Novel Trajectories of Bromocriptine Antidiabetic Action: Leptin-IL-6/ JAK2/p-STAT3/SOCS3, p-IR/p-AKT/GLUT4, PPAR-γ/Adiponectin, Nrf2/PARP-1, and GLP-1

Bromocriptine (BC), a sympatholytic dopaminergic D2 receptor agonist, has been comprehensively used in clinic to treat Parkinson’s disease (PD) and prolactinomas. Besides, BC represents a novel therapeutic option in type 2 diabetes (T2DM); however, the precise mechanisms are not completely unveiled. Hence, the objective of the current work is to clarify the potential molecular pathways of the insulin sensitizing effect of BC in the skeletal muscle of diabetic rats and to evaluate its possible interaction with sitagliptin (SG) as an add-on therapy. Here experimental model impersonates unhealthy dietary habit and T2DM was adopted, in which rats were fed high caloric diet of fat and fructose for 6 weeks followed by a single sub-diabetogenic dose of streptozotocin (STZ) (35 mg/kg; HF/Fr/STZ). Diabetic rats were treated with BC, SG at two dose levels (SG10 and SG20) and combination of BC + SG10 for 2 weeks. BC successfully corrected glucose/lipid profile, as well as leptin and GLP-1. On the muscular molecular level, BC curtailed the inflammatory signal IL-6/JAK2/p-STAT3/SOCS3, while enhanced the PPAR-γ/adiponectin signaling, resulting in activation of the insulin signaling pathway (p-IR/p-AKT/GLUT4). Moreover, BC confirmed its antioxidant capabilities by altering Nrf2 and PARP-1; the study also highlighted novel mechanisms for SG as well. On almost all tested parameters/pathways, the combination regimen surpassed each drug alone to reach a comparable level to the high dose of SG. In conclusion, our finding shed some light on novel anti-diabetic mechanisms of BC. The study also points to the potential use of BC as an adds-on to standard anti-diabetic therapies

Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect

Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis

Effect of topiramate on hepatic biomarkers.

<p>The panels illustrate the effect of topiramate (40 & 100 mg/kg, p.o; TPM₄₀, TPM₁₀₀) on hepatic (A, B) insulin receptor isoforms (high affinity, [HAIR, fmol/mg protein] and low affinity [LAIR, pmol/mg protein] insulin receptor), (C, D) adiponectin receptors (Adipo-R1, Adipo-R2 [ng/mg protein]), (E) protein tyrosine kinase (PTK [U/mg protein]), and (F) glucose transporter-2 (GLUT2 [mg/mg protein]) of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks (mean of 10 animals ± S.D.). Treatments were administered once daily for 2 weeks. As compared with normal control (^*), HFFD (<b>^†</b>) and HFFD+TPM40 ^(‡) groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Effect of topiramate on the indicators of glucose homeostasis of obese/insulin resistant rats.

<p>Effect of topiramate (40, 100 mg/kg; TPM₄₀, TPM₁₀₀) on serum levels of glucose, insulin, and fructosamine, HOMA-index and area under the curve of the GTT of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks. Values are means (± S.D.) of 10 animals. Treatments were administered once daily for 2 weeks. As compared with normal control (^*), HFFD (<b>^†</b>) and HFFD+TPM₄₀<b>(^‡)</b> groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Effect of topiramate on serum biomarkers.

<p>The panels illustrate the effect of topiramate (40 & 100 mg/kg, p.o; TPM₄₀, TPM₁₀₀) on serum (A) triglycerides (TGs, [mg/dl]), (B) total cholesterol(TC, [mg/dl]), (C) free fatty acids (FFAs, mmol/l]), (D)ALT (IU/L), (E) tumor necrosis alpha (TNF-α, [pg/ml]) and (F) adiponectin [ng/ml] of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks (mean of 10 animals ± S.D.). Treatments were administered once daily for 2 weeks. As compared with normal control (^*), HFFD (<b>^†</b>) and HFFD+TPM40 ^(<b>‡</b>) groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Correlation coefficient (<i>r</i>) between HOMA-I and serum adiponectin with hepatic GLUT2, adiponectin receptors (Adipo- R1, R2), insulin receptor isoforms (LAIR, HAIR), and tyrosine kinase.

<p>Correlation was carried out in untreated and treated hyperglycemic animals.</p

The glucose tolerance test (GTT).

<p>The curve depicts the changes in serum glucose response in normal control, non-treated obese/insulin-resistant rats (HFFD), and treated ones by either dose of topiramate (40 & 100 mg/kg;HFFD+TPM40, HFFD+TPM₁₀₀), after 0, 30, 60, 90, and 120 min following administration of glucose (2 g/kg, ip). Values are means (± S.D) of 10 animals; as compared with normal control (^*), and HFFD (<b>^†</b>) groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Effect of topiramate on serum and tissue biomarkers of normal control rat.

<p>Effect of 14 days administration of topiramate (40, 100 mg/kg) to normal control rats fed normal diet. The following markers were assessed: serum levels of glucose, insulin, and fructosamine, HOMA-index and area under the curve (AUC); serum triglycerides (TGs), total cholesterol (TC), free fatty acids (FFAs), ALT (IU/L), tumor necrosis alpha (TNF-α) and adiponectin; body weight (BW) and liver weight (LW)/−, visceral fat weight (VFW)/− and epididymal fat weight (EFW)/−BW ratio. Values are means (± S.D.) of 10 animals. Treatments were administered once daily for 2 weeks. Statistical analysis between groups was carried out using one-way ANOVA followed by Tukey-Kramer Test, <i>P</i><0.05.</p

Effect of topiramate on body-, liver- and fat weights of obese/insulin resistant rats.

<p>Effect of topiramate (40, 100 mg/kg; TPM₄₀, TPM₁₀₀) on body weight (BW) and liver weight (LW)/−, visceral fat weight (VFW)/− and epididymal fat weight (EFW)/−BW ratio of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks. Values are means (± S.D.) of 10 animals. Treatments were administered once daily for 2 weeks. As compared with normal control (<b>^*</b>), and HFFD (<b>^†</b>) groups (one-way ANOVA followed by Tukey-Kramer Test), <i>P</i><0.05.</p