Chronic Hyperglycemic Conditions Research Articles

Sustained exposure to high glucose induces differential expression of cellular senescence markers in murine macrophages but impairs immunosurveillance response to senescent cells secretome.

The influence of chronic diseases on various facets of macrophage cellular senescence is poorly understood. This study evaluated the impact of chronic hyperglycemia on the induction of cellular senescence and subsequent immunosurveillance functions in RAW264.7 macrophages. Macrophages were cultured under normal glucose (NG; 5mM), high glucose (HG; 20mM), and very high glucose (VHG; 40mM) conditions and assessed for markers of cellular senescence. Hyperglycemia induced strong upregulation of SA-β-gal activity, and loss ofPCNAandLamin B1gene expression while markers of cell cycle arrest generally decreased. Non-significant changes in SASP-related proteinswere observed while ROS levels slightly decreased and mitochondrial membrane potential increased. Protein concentration on the exosome membrane surface and their stability appeared to increase under hyperglycemic conditions. However, when macrophages were exposed to the secretory media (SM) of senescent preadipocytes, a dramaticincrease in the levels of all inflammatory proteins was recorded especially in the VHG group that was also accompanied by upregulation of NF-κB and NLRP3 gene expression. SM treatment to hyperglycemic macrophages activated theTLR-2/Myd88pathway but decreased the expression of scavenger receptorsRAGE, CD36, andOlr-1whileCD44andCXCL16expression increased. On exposure to LPS, a strong upregulation in NO, ROS, and inflammatory cytokines was observed. Together, these results suggest that primary markers of cellular senescence are aberrantly expressed under chronic hyperglycemic conditions in macrophages with no significant SASP activation. Nonetheless, hyperglycemia strongly deregulates macrophage functions leading to impaired immunosurveillance of senescent cells and aggravation of inflamm-aging. This work provides novel insights into howhyperglycemia-induced dysfunctions can impact the potency of macrophages to manage senescent cell burden in aging tissues.

Identification of isobenzofuranone derivatives as promising antidiabetic agents: Synthesis, in vitro and in vivo inhibition of α-glucosidase and α-amylase, computational docking analysis and molecular dynamics simulations

Diabetes mellitus, one of the major health challenges of the 21st century, is associated with numerous biomedical complications including retinopathy, neuropathy, nephropathy, cardiovascular diseases and liver disorders. To control the chronic hyperglycemic condition, the development of potential inhibitors of drug targets such as α-glucosidase and α-amylase remains a promising strategy and focus of continuous efforts. Therefore, in the present work, a concise library of isobenzofuranone derivatives (3a-q) was designed and synthesized using Suzuki-Miyaura cross-coupling approach. The biological potential of these heterocyclic compounds against carbohydrate-hydrolyzing enzymes; α-glucosidase and α-amylase, was examined. In vitro inhibitory results demonstrated that the tested isobenzofuranones were considerably more effective and potent inhibitors than the standard drug, acarbose. Compound 3d having an IC50 value of 6.82 ± 0.02 μM was emerged as the lead candidate against α-glucosidase with ⁓127-folds strong inhibition than acarbose. Similarly, compound 3g demonstrated ⁓11-folds higher inhibition strength against α-amylase when compared with acarbose. Both compounds were tested in vivo and results demonstrate that the treatment of diabetic rats with α-amylase inhibitor show more pronounced histopathological normalization in kidney and liver than with α-glucosidase inhibitor. The Lineweaver-Burk plot revealed an uncompetitive mode of inhibition for 3d against α-glucosidase whereas compound 3g exhibited mixed inhibition against α-amylase. Furthermore, in silico molecular docking and dynamics simulations validated the in vitro data for these compounds whereas pharmacokinetics profile revealed the druglike properties of potent inhibitors.

Food attitude among pregnant women with type 2 diabetes in the Kingdom of Saudi Arabia

Background: Diabetes mellitus (DM) is a chronic hyperglycemic condition attributed to defective insulin secretion, action, or both. Pregnant women with Type 2 Diabetes Mellitus (DM2) should adopt positive food attitudes to help them control their diet and glucose levels, thus avoiding serious complications that can affect both the pregnant women and their infants. The current study aims to assess food attitudes among pregnant women with type 2 DM in the Kingdom of Saudi Arabia. Methods: A cross-sectional study was conducted in Saudi Arabia during 2022, targeting all pregnant women with type 2 DM. The sample size was 243, with a margin of error determined as 5% and a confidence level of 95%. Data were collected using an electronic Google Form questionnaire initiated by the study researchers with the help of field experts. Results: Data analysis revealed that there were 243 pregnant women with type 2 diabetes. The participants\' average weight was 74.7 kg (±20.77), while the average age of the women was 39.08 (±9.96). More than 50% of study participants correctly answered at least nine questions (out of a total of 11 questions, with bold percentages indicating adequate food awareness). Participants who had previously experienced pregnancy difficulties demonstrated sufficient awareness, which was found to be statistically significant (p=0.03) when compared to other independent variables. Conclusion: Although more than half of the pregnant females demonstrated good dietary awareness about diabetes, no statistical significance could be established. The results of this study are not consistently in line with published studies. Social campaigns and programs to increase awareness and education among pregnant women with T2DM are advisable to reduce complications for both the mother and child.

Role of Ayurveda in the Management of Diabetes Mellitus: A Comprehensive Review to explore the awareness

Diabetes mellitus (DM) is very oldest and common metabolic disease, characterized by a chronic hyperglycemic condition over a prolong extent of time. The disease is resulting due to insufficient insulin secretion or defects in insulin action or both. Diabetes is classified under non communicable disease (NCD) and it is referred as fourth most common among all NCDs. Diabetes is one of the leading causes of mortality in India and near about one million patients are died every year due to diabetes. The prevalence of diabetic is increasing rapidly worldwide and WHO (world health organization) has predicted that by the end of 2030, the number of adults with diabetes would have almost doubled, from 177 million in 2000 to 370 million Diabetes is mainly classified under two classes Type-1 and Type-2 DM. In the late 1936, a distinction between Type-1 and Type-2 DM was clearly made. Type-1 diabetes is a result of an autoimmune reaction to proteins of islets cells of pancreas and Type-2 is result of impaired insulin resistance. Genetic and some environmental factors such as overeating, stress, obesity and lack of physical exercise, smoking may also play a key role in development of DM. There are various treatment approach are being used to reduce the burden of DM worldwide. These approaches include modern medicines (allopathic), Ayurvedic therapies and gene therapy. Ayurvedic system of treatment is a holistic science which is discovered several years ago and plays a very important role in the management of DM. Ayurvedic therapies are able to provide permanent cure of certain chronic disease are, which remains incurable in allopathic systems. Present review article aims to highlight the role of ayurveda in management of DM.

Neuroprotective effect of Hibiscus sabdariffa extract against high glucose-induced toxicity in Neuro-2a cells and Caenorhabditis elegans

BACKGROUND: Chronic hyperglycemic conditions can activate aberrant metabolic pathways causing neurotoxicity. OBJECTIVE: This study aimed to explore the effect of ethanol extract of Hibiscus sabdariffa calyxes (HS) against high glucose-induced neurotoxicity in Neuro-2a cells and Caenorhabditis elegans. METHODS: To ascertain the neuroprotective effect, Neuro-2a cells were pre-treated with HS followed by high glucose and assessed for cell viability, reactive oxygen species (ROS) generation, alterations in mitochondrial membrane potential (ΔΨm) using confocal microscopy, Real-Time PCR, Western blot and in silico approaches for the compounds identified through LC-MS/MS analysis. Further, C. elegans were treated with HS extract in the presence of glucose and analyzed for the neuroprotective effect. RESULTS: High glucose exhibited toxicity in Neuro-2a cells by ROS generation, disrupting ΔΨm, modulating stress response and lipid metabolism genes, altering signaling proteins (AKT, JNK), and apoptosis (P53, Caspase-3). However, pre-treatment with HS extract reversed the effect and exhibited neuroprotection. Compounds including allo-Aromadendrene, and N-Feruloyltyramine were identified through LC-MS/MS analysis. Docking studies against candidate protein targets indicated that the compounds of HS extract exhibit higher docking scores and can inhibit/activate the targets. Further, HS extended the lifespan of C. elegans (CL2006) from high glucose toxicity through the downregulation of A β. CONCLUSION: Our results propose that HS with its active constituents can be considered a promising therapeutic agent to treat hyperglycemia associated neurodegenerative diseases.

Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems

BackgroundHuman serum albumin (HSA) is the most abundant plasma protein and is sensitive to glycation in vivo. The chronic hyperglycemic conditions in patients with diabetes mellitus (DM) induce a nonenzymatic Maillard reaction that denatures plasma proteins and forms advanced glycation end products (AGEs). HSA-AGE is a prevalent misfolded protein in patients with DM and is associated with factor XII activation and downstream proinflammatory kallikrein-kinin system activity without any associated procoagulant activity of the intrinsic pathway. ObjectivesThis study aimed to determine the relevance of HSA-AGE toward diabetic pathophysiology. MethodsThe plasma obtained from patients with DM and euglycemic volunteers was probed for activation of FXII, prekallikrein (PK), and cleaved high-molecular-weight kininogen by immunoblotting. Constitutive plasma kallikrein activity was determined via chromogenic assay. Activation and kinetic modulation of FXII, PK, FXI, FIX, and FX via in vitro–generated HSA-AGE were explored using chromogenic assays, plasma-clotting assays, and an in vitro flow model using whole blood. ResultsPlasma obtained from patients with DM contained increased plasma AGEs, activated FXIIa, and resultant cleaved cleaved high-molecular-weight kininogen. Elevated constitutive plasma kallikrein enzymatic activity was identified, which positively correlated with glycated hemoglobin levels, representing the first evidence of this phenomenon. HSA-AGE, generated in vitro, triggered FXIIa-dependent PK activation but limited the intrinsic coagulation pathway activation by inhibiting FXIa and FIXa-dependent FX activation in plasma. ConclusionThese data indicate a proinflammatory role of HSA-AGEs in the pathophysiology of DM via FXII and kallikrein-kinin system activation. A procoagulant effect of FXII activation was lost through the inhibition of FXIa and FIXa-dependent FX activation by HSA-AGEs.

Potential Therapeutic Effect of TLR4-Primed Mesenchymal Stem Cells in Lessening Kidney Damages in Rat Model of Diabetic Nephropathy

Background and Aims: Substantial damage to the kidney tissue and diabetic nephropathy (DN) can be caused by chronic hyperglycemic conditions and exposure to a high level of blood glucose. In the current study, we explored the capability of adipose-derived mesenchymal stem cells (ADSCs) and Toll-like receptor-4-primed mesenchymal stem cells (TLR4-primed MSCs) on kidney regeneration, resolution of inflammation, and alleviation of diabetic nephropathy in DN in the rats.
 Materials and Methods: STZ-induced diabetic rat models were divided into 5 subgroups, including 1) DN group, 2) DN group received insulin, 3) DN group received human foreskin fibroblast (DN-HFF), 4) DN group received single pulse of 1×106 cells of MSCs and 5) DN group received single pulse of TLR4-primed MScs. Thereafter, biochemical and histological analysis was performed on DN-model groups. Biochemical analysis exhibited a blood urea nitrogen level recovery in both MSCs and TLR4-primed MSCs-treated groups. Administration of MSCs also up-regulated mRNA expression of Bcl-xL, while the expression of Bax was significantly down-regulated.
 Results: Histological and molecular results showed that TLR4-primed MSCs have an anti-inflammatory and anti-apoptotic effect on inflamed kidneys and effectively reduced DN indicators in the TLR4-primed MSCs group compared to the unprimed MSCs group.
 Conclusion: Priming with LPS improves the therapeutic effects of MSCs in the rat model of DN, consequently lessening the symptoms of DN rats. This study proposes that primed MSCs can be served as a potential therapeutic approach in diabetes mellitus and DN management.

Orphan GPR26 Counteracts Early Phases of Hyperglycemia-Mediated Monocyte Activation and Is Suppressed in Diabetic Patients.

Diabetes is the ninth leading cause of death, with an estimated 1.5 million deaths worldwide. Type 2 diabetes (T2D) results from the body’s ineffective use of insulin and is largely the result of excess body weight and physical inactivity. T2D increases the risk of cardiovascular diseases, retinopathy, and kidney failure by two-to three-fold. Hyperglycemia, as a hallmark of diabetes, acts as a potent stimulator of inflammatory condition by activating endothelial cells and by dysregulating monocyte activation. G-protein couple receptors (GPCRs) can both exacerbate and promote inflammatory resolution. Genome-wide association studies (GWAS) indicate that GPCRs are differentially regulated in inflammatory and vessel cells from diabetic patients. However, most of these GPCRs are orphan receptors, for which the mechanism of action in diabetes is unknown. Our data indicated that orphan GPCR26 is downregulated in the PBMC isolated from T2D patients. In contrast, GPR26 was initially upregulated in human monocytes and PBMC treated with high glucose (HG) levels and then decreased upon chronic and prolonged HG exposure. GPR26 levels were decreased in T2D patients treated with insulin compared to non-insulin treated patients. Moreover, GPR26 inversely correlated with the BMI and the HbA1c of diabetic compared to non-diabetic patients. Knockdown of GPR26 enhanced monocyte ROS production, MAPK signaling, pro-inflammatory activation, monocyte adhesion to ECs, and enhanced the activity of Caspase 3, a pro-apoptotic molecule. The same mechanisms were activated by HG and exacerbated when GPR26 was knocked down. Hence, our data indicated that GPR26 is initially activated to protect monocytes from HG and is inhibited under chronic hyperglycemic conditions.

A Critical Review on Role of Available Synthetic Drugs and Phytochemicals in Insulin Resistance Treatment by Targeting PTP1B

Insulin resistance (IR) is a condition of impaired response of cells towards insulin. It is marked by excessive blood glucose, dysregulated insulin signalling, altered pathways, damaged pancreatic β-cells, metabolic disorders, etc. Chronic hyperglycemic conditions leads to type 2 diabetes mellitus (T2DM) which causes excess generation of highly reactive free radicals, causing oxidative stress, further leading to development and progression of complications like vascular dysfunction, damaged cellular proteins, and DNA. One of the causes for IR is dysregulation of protein tyrosine phosphatase 1B (PTP1B). Advancements in drug therapeutics have helped people manage IR by regulating PTP1B, however have been reported to cause side effects. Therefore, there is a growing interest on usage of phytochemical constituents having IR therapeutic properties and aiding to minimize these complications. Medicinal plants have not been utilized to their full potential as a therapeutic drug due to lack of knowledge of their active and effective chemical constituents, mode of action, regulation of IR parameters, and dosage of administration. This review highlights phytochemical constituents present in medicinal plants or spices, their potential effectiveness on proteins (PTP1B) regulating IR, and reported possible mechanism of action studied on in vitro models. The study gives current knowledge and future recommendations on the above aspects and is expected to be beneficial in developing herbal drug using these phytochemical constituents, either alone or in combination, for medication of IR and diabetes.

Chest X-Ray pattern and lung severity score in COVID-19 patients with diabetes mellitus: A cross sectional study

BackgroundDiabetes mellitus is a chronic hyperglycemic condition that can affect the body's immune response to SARS-CoV-2 This study aimed to determine the relationship between diabetes mellitus and lung severity in COVID-19 patients. Methods: A cross-sectional design was conducted at Hasan Sadikin General Hospital during the January–May 2021 period. Data were based on medical records of patients aged 18 years and over with COVID-19. The chi-square test was performed to assess the relationship between diabetes mellitus and lung severity based on the BRIXIA score. Results: This study included 538 subjects, mostly aged <60 years (71.9%) and female (60.2%). A total of 125 subjects had abnormal blood glucose levels with an average HbA1c of 9.00 ± 1.77% in patients with diabetes mellitus and a median HbA1c of 5.85% (4.5–6.4%) in patients with reactive hyperglycemia. Lung abnormalities were found in 357 subjects (66.4%). The results of the BRIXIA score to assess lung severity found as many as 77 subjects (14.3%) had a score of 11–18 with 14 people with diabetes mellitus, five people with reactive hyperglycemia. In the population aged ≥60 years, as many as 32 people had a score of 11–18 with three people with diabetes mellitus, two with reactive hyperglycemia and 27 with normal blood glucose. A significant relationship was found between diabetes mellitus and lung severity (p = 0.024). Conclusion: There is a significant relationship between diabetes mellitus and lung severity in COVID-19 patients aged ≥60 years.

Pathogenesis Aspects of Microvascular Complications in Diabetic Retinopathy: Narrative Literature Review

Chronic hyperglycemic conditions in diabetes mellitus can cause changes that result in chronic complications, both macrovascular and microvascular. There are several mechanisms thought to cause microvascular damage and retinopathy in diabetes, namely the polyol pathway, formation of advanced glycation end products (AGE), activation of protein kinase C (PKC), oxidative stress, and increased activity of the hexosamine pathway.

Aktivitas Antibakteri Ekstrak dan Fraksi dari Ekstrak Metanol Daun Manggis (Garcinia mangostana) pada Bakteri Penyebab Ulkus Diabetik

Diabetes mellitus (DM) is a degenerative disease due to metabolic disorders with acute to chronic hyperglycemic conditions. The complication of this disease is peripheral neuropathy exacerbated by bacterial infection, causing ulcers (sores) on the feet, hands, knees, back, and other parts of the body. The mangosteen plant (Garcinia mangostana) is empirically believed to have antidiabetic and cure diabetic ulcers. This study aims to compare the antibacterial activity of extracts and fractions of methanol extract of mangosteen leaves at concentrations of 20%, 40%, 60%, 80%, and 100% against the bacteria causing diabetic ulcers in vitro. The research began with the maceration of mangosteen leaf powder extraction using methanol as a solvent. The fractions were obtained by the vacuum liquid chromatography (KCV) method. The bacteria that cause diabetic ulcers are obtained from ulcer specimens of diabetic ulcer patients. Antibacterial activity of extracts and fractions at 5 concentration series was tested using the disc diffusion method with 10% DMSO negative control and positive controls, namely Amoxicillin, Ampicillin, Ciprofloxacin, Cefotaxime, Gentamycin, Erythromycin, and Doxycycline. Antibacterial activity was expressed by the large area of the inhibition zone on the media inoculated with ulcer bacteria and incubated for 24 hours at 370 C. The results showed that there were 5 dominant bacteria found in the diabetic ulcer specimens, namely Escherichia spp, Klebsiella spp, Staphylococcus spp, salmonella spp, and Shigella spp. The results of the antibacterial sensitivity test showed that ciprofloxacin had the largest area of inhibition zone compared to Amoxicillin, Ampicillin, Cefotaxime, Gentamycin, Erythromycin, and Doxycycline so that Ciprofloxacin could be used as a positive control. The results of the antibacterial activity test for the methanol extract of mangosteen leaves with a concentration of 100% produced the largest inhibition zone, namely 27.10 mm ± 0.1 compared to methanol extract, fractions A, B, and C in all concentration series. However, the inhibition zone of the 100% concentration of mangosteen leaves methanol extract was smaller than the positive control of ciprofloxacin 5 μg / disk, which was 35.01 mm ± 0.1.

Hypolipidemic Effects of Rosa Damascena Mill. Extract in Streptozotocin-induced Diabetic Rats

Background: Diabetes mellitus is a chronic hyperglycemic condition with a lot of complication which canlead to death. Vascular complication in diabetes commonly caused by dyslipidemia which characterizedby decreased HDL, elevated LDL, Cholesterol and Triglyceride. Rosa damascena- an ornamental plantthoughts to have anti-hyperglycemia and antioxidant effects because of its large amount of polyphenoliccomponents . This study analyzed hypolipidemic activity properties of an ethanol extract of Rosa damascenaby measuring the lipid profile using various doses. Methods: This research is experimental study withrandomized post-test only control group design. Twenty male Wistar rats divided into 5 groups; The groupswere Healthy Control Group (HCG), Diabetes Group (DG), and Extract Group: P1 (250 mg/kgBW), P2(500 mg/kgBW), P3 (1000 mg/kgBW). All treatment groups were injected by single-dose streptozotocin50 mg/kgBW to induce diabetes, and given the Rosa damascena ethanolic extract oral treatment for 2weeks. Statistical results showed that Rosa damascena significantly decrease cholesterol (58.2±15.19), LDL(11±2.44) optimally in dose 250 mg/KgBW and triglyceride (96.7±44.2) optimally in dose 500 mg/kgBWafter 14 days. Conclusion: Rosa damascena extract seems to be great candidate for anti-hyperlipidemicdrugs.

&lt;p&gt;&lt;strong&gt;Correlation between prolidase activity and spatial memory functions in &lt;/strong&gt;&lt;strong&gt;streptozotocin-induced diabetic rats&lt;/strong&gt;&lt;/p&gt;

The aim of the present study is to investigate the association of prolidase activity in streptozotocin (STZ) induced diabetic rat model with hippocampus-dependent spatial memory functions in chronic hyperglycemic conditions. Towards this, a single dose of STZ (30mg/kg, i.p) was administered to four-month-old female Sprague Dawley rats and hyperglycemia was confirmed in all the STZ treated rats. To assess the spatial memory, at the time intervals of 9 days, 30 days and 90 days post STZ administration, the animals were subjected to Barnes maze task. Prolidase activity and glucose concentration in the serum were measured at these time points. With prolonged duration of hyperglycemia, severe impairment in spatial memory functions was seen in STZ-rats which was co-relatable with reduction in prolidase levels (P<0.05) thus suggesting that the alterations in synaptic integrity due to prolidase mediated extracellular matrix remodeling as the possible mechanism of memory defects seen in chronic diabetes.

Potential Biological Activities of &lt;i&gt;Clausena&lt;/i&gt; Essential Oils for the Treatment of Diabetes

Diabetes mellitus constitutes one of the most important public health problems. It is defined as a metabolic disorder characterized by a chronic hyperglycemic condition. The inhibition of α-glucosidase and inflammation effects is still considered a strategy for the treatment of diabetes. The aim of this study was to search for new and effective natural functional foods agents for the complementary treatment of diabetes and other related complications. The essential oils from the leaves of three Clausena plants collected in Thailand: C. harmandiana, C. guillauminii and C. excavata were obtained by hydrodistillation. The chemical compositions, antioxidant, anti-α-glucosidase and anti-inflammatory activities of these essential oils were evaluated. The C. excavata and C. harmandiana essential oils contained seselin and terpinen-4-ol, respectively, as the major components and showed strong inhibition of DPPH free radical, α-glucosidase, lipoxygenase and nitric oxide activities with the IC50 values ranging from 0.031±0.005 to 0.702±0.003 mg/mL. From these results, it may be concluded that seselin and terpinen-4-ol are important for high antioxidant, anti-α-glucosidase, and anti-inflammatory activities. Therefore, these Clausena essential oils may be useful in industrial applications for the treatment of diabetes and other related complications.

AGE-RAGEsynergy influences programmed cell death signaling to promote cancer.

Advanced glycation end products (AGEs) are formed as a result of non-enzymatic reaction between the free reducing sugars and proteins, lipids, or nucleic acids. AGEs are predominantly synthesized during chronic hyperglycemic conditions or aging. AGEs interact with their receptor RAGE and activate various sets of genes and proteins of the signal transduction pathway. Accumulation of AGEs and upregulated expression of RAGE is associated with various pathological conditions including diabetes, cardiovascular diseases, neurodegenerative disorders, and cancer. The role of AGE-RAGE signaling has been demonstrated in the progression of various types of cancer and other pathological disorders. The expression of RAGE increases manifold during cancer progression. The activation of AGE-RAGE signaling also perturbs the cellular redox balance and modulates various cell death pathways. The programmed cell death signaling often altered during the progression of malignancies. The cellular reprogramming of AGE-RAGE signaling with cell death machinery during tumorigenesis is interesting to understand the complex signaling mechanism of cancer cells. The present review focus on multiple molecular paradigms relevant to cell death particularly Apoptosis, Autophagy, and Necroptosis that are considerably influenced by the AGE-RAGE signaling in the cancer cells. Furthermore, the review also attempts to shed light on the provenienceof AGE-RAGE signaling on oxidative stress and consequences of cell survival mechanism of cancer cells.

The safety and efficacy of Momordica charantia L. in animal models of type 2 diabetes mellitus: A systematic review and meta-analysis.

Type 2 diabetes mellitus is a chronic hyperglycemic condition due to progressively impaired glucose regulation. Momordica charantia L. could potentially improve hyperglycemia because its fruit extracts can alleviate insulin resistance, beta-cell dysfunction, and increase serum insulin level. We evaluated the effect of M. charantia L. in comparison with a vehicle on glycemic control in animal models of type 2 diabetes mellitus. MEDLINE, Web of Science, Scopus, and CINAHL databases were searched without language restriction through April 2019. About 66 studies involving 1861 animals that examined the effect of M. charantia L. on type 2 diabetes mellitus were included. Fruits and seed extracts reduced fasting plasma glucose (FPG) and glycosylated hemoglobin A1c in comparison to vehicle control: (42 studies, 815 animals; SMD, -6.86 [95% CI; -7.95, -5.77], 3 studies, 59 animals; SMD; -7.76 [95% CI; -12.50, -3.01]) respectively. Also, the extracts have hepato-renal protective effects at varying doses and duration of administration. Despite the observed significant glycemic control effect, poor methodological quality calls for future researches to focus on standardizing extract based on chemical markers and adopt measures to improve the quality of preclinical studies such as sample size calculation, randomization, and blinding.

A Review on Mechanistic and Pharmacological Findings of Diabetic Peripheral Neuropathy including Pharmacotherapy.

Chronic hyperglycemia and related complications involving peripheral nerves in diabetes are one of the most severe microvascular complications with an average prevalence of 50-60%. Diabetic neuropathy is among the vascular disorders of diabetes, the most debilitating and crippled, lethal condition impacting patients's quality of life. In the present review article, several hypotheses associated with the pathogenesis of Diabetic Peripheral Neuropathy (DPN) have been introduced, among them metabolic pathways associated with polyol pathway, oxidative stress, production of reactive oxygen species (ROS) amplified under chronic hyperglycemic conditions and activation of transcription factor Nuclear factor-κB (NF- κB). The review article also possesses pathogenetic and pharmacologic treatments along with others, including acupressure, lidocaine, and capsaicin for DPN. It may be concluded that we can combat the pathogenesis of DPN with different suggested treatments.

Human islet amyloid polypeptide (hIAPP) - a curse in type II diabetes mellitus: insights from structure and toxicity studies.

The human islet amyloid polypeptide (hIAPP) or amylin, a neuroendocrine peptide hormone, is known to misfold and form amyloidogenic aggregates that have been observed in the pancreas of 90% subjects with Type 2 Diabetes Mellitus (T2DM). Under normal physiological conditions, hIAPP is co-stored and co-secreted with insulin; however, under chronic hyperglycemic conditions associated with T2DM, the overexpression of hIAPP occurs that has been associated with the formation of amyloid deposits; as well as the death and dysfunction of pancreatic β-islets in T2DM. Hitherto, various biophysical and structural studies have shown that during this process of aggregation, the peptide conformation changes from random structure to helix, then to β-sheet, subsequently to cross β-sheets, which finally form left-handed helical aggregates. The intermediates, formed during this process, have been shown to induce higher cytotoxicity in the β-cells by inducing cell membrane disruption, endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, islet inflammation, and DNA damage. As a result, several research groups have attempted to target both hIAPP aggregation phenomenon and the destabilization of preformed fibrils as a therapeutic intervention for T2DM management. In this review, we have summarized structural aspects of various forms of hIAPP viz. monomer, oligomers, proto-filaments, and fibrils of hIAPP. Subsequently, cellular toxicity caused by toxic conformations of hIAPP has been elaborated upon. Finally, the need for performing structural and toxicity studies in vivo to fill in the gap between the structural and cellular aspects has been discussed.

Influence of a state of chronic hyperglycemia on guided bone regeneration—A systematic review of studies on animal-models

• The aim was to systematically review the influence of chronic hyperglycemia on GBR. • Ten studies on animal-models were included. • In animal models, GBR is effective under hyperglycemic conditions. • The clinical efficacy of GBR in hyperglycemic patients needs further investigations. The aim was to systematically review indexed literature regarding the influence of a state of chronic hyperglycemia on guided bone regeneration (GBR). The addressed focused question was "What is the influence of a state of chronic hyperglycemia on GBR?”. Databases were searched using different combinations of the following key words: “hyperglycemia”, “diabetes”, “guided bone regeneration”, “bone formation”. Full-texts of articles judged by title and abstract to be relevant were read and independently evaluated for the eligibility criteria. Letters to the editor, historic reviews, case reports, case-series and unpublished articles were excluded. Ten experimental studies involving animal-models were included. Six studies were performed in rats and four studies were performed in rabbits. Total number of subjects ranged from 14 to 68 animals with a mean age range of 4 to 22 weeks. GBR was performed on maxillary, mandibular and parietal bones in one, one and eight studies respectively. Substances used for GBR included polytetrafluoroethylene (PTFE) membrane, titanium reinforced PTFE membrane, porous chitosan scaffold, methyl methacrylate hemispheres and titanium domes. Four studies showed comparable outcomes for new bone formation (NBF), among diabetics with GBR and healthy animals. Four out of five studies showed comparable outcomes in terms of NBF at follow up among animals in the diabetic and control-groups. Two studies showed comparable amounts of NBF in animals with poorly- and well-controlled diabetes after GBR. In animal-models with experimental diabetes, GBR is effective in inducing NBF; however, the effectiveness of GBR in patients with chronic hyperglycemic conditions (such as poorly controlled diabetes and prediabetes) warrants further studies.