Kanwal Rehman

Role of inflammatory mechanisms in pathogenesis of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is characterized by progressive β‐cell dysfunctioning and insulin resistance. This article reviews recent literature with special focus on inflammatory mechanisms that provoke the pathogenesis of T2DM. We have focused on the recent advances in progression of T2DM including various inflammatory mechanisms that might induce inflammation, insulin resistance, decrease insulin secretion from pancreatic islets and dysfunctioning of β‐cells. Here we have also summarized the role of various pro‐inflammatory mediators involved in inflammatory mechanisms, which may further alter the normal structure of β‐cells by inducing pancreatic islets apoptosis. In conclusion, it is suggested that the role of inflammation in pathogenesis of T2DM is crucial and cannot be neglected. Moreover, the insight of inflammatory responses in T2DM may provide a new gateway for the better treatment of diabetes mellitus. J. Cell. Biochem. 114: 525–531, 2013.

Recent progress in biomedical applications of Pluronic (PF127): Pharmaceutical perspectives.

Most of the administered anti-cancer drugs are hydrophobic in nature and are known to have poor water solubility, short residence time, rapid clearance from the body and systemic side effects. Polymeric-based targeted particulate carrier system has shown to directly deliver the encapsulated anti-cancer drug to the desired site of action and prevent the interaction of encapsulated drug with the normal cells. Pluronic F127 (PF127) has been widely investigated for its broad-range of therodiagnostic applications in biomedical and pharmaceutical sciences, but rapid dissolution in the physiological fluids, short residence time, rapid clearance, and weak mechanical strength are the main shortcomings that are associated with PF127 and have recently been overcome by making various modifications in the structure of PF127 notably through preparation of PF127-based mixed polymeric micelles, PF127-conjugated nanoparticles and PF127-based hydrophobically modified thermogels. In this article, we have briefly discussed the recent studies that have been conducted on various anti-cancer drugs using PF127 as nano-carrier modified with other copolymers and/or conjugated with magnetic nanoparticles. The key findings of these studies demonstrated that the modified form of PF127 can significantly increase the stability of incorporated hydrophobic drugs with enhanced in vitro cytotoxicity and cellular uptake of anti-cancer drugs. Moreover, the modified form of PF127 has also shown its therapeutic potentials as therodiagnostics in various types of tumors and cancers. Hence, it can be concluded that the modified form of PF127 exhibits significant therodiagnostic effects with increased tumor-specific delivery of anti-cancer drugs having minimal toxic effects as compared to PF127 alone and/or other copolymers.

Effects of coffee on type 2 diabetes mellitus

This review provides the epidemiologic and research evidences documenting the effects of coffee consumption on type 2 diabetes mellitus (T2DM). We summarize the literature concerning the effects of coffee consumption on different mechanistic factors involving in pathogenesis of T2DM, such as glucose tolerance, insulin sensitivity, insulin resistance, glucose-6-phosphatase, intestinal glucose absorption, antioxidant activity, inflammatory biomarkers, nuclear factor-κB inhibition, glucose uptake, glucose homeostasis, glucose metabolism, and insulin secretion. These factors play a crucial role in influencing the normal levels of glucose in blood. Overall, the experimental and epidemiologic evidences presented here elucidate the protective effects of coffee consumption on T2DM, involving multiple preventive mechanisms. Despite the firm evidences available through a growing literature base, it is still uncertain whether the use of coffee should be recommended to patients with diabetes and/or any patient who might be at the risk of T2DM as a supplementary therapy to prevent further progression of T2DM.

Sustained Delivery of IL-1Ra from Pluronic F127-Based Thermosensitive Gel Prolongs its Therapeutic Potentials

PurposePluronic F-127 (PF127) has previously shown to prolong the sustained release of various proteinous drugs and their serum half-lives. Subsequently, we have extended this approach to look at in vitro release, in vivo efficacy and pharmacokinetics of interleukin-1 receptor antagonist (IL-1Ra).MethodsVarious concentrations of PF127 gels were prepared using cold method. In vitro drug release kinetic studies were performed using membraneless dissolution method. Stability of IL-1Ra was assessed by SDS-PAGE. In vivo studies and in vivo bioactivity of IL-1Ra were also performed on wistar rats.ResultsIL-1Ra loaded PF127 gels showed in vitro sustained release of IL-1Ra, depending on the concentration of gel used. SDS-PAGE confirmed the stability of protein during its in vitro release. PF127 gel also exhibited prolonged release of IL-1Ra in rats as compared to that of IL-1Ra aq. solution. In vivo bioactivity of IL-1Ra loaded in gel was confirmed by its ability to inhibit IL-1β-stimulated induction of IL-6.ConclusionsWhen compared directly, IL-1Ra loaded PF127 gel exhibited prolonged in vitro and in vivo release, greater efficacy to induce hypoglycemia and inhibited IL-1β-stimulated production of IL-6 as compared to IL-1Ra aq. solution. We believe that this methodology for sustained delivery of IL-1Ra probably be suitable for the convenience of patients to achieve desired therapeutic potentials without exceeding dose limits and frequent administration.

Spice plant Allium cepa: Dietary supplement for treatment of type 2 diabetes mellitus

OBJECTIVE Diabetes mellitus (DM) is associated with significant morbidity and mortality and its prevalence is increasing worldwide. Although conventional antidiabetic agents are known to ameliorate the symptoms of diabetes, they also may cause adverse effects. The purpose of this review was to organize and discuss various studies that have been previously conducted indicating the efficacy of Allium cepa in DM. METHODS A comprehensive English literature search was conducted using various electronic search databases. Different search terms were used and an advanced search was conducted by combining all the search fields in abstracts, keywords, and titles. RESULTS Allium cepa, a spice plant, is commonly known as onion and belongs to the family liliaceae. Since ancient times, it has been used traditionally for the treatment of different diseases. Among various activities of Allium cepa, regulation of hypoglycemic activity is considered one of its important effects in DM. Sulfur compounds including S-methylcysteine and flavonoids such as quercetin are mainly responsible for the hypoglycemic activity of Allium cepa. S-methylcysteine and flavonoids help to decrease the levels of blood glucose, serum lipids, oxidative stress, and lipid peroxidation, as well as increasing antioxidant enzyme activity and insulin secretion. Extracts of onion also have been shown to have hypoglycemic and hypolipidemic effects by normalizing the activities of liver hexokinase, glucose 6-phosphatase and HMG coenzyme-A reductase. In preliminarily clinical trials, patients with diabetes safely consumed slices of Allium cepa, exhibiting sufficient hypoglycemic activity. In the future, further studies must be conducted to investigate and confirm the hypoglycemic activities of Allium cepa and its constituents and/or their synthetic analogs. CONCLUSION This review will not only elucidate the nutritious facts of Allium cepa but may also help in understanding the molecular basis of its effects in DM. This review will explore in particular the medicinal characteristics of Allium cepa supporting that the consumption of dietary onion could lower blood glucose levels, thus contributing to the reduction of risk factors associated with DM.

Goto-kakizaki Rats: Its Suitability as Non-obese Diabetic Animal Model for Spontaneous Type 2 Diabetes Mellitus

β-cell dysfunction and apoptosis are recognized as a major cause of insufficient insulin secretion in response to high blood glucose and metabolic demand. As a consequence, type 2 diabetes mellitus (T2DM) is known to occur. Taking into account the etiology of T2DM, to conduct investigational studies directly on human diabetic patients seems to be unsuitable; thereby, various animal models have been established to investigate the pathogenesis of T2DM. Among these models, Goto-Kakizaki (GK) rats have been considered as one of the best non-obese type 2 diabetic animal model. GK rats exhibit valuable characteristic tools that are more or less common and functionally present in human diabetic patients. This animal model is considered appropriate to inspect various pathologic mechanisms of T2DM. Thereby, in our present article, we have comprehensively summarized the information relating the characteristics of abnormalities including a description of assorted mechanisms involved in pathogenesis of T2DM in GK rats. This might help to investigate various aspects of spontaneous T2DM.

An Overview of Valuable Scientific Models for Diabetes Mellitus

Diabetes mellitus is one of the major clinical problems worldwide. Previously, most of the investigational studies for identification of disease and new therapies were based on animal studies; however, present research methods involve high throughput screening, molecular targeting, nanotechnology for recent discovery of drugs and disease identification to combat against hazardous diseases like diabetes mellitus. In this review, we have depicted outlines enfolding various disease-specific animal modeling, sensing technologies, biomarker analysis, and novel scientific techniques that could be helpful in exploring the impending strategies for diabetes detection and treatment. To conclude, we believe that endorsement and upgrading of such novel high throughput screening assays and nanotechnology described herein may surely represent a significant improvement in the capability for screening and identifying the population at elevated risk of expected diabetes. Thereby in future, appreciation of such investigational techniques and technologies including metabolomics and genetic screening may help in early prediction of diabetes in patients at risk and may display a significant improvement over the researchers conducted after the declaration of the disease.

Sustained Delivery of IL-1Ra from PF127-Gel Reduces Hyperglycemia in Diabetic GK-Rats

Interleukin-1beta (IL-1β) is a major cause for induction of various inflammatory mechanisms that are decisively involved to provoke pathogenesis of type 2 diabetes mellitus (T2DM). Interleukin-1 receptor antagonist (IL-1Ra) a naturally occurring anti-inflammatory antagonist of IL-1β has been recently approved for treatment of T2DM but due to its short half-life, higher doses and frequent dosing intervals are required. Pluronic F-127 (PF127) has previously shown to prolong the release of various proteinous drugs and their serum half-lives. Subsequently, in our previous work, we developed a new dosage form of IL-1Ra using PF127 and investigated its in-vitro and in-vivo effects. Here in present work, we have extended this approach using diabetic Goto-kakizaki (GK) rats. We administered IL-1Ra loaded in PF127 gel subcutaneously for one month into GK rats. IL-1Ra loaded in PF127 gel exhibited a sustained and prolonged hypoglycemic effects on treated animals. Intraperitoneal glucose tolerance test (IPGTT) results showed that IL-1Ra loaded in PF127 gel increased glucose tolerance along with increased insulin sensitivity and β-cell’s secretory function in treated rats. Moreover, significant reduction in pro-insulin/insulin ratio, lipid profiles and interleukin 6 (IL-6) were also observed. Immunohistochemical analysis showed slight macrophages infiltration in pancreatic islets. Histochemical analysis revealed no PF127-induced alteration in the normal physiology of skin and kidney of treated animals. Hence, we concluded that IL-1Ra loaded in PF127 gel has potential to exhibit broad spectrum anti-inflammatory effects alleviating the symptoms of T2DM.

Interleukin-1 receptor antagonist improves normoglycemia and insulin sensitivity in diabetic Goto-Kakizaki-rats

Type 2 diabetes mellitus has been considered as an auto-inflammatory syndrome. Interleukin-1 receptor antagonist (IL-1Ra) has attained considerable attention due to its broad spectrum anti-inflammatory therapeutic effects against various auto-immune diseases. The purpose of our study was to investigate its therapeutic effects of IL-1Ra on none-obese diabetic Goto-Kakizaki (GK) rats. We administered IL-1Ra subcutaneously for one month into GK rats. Insulin sensitivity and β-cell function was calculated by homeostatic model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) models. IL-1Ra decreased the onset of hyperglycemia and did not impact the body weight and/or food intake. Insulin tolerance test (ITT) and intraperitoneal glucose tolerance test (IPGTT) results showed that IL-1Ra improved insulin sensitivity and glucose tolerance. The results of HOMA and QUICKI models revealed that IL-1Ra improved insulin sensitivity and β-cell function. Moreover, significant reduction of pro-insulin/insulin ratio and lipid profiles also exhibited significant therapeutic effects of IL-1Ra. Immunohistochemical analysis showed minimal macrophage infiltration in pancreatic islets demonstrating decreased intra-islet inflammation in IL-1Ra treated GK rats. The results of our present study revealed that IL-1Ra has broad spectrum therapeutic potentials but due to its short biological half-life (6-8h) high doses with frequent dosing intervals are required. Therefore, there is a need for the development of such dosage form that may prolong its half-life via extended release.

The endoplasmic reticulum is a target organelle for trivalent dimethylarsinic acid (DMAIII)-induced cytotoxicity

The purpose of present study was to characterize the endoplasmic reticulum stress and generation of ROS in rat liver RLC-16 cells by exposing to trivalent dimethylarsinous acid (DMAIII) and compared with that of trivalent arsenite (iAsIII) and monomethylarsonous acid (MMAIII). Protein kinase-like endoplasmic reticulum kinase (PERK) phosphorylation was significantly induced in cells exposed to DMAIII, while there was no change in phosphorylated PERK (P-PERK) detected in cells after exposure to iAsIII or MMAIII. The generation of reactive oxygen species (ROS) after DMAIII exposure was found to take place specifically in the endoplasmic reticulum (ER), while previous reports showed that ROS was generated in mitochondria following exposure to MMAIII. Meanwhile, cycloheximide (CHX) which is an inhibitor of protein biosynthesis strongly inhibited the DMAIII-induced intracellular ROS generation in the ER and the phosphorylation of PERK, suggesting the induction of ER stress probably occurs through the inhibition of the protein folding process. Activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) mRNA were induced by all three arsenic species, however, evidence suggested that they might be induced by different pathways in the case of iAsIII and MMAIII. In addition, ER resident molecular chaperone glucose-regulated protein78 (GRP78) was not affected by trivalent arsenicals, while it was induced in positive control only at high concentration (Thapsigargin;Tg), suggesting the GRP78 is less sensitive to low levels of ER stress. In summary, our findings demonstrate that the endoplasmic reticulum is a target organelle for DMAIII-induced cytotoxicity.