Phloridzin Acts as an Inhibitor of Protein-Tyrosine Phosphatase MEG2 Relevant to Insulin Resistance

Inhibition of the megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2, also named PTPN9) activity has been shown to be a potential therapeutic strategy for the treatment of type 2 diabetes. Previously, we reported that PTP-MEG2 knockdown enhances adenosine monophosphate activated protein kinase (AMPK) phosphorylation, suggesting that PTP-MEG2 may be a potential antidiabetic target. In this study, we found that phloridzin, isolated from Ulmus davidiana var. japonica, inhibits the catalytic activity of PTP-MEG2 (half-inhibitory concentration, IC50 = 32 ± 1.06 μM) in vitro, indicating that it could be a potential antidiabetic drug candidate. Importantly, phloridzin stimulated glucose uptake by differentiated 3T3-L1 adipocytes and C2C12 muscle cells compared to that by the control cells. Moreover, phloridzin led to the enhanced phosphorylation of AMPK and Akt relevant to increased insulin sensitivity. Importantly, phloridzin attenuated palmitate-induced insulin resistance in C2C12 muscle cells. We also found that phloridzin did not accelerate adipocyte differentiation, suggesting that phloridzin improves insulin sensitivity without significant lipid accumulation. Taken together, our results demonstrate that phloridzin, an inhibitor of PTP-MEG2, stimulates glucose uptake through the activation of both AMPK and Akt signaling pathways. These results strongly suggest that phloridzin could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.

Download Full-text

Inhibition of Protein Tyrosine Phosphatase-1B with Antisense Oligonucleotides Improves Insulin Sensitivity and Increases Adiponectin Concentrations in Monkeys

Endocrinology ◽

10.1210/en.2008-0885 ◽

2009 ◽

Vol 150 (4) ◽

pp. 1670-1679 ◽

Cited By ~ 43

Author(s):

Michael M. Swarbrick ◽

Peter J. Havel ◽

Arthur A. Levin ◽

Andrew A. Bremer ◽

Kimber L. Stanhope ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Protein Tyrosine Phosphatase ◽

Antisense Oligonucleotides ◽

Tyrosine Phosphatase ◽

Ptp 1B ◽

Insulin Responses

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40–50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1–10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = −0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.

Download Full-text

PROTEIN TYROSINE PHOSPHATASE 1B (PTP1B) IN OBESITY AND TYPE 2 DIABETES

Acta Medica Saliniana ◽

10.5457/ams.v38i1.23 ◽

2009 ◽

Vol 38 (1) ◽

pp. 2-7 ◽

Cited By ~ 6

Author(s):

Mirela Delibegovic ◽

Nimesh Mody

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Developed Countries ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

The Developed Countries

Increased incidence in obesity is reaching epidemic proportions and is placing a major burden on the healthcare systems in the developed countries. Obesity is a major risk factor for the development of type 2 diabetes, metabolic syndrome, cardiovascular disease and cancer. Thus, the search for molecules that regulate the development of obesity and its associated pathologies is ongoing. Protein tyrosine phosphatase 1B (PTP1B) has been found to be a major regulator of body fat stores, energy balance, and insulin sensitivity in vivo. Increased expression of PTP1B is associated with insulin resistance in rodents and humans and deletion of PTP1B leads to leanness and insulin sensitivity in rodents, suggesting that PTP1B may be a very attractive molecular target for anti-obesity, anti-diabetic agents.

Download Full-text