Efficacy and safety of fixed dose combination of Sitagliptin, metformin, and pioglitazone in type 2 Diabetes (IMPACT study): a randomized controlled trial.

BACKGROUND: Due to the progressive decline in ß-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM). METHODS: In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0-11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability. RESULTS: Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (- 1.64) vs. MS (- 1.32); between groups was [- 0.32% (95% CI, - 0.59, - 0.05)], P = 0.0208. Similar reductions were found in FPG [- 13.2 mg/dL (95% CI, - 22.86, - 3.71)], P = 0.0068, and PPG [- 20.83 mg/dL (95% CI, - 34.11, - 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug. CONCLUSION: The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM. TRIAL REGISTRATION: Clinical Trials Registry of India, CTRI/2021/10/037461.

Assessment of Biotransformed Silica Nanoparticle on Blood Glucose Level in Human: An In Vitro Investigation.

Diabetes has affected nearly half a billion people worldwide. According to current guidelines, glycemic control is essential to mitigate diabetic complications. The antihyperglycemic effects of various chemically synthesized nanoparticles have been reported in animal models. However, their impact on humans has not been previously reported. This study was conducted to biosynthesize and assess the antihyperglycemic property of silica nanoparticles (SiO2-NPs) since they are non-toxic and biocompatible. SiO2-NPs biosynthesized using the endophytic fungus Fusarium oxysporum. In this collaborative study, 26 people, either hyperglycemic or euglycemic, diagnosed at the Endocrinology Outpatients, according to the American Diabetes Association, USA, were recruited. Silica nanoparticles were characterized and assessed for in vitro antihyperglycemic property using blood samples. Particle size distribution based on TEM images confirms that the average size of silica nanoparticle is 25 nm and is monodispersed in nature. The XRD pattern shows that only one broad peak at 2θ = 220 corresponds to the plane (101) of silica nanoparticles. UV Visible spectra show the λmax at 270 nm, peaks in FTIR at 1536 cm-1, 1640 cm-1, and 3420 cm-1 for the protein cap. The mean blood glucose was 120.2 mg/dL in the 'SiO2-NP untreated' group and decreased to 97.24 mg/dL in the 'SiO2-NP treated' group. A paired t-test (P-value < 0.0001) indicates a strong relationship between antihyperglycemia and silica NP. In our study, it has been observed that the biosynthesized silica nanoparticles using the endophytic fungus Fusarium oxysporum show antihyperglycemic property in vitro.

Effect of Obstructive Sleep Apnea on Bone Mineral Density.

OBJECTIVE: Various studies have suggested that obstructive sleep apnea (OSA) affects bone metabolism. One of the most significant factors is hypoxia which induces certain transcription factors that stimulate bone osteoclastic activity. It also induces respiratory acidosis and oxidative stress which enhances bone resorption. Leptin and melatonin secretions are regulated by the circadian system which is affected due to sleep fragmentation in OSA. Other comorbidities associated with OSA such as vitamin D deficiency, hypogonadism, obesity, and insulin resistance are indirect mechanisms that affect bone mineral density (BMD). MATERIAL AND METHODS: This is a prospective case-control study. All patients having symptoms of sleep-related breathing disorder (excluding post-menopausal females or patients with known case of osteoporosis or any other clinical illness which is a direct cause of osteoporosis) attending the Sleep Out Patient Department (OPD) were screened for OSA as per the STOPBANG questionnaire scoring system. Participants having score >2 constituted the final study population and were subjected to the polysomnography test. Participants with an apnea-hypopnea index (AHI) > 5 in polysomnography were considered as cases and those with AHI <5 were considered as controls. Both the groups were then subjected for dual-energy X-ray absorptiometry (DEXA) scan and vitamin D to establish a comparison. RESULTS: Out of 93 participants, 59 were taken as cases (OSA group), whose mean age was 48.02 (±8.435) years, mean body mass index (BMI) was 33.73 (±7.48) kg/m2, mean neck circumference was 37.8 cm (±5.08) as compared with the age, sex, and BMI matched non-OSA control group (n = 34). Mean BMD in the case group was found to be significantly on the lower side as compared with the control group (-2.02 ± 1.09 vs. -1.03 ± 0.97) (P < .001) when compared in Z score, while (0.885 ± 0.535 vs. 0.933 ± 0.616) when compared in g/cm2 (P < .001), with negative correlation between AHI and BMD (r = -0.507, P < .001). Mean vitamin D level in the case group was at a lower level as compared to the control group (21.02 ± 7.27 vs. 24.48 ± 6.92, P < .05), with negative correlation between AHI and serum vitamin D level (P < .001, r = -0.286). CONCLUSION: OSA affects BMD by various pathophysiologic mechanisms. The AHI is inversely correlated with BMD; that is, with increasing severity of OSA, there is a decrease in BMD.

Biophysical and immunological characterization of 2-dRib modified HSA and its implications in diabetes mellitus.

Glycoxidation of protein may lead to develop diabetes. In the present study, different concentrations of 2-deoxy d-ribose (2-dRib) were used to modify human serum albumin (HSA). Nitro Blue Tetrazolium (NBT) assay results showed that yield of the fructosamine content was directly proportional to the concentration of 2-dRib. UV and fluorescence spectroscopy results showed an increment in hyperchromicity and decrease in fluorescence intensity of 2-dRib modified HSA as compared to native HSA. Further secondary structural changes were confirmed by UV-circular dichroism (UV-CD) and Fourier transform infrared spectroscopy (FT-IR). To evaluate the immunogenicity of 2-dRib modified HSA, rabbits were immunized with native and 2-dRib modified HSA. Modified HSA sera showed high antibodies titre as compared to native HSA. Moreover, the binding affinity of native and modified HSA with diabetic patient's sera has been evaluated by direct binding ELISA. It was found that diabetic patient's sera showed high binding affinity with the modified HSA as compared to native HSA. On the basis of above findings, it can be concluded that 2-dRib is a potential glycating agent that can cause alteration in HSA structure and make HSA more immunogenic that might play a role in onset and progression of diabetes mellitus and its complications.

Prevalence of thyroid disorders in North Indian Type 2 diabetic subjects: A cross sectional study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major health burden worldwide with many patients encountering thyroid dysfunction later in their life. Various studies have found that diabetes and thyroid disorders mutually influence each other and both disorders tend to coexists. However, the prevalence of thyroid dysfunction and associated clinical variables in these patients has not been investigated. OBJECTIVES: The study aimed at determining the incidence and prevalence of thyroid dysfunction in patients with T2DM in relation to age, sex, metabolic syndrome and other co-morbid conditions. RESEARCH DESIGNS & METHODS: In this cross-sectional study, 250 Type 2 DM patients were enrolled aged between 40 and 75 years. All the patients were evaluated for thyroid dysfunction by testing thyroid profile (T3, T4 and TSH. These subjects were also investigated for fasting blood sugar (FBS), post prandial glucose (PPG) glycosylated hemoglobin (HbA1c), serum cholesterol, serum triglycerides, high density lipoprotein (HDL), low density lipoprotein(LDL), very low density lipoprotein(VLDL), blood urea, serum creatinine and presence of other co-morbid conditions. The observations and interpretations were recorded and results obtained were statistically analyzed. RESULTS: A high prevalence of thyroid dysfunction (28%) was observed in type 2 diabetic patients with subclinical hypothyroidism (18.8%) as the commonest thyroid disorder. Thyroid dysfunction was more prevalent in females, with presence of dyslipidemia, retinopathy, poor glycemic state (HbA1c ≥7) and longer duration of diabetes as significant contributing factors associated. CONCLUSIONS: In addition to glycemic status, screening of thyroid disorder should be routinely done in type 2 diabetic subjects along with other comorbid conditions.

A study of bone turnover markers in gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes is defined as carbohydrate intolerance resulting in hyperglycemia of variable severity with the first recognition during pregnancy. Established risk factors for gestational diabetes mellitus (GDM) are maternal age, obesity, family history of diabetes, etc. Vitamin D, parathyroid hormone (PTH), and various other hormones are known for their function in maintaining calcium and phosphorous homeostatic. Furthermore, Vitamin D, PTH serum ionized calcium, and alkaline phosphatase (ALP) have been reported to be altered with glucose homeostasis. The present study compares the bone markers in pregnant women with and without gestational diabetes. MATERIALS AND METHODS: This cross-sectional study was conducted at outpatient antenatal check-up clinic and outpatient diabetic clinics at J. N. Medical College and Hospital, Aligarh. One hundred pregnant females, of which fifty with GDM and fifty without GDM, were included in the study from January 2014 to November 2015. Detailed history, physical examination, and anthropometric measurement were done. Bone turnover markers in the form of Vitamin D, parathyroid hormone, serum ionized calcium, and serum ALP were measured in pregnant women who had gestational diabetes which was compared with normal pregnant women. RESULTS: In our study, the mean age of participate of GDM group was 28.2 ± 3 years, while the mean age group in non-GDM group was 25.44 ± 2.78 years. Ionized calcium in GDM was found to be 4.606 ± 0.354 mEq/L, while in non-GDM, it was 4.548 ± 0.384 mEq/L, P = 0.430. Vitamin D came out to be 21.80 ± 9.48 ng/ml, while it was 32.346 ± 8.37 ng/ml in non-GDM group. Serum PTH in GDM group was 71.436 ± 36.189 pg/ml and 37.168 ± 8.128 pg/ml in nondiabetic gestational group. Serum ALP in GDM group was 9.1 ± 4.56 KA U/dl and 6.98 ± 2.2 KA U/dl in nondiabetic gestational group, P - 0.0038. In GDM group, there was a significant negative linear correlation between PTH and 25-hydroxyvitamin D with research correlation coefficient r = -0.9073, P = 0; there was a significant positive linear correlation coefficient between PTH and ALP with Persian correlation coefficient r = 0.6597, P = 0; there was no statistically significant correlation between PTH and ionized calcium r = 0.1416, P = 0.3267. CONCLUSION: All GDM subjects should ideally be screened for serum calcium, vitamin D, PTH, ALP. If found impaired should immediately be corrected in order to prevent its adverse effects on maternal and fetal outcome. Vitamin D supplementation should ideally be initiated in all GDM females even if the above parameters are not investigated in Indian setup.

Levels of anti-fructose-modified HSA antibodies correlate with disease status in diabetic subjects.

OBJECTIVE: This study aimed to assess the changes induced in HSA upon fructose-modification and to use the modified protein as an antigen for studying the presence of antibodies in diabetic patients. Further, magnitude of oxidative stress was also assessed. METHODS: HSA was modified with fructose, changes induced were studied by DSC measurements and near-UV CD. The binding characteristics of antibodies in the sera of diabetes patients to native and modified-HSA was assessed by ELISA and band shift assay. The oxidative stress in these patients was studied by carbonyl content estimation, FRAP assay and TBARS determination RESULTS: DSC revealed that fructose modified-HSA was more thermostable than its native form. Changes in tertiary structure of fructose-modified HSA were seen in near-UV CD. Patient studies showed that fructose-modified HSA acts as a potent immunogen compared to its native form and the levels of antibodies against fructose-modified HSA served as a parameter for tracking the glycemic control and oxidative stress parameters (carbonyl content, FRAP value and MDA level) in diabetic patients. CONCLUSIONS: Fructose-modification of HSA causes perturbations in its structure and function, thereby, making the protein antigenic besides decreasing its antioxidant capacity. This study suggests that fructose-modified-HSA is an important contributor in diabetic pathophysiology.

Fructosylation generates neo-epitopes on human serum albumin.

Hyperglycemia is the defining feature of diabetes mellitus. The persistently high levels of reducing sugars like glucose and fructose cause glycation of various macromolecules in the body. Human serum albumin (HSA), the most abundant serum protein with a myriad of functions, is prone to glycation and consequent alteration in its structural and biological properties. This study aimed to assess the role of fructose-modified human serum albumin as a marker of diabetic pathophysiology. We carried out modification of HSA with fructose and the changes induced were studied by various physicochemical studies. Fructose modified-HSA showed hyperchromicity in UV spectrum and increased AGE-specific fluorescence as well as quenching of tryptophan fluorescence. In SDS-PAGE protein aggregation was seen. Amadori products were detected by NBT. The fructose modified HSA had higher content of carbonyls along with perturbations in secondary structure as revealed by CD and FT-IR. A greater hydrodynamic radius of fructose-modified HSA was evident by DLS measurement. The fructose-modified HSA induced high titre antibodies in experimental animals exhibiting high specificity towards the immunogen.