The Longitudinal Effect of Diabetes-Associated Variation in TCF7L2 on Islet Function in Humans

Area of Science:

• Genetics
• Endocrinology
• Metabolic Diseases

Background:

• The T allele at rs7903146 in TCF7L2 is linked to increased type 2 diabetes risk.
• This genetic variant is associated with impaired beta-cell function and defective glucose suppression of alpha-cell secretion.
• The precise timing of these islet cell abnormalities is not well understood.

Purpose of the Study:

• To investigate the longitudinal changes in islet function in relation to the TCF7L2 rs7903146 genotype.
• To determine the temporal relationship between alpha-cell and beta-cell dysfunction in the development of glucose intolerance.

Main Methods:

• Recruited 128 subjects, 67 with TT genotype and 61 with protective genotype at rs7903146.
• Subjects underwent oral glucose tolerance tests at baseline and 3 years later.
• Quantified beta-cell function using the oral minimal model and estimated glucagon secretion rates via deconvolution.

Main Results:

• Glucose tolerance deteriorated over 3 years in subjects with the TT genotype.
• The TT genotype was associated with impaired post-challenge glucagon suppression.
• Beta-cell responsiveness to glucose remained appropriate, suggesting alpha-cell dysfunction occurs earlier.

Conclusions:

• Alpha-cell abnormalities associated with the TCF7L2 TT genotype (rs7903146) appear early in the progression to type 2 diabetes.
• These alpha-cell defects may precede the development of beta-cell dysfunction.
• Understanding this sequence can inform strategies for preventing type 2 diabetes.