ABSTRACT
Type 1 diabetes mellitus (T1DM) is an autoimmune condition that results in low plasma insulin levels by destruction of beta cells of the pancreas. As part of the natural progression of this disease, some patients regain beta cell activity transiently. This period is often referred to as the 'honeymoon period' or remission of T1DM. During this period, patients manifest improved glycemic control with reduced or no use of insulin or anti-diabetic medications. The incidence rates of remission and duration of remission is extremely variable. Various factors seem to influence the remission rates and duration. These include but are not limited to C-peptide level, serum bicarbonate level at the time of diagnosis, duration of T1DM symptoms, haemoglobin A1C (HbA1C) levels at the time of diagnosis, sex, and age of the patient. Mechanism of remission is not clearly understood. Extensive research is ongoing in regard to the possible prevention and reversal of T1DM. However, most of the studies that showed positive results were small and uncontrolled. We present a 32-year-old newly diagnosed T1DM patient who presented with diabetic ketoacidosis (DKA) and HbA1C of 12.7%. She was on basal bolus insulin regimen for the first 4 months after diagnosis. Later, she stopped taking insulin and other anti-diabetic medications due to compliance and logistical issues. Eleven months after diagnosis, her HbA1C spontaneously improved to 5.6%. Currently (14 months after T1DM diagnosis), she is still in complete remission, not requiring insulin therapy.
ABSTRACT
CONTEXT: Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized by partial insensitivity to glucocorticoids, caused by mutations in the glucocorticoid receptor (GR) gene. Most of the reported cases are adults, demonstrating symptoms associated with mineralocorticoid and/or adrenal androgen excess caused by compensatively increased secretion of the adrenocorticotropic hormone. PATIENT: We identified a new 2-yr-old female case of generalized glucocorticoid resistance syndrome. The patient (TJ) presented with a generalized seizure associated with hypoglycemia and hypokalemia. She also had hypertension and premature pubarche, whereas dexamethasone effectively suppressed these clinical manifestations. RESULTS: The patient's GR gene had a heterozygotic mutation (G-->A) at nucleotide position 2141 (exon 8), which resulted in substitution of arginine by glutamine at amino acid position 714 in the ligand-binding domain (LBD) of the GR alpha. Molecular analysis revealed that the mutant receptor had significantly impaired transactivation activity with a 2-fold reduction in affinity to ligand. It showed attenuated transactivation of the activation function (AF)-2 and reduced binding to a p160 nuclear receptor coactivator. Computer-based structural analysis revealed that replacement of arginine by glutamine at position 714 transmitted a conformational change to the LBD and the AF-2 transactivation surface, resulting in a decreased binding affinity to ligand and to the LXXLL coactivator motif. CONCLUSIONS: Dexamethasone treatment is effective in controlling the premature pubarche, hypoglycemia, hypertension, and hypokalemia in this child case, wherein arginine 714 plays a key role in the proper formation of the ligand-binding pocket and the AF-2 surface of the GR alpha LBD.
