Reducing Glucokinase Activity Restores Endogenous Pulsatility and Enhances Insulin Secretion in Islets From db/db...

Area of Science:

• Endocrinology
• Metabolic Diseases
• Cell Biology

Background:

• Type 2 diabetes (T2D) is characterized by impaired insulin secretion patterns, specifically loss of pulsatility.
• This dysfunction is linked to altered glucose sensing, leading to relative hyperinsulinemia and eventual beta-cell exhaustion.

Purpose of the Study:

• To investigate if reducing glucokinase activity in diabetic islets can restore normal pulsatile insulin release and improve beta-cell function.
• To examine the effects of the glucokinase inhibitor d-mannoheptulose (MH) on intracellular calcium oscillations and insulin secretion in diabetic models.

Main Methods:

• Isolated islets from control and db/db mice were treated with varying concentrations of d-mannoheptulose (MH).
• Intracellular calcium ([Ca2+]i) oscillations and insulin secretion were measured using fura-2 imaging and simultaneous measurements.
• The impact of MH on glucose-stimulated insulin secretion and [Ca2+]i dynamics was analyzed.

Main Results:

• Acute MH treatment dose-dependently reduced [Ca2+]i oscillations in control islets under high glucose.
• Overnight treatment with 1 mM MH in db/db mouse islets restored [Ca2+]i oscillations and enhanced insulin secretion.
• Insulin secretion rates positively correlated with the amplitude of MH-induced [Ca2+]i oscillations.

Conclusions:

• Modulating glucokinase activity by reducing its excessive function can restore pulsatile insulin secretion in diabetic islets.
• Improved insulin pulsatility, driven by restored calcium oscillations, is directly linked to enhanced insulin secretion in T2D.
• Targeting glucokinase offers a potential therapeutic strategy for improving beta-cell function in type 2 diabetes.