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Role of surface-exposed charged basic amino acids (Lys, Arg) and guanidination in insulin on the interaction and stability of insulin-insulin receptor complex

Lee VS, Sukumaran SD, Tan PK, Kuppusamy UR, Arumugam B

Comput Biol Chem, 2021 Jun;92:107501.
PMID: 33989998 DOI: 10.1016/j.compbiolchem.2021.107501

Naturally occurring proteins are emerging as novel therapeutics in the protein-based biopharmaceutical industry for the treatment of diabetes and obesity. However, proteins are not suitable for oral delivery due to short half-life, reduced physical and chemical stability and low permeability across the membrane. Chemical modification has been identified as a formulation strategy to enhance the stability and bioavailability of protein drugs. The present study aims to study the effect of charge-specific modification of basic amino acids (Lys, Arg) and guanidination on the interaction of insulin with its receptor using molecular modelling. Our investigation revealed that the guanidination of insulin (Lys-NHC = NHNH2) enhanced and exerted stronger binding of the protein to its receptor through electrostatic interaction than native insulin (Lys-NH3+). Point mutations of Lys and Arg (R22, K29; R22K, K29; R22, K29R; R22K, K29R) were attempted and the effects on the interaction and stability between insulin/modified insulins and insulin receptor were also analyzed in this study. The findings from the study are expected to provide a better understanding of the possible mechanism of action of the modified protein at a molecular level before advancing to real experiments.

Matched MeSH terms: Receptor, Insulin/chemistry*
Crosstalk between insulin and Toll-like receptor signaling pathways in the central nervous system

Hemmati F, Ghasemi R, Mohamed Ibrahim N, Dargahi L, Mohamed Z, Raymond AA, et al.

Mol Neurobiol, 2014 Dec;50(3):797-810.
PMID: 24464263 DOI: 10.1007/s12035-013-8631-3

Neuroinflammation is known as a key player in a variety of neurodegenerative and/or neurological diseases. Brain Toll-like receptors (TLRs) are leading elements in the initiation and progression of neuroinflammation and the development of different neuronal diseases. Furthermore, TLR activation is one of the most important elements in the induction of insulin resistance in different organs such as the central nervous system. Involvement of insulin signaling dysregulation and insulin resistance are also shown to contribute to the pathology of neurological diseases. Considering the important roles of TLRs in neuroinflammation and central insulin resistance and the effects of these processes in the initiation and progression of neurodegenerative and neurological diseases, here we are going to review current knowledge about the potential crosstalk between TLRs and insulin signaling pathways in neuroinflammatory disorders of the central nervous system.

Matched MeSH terms: Receptor, Insulin/metabolism*
Evaluation of hypoglycemic activity and toxicity profiles of the leaves of Ficus deltoidea in rodents

Ilyanie Y, Wong TW, Choo CY

J Complement Integr Med, 2011 Jan;8.
PMID: 22754938 DOI: 10.2202/1553-3840.1469

Ficus deltoidea Jack (Moraceae) leaf extract is used as an antidiabetic in traditional medicine. Its widespread usage is reflected by the available preparations in the present commercial market. The efficacy of other Ficus species has not been entirely satisfactory and many antidiabetic herbs have demonstrated poor safety profiles. This study examined hypoglycemic and toxicity profiles of F. deltoidea leaf extract in rodent models. Extracts of dried powdered leaves were obtained using methanol solution, n-hexane, chloroform, and n-butanol. These extracts were orally administered to rodents. Their blood glucose and insulin levels, acute and subchronic toxicity, biochemical and histological profiles of liver and kidney were determined. Methanol extract exhibited blood glucose lowering activity in mildly insulin resistant diabetic rats as well as in normoglycemic mice unlike hydrophilic butanol subextract which only expressed its activity in normoglycemic mice. Methanol extract could contain both insulin receptor sensitization and secretagogue constituents. Different from toxic chloroform and hexane subextracts, hydrophilic methanol extract gave zero percent mortality up to 6400 mg/kg in 14 days. It did not induce liver and kidney toxicity upon four-week consumption at 200 mg/kg. The methanol extract possessed mixed antidiabetic actions and exhibited a low level of oral toxicity.

Matched MeSH terms: Receptor, Insulin/metabolism
Molecular basis of the anti-diabetic properties of camel milk through profiling of its bioactive peptides on dipeptidyl peptidase IV (DPP-IV) and insulin receptor activity

Ashraf A, Mudgil P, Palakkott A, Iratni R, Gan CY, Maqsood S, et al.

J Dairy Sci, 2021 Jan;104(1):61-77.
PMID: 33162074 DOI: 10.3168/jds.2020-18627

The molecular basis of the anti-diabetic properties of camel milk reported in many studies and the exact active agent are still elusive. Recent studies have reported effects of camel whey proteins (CWP) and their hydrolysates (CWPH) on the activities of dipeptidyl peptidase IV (DPP-IV) and the human insulin receptor (hIR). In this study, CWPH were generated, screened for DPP-IV binding in silico and inhibitory activity in vitro, and processed for peptide identification. Furthermore, pharmacological action of intact CWP and their selected hydrolysates on hIR activity and signaling and on glucose uptake were investigated in cell lines. Results showed inhibition of DPP-IV by CWP and CWPH and their positive action on hIR activation and glucose uptake. Interestingly, the combination of CWP or CWPH with insulin revealed a positive allosteric modulation of hIR that was drastically reduced by the competitive hIR antagonist. Our data reveal for the first time the profiling and pharmacological actions of CWP and their derived peptides fractions on hIR and their pathways involved in glucose homeostasis. This sheds more light on the anti-diabetic properties of camel milk by providing the molecular basis for the potential use of camel milk in the management of diabetes.

Matched MeSH terms: Receptor, Insulin/metabolism*
Fulltext Development of a novel in vitro insulin resistance model in primary human tenocytes for diabetic tendinopathy research

Tan HY, Tan SL, Teo SH, Roebuck MM, Frostick SP, Kamarul T

PeerJ, 2020;8:e8740.
PMID: 32587790 DOI: 10.7717/peerj.8740

Background: Type 2 diabetes mellitus (T2DM) had been reported to be associated with tendinopathy. However, the underlying mechanisms of diabetic tendinopathy still remain largely to be discovered. The purpose of this study was to develop insulin resistance (IR) model on primary human tenocytes (hTeno) culture with tumour necrosis factor-alpha (TNF-α) treatment to study tenocytes homeostasis as an implication for diabetic tendinopathy.
Methods: hTenowere isolated from human hamstring tendon. Presence of insulin receptor beta (INSR-β) on normal tendon tissues and the hTeno monolayer culture were analyzed by immunofluorescence staining. The presence of Glucose Transporter Type 1 (GLUT1) and Glucose Transporter Type 4 (GLUT4) on the hTeno monolayer culture were also analyzed by immunofluorescence staining. Primary hTeno were treated with 0.008, 0.08, 0.8 and 8.0 µM of TNF-α, with and without insulin supplement. Outcome measures include 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) assay to determine the glucose uptake activity; colourimetric total collagen assay to quantify the total collagen expression levels; COL-I ELISA assay to measure the COL-I expression levels and real-time qPCR to analyze the mRNA gene expressions levels of Scleraxis (SCX), Mohawk (MKX), type I collagen (COL1A1), type III collagen (COL3A1), matrix metalloproteinases (MMP)-9 and MMP-13 in hTeno when treated with TNF-α. Apoptosis assay for hTeno induced with TNF-α was conducted using Annexin-V FITC flow cytometry analysis.
Results: Immunofluorescence imaging showed the presence of INSR-β on the hTeno in the human Achilles tendon tissues and in the hTeno in monolayer culture. GLUT1 and GLUT4 were both positively expressed in the hTeno. TNF-α significantly reduced the insulin-mediated 2-NBDG uptake in all the tested concentrations, especially at 0.008 µM. Total collagen expression levels and COL-I expression levels in hTeno were also significantly reduced in hTeno treated with 0.008 µM of TNF-α. The SCX, MKX and COL1A1 mRNA expression levels were significantly downregulated in all TNF-α treated hTeno, whereas the COL3A1, MMP-9 and MMP-13 were significantly upregulated in the TNF-α treated cells. TNF-α progressively increased the apoptotic cells at 48 and 72 h.
Conclusion: At 0.008 µM of TNF-α, an IR condition was induced in hTeno, supported with the significant reduction in glucose uptake, as well as significantly reduced total collagen, specifically COL-I expression levels, downregulation of candidate tenogenic markers genes (SCX and MKX), and upregulation of ECM catabolic genes (MMP-9 and MMP-13). Development of novel IR model in hTeno provides an insight on how tendon homeostasis could be affected and can be used as a tool for further discovering the effects on downstream molecular pathways, as the implication for diabetic tendinopathy.

Matched MeSH terms: Receptor, Insulin
Fulltext Maternal Cognitive Impairment Associated with Gestational Diabetes Mellitus-A Review of Potential Contributing Mechanisms

John CM, Mohamed Yusof NIS, Abdul Aziz SH, Mohd Fauzi F

Int J Mol Sci, 2018 Dec 05;19(12).
PMID: 30563117 DOI: 10.3390/ijms19123894

Gestational diabetes mellitus (GDM) carries many risks, where high blood pressure, preeclampsia and future type II diabetes are widely acknowledged, but less focus has been placed on its effect on cognitive function. Although the multifactorial pathogenesis of maternal cognitive impairment is not completely understood, it shares several features with type 2 diabetes mellitus (T2DM). In this review, we discuss some key pathophysiologies of GDM that may lead to cognitive impairment, specifically hyperglycemia, insulin resistance, oxidative stress, and neuroinflammation. We explain how these incidents: (i) impair the insulin-signaling pathway and/or (ii) lead to cognitive impairment through hyperphosphorylation of τ protein, overexpression of amyloid-β and/or activation of microglia. The aforementioned pathologies impair the insulin-signaling pathway primarily through serine phosphorylation of insulin receptor substances (IRS). This then leads to the inactivation of the phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) signaling cascade, which is responsible for maintaining brain homeostasis and normal cognitive functioning. PI3K/AKT is crucial in maintaining normal cognitive function through the inactivation of glycogen synthase kinase 3β (GSκ3β), which hyperphosphorylates τ protein and releases pro-inflammatory cytokines that are neurotoxic. Several biomarkers were also highlighted as potential biomarkers of GDM-related cognitive impairment such as AGEs, serine-phosphorylated IRS-1 and inflammatory markers such as tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), leptin, interleukin 1β (IL-1β), and IL-6. Although GDM is a transient disease, its complications may be long-term, and hence increased mechanistic knowledge of the molecular changes contributing to cognitive impairment may provide important clues for interventional strategies.

Matched MeSH terms: Receptor, Insulin
Fulltext Association between polymorphisms of insulin and insulin receptor gene with childhood obesity in malay population

Christinal Teh Pey Wen, Nurul Adibah Nizam, Abdul Rahman Jamal, Wan Zurinah Wan Ngah, Chong, Pei Nee, Poh, Bee Koon

Jurnal Sains Kesihatan Malaysia, 2016;14(1):5-9.
MyJurnal

Childhood obesity is a global epidemic, which leads to the increasing number of studies on genetic locations associated with obesity-related traits. Polymorphisms of insulin (INS) gene have been shown to be associated with obesity-related phenotypes in Europeans; while insulin receptor (INSR) gene has been associated with energy regulation. Therefore, this study was conducted to investigate the association between the INS (rs689) and INSR (rs3745551) gene polymorphisms with childhood obesity risk in a Malay childhood population. Normal weight (538) and overweight or obese (557) children aged 6-12 years old were genotyped using semi-automated Sequenom iPLEX® Gold. Body mass index (BMI) was calculated from measured body weight and height. The rs689 (T/T: 0.006, A/T: 0.159 and A/A: 0.835) and rs3745551 (G/G: 0.054, A/G: 0.378 and A/A: 0.568) genotype distributions were consistent with Hardy Weinberg equilibrium. The T-minor allele frequency for rs689 was 8.6% and G-minor allele frequency for rs3745551 was 24.3%. Minor allele of INS gene polymorphisms significantly increased risk of obesity among Malay children (sex- and age-adjusted
OR=1.580; 95%CI: 1.134-2.201). However, INSR gene polymorphisms were not significantly associated with childhood obesity. In conclusion, the polymorphisms of INS gene, rather than INSR gene, were associated with childhood obesity in the Malay population.

Matched MeSH terms: Receptor, Insulin
Insulin Receptor Isoform Variations in Prostate Cancer Cells

Perks CM, Zielinska HA, Wang J, Jarrett C, Frankow A, Ladomery MR, et al.

Front Endocrinol (Lausanne), 2016;7:132.
PMID: 27733843

Men who develop prostate cancer (PCa) increasingly have one of the co-morbidities associated with a Western lifestyle that are characterized by hyperinsulinemia, hyperglycemia and increased expression of insulin-like growth factors-I (IGF-I) and IGF-II. Each have been associated with poor prognosis and more aggressive cancers that exhibit increased metabolism and increased glucose uptake. The insulin receptor (IR) has two splice isoforms IR-A and IR-B: IR-A has a higher affinity for IGF-II comparable to that for insulin, whereas the IR-B isoform predominantly just binds to insulin. In this study, we assessed alterations in the IR-A and IR-B isoform ratio and associated changes in cell proliferation and migration of PCa cell lines following exposure to altered concentrations of glucose and treatment with IGF-II and insulin. We observed that where IR-B predominated insulin had a greater effect on migration than IGF-II and IGF-II was more effective when IR-A was the main isoform. With regard to proliferation IGF-II was more effective than insulin regardless of which isoform was dominant. We assessed the abundance of the IR isoforms both in vivo and in vitro and observed that the majority of the tissue samples and cell lines expressed more IR-A than IR-B. Alterations in the isoforms in response to changes in their hormonal milieu could have a profound impact on how malignant cells behave and play a role in promoting carcinogenesis. A greater understanding of the mechanisms underlying changes in alternative splicing of the IR may provide additional targets for future cancer therapies.

Matched MeSH terms: Receptor, Insulin
Fulltext Polymorphisms at Locus 4p14 of Toll-Like Receptors TLR-1 and TLR-10 Confer Susceptibility to Gastric Carcinoma in Helicobacter pylori Infection

Ravishankar Ram M, Goh KL, Leow AH, Poh BH, Loke MF, Harrison R, et al.

PLoS One, 2015;10(11):e0141865.
PMID: 26559190 DOI: 10.1371/journal.pone.0141865

Helicobacter pylori (H. pylori) -induced gastric inflammation impacts the functions of leptin- and ghrelin-producing cells in the gastroduodenum. Inflammation resulting from H. pylori sensing via Toll-like receptors (TLRs) and the associated downstream signaling largely remain ambiguous. Here, we investigated the role of gut hormones, pro-inflammatory cytokines and single nucleotide polymorphisms (SNPs) associated with TLR 4p14 in H. pylori disease in 30 subjects with non-ulcer dyspepsia (NUD), 40 with peptic ulcer disease (PUD) and 15 with gastric cancer (GC) subjects positive and negative for H. pylori infection. The level of pro-inflammatory cytokines was directly proportional to the severity of gastritis, and disease status influenced the levels of gut hormones and pro-inflammatory cytokines. TLR-1 SNPs rs4833095 and TLR-10 SNPs rs10004195 and were directly associated with H. pylori disease, and were up-regulated in the presence of H. pylori in a genotype-independent manner. We concluded that TLR-1 rs4833095 and TLR10 rs10004195 confer susceptibility to development of gastroduodenal disease, especially GC in H.pylori disease.

Matched MeSH terms: Receptor, Insulin/blood
Coumarin-chalcone hybrids targeting insulin receptor: Design, synthesis, anti-diabetic activity, and molecular docking

Konidala SK, Kotra V, Danduga RCSR, Kola PK

Bioorg Chem, 2020 11;104:104207.
PMID: 32947135 DOI: 10.1016/j.bioorg.2020.104207

Four series of thirteen new coumarin-chalcone hybrids (DPCU 1-13, DPCT 1-13, DCCU 1-13 and DCCT 1-13) were designed and synthesized using Biginelli synthesis, Pechmann condensation, Acetylation, and Claisen-Schmidt reactions. Synthesized compounds were tested for insulin receptor in silico docking studies (PDB ID: 1IR3); DCCU 13 and DCCT 13 derivatives received the lowest docking score; Streptozocin (STZ) and Nicotinamide (NA) induced type II diabetes was tested for their anti-diabetic activity in rats. In vivo tests suggested that fasting blood glucose levels of animals treated with DCCU 13 (30 mg/kg body weight) and DCCT 13 (30 mg/kg body weight) were significantly and moderately suppressed, respectively, relative to fasting blood glucose levels of diabetic control animals. Similarly, therapy with DCCU 13 and DCCT 13 attenuated oxidative stress parameters such as lipid peroxidation (MDA), superoxide dismutase (SOD) and increased the glutathione (GSH) in the liver and pancreas in a dose-dependent manner. In comparison, therapy with DCCU 13 (30 mg/kg body weight) mitigated alterations in the histological architecture of the liver and pancreatic tissue. These results indicated that the hybrids DUUC 13 and DCCT 13 at 30 mg/kg had an anti-hyperglycemic and antioxidant impact on STZ + NA mediated type II diabetes in rats. Further detailed work could be required to determine the precise mode of action of the anti-diabetic behavior of hybrids.

Matched MeSH terms: Receptor, Insulin/antagonists & inhibitors*

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