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J Clin Endocrinol Metab ; 102(1): 1-5, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27802092


Context: The most common genetic cause of permanent neonatal diabetes mellitus is activating mutations in KCNJ11, which can usually be treated using oral sulfonylureas (SUs) instead of insulin injections, although some mutations are SU unresponsive. In this work, we provide a report of the pancreatic islet endocrine cell composition and area in a patient with an SU-unresponsive KCNJ11 mutation (p.G334D), in comparison with age-matched controls. Case Description: Pancreatic autopsy tissue sections from a 2-year-old female child diagnosed with KCNJ11-related diabetes at 4 days of age and 13 age-matched controls were stained with insulin, glucagon, somatostatin, pancreatic polypeptide, and Ki67 antibodies to determine islet endocrine cell composition and area. ß-cell ultrastructure was assessed by electron microscopic (EM) analysis. The patient's pancreas (sampling from head to tail) revealed insulin-positive cells in all regions. The pancreatic ß-cell (insulin) area was significantly reduced compared with controls: 0.50% ± 0.04% versus 1.67% ± 0.20%, respectively (P < 0.00001). There were no significant differences in α-cell (glucagon) or δ-cell (somatostatin) area. EM analysis revealed secretory granules with a dense core typical of mature ß-cells as well as granules with a lighter core characteristic of immature granules. Conclusions: Our results suggest that mechanisms exist that allow preservation of ß-cells in the absence of insulin secretion. It remains to be determined to what extent this reduction in ß-cells may be reversible.

Diabetes Mellitus/tratamento farmacológico , Células Secretoras de Insulina/patologia , Insulina/metabolismo , Mutação/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Compostos de Sulfonilureia/farmacologia , Autopsia , Biomarcadores/análise , Glicemia/análise , Estudos de Casos e Controles , Pré-Escolar , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Resistência a Medicamentos , Feminino , Humanos , Lactente , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Prognóstico
Acta Diabetol ; 53(5): 703-8, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27106716


AIMS: GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our US cohort of GCK-MODY. METHODS: We examined the rates of detection of heterozygous mutations in the GCK gene in individuals referred to the US Monogenic Diabetes Registry with a phenotype consistent with GCK-MODY. We also assessed referral patterns, treatment and demography, including ethnicity, of the cohort. RESULTS: Deleterious heterozygous GCK mutations were found in 54.7 % of Registry probands selected for GCK sequencing for this study. Forty-nine percent were previously unnecessarily treated with glucose-lowering agents, causing hypoglycemia and other adverse effects in some of the subjects. The proportion of probands found to have a GCK mutation through research-based testing was similar across each ethnic group. However, together African-American, Latino and Asian subjects represented only 20.5 % of screened probands and 17.2 % of those with GCK-MODY, despite higher overall diabetes prevalence in these groups. CONCLUSIONS: Our data show that a high detection rate of GCK-MODY is possible based on clinical phenotype and that prior to genetic diagnosis, a large percentage are inappropriately treated with glucose-lowering therapies. We also find low minority representation in our Registry, which may be due to disparities in diagnostic diabetes genetic testing and is an area needing further investigation.

Diabetes Mellitus Tipo 2/epidemiologia , Glucoquinase/genética , Sistema de Registros/normas , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Viés de Seleção , Estados Unidos