Date of Award
Master of Science (MS)
Maturity Onset Diabetes of the Young (MODY) is a type of diabetes, distinct from either type I or type II, that happens before age 25 (MedlinePlus, 2022). Unlike the other two more common forms of diabetes, MODY is classified as a series of monogenetic disorders (American Diabetes Association Professional Practice Committee, 2021), caused by autosomal mutations. MODY is typically characterized by insufficient secretion of insulin, a similar symptom to type I diabetes, classified into 14 different types based on mutations found on different genes. Among them, subtypes 12 and 13, also called neonatal diabetes mellitus (NDM), are caused by gain-of-function mutations in Kir6.2 or SUR1, subunits of ATP-sensitive potassium (KATP) channels, and result from overactive KATP -driven loss of insulin secretion.
KATP channels are a type of potassium channels that are gated by the concentration of intracellular ATP and ADP, and consist of tetramers of inward-rectifier potassium channel (Kir6.x) subunits, surrounded by 4 regulator sulfonylurea receptors (SUR) subunits. They are widely found in human tissues, including cardiac, brain, skeletal muscles, smooth muscles, pancreas, and neurons. KATP channel function in pancreatic β-cells was first described in 1984 in rat pancreas islets. In contrast to NDM, congenital hyperinsulinism (CHI) results from loss of function of KATP channels, which leads to hypersecretion of insulin. However, clinical data show that CHI patients frequently experience a transition from hypersecretion of insulin to a high blood glucose level, although there are few previous studies that highlight this transition, and the nature of the ensuing diabetes is unknown.
Our collaborators in India have identified a large number of NDM and CHI patients, but also a number of patients diagnosed with MODY, but not NDM, and harboring KATP channel mutations. The goal of this study was to analyze the functional consequences of the associated KATP mutations, in order to shed light on the mechanisms underlying the resultant diabetes.
In this project, I used fluorescence-based Dibac4(3) and thallium flux assays to investigate the effect of mutations on channel expression and function. The signals captured by these two assays illustrate the activities of mutated channels, reflecting the channel conductance. From the results, it is clear that the MODY-associated mutants are expressing loss of function behaviors. In particular, G163S and R1436P in SUR1 generate no channel activity, even after channel activators are applied to the cells. The results are not consistent with the idea that these MODY patients suffer from MODY 12 and 13 (i.e. NDM), but instead suggest that they should suffer from hypersecretion of insulin. Thus, the reasons for high blood glucose level in these MODY patients is unclear. It is possible that these patients are all CHI patients who have experienced a crossover from hyperinsulinism to diabetes, potentially explaining why KATP inhibitor therapy is unsuccessful in them. The mechanism of the transition process remains unclear, providing a future research direction to assess the transition mechanism, as well as pointing to a new sub-classification of MODY.
Colin Nichols Sunjoo Lee Maria Remedi Jonathan Silva
Available for download on Sunday, December 31, 2023