic status. The frequencies of glutathione-S-transferase and proliferating cell nuclear antigen, markers of S phase progression, were markedly reduced during TX treatment. TX also modulated the imbalance in the MDM2-p53 interaction. The molecular docking results confirmed the interaction of TX with the upstream kinases that regulate apoptosis. This study provides evidence that a copious dose of TX is required to counteract the differential mitoinhibitory effect of 2-AAF in NDEA initiated hepatomas, and TX exhibits an anti-tumoral effect via suppressing oxidative stress, regulating liver function enzymes, inhibiting inflammatory responses and modulating MDM2-p53 interactions, thus inducing apoptosis, and thereby suggesting that TX may provide promising therapeutic effects for the chemoprevention of HCC.

Asiatic acid attenuates pre-neoplastic lesions, oxidative stress, biotransforming enzymes and histopathological alterations in 1,2-dimethylhydrazine-induced experimental rat colon carcinogenesis.

Asiatic acid (AA), a pentacyclic triterpenoid, derived from the tropical medicinal plant Centella asiatica is known to exhibit numerous pharmacological properties. We hypothesized that AA will have chemopreventive potential against 1,2-dimethylhydrazine (DMH)-induced experimental colon carcinogenesis in male Wistar rats. Rats were arbitrarily divided into six groups. Group I rats were processed as control. Group II rats received AA (8 mg/kg b.w., p.o.) and groups III-VI rats received subcutaneous injections of DMH (20 mg/kg b.w.) once a week, for the first four weeks. In addition, groups IV-VI rats received AA at the doses of 2, 4 and 8 mg/kg b.w., respectively, for 16 weeks. Our results discovered that supplementation with AA to the DMH-exposed rats significantly decreased the incidence of polyps and Aberrant crypt foci (ACF) as compared to the DMH-alone-exposed rats. Moreover, in the AA-supplemented DMH-exposed rats, we ascertained increased activities of the antioxidants and decreased levels of lipid peroxidation (LPO) in the liver and circulation and enhanced levels of both LPO and antioxidants in the colon, which were altered in the DMH-alone-exposed rats. Furthermore, we also observed altered activities of vitamins C and E and biotransforming enzymes in DMH-alone-exposed rats, which were reversed on AA supplementation. All the observations were supported by our histological findings. Thus, we can conclude that, AA could be used as an effective chemopreventive agent against DMH-induced colon carcinogenesis.

The in vivo antineoplastic and therapeutic efficacy of troxerutin on rat preneoplastic liver: biochemical, histological and cellular aspects.

PURPOSE: Troxerutin (TXER), a trihydroxyethylated derivative of the natural bioflavonoid rutin, abundantly found in tea, various fruits and vegetables, is known to exhibit ample pharmacological properties. In the present investigation, we examined the antineoplastic, therapeutic efficacy and furthermore the possible mechanisms of action of TXER against NAFLD/NASH progression to hepatocarcinogenesis. METHODS: The effect of TXER (12.5, 25 or 50 mg/kg b.w/day) was evaluated on the nitrosodiethylamine (NDEA) model of hepatocarcinogenesis in rats, after 16 weeks of oral treatment, with special focus on liver specific enzymes, xenobiotic metabolizing enzymes, antioxidant status, lipid peroxidation profile, DNA damage, fibrosis, cell proliferation and inflammatory status. RESULTS: Administration of TXER to hepatocellular carcinoma-bearing rats restored the enzyme activities and the hepatic architecture. Furthermore, TXER significantly curtailed NDEA-induced DNA damage, cell proliferation, inflammation, fibrosis and hepatic hyperplasia. CONCLUSION: This study provides the evidence that troxerutin exerts a significant therapeutic effect against liver cancer by modulating liver function enzymes, xenobiotic enzymes, oxidative damage, inhibiting cell proliferation, suppressing inflammatory response and induction of apoptosis.

Pulmonary surfactant mitigates silver nanoparticle toxicity in human alveolar type-I-like epithelial cells.

Accompanying increased commercial applications and production of silver nanomaterials is an increased probability of human exposure, with inhalation a key route. Nanomaterials that deposit in the pulmonary alveolar region following inhalation will interact firstly with pulmonary surfactant before they interact with the alveolar epithelium. It is therefore critical to understand the effects of human pulmonary surfactant when evaluating the inhalation toxicity of silver nanoparticles. In this study, we evaluated the toxicity of AgNPs on human alveolar type-I-like epithelial (TT1) cells in the absence and presence of Curosurf(®) (a natural pulmonary surfactant substitute), hypothesising that the pulmonary surfactant would act to modify toxicity. We demonstrated that 20nm citrate-capped AgNPs induce toxicity in human alveolar type I-like epithelial cells and, in agreement with our hypothesis, that pulmonary surfactant acts to mitigate this toxicity, possibly through reducing AgNP dissolution into cytotoxic Ag(+) ions. For example, IL-6 and IL-8 release by TT1 cells significantly increased 10.7- and 35-fold, respectively (P<0.01), 24h after treatment with 25µg/ml AgNPs. In contrast, following pre-incubation of AgNPs with Curosurf(®), this effect was almost completely abolished. We further determined that the mechanism of this toxicity is likely associated with Ag(+) ion release and lysosomal disruption, but not with increased reactive oxygen species generation. This study provides a critical understanding of the toxicity of AgNPs in target human alveolar type-I-like epithelial cells and the role of pulmonary surfactant in mitigating this toxicity. The observations reported have important implications for the manufacture and application of AgNPs, in particular for applications involving use of aerosolised AgNPs.

Molecular aspects and chemoprevention of dimethylaminoazobenzene-induced hepatocarcinogenesis: A review.

The lipophilic azo dye dimethylaminoazobenzene (DAB) is a potent hepatocarcinogen accounted as a group-2B carcinogen causing risk to humans. DAB is commonly used as a coloring agent in food, pharmaceuticals, beverages, soap and polishes. The exploration of DAB-induced hepatocarcinogenesis in animal models helped to an extent to perceive the histological, biochemical and molecular mechanisms of DAB carcinogenesis and also the severity of DAB exposure to humans. In experimental animal models, it is well-proved that the procarcinogen DAB is predominantly metabolized by cytochrome P450 enzymes giving rise to the formation of toxic electrophiles and reactive oxygen species (ROS), which further forms DNA adducts leading to the development of hepatic tumors. Recently, research evidence suggests that dietary phytochemicals and plant polyphenols are promising agents to control the incidence of DAB-induced hepatocarcinogenesis by preventing the generation of toxic electrophiles and ROS thereby inhibiting the formation of DNA adducts. This review highlights the role of specific dietary factors, biotransformation of DAB, phenotypic and genotypic alterations, and significance of certain chemopreventive agents against DAB-induced hepatocarcinogenesis.

Radioprotective Effect of Carvacrol Against X-Radiation-Induced Cellular Damage in Cultured Human Peripheral Blood Lymphocytes.

In the present study, we evaluated the radioprotective effect of carvacrol (CVC) against X-radiation-induced cellular damage in cultured human blood lymphocytes. By MTT assay, the LD50 doses of CVC and X-radiation to lymphocytes were determined to be 100 µg/ml and 4 Gy, respectively. To explore the radioprotective effect of CVC, the cultured lymphocytes were treated with 100 µg/mL of CVC 30 min prior to 4 Gy irradiation. Subsequently, the radiation-induced damage was screened by micronuclei (MN) and dicentric chromosome (DC) frequencies and comet assay. The percentage of cell death was evaluated by acridine orange/ethidium bromide (AO/EB) staining. The radiation-induced oxidative stress was estimated by assessing the changes in the levels of enzymatic antioxidants and lipid peroxidation markers. Compared with the sham control, we observed increases in MN and DC frequencies, comet attributes, % cell death, and lipid peroxidation with a concomitant decrease in the antioxidant status of the lymphocytes treated with radiation alone. Pre-treatment of lymphocytes with CVC (100 µg/mL) altered those changes mediated by radiation. These results clearly indicate that CVC may be an effective radioprotector against X-radiation. It has the ability to scavenge the free radicals produced and to protect cells from radiation-induced cell damage.

Combined therapeutic efficacy of carvacrol and X-radiation against 1,2-dimethyl hydrazine-induced experimental rat colon carcinogenesis.

Colon cancer is one of the most commonly diagnosed cancers, and is a major cause of cancer morbidity and mortality worldwide. The objective of the present study is to evaluate the combined therapeutic efficacy of carvacrol (CVC) and X-radiation against 1,2-dimethylhydrazine-induced colon cancer. Male albino Wistar rats were randomly divided into six groups. Group 1 served as control; group 2 received 40 mg/kg b.wt of CVC orally everyday throughout the experimental period (32 weeks); groups 3-6 received subcutaneous injections of DMH (20 mg/kg b.wt), once a week for the first 15 weeks; group 4 received a single dose of X-radiation at the 31st week; group 5 received CVC (40 mg/kg b.wt) two days after the last injection of DMH and continued everyday till the end of the experimental period; group 6 received CVC as in group 5 and radiation as in group 4. DMH-treated rats showed increased incidence of aberrant crypt foci (ACF), dysplastic aberrant crypt foci (DACF), mast cell number, argyrophilic nucleolar organizer regions; elevated activities of phase I enzymes, decreased activities of phase II enzymes, decreased mucin content and altered colonic and liver histology as compared to control rats. Though the individual treatments with CVC and X-radiation to DMH-treated rats reversed the above changes, the combined treatment with both CVC and X-radiation showed a marked effect. Our findings emphasize the potential role of combined therapeutic effect of CVC and X-radiation against DMH-induced colon carcinogenesis.

Psychological Insulin Resistance in Patients with Type 2 Diabetes.

AIMS/HYPOTHESIS: To identify risk factors associated with psychological insulin resistance (PIR) in Indian type 2 diabetes (T2DM) population. METHODS: Patients with T2DM, aged 18 years, undergoing treatment with oral hypoglycaemic agents and providing written informed consent were considered eligible for the study. Patient's data was collected by face-to-face interaction using 5 validated diabetes questionnaires--Diabetes Attitude Scale, Diabetes Knowledge Test, Diabetes Self-Efficacy Scale, Interpersonal Processes of Care Survey-29, and Barriers to Insulin Treatment scale. Demographic variables, categories of patients based on their annual family income, education, glycosylated haemoglobin (HbA1c), occupation and type of healthcare setup were correlated with overall scores of validated questionnaires. Statistical analyses were performed using Pearson correlation coefficients, analysis of variance, two-group t-test and hierarchical multiple regression. RESULTS: One hundred ninty-eight patients with T2DM were enrolled where 63% were males, 52% had HbA1c <7% (<53 mmol/mol), 32% were in service, 35% had the annual family income between Rs 100,000-500,000, 50% were graduates and 81% were enrolled from private healthcare set ups. Significant high opposition to use insulin was observed in females, patients based at home, patients with insufficient education, and patients visiting government set-ups compared to males, service-class patients, graduates, and patients approaching private set-ups, respectively. CONCLUSIONS: In India, major factors contributing to PIR were fear of injection or fear of pain during injection, fear of hypoglycemia, social stigma and lack of education. Effective interpersonal interactions with healthcare providers could help to counteract PIR, especially in patients who are not sufficiently literate highlighting the need of skilled healthcare staffs in Indian public hospitals.