Tirzepatide as an insulin sensitizer

2021 ◽  
Author(s):  
Ele Ferrannini
Keyword(s):  
Insulin Sensitizer

scholarly journals Activation of PI3K/Akt Signaling Pathway in Rat Hypothalamus Induced by an Acute Oral Administration of D-Pinitol

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2268
Author(s):  
Dina Medina-Vera ◽  
Juan Antonio Navarro ◽  
Rubén Tovar ◽  
Cristina Rosell-Valle ◽  
Alfonso Gutiérrez-Adan ◽  
...  
Keyword(s):  
Oral Administration ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Insulin Response ◽  
Pharmacological Action ◽  
Akt Signaling ◽  
Insulin Signaling Pathway ◽  
Acute Administration ◽  
Insulin Sensitizer ◽  
Peripheral Tissues

D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.

scholarly journals Insulin-mimetic and insulin-sensitizing activities of a pentacyclic triterpenoid insulin receptor activator

2007 ◽  
Vol 403 (2) ◽  
pp. 243-250 ◽  
Author(s):  
Seung H. Jung ◽  
Yun J. Ha ◽  
Eun K. Shim ◽  
Soo Y. Choi ◽  
Jing L. Jin ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Transporter ◽  
Glycogen Synthase ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Β Subunit ◽  
Insulin Sensitizer ◽  
Insulin Mimetic ◽  
Pentacyclic Triterpenoid

Five pentacyclic triterpenoids isolated from Campsis grandiflora were tested for insulin-mimetic and insulin-sensitizing activity. The compounds enhanced the activity of insulin on tyrosine phosphorylation of the IR (insulin receptor) β-subunit in CHO/IR (Chinese-hamster ovary cells expressing human IR). Among the compounds tested, CG7 (ursolic acid) showed the greatest enhancement and CG11 (myrianthic acid) the least. We characterized the effect of CG7 further, and showed that it acted as an effective insulin-mimetic agent at doses above 50 μg/ml and as an insulin-sensitizer at doses as low as 1 μg/ml. Additional experiments showed that CG7 increased the number of IRs that were activated by insulin. This indicates that a major mechanism by which CG7 enhances total IR auto-phosphorylation is by promoting the tyrosine phosphorylation of additional IRs. CG7 not only potentiated insulin-mediated signalling (tyrosine phosphorylation of the IR β-subunit, phosphorylation of Akt and glycogen synthase kinase-3β), but also enhanced the effect of insulin on translocation of glucose transporter 4 in a classical insulin-sensitive cell line, 3T3-L1 adipocytes. The results of the present study demonstrate that a specific pentacyclic triterpenoid, CG7, exerts an insulin-sensitizing effect as an IR activator in CHO/IR cells and adipocytes. The enhancement of insulin activity by CG7 may be useful for developing a new class of specific IR activators for treatment of Type 1 and Type 2 diabetes.

scholarly journals Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis

2016 ◽  
Vol 310 (11) ◽  
pp. H1423-H1438 ◽  
Author(s):  
Petra Haberzettl ◽  
James P. McCracken ◽  
Aruni Bhatnagar ◽  
Daniel J. Conklin
Keyword(s):  
Insulin Resistance ◽  
Bone Marrow ◽  
Particulate Matter ◽  
Insulin Sensitivity ◽  
Ambient Air ◽  
Air Pollutant ◽  
Ambient Air Pollution ◽  
Endothelial Progenitor ◽  
Insulin Sensitizer ◽  
Circulating Levels

Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1+/Sca-1+ cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/particulate-matter-induced-vascular-insulin-resistance/ .

scholarly journals Mitochondrial Biogenesis and Remodeling during Adipogenesis and in Response to the Insulin Sensitizer Rosiglitazone

2003 ◽  
Vol 23 (3) ◽  
pp. 1085-1094 ◽  
Author(s):  
Leanne Wilson-Fritch ◽  
Alison Burkart ◽  
Gregory Bell ◽  
Karen Mendelson ◽  
John Leszyk ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Gradient Centrifugation ◽  
Light And Electron Microscopy ◽  
Fold Increase ◽  
Mitochondrial Proteins ◽  
Whole Body ◽  
Brown Adipocyte ◽  
Insulin Sensitizer ◽  
Adipose Differentiation ◽  
Whole Body Metabolism

ABSTRACT White adipose tissue is an important endocrine organ involved in the control of whole-body metabolism, insulin sensitivity, and food intake. To better understand these functions, 3T3-L1 cell differentiation was studied by using combined proteomic and genomic strategies. The proteomics approach developed here exploits velocity gradient centrifugation as an alternative to isoelectric focusing for protein separation in the first dimension. A 20- to 30-fold increase in the concentration of numerous mitochondrial proteins was observed during adipogenesis, as determined by mass spectrometry and database correlation analysis. Light and electron microscopy confirmed a large increase in the number of mitochondrion profiles with differentiation. Furthermore, mRNA profiles obtained by using Affymetrix GeneChips revealed statistically significant increases in the expression of many nucleus-encoded mitochondrial genes during adipogenesis. Qualitative changes in mitochondrial composition also occur during adipose differentiation, as exemplified by increases in expression of proteins involved in fatty acid metabolism and of mitochondrial chaperones. Furthermore, the insulin sensitizer rosiglitazone caused striking changes in mitochondrial shape and expression of selective mitochondrial proteins. Thus, although mitochondrial biogenesis has classically been associated with brown adipocyte differentiation and thermogenesis, our results reveal that mitochondrial biogenesis and remodeling are inherent to adipose differentiation per se and are influenced by the actions of insulin sensitizers.

scholarly journals Analysis of the formation of dysglycemia in the substantiation of early pathogenetic therapy of diabetes mellitus

2021 ◽  
pp. 33-44
Author(s):  
L. A. Ruyatkina ◽  
D. S. Ruyatkin ◽  
I. S. Iskhakova
Keyword(s):  
Diabetes Mellitus ◽  
Postmenopausal Women ◽  
Metabolic Memory ◽  
Β Cells ◽  
Insulin Sensitizer ◽  
Dipeptidyl Peptidase 4 ◽  
Group 2 ◽  
Glucose Lowering Therapy ◽  
Secretory Capacity ◽  
Hba1c Levels

Introduction. To control carbohydrate metabolism disorders (CMD), which are closely related to the effect on the prognosis of cardiovascular diseases (CVD), their early, pathogenetically substantiated and prognosis-oriented therapy is required with a view to positive metabolic memory. The choice of drugs is based on the analysis of the formation of pre-nosological CMD - variants of prediabetes. The indices of the homeostatic model HOMA and the TyG family are most often used to assess the main links in the pathogenesis of CMD, IR and the secretory capacity of β-cells.Objective: to assess the basic pathogenetic links in prenosological CMD in comparison with type 2 diabetes mellitus (DM2) using a cohort of postmenopausal women: parameters of IR and secretory capacity of β-cells according to the TyG and HOMA-2 indices. Materials and methods. The examined 94 postmenopausal women 58.0 (53.0; 63.0) years old were divided into groups by history and HbA1c levels (%). Group 1 consisted of patients with T2DM (7.20: 6.60; 7.98) with a duration of 4.0 (2.0; 7.0) years; women with two-fold fasting normoglycemia without a history of CMD were classified according to their HbA1c levels into group 2 (prediabetes) and 3 (without CMD) twice: according to WHO criteria - 6.15 (6.03; 6.30) and 5.45 (5.20; 5.80); and ADA - 6.00 (5.80; 6.23) and 5.35 (5.05; 5.40), respectively. The indices TyG, HOMA2-IR, HOMA2-%S, and HOMA2-%B were determined (based on C-peptide calculations).Results and discussion. The performed analysis confirms the contribution of IR/insulin sensitivity to the progression of CMD with the participation of the phenomenon of lipoglucotoxicity at the prenosological stage of their formation, starting with HbA1c ≥ 5.7% levels. The inadequate secretory response of β-cells reflects an early decline in their functional abilities even at the stage of prediabetes. This limits the effectiveness of the classical stepwise scheme for intensifying glucose-lowering therapy with a T2DM duration of less than 10 years.Conclusions. Along with the timely diagnosis of dysglycemia, to control the cardiometabolic risk, it is advisable to use drug combinations early in terms of their effect on the key links in the pathogenesis of CMD: insulin resistance and β-cell dysfunction. Pioglitazone has been substantiated as an insulin sensitizer, which has a proven effect on the regression of early CMD and a decrease in the risk of cardiovascular events. In order to eliminate incretin dysfunction, which is closely related to the adequacy of the secretory capabilities of β-cells to the needs of impaired glucose homeostasis, a rational combination with an inhibitor of dipeptidyl peptidase-4.

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