Clinical effects of insulin glargine combined with repaglinide in the treatment of type 2 diabetes.

OBJECTIVE: To analyze the clinical effects of insulin glargine combined with repaglinide on the treatment of type 2 diabetes (T2D). METHODS: One hundred and twelve T2D patients were divided into two groups based on the treatment strategy, the control group (N=56) receiving insulin glargine and the experimental group (N=56) receiving insulin glargine combined with repaglinide. Clinical effects were analyzed and compared between the two groups. RESULTS: After treatment, the levels of fasting blood glucose (FBG), 2h-postprandial blood glucose (2h-PBG), and glycosylated hemoglobin of the experimental group were significantly lower than those of the control group (P<0.05). The levels of fasting C-peptide (FCP) and 2h-postprandial C-peptide (2h-PCP) of the experimental group were significantly higher than those of the control group (P<0.05) after treatment. Compared with the control group, the therapeutic efficacy was significantly higher (P<0.05), the time to normal blood glucose was notably shorter (P<0.05), and the insulin dosage was considerably lower in the experimental group (P<0.05). The incidence of adverse effects of the experimental group was significantly lower than that of the control group (P<0.05), and the treatment satisfaction of the experimental group was significantly higher than that of the control group (P<0.05). CONCLUSION: Insulin glargine combined with repaglinide is an effective and safe regimen in clinical practice, which can effectively control the blood glucose level, lower insulin dosage, and reduce adverse effects of T2D.

Paxillin S273 Phosphorylation Regulates Adhesion Dynamics and Cell Migration through a Common Protein Complex with PAK1 and ßPIX.

Cell migration is an important biological phenomenon involved in many homeostatic and aberrant physiological processes. Phosphorylation of the focal adhesion adaptor protein, paxillin, on serine 273 (S273) has been implicated as a key regulator of cell migration. Here, it is shown that phosphorylation on paxillin S273 leads to highly migratory cells with small dynamic adhesions. Adhesions at protrusive edges of the cell were more dynamic than adhesions at retracting edges. Temporal image correlation microscopy revealed that these dynamic adhesions undergo rapid binding of paxillin, PAK1 and ßPIX. We identified membrane proximal adhesion subdomains in protrusive regions of the cell that show rapid protein binding that is dependent on paxillin S273 phosphorylation, PAK1 kinase activity and phosphatases. These dynamic adhesion subdomains corresponded to regions of the adhesion that also show co-binding of paxillin/PAK1 and paxillin/ßPIX complexes. It is likely that parts of individual adhesions are more dynamic while others are less dynamic due to their association with the actin cytoskeleton. Variable adhesion and binding dynamics are regulated via differential paxillin S273 phosphorylation across the cell and within adhesions and are required for regulated cell migration. Dysregulation through phosphomutants, PAK1-KD or ßPIX mutants resulted in large stable adhesions, long protein binding times and slow cell migration. Dysregulation through phosphomimics or PAK1-CA led to small dynamic adhesions and rapid cell migration reminiscent of highly migratory cancer cells. Thus, phosphorylation of paxillin S273 is a key regulator of cell migration through recruitment of ßPIX and PAK1 to sites of adhesion.

Paxillin phosphorylation at serine 273 and its effects on Rac, Rho and adhesion dynamics.

Focal adhesions are protein complexes that anchor cells to the extracellular matrix. During migration, the growth and disassembly of these structures are spatiotemporally regulated, with new adhesions forming at the leading edge of the cell and mature adhesions disassembling at the rear. Signalling proteins and structural cytoskeletal components tightly regulate adhesion dynamics. Paxillin, an adaptor protein within adhesions, is one of these proteins. Its phosphorylation at serine 273 (S273) is crucial for maintaining fast adhesion assembly and disassembly. Paxillin is known to bind to a GIT1-ßPIX-PAK1 complex, which increases the local activation of the small GTPase Rac. To understand quantitatively the behaviour of this system and how it relates to adhesion assembly/disassembly, we developed a mathematical model describing the dynamics of the small GTPases Rac and Rho as determined by paxillin S273 phosphorylation. Our model revealed that the system possesses bistability, where switching between uninduced (active Rho) and induced (active Rac) states can occur through a change in rate of paxillin phosphorylation or PAK1 activation. The bistable switch is characterized by the presence of memory, minimal change in the levels of active Rac and Rho within the induced and uninduced states, respectively, and the limited regime of monostability associated with the uninduced state. These results were validated experimentally by showing the presence of bimodality in adhesion assembly and disassembly rates, and demonstrating that Rac activity increases after treating Chinese Hamster Ovary cells with okadaic acid (a paxillin phosphatase inhibitor), followed by a modest recovery after 20 min washout. Spatial gradients of phosphorylated paxillin in a reaction-diffusion model gave rise to distinct regions of Rac and Rho activities, resembling polarization of a cell into front and rear. Perturbing several parameters of the model also revealed important insights into how signalling components upstream and downstream of paxillin phosphorylation affect dynamics.