Hydrogen Sulfide Treatment Promotes Glucose Uptake by Increasing Insulin Receptor Sensitivity and Ameliorates Kidney Lesions in Type 2 Diabetes

Abstract

Aims: To examine if hydrogen sulfide (H 2 S) can promote glucose uptake and provide amelioration in type 2 diabetes. Results: Treatment with sodium hydrosulfide (NaHS, an H 2 S donor) increased glucose uptake in both myotubes and adipocytes. The H 2 S gas solution showed similar effects. The NaHS effects were blocked by an siRNA-mediated knockdown of the insulin receptor (IR). NaHS also increased phosphorylation of the IR, PI3K, and Akt. In Goto-Kakizaki (GK) diabetic rats, chronic NaHS treatment (30 lmol$kg -1 $day -1 ) decreased fasting blood glucose, increased insulin sensitivity, and increased glucose tolerance with increased phosphorylation of PI3K and Akt in muscles. Similar insulin-sensitizing effects of NaHS treatment were also observed in Wistar rats. Moreover, glucose uptake was reduced in the cells with siRNA-mediated knockdown of the H 2 S-generating enzyme cystathionine c-lyase in the presence or absence of exogenous H 2 S. Moreover, chronic NaHS treatment reduced oxygen species and the number of crescentic glomeruli in the kidney of GK rats. Innovation and Conclusion: This study provides the first piece of evidence for the insulin-sensitizing effect of NaHS/H 2 S in the both in vitro and in vivo models of insulin resistance. Rebound Track: This work was rejected during a standard peer review and rescued by the Rebound Peer Review (Antoxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers:

Hydrogen sulfide exhibits cardioprotective effects by decreasing endoplasmic reticulum stress in a diabetic cardiomyopathy rat model

“…A number of studies have demonstrated that as H 2 S improves insulin resistance, inhibits the activity of α-glucosidase and increases hepatic glucokinase activity and glycogen storage, it can reduce blood glucose (94)(95)(96). Conversely, the present study shows no significant effect of H 2 S on blood glucose.…”

Hydrogen Sulfide Targets EGFR Cys797/Cys798 Residues to Induce Na+/K+-ATPase Endocytosis and Inhibition in Renal Tubular Epithelial Cells and Increase Sodium Excretion in Chronic Salt-Loaded Rats

“…These results showed that NaHS inhibited the binding affinity of NaH 35 S in a concentration-dependent manner, and these data could be fit to a single binding site model (Fig. 6C).…”

“…(B-E) NaH 35 S incubated with EGFR for different time scales (0-90 min) at 37°C (B) (n = 6). Homologous competition curve for NaH 35 S binding against EGFR in vitro. Data were transformed into percentage of specific binding (%) and described by the one-site model (C) (n = 6).…”

“…In a homologous competition experiment, EGFR was incubated with NaH 35 S in the presence of increasing concentrations (10 -8 -10 -1 M) of unlabeled NaHS. These results showed that NaHS inhibited the binding affinity of NaH 35 S in a concentration-dependent manner, and these data could be fit to a single binding site model (Fig.…”

Decreased Cystathionine-γ-lyase (CSE) Activity in Livers of Type 1 Diabetic Rats and Peripheral Blood Mononuclear Cells (PBMC) of Type 1 Diabetic Patients

“…In contrast, high glucose stimulation has been reported to decrease CSE protein expression in rodent INS-1E ␤-cells (58). Xue et al (59) reported that siRNA-mediated knockdown of CSE decreased the glucose uptake in 3T3L1 adipocyte and L6 myotube cells supplemented with NaHS (exogenous source of H 2 S). Our previous studies have also shown that high glucose stimulation decreased the CSE protein expression in both U937 monocytes (3) and 3T3L1 adipocytes (39); in addition, siRNA-mediated CSE knockdown also decreased the glucose utilization compared with that seen in controls (3).…”