Glucose-lowering Strategies in Diabetes: Pharmacological Development of New Antidiabetic Drugs

2018 ◽  
Vol 24 (9) ◽  
pp. 1007-1011 ◽  
Author(s):  
Polina Schwartsburd
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Blood Glucose ◽  
Side Effects ◽  
Glucose Uptake ◽  
Glucose Level ◽  
Glucose Production ◽  
Exogenous Insulin ◽  
Glucose Lowering ◽  
Additional Weight

Background: Insulin increases glucose uptake in muscles and fat and inhibits hepatic glucose production, thus serving as the primary regulator of the blood glucose level. In type 2 diabetes, insufficient insulin release and suppressed insulin action [named insulin resistance] lead to increased glucose production in liver and decreased glucose uptake by muscles and fat tissues, resulting in elevated blood glucose concentration which is dangerous to human health. Therefore, the anti-diabetic therapies are aimed at inhibiting excess blood glucose. Methods: A comparative analysis of two distinct glucose-lowering modes was used to develop a new feedback model for the purpose of identification of pharmacological targets in diabetes treatment. Results: The current brief opinion proposes an original feedback control of glucose-lowering regulation and its models which allow comparing two distinct strategies of glucose level correction, i.e., one of them allows reducing the increased threshold of insulin resistance, whereas the other allows overcoming this threshold/barrier using exogenous insulin treatment. Also, this analytic research presents selected examples comparing the influence of the two analyzed strategies on the normalization of glucose metabolism, their therapeutic potential and side effects associated with additional weight gain. These models show the pathological mechanism by which exogenous insulin provokes formation of a «vicious cycle» by its side effects associated with additional weight gain. Conclusion: The presented model and findings can contribute to the development of new anti-diabetic targets and drugs with minimal side effects.

scholarly journals Hypoglycemic Effect of Vitexin in C57BL/6J Mice and HepG2 Models

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Weidong Xu ◽  
Jiayao Li ◽  
Weipeng Qi ◽  
Ye Peng
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Weight Gain ◽  
Blood Glucose ◽  
Glucose Uptake ◽  
Lipid Content ◽  
Hepg2 Cells ◽  
Body Weight Gain ◽  
Tnf Α ◽  
Hepatic Lipid Content

Apigenin-8-C-glucoside (vitexin), a natural phytochemical contained in hawthorn, has been reported to have versatile beneficial bioactivities, such as antioxidation, anticancer property, and adipogenesis inhibition. The present research aimed to determine the influence of vitexin on insulin resistance elicited by HFD in mice and HepG2 cells. Vitexin markedly alleviated body weight gain and improved glucose and insulin intolerance induced by HFD. Vitexin partially normalized blood glucose, cholesterol, TNF-α, and hepatic lipid content. Moreover, vitexin recovered the reduced glucose uptake induced by glucosamine. The present results indicate that vitexin prevents HFD-induced insulin resistance.

scholarly journals Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion

2019 ◽  
Author(s):  
Xiuqing Han ◽  
Steffen H. Raun ◽  
Michala Carlsson ◽  
Kim A. Sjøberg ◽  
Carlos Henriquez-Olguín ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Blood Glucose ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Microvascular Perfusion ◽  
Glucose Lowering ◽  
Tumor Bearing ◽  
Hepatic Glucose

AbstractBackgroundRedirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor’s energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying cancer-induced metabolic perturbations.MethodsGlucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic acid or etomoxir.ResultsLLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose uptake was 30-40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4Thr642 (+18%), AKTSer474 (+65%), and AKTThr309 (+86%) in muscle. Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) basal (not insulin-stimulated) hepatic glucose production.ConclusionsCancer can result in marked perturbations on at least six metabolically essential functions; i) insulin’s blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.

Rosemary Extract Activates AMPK, Inhibits mTOR and Attenuates the High Glucose and High Insulin-Induced Muscle Cell Insulin Resistance

2021 ◽  
Author(s):  
Hesham Shamshoum ◽  
Filip Vlavcheski ◽  
Rebecca E.K. MacPherson ◽  
Evangelia Tsiani
Keyword(s):  
Insulin Resistance ◽  
Plasma Membrane ◽  
Blood Glucose ◽  
Glucose Uptake ◽  
Muscle Cell ◽  
High Glucose ◽  
Serine Phosphorylation ◽  
Rosemary Extract ◽  
Insulin Levels ◽  
High Insulin

Impaired action of insulin in skeletal muscle, termed insulin resistance, leads to increased blood glucose levels resulting in compensatory increase in insulin levels. The elevated blood glucose and insulin levels exacerbate insulin resistance and contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). In previous studies we found attenuation of free fatty acid-induced muscle cell insulin resistance by rosemary extract (RE). In the present study we investigated the effects of RE on high glucose (HG) and high insulin (HI)-induced muscle cell insulin resistance. Exposure of L6 myotubes to 25 mM glucose and 100 nM insulin for 24 h, to mimic hyperglycemia and hyperinsulinemia, abolished the acute insulin-stimulated glucose uptake, increased the serine phosphorylation of IRS-1 and the phosphorylation/ activation of mTOR and p70S6K. Treatment with RE significantly improved the insulin-stimulated glucose uptake and increased the acute insulin-stimulated tyrosine phosphorylation while reduced the HG+HI-induced serine phosphorylation of IRS-1 and phosphorylation of mTOR and p70S6K. Additionally, treatment with RE significantly increased the phosphorylation of AMPK, its downstream effector ACC and the plasma membrane GLUT4 levels. Our data indicate a potential of RE to counteract muscle cell insulin resistance and more studies are required to investigate its effectiveness in vivo. Novelty: • Rosemary extract (RE) phosphorylated muscle cell AMPK and ACC under both normal and high glucose (HG)/high insulin (HI) conditions. • The HG/HI-induced serine phosphorylation of IRS-1 and activation of mTOR and p70S6K were attenuated by RE. • RE increased the insulin-stimulated glucose uptake by enhancing GLUT4 glucose transporter translocation to plasma membrane.

Abstract 015: Increased 20-HETE Levels Contribute to Impaired Glucose Metabolism and Type 2 Diabetes in Cyp4a14 Knockout Mice Fed on High Fat Diet.

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Varunkumar G Pandey ◽  
Lars Bellner ◽  
Victor Garcia ◽  
Joseph Schragenheim ◽  
Andrew Cohen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Weight Gain ◽  
Blood Glucose ◽  
High Fat Diet ◽  
Plasma Insulin ◽  
High Fat ◽  
Plasma Insulin Levels

20-HETE (20-Hydroxyeicosatetraenoic acid) is a cytochrome P450 ω-hydroxylase metabolite of arachidonic acid that promotes endothelial dysfunction, microvascular remodeling and hypertension. Previous studies have shown that urinary 20-HETE levels correlate with BMI and plasma insulin levels. However, there is no direct evidence for the role of 20-HETE in the regulation of glucose metabolism, obesity and type 2 diabetes mellitus. In this study we examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water-soluble 20-HETE antagonist, on blood pressure, weight gain and blood glucose in Cyp4a14 knockout (Cyp4a14-/-) mice fed high-fat diet (HFD). The Cyp4a14-/- male mice exhibit high vascular 20-HETE levels and display 20-HETE-dependent hypertension. There was no difference in weight gain and fasting blood glucose between Cyp4a14-/- and wild type (WT) on regular chow. When subjected to HFD for 15 weeks, a significant increase in weight was observed in Cyp4a14-/- as compared to WT mice (56.5±3.45 vs. 30.2±0.7g, p<0.05). Administration of 20-SOLA (10mg/kg/day in drinking water) significantly attenuated the weight gain (28.7±1.47g, p<0.05) and normalized blood pressure in Cyp4a14-/- mice on HFD (116±0.3 vs. 172.7±4.6mmHg, p<0.05). HFD fed Cyp4a14-/- mice exhibited hyperglycemia as opposed to normal glucose levels in WT on a HFD (154±1.9 vs. 96.3±3.0 mg/dL, p<0.05). 20-SOLA prevented the HFD-induced hyperglycemia in Cyp4a14-/- mice (91±8mg/dL, p<0.05). Plasma insulin levels were markedly high in Cyp4a14-/- mice vs. WT on HFD (2.66±0.7 vs. 0.58±0.18ng/mL, p<0.05); corrected by the treatment with 20-SOLA (0.69±0.09 ng/mL, p<0.05). Importantly, glucose and insulin tolerance tests showed impaired glucose homeostasis and insulin resistance in Cyp4a14-/- mice on HFD; ameliorated by treatment with 20-SOLA. This novel finding that blockade of 20-HETE actions by 20-SOLA prevents HFD-induced obesity and restores glucose homeostasis in Cyp4a14-/- mice suggests that 20-HETE contributes to obesity, hyperglycemia and insulin resistance in HFD induced metabolic disorder. The molecular mechanisms underlying 20-HETE mediated metabolic dysfunction are being currently explored.

scholarly journals Effects of Fruits Extracts of Three Medicinal Plants on the Blood Glucose Level of Glucose-induced Hyperglycemic and Normal Rabbit Models

2012 ◽  
Vol 3 (1) ◽  
Author(s):  
Ikram Ilahi ◽  
Asghar Khan ◽  
Ubaid Ullah ◽  
Imran Khan ◽  
Jawad Ali ◽  
...  
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Medicinal Plants ◽  
Blood Glucose Level ◽  
Glucose Level ◽  
Methanol Extract ◽  
Second Phase ◽  
Glucose Lowering ◽  
Fruit Extracts ◽  
Lowering Activity

The fruits of Pistacia integerrima (PI), Withania coagulans (WC) and Withania somnifera (WS) have been reported for their medicinal values. The aim of the present study was to compare the glucose lowering activities of the fruit extracts of these three medicinal plants in glucose induced non-diabetic hyperglycemic and normal rabbit models. During the first phase of experiments, the effects of oral administration of 70% methanol extract of each plant fruit (600 mg/kg body weight) and glibenclamide (5 mg/kg body weight) were studied on the glucose level of glucose induced hyperglycemic rabbits, while in the second phase of experiments, the effects of each fruit extract (600 mg/kg body weight) and glibenclamide (5 mg/kg body weight) were assessed on the glucose level of normal rabbits. Among the three fruit extracts, maximum reduction in the blood glucose level was caused by the PI extract (P ˂0.05). The glucose lowering activity of the PI extract was greater than that of the standard, glibenclamide (5mg/kg), during the first phase of experiments. However during the second phase of experiments the hypoglycemic effect of the PI extract was comparable to that of the standard, glibenclamide (5mg/kg). In conclusion the present study reveals that the 70% methanol extract of Pistacia integerrima fruit can decrease glucose level significantly in glucose induced non-diabetic hyperglycemic and normal rabbit models.

scholarly journals 345. Acute Onset Diabetic Ketoacidosis/Hyperosmolar Hyperglycemic State in Patients Taking Integrase Strand Transfer Inhibitors

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S183-S184 ◽  
Author(s):  
Afua Duker Ntem-Mensah ◽  
Nina Millman ◽  
Niyati Jakharia ◽  
Amanda Theppote ◽  
Mona-Gekanju Toeque ◽  
...  
Keyword(s):  
Weight Gain ◽  
Blood Glucose ◽  
Blood Glucose Level ◽  
Diabetic Ketoacidosis ◽  
Glucose Level ◽  
Case Reports ◽  
Acute Onset ◽  
Anion Gap ◽  
Hyperosmolar Hyperglycemic State ◽  
Hba1c Levels

Abstract Background A few case reports have noted uncontrolled hyperglycemia in patients switched to dolutegravir. Several cohort studies have found increased weight gain among patients treated with integrase inhibitors (INSTI). We present clinical observations among 3 patients admitted to hospital for diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) while receiving INSTIs for the management of HIV. Methods Case 1: A 44-year-old man with HIV and dyslipidemia presented with altered mental status and lethargy. A fingerstick glucose was >600 mg/dL. Chemistries revealed glucose of 1,600 mg/dL and an elevated β-hydroxybutyrate. HbA1c was 12.4%. His antiretroviral regimen consisted of cEVG/TAF/FTC for the last 3 years. Previous HbA1c levels were 5.7% and 6.2% (Figure 1). Case 2: A 55-year-old woman with HIV, hypertension, dyslipidemia, and obesity presented with polyuria and polydipsia. The blood glucose level was >1,200 mg/dL with an anion gap >30 and HbA1c of 15%. Previous HbA1c levels ranged between 5.6 and 5.8% (Figure 2). She had been taking ABC/FTC/DTG for 2 years. Case 3: A 64 yo man with a history of HIV, hypertension, and obesity presented with polyuria and polydipsia. The blood glucose level was 1,152 mg/dL with no anion gap and HbA1c of 13.4%. Six months before, he had been switched from a c/DRV- based ART regimen to ABC/FTC/DTG. Previous HbA1c levels ranged between 5.8% and 6.2% (Figure 3). Results Discussion: In the first 2 patients, the presentation with acute onset DKA occurred more than a year after being on an INSTI-based regimen; however, the latter patient presented with HHS within 6 months of being switched to an INSTI-containing regimen. The mechanism of action of INSTIs causing weight gain or an association with hyperglycemia is still under investigation. Conclusion Although the temporal onset of DKA and HHS while receiving INSTIs was not precise, the possible association of INSTIs and their direct effects on insulin resistance and diabetes warrant additional attention from post-market data. Meanwhile, providers should monitor INSTI-treated patients closely, especially those with features of metabolic syndrome. Disclosures All authors: No reported disclosures.

scholarly journals Effects of insulin resistance on substrate utilization during exercise in overweight women

2004 ◽  
Vol 97 (3) ◽  
pp. 991-997 ◽  
Author(s):  
Barry Braun ◽  
Carrie Sharoff ◽  
Stuart R. Chipkin ◽  
Francesca Beaudoin
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Glucose Uptake ◽  
Body Fat ◽  
Muscle Glycogen ◽  
Substrate Oxidation ◽  
In Vivo Studies ◽  
Sensitivity Index ◽  
Total Carbohydrate ◽  
Insulin Resistant

During exercise, obese individuals oxidize less glycogen and more fat than their lean counterparts, but the shift in substrate use may be mediated by insulin resistance rather than body fat per se. In addition, individuals with Type 2 diabetes are not resistant to contraction-mediated glucose uptake during exercise, but in vivo studies uncomplicated by hyperglycemia are lacking. The purpose of this study was to compare blood glucose uptake and the balance between carbohydrate and fat utilization during exercise in insulin-resistant (IR) and insulin-sensitive (IS) women of equivalent body fatness and maximal oxygen consumption (V̇o2 max). Twelve overweight sedentary women were divided into two groups with similar body mass index (IR = 28.5 ± 1.6, IS = 27.5 ± 1.9), lean mass (IR = 42.4 ± 1.8 kg, IS = 41.5 ± 1.9 kg), and V̇o2 max (IR = 29.7 ± 3.5 ml·kg−1·min−1, IS = 30.7 ± 3.9 ml·kg−1·min−1) but a markedly different composite insulin sensitivity index (IR = 3.0 ± 0.7, IS = 7.7 ± 0.9). Blood glucose kinetics and substrate oxidation were assessed by stable isotope dilution and indirect calorimetry during 50 min of treadmill walking at 45% V̇o2 max. Total carbohydrate oxidation and estimated muscle glycogen use were significantly lower in the IR group. Blood glucose uptake was the same in the IR and IS groups. These data suggest that insulin resistance, independent of body fat, spares muscle glycogen and shifts substrate oxidation toward less carbohydrate use during exercise. Insulin-resistant individuals with normoglycemia appear to have no defect in blood glucose uptake during exercise.

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