Increased Insulin Receptor Research Articles

Sustained caloric restriction potentiates insulin action by activating prostacyclin synthase.

Caloric restriction (CR) is known to enhance insulin sensitivity and reduce the risk of metabolic disorders; however, its molecular mechanisms are not fully understood. This study aims to elucidate specific proteins and pathways responsible for these benefits. We examined adipose tissue from participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE 2) study, comparing proteomic profiles from individuals after 12 and 24 months of CR with baseline and an ad libitum group. Biochemical and cell-specific physiological approaches complemented these analyses. Our data revealed that CR upregulates prostacyclin synthase (PTGIS) in adipose tissue, an enzyme crucial for producing prostacyclin (PGI2). PGI2 improves the ability of insulin to stimulate the tether-containing UBX domain for GLUT4 (TUG) cleavage pathway, which is essential for glucose uptake regulation. Additionally, iloprost, a PGI2 analog, was shown to increase insulin receptor density on cell membranes, increasing glucose uptake in human adipocytes. CR also reduces carbonylation of GLUT4, a modification that is detrimental to GLUT4 function. CR enhances insulin sensitivity by promoting PTGIS expression and stimulating the TUG cleavage pathway, leading to increased GLUT4 translocation to the cell surface and decreased GLUT4 carbonylation. These findings shed light on the complex molecular mechanisms through which CR favorably impacts insulin sensitivity and metabolic health.

GAS6 and AXL Promote Insulin Resistance by Rewiring Insulin Signaling and Increasing Insulin Receptor Trafficking to Endosomes.

Growth-arrest specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL and MERTK). In humans, GAS6 circulating levels and genetic variations in GAS6 are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here, we show that Gas6 deficiency in mice increases insulin sensitivity and protects from diet-induced insulin resistance. Conversely, increasing GAS6 circulating levels is sufficient to reduce insulin sensitivity in vivo. GAS6 inhibits the activation of the insulin receptor (IR) and reduces insulin response in muscle cells in vitro and in vivo. Mechanistically, AXL and IR form a complex, while GAS6 reprograms signaling pathways downstream of IR. This results in increased IR endocytosis following insulin treatment. This study contributes to a better understanding of the cellular and molecular mechanisms by which GAS6 and AXL influence insulin sensitivity.

Shuangdong Capsule Activates Insulin Signal Pathway to Improve Urinary Tract Infection in Diabetic Rats.

Diabetes and Urinary Tract Infections (UTIs) are both common and serious health problems. Shuangdong capsule, a Chinese patent medicine, has been used to treat these conditions. This study assesses its efficacy and mechanism in treating diabetes combined with UTIs. We induced diabetes in rats using streptozotocin and UTIs with Escherichia coli, dividing the rats into five groups: control, model, levofloxacin, Shuangdong capsule, and levofloxacin + Shuangdong capsule. After two weeks, we measured blood glucose, insulin, infection indicators, and bladder histology. We also detected the expression of insulin receptor substrate 1 (IRS1)-phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)-C-X-C motif chemokine ligand 2 (CXCL2) signaling pathway by Western Blot and the myeloperoxidase (MPO) levels by Enzyme-Linked Immunosorbent Assay (ELISA). Additionally, we conducted a Mendelian randomization study using genetic variants of the insulin receptor to assess its causal effect on UTI risk. Shuangdong capsule improved bladder pathology and infection indicators, similar to levofloxacin. It did not affect blood glucose or insulin levels. Moreover, it reversed the suppression of the IRS1-PI3K-Akt-CXCL2 pathway and MPO levels caused by UTI in diabetic rats. The Mendelian randomization study showed that increased insulin receptor expression reduced UTI risk, which was consistent with the results of the animal experiments. The Shuangdong capsule was effective in treating diabetes with UTIs. It may function by activating the IRS1-PI3K-Akt signaling pathway, thereby increasing CXCL2 and MPO levels, enhancing innate immunity, and promoting bacterial clearance. The Mendelian randomization study provided further evidence supporting the causal role of the insulin receptor in UTI prevention.

ROCK1 deficiency preserves caveolar compartmentalization of signaling molecules and cell membrane integrity.

In this study, we investigated the roles of ROCK1 in regulating structural and functional features of caveolae located at the cell membrane of cardiomyocytes, adipocytes, and mouse embryonic fibroblasts (MEFs) as well as related physiopathological effects. Caveolae are small bulb-shaped cell membrane invaginations, and their roles have been associated with disease conditions. One of the unique features of caveolae is that they are physically linked to the actin cytoskeleton that is well known to be regulated by RhoA/ROCKs pathway. In cardiomyocytes, we observed that ROCK1 deficiency is coincident with an increased caveolar density, clusters, and caveolar proteins including caveolin-1 and -3. In the mouse cardiomyopathy model with transgenic overexpressing Gαq in myocardium, we demonstrated the reduced caveolar density at cell membrane and reduced caveolar protein contents. Interestingly, coexisting ROCK1 deficiency in cardiomyocytes can rescue these defects and preserve caveolar compartmentalization of β-adrenergic signaling molecules including β1-adrenergic receptor and type V/VI adenylyl cyclase. In cardiomyocytes and adipocytes, we detected that ROCK1 deficiency increased insulin signaling with increased insulin receptor activation in caveolae. In MEFs, we identified that ROCK1 deficiency increased caveolar and total levels of caveolin-1 and cell membrane repair ability after mechanical or chemical disruptions. Together, these results demonstrate that ROCK1 can regulate caveolae plasticity and multiple functions including compartmentalization of signaling molecules and cell membrane repair following membrane disruption by mechanical force and oxidative damage. These findings provide possible molecular insights into the beneficial effects of ROCK1 deletion/inhibition in cardiomyocytes, adipocytes, and MEFs under certain diseased conditions.

Leptin-dependent differential remodeling of visceral and pericardial adipose tissue following chronic exercise and psychosocial stress.

Obesity is driven by an imbalance between caloric intake and energy expenditure, causing excessive storage of triglycerides in adipose tissue at different sites around the body. Increased visceral adipose tissue (VAT) is associated with diabetes, while pericardial adipose tissue (PAT) is associated with cardiac pathology. Adipose tissue can expand either through cellular hypertrophy or hyperplasia, with the former correlating with decreased metabolic health in obesity. The aim of this study was to determine how VAT and PAT remodel in response to obesity, stress, and exercise. Here we have used the male obese Zucker rats, which carries two recessive fa alleles that result in the development of hyperphagia with reduced energy expenditure, resulting in morbid obesity and leptin resistance. At 9 weeks of age, a group of lean (Fa/Fa or Fa/fa) Zucker rats (LZR) and obese (fa/fa) Zucker rats (OZR) were treated with unpredictable chronic mild stress or exercise for 8 weeks. To determine the phenotype for PAT and VAT, tissue cellularity and gene expression were analyzed. Finally, leptin signaling was investigated further using cultured 3T3-derived adipocytes. Tissue cellularity was determined following hematoxylin and eosin (H&E) staining, while qPCR was used to examine gene expression. PAT adipocytes were significantly smaller than those from VAT and had a more beige-like appearance in both LZR and OZR. In the OZR group, VAT adipocyte cell size increased significantly compared with LZR, while PAT showed no difference. Exercise and stress resulted in a significant reduction in VAT cellularity in OZR, while PAT showed no change. This suggests that PAT cellularity does not remodel significantly compared with VAT. These data indicate that the extracellular matrix of PAT is able to remodel more readily than in VAT. In the LZR group, exercise increased insulin receptor substrate 1 (IRS1) in PAT but was decreased in the OZR group. In VAT, exercise decreased IRS1 in LZR, while increasing it in OZR. This suggests that in obesity, VAT is more responsive to exercise and subsequently becomes less insulin resistant compared with PAT. Stress increased PPAR-γ expression in the VAT but decreased it in the PAT in the OZR group. This suggests that in obesity, stress increases adipogenesis more significantly in the VAT compared with PAT. To understand the role of leptin signaling in adipose tissue remodeling mechanistically, JAK2 autophosphorylation was inhibited using 5 μM 1,2,3,4,5,6-hexabromocyclohexane (Hex) in cultured 3T3-derived adipocytes. Palmitate treatment was used to induce cellular hypertrophy. Hex blocked adipocyte hypertrophy in response to palmitate treatment but not the increase in lipid droplet size. These data suggest that leptin signaling is necessary for adipocyte cell remodeling, and its absence induces whitening. Taken together, our data suggest that leptin signaling is necessary for adipocyte remodeling in response to obesity, exercise, and psychosocial stress.

Ginsenoside F4 Alleviates Skeletal Muscle Insulin Resistance by Regulating PTP1B in Type II Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with increasing morbidity. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of the insulin signaling cascade and has attracted intensive investigation in the T2DM study. Ginseng is widely used to treat metabolic diseases, while the effects of ginsenoside F4 (F4) on T2DM have remained unknown. Here, we identify F4 as an inhibitor of skeletal muscle insulin resistance. The results showed that F4 significantly improved the hyperglycemic state of db/db mice, alleviated dyslipidemia, and promoted skeletal muscle glucose uptake. This phenomenon was closely related to the inhibition of the PTP1B activity. On the one hand, the inhibition of PTP1B activity by F4 resulted in increased insulin receptor (INSR) and insulin receptor substrate 1 tyrosine phosphorylation and enhanced insulin sensitivity. On the other hand, F4 as a PTP1B inhibitor inhibited the inositol-requiring enzyme 1 (IRE-1)/recombinant TNF receptor associated factor 2 (TRAF2)/c-Jun N-terminal kinase signaling pathway and alleviated skeletal muscle endoplasmic reticulum (ER) stress, thereby reducing IRS-1 serine phosphorylation. Both finally activated the PI3K/AKT signaling pathway and promoted glucose transporter protein 4 translocation to the cell membrane for glucose uptake. Taken together, our experiments demonstrate that F4 activates the insulin signaling pathway by inhibiting the activity of PTP1B while inhibiting the IRE-1/TRAF2/JNK signaling pathway, enhancing insulin sensitivity, and alleviating ER stress in the skeletal muscle of db/db mice. Our results indicate that F4 can be used as a PTP1B inhibitor for the treatment of T2DM.

Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma.

Insulin feedback is a critical mechanism responsible for the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma (GBM). We investigated combination anti-hyperglycemic therapy in a mouse model of GBM and evaluated the association of glycemic control in clinical trial data from patients with GBM. The effect of the anti-hyperglycemic regimens, metformin and the ketogenic diet, was evaluated in combination with PI3K inhibition in patient-derived GBM cells and in an orthotopic GBM mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent GBM. We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves the treatment efficacy in an orthotopic GBM xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with GBM. We also found that PI3K inhibition increased insulin receptor activation and T-cell and microglia abundance in tumor tissue from these patients. Reducing insulin feedback improves the efficacy of PI3K inhibition in GBM in mice, and hyperglycemia worsens progression-free survival in patients with GBM treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in GBM and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in GBM patients.

1511-P: Identifying How Endothelial Protease-Activated Receptors Control Insulin Signaling—Implications for Diabetes

Endothelial cell (EC) dysfunction occurs in diabetes. Thrombin, a circulating serine protease with increased activity in diabetics, signals through protease-activated receptors 1 and 4 (PAR1/PAR4). To determine EC-specific roles of PARs in diabetes, we generated Par1fl//fl; Par4fl/fl; iCdh5 (PAC)-CreERT2 (Par1/4dECko) mice and challenged them with streptozotocin (STZ) to induce hyperglycemia. STZ-treated Par1/4dECko mice had reduced blood glucose levels, weighed significantly more, and lost less abdominal fat than control littermates. Neither Par4ECko nor Par1ECko mice phenocopied Par1/4ECko mutants, suggesting that loss of both thrombin receptors is required to drive these phenotypes. Notably, STZ-treated Par1/4dECko mice showed comparable insulin levels to their STZ-treated littermates, suggesting mutant mice had heightened insulin sensitivity, which was verified by insulin/glucose tolerance testing. Using primary human ECs that express PAR1 but not PAR4, we found that PAR1/4 depletion increased basal insulin receptor (IR) activity as measured by the uptake of a glucose-analog. PAR1/4-depleted ECs also showed increased insulin receptor Type-A (IR-A) spliceform expression, which has high insulin-independent basal activity. Conversely, treatment of ECs with a PAR1 ligand upregulated the insulin-dependent IR Type-B (IR-B) spliceform, suggesting that endothelial PAR1/4 can modulate IR splicing/activity. Additionally, we found that ECs in many wildtype mouse organs, including skeletal muscle, predominantly express IR-B in vivo. Therefore, a switch to IR-A expression in Par1/4dECko mice may enhance endothelial IR activity. IR activity in ECs regulates insulin transport from the bloodstream to the parenchyma. We propose that loss of EC PAR1/4 elevates whole-body insulin sensitivity by increasing IR splicing/activity and subsequent transcytosis to the parenchyma. Thus, EC PAR1/4 modulation may hold promise for treating diabetes. Disclosure R.Rajala: None. C.Griffin: None. Funding American Heart Association (23PRE1014240); National Institutes of Health (HL144605)

Pancreatic islet remodeling in cotadutide-treated obese mice

Obesity and type 2 diabetes mellitus (T2DM) cause morphofunctional alterations in pancreatic islet alpha and beta cells. Therefore, we hypothesize that the new GLP-1/Glucagon receptor dual agonist cotadutide may benefit islet cell arrangement and function. Twelve-week-old C57BL/6 male mice were fed a control diet (C, 10 % kJ fat) or a high-fat diet (HF, 50 % kJ fat) for ten weeks. Then, the animals were divided into four groups for an additional 30 days and daily treated with subcutaneous cotadutide (30 nmol/kg) or vehicle: C, CC (control+cotadutide), HF, and HFC (high-fat+cotadutide). Cotadutide led to weight loss and reduced insulin resistance in the HFC group, increasing insulin receptor substrate 1 and solute carrier family 2 gene expressions in isolated islets. Also, cotadutide enhanced transcriptional factors related to islet cell transdifferentiation, decreasing aristaless-related homeobox and increasing the paired box 4 and 6, pancreatic and duodenal homeobox 1, v-maf musculoaponeurotic fibrosarcoma oncogene family protein A, neurogenin 3, and neurogenic differentiation 1. In addition, cotadutide improved the proliferating cell nuclear antigen, NK6 homeobox 1, B cell leukemia/lymphoma 2, but lessening caspase 3. Furthermore, cotadutide mitigated the endoplasmic reticulum (ER) stress-responsive genes, reducing transcription factor 4, DNA-damage-inducible transcript 3, and growth arrest and DNA-damage-inducible 45. In conclusion, our data demonstrated significant beneficial actions of cotadutide in DIO mice, such as weight loss, glycemic control, and insulin resistance improvement. In addition, cotadutide counteracted the pathological adaptive cellular arrangement of the pancreatic islet in obese mice, improving the markers of the transdifferentiating pathway, proliferation, apoptosis, and ER stress.

A healthy lifestyle of the diabetic sufferer to avoid the risk of complications: Literature Review

Diabetes Mellitus (DM) is a chronic disease with high blood sugar levels in the blood. DM can cause complications of various diseases because the body can not use blood sugar in the blood cannot be used. The number of DM sufferers, both in the world and in Indonesia, continues to increase from time to time, so this disease is a scourge for everyone. Writing this paper aims to discuss the healthy lifestyle of diabetics to avoid the risk of complications. The most severe disorder of this disease is a chronic metabolic disorder because the pancreas does not produce enough insulin hormone, which has the principal role in regulating and controlling glucose metabolism into energy. Over time, diabetes can interfere with the function of human organs. For example, some organs work improperly, and some should be amputated. One of the most effective efforts to keep blood sugar levels stable is dietary compliance in people with diabetes mellitus has role function. The impact of dietary regulation is maintaining normal-body weight, reducing systolic and diastolic blood pressure, lowering blood glucose levels, improving lipid profiles, increasing insulin receptor sensitivity, and improving the blood coagulation system. This disease requires continuous medical care by carrying out independent health management in patients to prevent acute complications and reduce the risk of long-term complications. It is principal to adopt a healthy lifestyle for diabetic patients in a frame to anticipate the risk of complications.

Sacha Inchi (Plukenetia volubilis L.) Oil Improves Hepatic Insulin Sensitivity and Glucose Metabolism through Insulin Signaling Pathway in a Rat Model of Type 2 Diabetes.

This study aimed to evaluate the role of sacha inchi oil (SI) in alleviating hepatic insulin resistance and improving glucose metabolism by inhibiting oxidative stress and inflammation in a rat model of type 2 diabetes. This model was established by providing a high-fat diet and streptozotocin to the rats, thereby inducing diabetes. The diabetic rats were treated orally with 0.5, 1, and 2 mL/kg body weight (b.w.) of SI or 30 mg/kg b.w. of pioglitazone daily for 5 weeks. Blood and hepatic tissues were used for insulin sensitivity, carbohydrate metabolism, oxidative stress, and inflammatory status assessment. Treatment with SI attenuated hyperglycemia and insulin resistance indices, and improved hepatic histopathological alterations in the diabetic rats in a dose-dependent manner, which is correlated with the decreased serum levels of the liver enzymes, alanine transaminase and aspartate transaminase. SI significantly diminished the hepatic oxidative status of the diabetic rats by inhibiting malondialdehyde and enhancing the antioxidant superoxide dismutase, catalase, and glutathione peroxidase activities. Moreover, pro-inflammatory cytokine levels, including tumor necrosis factor-α and interleukin-6, in the liver of the diabetic rats were significantly decreased by the SI. Furthermore, SI treatment enhanced the hepatic insulin sensitivity of the diabetic rats, as shown by the increased insulin receptor substrate-1 and p-Akt protein expression, decreased phosphoenolpyruvate carboxykinase-1 and glucose-6-phospatase protein expression, and increased hepatic glycogen content. Overall, these findings suggest that SI exerts a potential hepatic insulin-sensitizing effect and an improvement in glucose metabolism in the type 2 diabetic rats, at least in part through enhancing insulin signaling, antioxidant defense, and inhibiting inflammation.

Chemical constituents isolated from Actinidia polygama and their α-glucosidase inhibitory activity and insulin secretion effect

Actinidia polygama has been used as a traditional medicine for treating various diseases. In the present study, 13 compounds, including three new monoterpenoids (1–3), were isolated from the leaves of A. polygama to investigate the bioactive constituents of the plant. The structures were characterized by analyzing spectroscopic and chiroptical data. These compounds were preliminarily screened for their ability to increase insulin secretion levels after glucose stimulation. Of these, 3-O-coumaroylmaslinic acid (4) and jacoumaric acid (5) showed activity. In further biological studies, these compounds exhibited increased glucose‐stimulated insulin secretion (GSIS) activity without cytotoxicity in rat INS-1 pancreatic β-cells as well as α-glucosidase inhibitory activity. Furthermore, both compounds increased insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), pancreatic and duodenal homeobox-1 (PDX-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) expression. Hence, these compounds may be developed as potential antidiabetic agents.

Association between insulin, glucagon, high sensitive c-reactive protein, insulin resistance with visceral adipose tissue-derived serine protease inhibitor (VASPIN) in obese population

Background: Obesity is an inflammatory condition that results in an increase in high sensitive C-Reactive Protein (hs-CRP), a risk for insulin resistance (IR). Vaspin has the effect of increasing insulin receptor sensitivity and on the other hand is a compensatory response to insulin resistance, one of which is measured by homeostasis models assessment-insulin resistance (HOMA-IR). This study was an analytical cross-sectional observational design, to determine the association between insulin, glucagon, CRP, and HOMA-IR levels with serum vaspin in obesity. Method: This study is an analytical study with a cross-sectional design. Criteria of inclusion were subjects in the range 18-60 years Denpasar citizen with BMI above 25 kg/m2 and willing to be involved in this study, while exclusion criteria were with either chronic conditions or acute inflammation such as infection, cancer, tumor, or chronic disease which is altered and threatening life. Correlation tests using spearman analysis. Results: From 131 obese subjects in this study, there were 72 (55%) men and 59 (45%) women. Median age: 33 (22-57) years, fasting insulin: 8.90 (2.20-74.50) ìIU/mL, glucagon: 48.10 (7.58-293.90) pq/mL, hs-CRP: 1.90 (0.20-9.50) mg/L, HOMA-IR: 2 (0.50-23.15), and vaspin levels: 0.16 (0.04-1.46) ng/mL. There was a significant positive correlation between HOMA-IR, insulin and glucagon with vaspin (r = 0.20, p = 0.020; r = 0.20, p = 0.022; and r = 0.28, p = 0.001), and a significant negative correlation between hs-CRP and vaspin (r = -0.24, p = 0.005) in obesity. In the path analysis, there was a direct and total negative effect of hs-CRP on vaspin (coefficient = -0.19; p = 0.027 and coefficient = -0.02; p = 0.038). Conclusion: This study shows a positive association between insulin, glucagon, and HOMA-IR with serum vaspin, while CRP is negatively associated with serum vaspin in obesity.

Oxidative Stress Kinase Activation and Impaired Insulin Receptor Signaling Precede Overt Alzheimer's Disease Neuropathology.

The cascade of events that lead to Alzheimer's disease (AD) consists of several possible underlying signal transduction pathways. Apoptosis signal-regulating kinase 1 (ASK1) and insulin receptor (IR) signaling are implicated in AD. We aimed to determine whether ASK1 activation and IR signaling impairment occurred prior to and during overt AD. Immunostaining, immunoblotting, and quantitative PCR were used to assess the levels of ASK1 and IR signaling intermediates. Glucose uptake was determined in AD-patient derived inducible pluripotent stem cells (iPSCs). ASK1 signaling was activated in postmortem brain tissues acquired from APOE4 carriers, a causative heritable factor, and in brain tissues of AD subjects in comparison with those harboring the normal APOE3 variant, which was manifested with an increased phosphorylated ASK1 (p-ASK1) and reduced thioredoxin 1 (TRX1). ASK1 downstream signaling effectors were also significantly elevated in these APOE4 carriers and AD brain tissues. Increased insulin receptor substrate 1 (IRS1) phosphorylation at serine residues, and decreased p-AKT1, p-IRβ, and GLUT3 expression were present in all APOE4 carriers and AD samples, suggesting impaired IR signaling leading to insulin resistance. ASK1 activation, IR signaling impairment, and GLUT3 reduction were also present in young AD transgenic mice prior to AD syndromes, AD mice at AD neuropathology onset, and AD iPSCs and their derived neurons prior to p-Tau aggregation. We conclude that the activation of oxidative stress-responsive kinases and reduced IR signaling precede and are persistent in AD pathogenesis. Our data further suggest possible crosstalk between ASK1 signaling and insulin resistance in AD etiology.

POTENSI SIANIDIN POLY(LACTIC-CO-GLYCOLIC ACID)-POLYETHYLEN GLYCOL YANG DIMODIFIKASI FUSED FOLLICLE UNTUK MENINGKATKAN SENSITIVITAS DAN SEKRESI INSULIN DALAM MENANGANI PENYAKIT DIABETES MELITUS TIPE 2

ABSTRACT
 Introduction: Type 2 diabetes mellitus is one of the four priority non-communicable diseases according to WHO. WHO data in 2015 showed that as many as 415 million people in the world suffer from type 2 diabetes mellitus. Even in Indonesia in 2013, the prevalence of people with diabetes has increased to 6.9%. Currently, the most common treatment for type 2 diabetes mellitus is the administration of metformin. However, long-term administration will cause lactic acidosis and kidney damage. Because of this, new alternatives are needed that minimize the side effects, for example by using herbal ingredients. Cyanidin is a natural flavonoid that has the effect of increasing insulin sensitivity and secretion.
 
 Discussion: Cyanidin has the potential to increase insulin receptor sensitivity and increase insulin secretion. To increase insulin sensitivity, cyanidin can inhibit the downregulation of Glut4 expression and decrease the level of RBP 4 expression. As an increase in insulin secretion Cyanidin increases the expression of GLUT2, Kir6.2, and Cav1.2 genes that play a role in insulin secretion. Unfortunately, Cyanidin has low bioavailability and is unstable. Therefore, Cyanidin encapsulation will increase the availability of cyanidin in the blood and is easily concentrated into pancreatic cells
 Conclusion: The Fc-modified Cyanidin PLGA-PEG combination has the potential to be a new alternative in the treatment of type 2 diabetes mellitus
 Keywords: Type 2 Diabetes Mellitus, Cyanidin, Fc-modified Cyanidin PLGA-PEG

Molecular Basis of Irisin Regulating the Effects of Exercise on Insulin Resistance

Insulin resistance is recognized as one major feature of metabolic syndrome, and frequently emerges as a difficult problem encountered during long-term pharmacological treatment of diabetes. Insulin resistance often causes organs or tissues, such as skeletal muscle, adipose, and liver, to become less responsive or resistant to insulin. Exercise can promote the physiological function of those organs and tissues and benefits insulin action via increasing insulin receptor sensitivity, glucose uptake, and mitochondrial function. This is done by decreasing adipose tissue deposition, inflammatory cytokines, and oxidative stress. However, understanding the mechanism that regulates the interaction between exercise and insulin function becomes a challenging task. As a novel myokine, irisin is activated by exercise, released from the muscle, and affects multi-organ functions. Recent evidence indicates that it can promote glucose uptake, improve mitochondrial function, alleviate obesity, and decrease inflammation, as a result leading to the improvement of insulin action. We here will review the current evidence concerning the signaling pathways by which irisin regulates the effect of exercise on the up-regulation of insulin action in humans and animals.

Differential remodelling of visceral and pericardial adipose tissue in response to stress and exercise

Obesity is driven by an imbalance between caloric intake and energy expenditure, causing excessive storage of nutrients in adipose tissue at different sites around the body. Increased visceral adipose tissue (VAT) is associated with diabetes, whilst pericardial adipose tissue (PAT) is associated with cardiac pathology. Adipose tissue can expand either through cellular hypertrophy or hyperplasia, with the former correlating with decreased metabolic health in obesity. The aim of this study was to determine how VAT and PAT remodel in response to obesity, stress and exercise.Here we have used the obese Zucker rats which develop hyperphagia with reduced energy expenditure, resulting in morbid obesity as a result of leptin resistance. At 9 weeks of age lean (LZR) and obese (OZR) Zucker male rats were treated with or without unpredictable chronic mild stress or exercise for 8 weeks. To determine the phenotype for PAT and VAT, tissue cellularity and gene expression were analyzed. Tissue cellularity was determined following haematoxylin and eosin staining, whilst qPCR was used to examine gene expression.PAT adipocytes were significantly smaller than those from VAT and had a more biege‐like appearance. In the OZR group, VAT adipocyte cell size increased significantly compared with LZR, whilst PAT showed no change. Exercise and stress resulted in a significant reduction in VAT cellularity in OZR, whilst PAT showed no change. This suggests that PAT cellularity does not remodel significantly compared with VAT. Picro sirus red staining indicated that PAT had significantly more fibrosis than VAT. However, this fibrosis was decreased following stress treatment. This data indicate that the extracellular matrix of PAT is able to remodel more readily than in VAT.Gene expression analysis showed that PAT expressed higher levels of UCP1 compared with VAT, indicating that it has a more brown‐like phenotype. In the LZR group, exercise increased insulin receptor substrate 1 (IRS1) in PAT, but was decreased in the OZR group. On the other hand, in VAT, exercise decreased IRS1 in LZR, whilst increasing it in the OZR. This suggests that in obesity, VAT is more responsive to exercise and subsequently becomes less insulin resistant compared with PAT. In VAT, stress increased PPAR‐γ expression in the OZR group but decreased it in the PAT. This suggests that in obesity, stress increases adipogenesis more significantly in the VAT compared with PAT.Taken together, our data suggest that VAT is considerably more plastic than PAT and remodels rapidly in response to obesity, exercise and psychological stress.

Pioglitazone Synthetic Analogue Ameliorates Streptozotocin-Induced Diabetes Mellitus through Modulation of ACE 2/Angiotensin 1-7 via PI3K/AKT/mTOR Signaling Pathway.

The renin angiotensin aldosterone system has a localized key regulatory action, especially in liver and body circulation. Furthermore, it accomplishes a significant role in the downregulation of the PI3K/AKT/mTOR signaling pathway that is involved in type II diabetes mellitus pathogenesis. The current study aimed to evaluate the effect of a synthetic pioglitazone analogue (benzenesulfonamide derivative) compared to the standard pioglitazone hypoglycemic drug on enhancing liver insulin sensitivity via ACE 2/Ang (1–7)/PI3K/AKT/mTOR in experimental STZ-induced diabetes. After the model was established, rats were distributed into the normal control group, diabetic group, pioglitazone group (20 mg/kg), and a benzenesulfonamide derivative group (20 mg/kg), with the last 2 groups receiving oral treatment for 14 consecutive days. Our results suggested enhancing liver insulin sensitivity against the ACE2/Ang (1–7)/PI3K/AKT/mTOR pathway. Moreover, the synthetic compound produced a reduction in blood glucose levels, restored hyperinsulinemia back to normal, and enhanced liver glycogen deposition. In addition, it up regulated the ACE2/Ang (1–7)/PI3K/AKT/mTOR signaling pathway via increasing insulin receptor substrate 1 and 2 sensitivity to insulin, while it increased glucose transporter 2 expression in the rat pancreas. The study findings imply that the hypoglycemic effect of the benzenesulfonamide derivative is due to enhancing liver sensitivity to regulate blood glucose level via the ACE2/Ang (1–7)/PI3K/AKT/mTOR pathway.

Cycling to Regulate Random Blood Glucose Levels in Individuals with Diabetes

BACKGROUND: In Indonesia, the four pillars of diabetes management include health education, food planning, physical exercise, and drug adherence. However, the most common imprudence in those four pillars was ignoring physical activity. Cycling has become a new social activity and a lifestyle among the community during the COVID-19 pandemic. It is an aerobic exercise that increases insulin receptor sensitivity. AIM: This study aims to analyze the effect of cycling on Random Blood Glucose (RBG) levels in individuals with diabetes. METHODOLOGY: This paper used a quasi-experiment pre-post test design with the control group. It utilized total sampling with 60 respondents. The independent variable was cycling using a dynamic bicycle. Meanwhile, the dependent variable was RBG levels with a glucometer as the instrument. The procedure in the intervention group was cycling using a dynamic bicycle twice a week with a distance of 2–3 kilometers each session. The data analysis used a paired T-test and independent sample T-test. RESULTS: After cycling, the independent T-test result was p = 0.00 (p < 0.05). Thus, there was a difference in the mean RBG levels between the intervention and control groups after cycling. There was a decrease in mean RBG levels in the intervention group (206.67 ± 69.887 in pre-test and 114.60 ± 30.395 in post-test). In addition, the paired T-test resulted in p = 0.00 (p < 0.05). Thus, there was a difference in the intervention group’s mean RBG levels before and after cycling CONCLUSION: Cycling can lower RBG levels in individuals with diabetes.

Djulis Hull Improves Insulin Resistance and Modulates the Gut Microbiota in High-Fat Diet (HFD)-Induced Hyperglycaemia.

In this study, we annotated the major flavonoid glycoside, rutin, of djulis hull crude extract using a Global Natural Products Social Molecular Networking (GNPS) library and its MS/MS spectra. To evaluate the protective effect of djulis hull crude extract and rutin on glucose tolerance, we fed mice a high-fat diet (HFD) for 16 weeks to induce hyperglycaemia. These results showed that crude extract significantly decreased HFD-induced elevation in the area under the curve (AUC) of weekly random blood glucose and oral glucose tolerance tests (OGTT), homeostasis model assessment (HOMA-IR), and advanced glycation end product (AGE) levels, and significantly increased pIRS1 and Glut4 protein expression in epididymal white adipose tissue (eWAT) and liver. Furthermore, the HFD-induced reduction in the activity of glutathione peroxidase (GPx) and catalase (CAT) was reversed by crude extract. In addition, ZO-1 and occludin protein expression in the colon was markedly downregulated in HFD-fed mice, resulting in decreased intestinal permeability and lipopolysaccharide (LPS) translocation, but were restored following crude extract. Moreover, the crude extract intervention had a profound effect on the alpha diversity and microbial community in the gut microbiota. Therefore, djulis hull crude extract could improve blood glucose and increase insulin receptor sensitivity in HFD-induced hyperglycaemia, which is likely due to its modulation of the gut microbiota, preservation of the integrity of the intestinal barrier to reduce body inflammation, increased antioxidant activity, and modulation of insulin signalling.