Constitutively active heat shock factor 1 enhances glucose-driven insulin secretion

Area of Science:

• Endocrinology
• Molecular Biology
• Gene Therapy

Background:

• Weak pancreatic beta-cell function is a key factor in type 2 diabetes mellitus.
• Glucokinase plays a crucial role in regulating insulin secretion through glucose phosphorylation.
• Developing strategies to enhance insulin secretion without inducing hypoglycemia is critical for diabetes treatment.

Purpose of the Study:

• To investigate the potential of expressing constitutively active human heat shock factor 1 (CA-hHSF1) to enhance insulin secretion.
• To evaluate the efficacy of an adenoviral vector expressing Ins-CA-hHSF1 in improving glycemic control in diabetic models.
• To assess the safety of this approach regarding the induction of hypoglycemia.

Main Methods:

• Generated adenoviruses expressing CA-hHSF1 under cytomegalovirus (CMV) and human insulin (Ins) promoters.
• Infected mouse insulinoma MIN6 cells and Wistar rats (healthy and type 2 diabetes mellitus models).
• Assessed insulin secretion, blood glucose levels, serum insulin, and oral glucose tolerance.

Main Results:

• CA-hHSF1 expression increased insulin secretion by 1.27-fold in MIN6 cells, mediated by HSP90 and glucokinase activation.
• The mechanism involves the activation of glucokinase and neuronal nitric oxide synthase.
• Ins-CA-hHSF1 improved blood glucose in diabetic rats and reduced oral glucose tolerance test results in healthy rats without causing hypoglycemia.

Conclusions:

• CA-hHSF1 effectively induces insulin secretion both in vitro and in vivo.
• Gene therapy using Ins-CA-hHSF1 holds potential for treating type 2 diabetes mellitus and impaired glucose tolerance.
• This therapeutic strategy appears safe, as it does not induce hypoglycemia during fasting.