ABSTRACT
Obesity is a major public health concern, and complementary research strategies have been directed toward the identification of the underlying causative gene mutations that affect the normal pathways and networks that regulate energy balance. Here, we describe an autosomal-recessive morbid-obesity syndrome and identify the disease-causing gene defect. The average body mass index of affected family members was 48.7 (range = 36.7-61.0), and all had features of the metabolic syndrome. Homozygosity mapping localized the disease locus to a region in 3q29; we designated this region the morbid obesity 1 (MO1) locus. Sequence analysis identified a homozygous nonsense mutation in CEP19, the gene encoding the ciliary protein CEP19, in all affected family members. CEP19 is highly conserved in vertebrates and invertebrates, is expressed in multiple tissues, and localizes to the centrosome and primary cilia. Homozygous Cep19-knockout mice were morbidly obese, hyperphagic, glucose intolerant, and insulin resistant. Thus, loss of the ciliary protein CEP19 in humans and mice causes morbid obesity and defines a target for investigating the molecular pathogenesis of this disease and potential treatments for obesity and malnutrition.
Subject(s)
Cell Cycle Proteins/genetics , Gene Silencing , Obesity, Morbid/genetics , Adult , Amino Acid Sequence , Animals , Cloning, Molecular , Consanguinity , Conserved Sequence , Disease Models, Animal , Female , Gene Order , Gene Targeting , Genetic Association Studies , Genetic Linkage , Genotype , Glucose Tolerance Test , Humans , Insulin/metabolism , Insulin Resistance/genetics , Male , Mice , Mice, Knockout , Molecular Sequence Data , Mutation , Obesity, Morbid/diagnosis , Pedigree , Phenotype , Physical Chromosome Mapping , Signal Transduction , Young AdultABSTRACT
OBJECTIVE: The study objective was to assess the relationship between ß-cell function and HbA(1c). RESEARCH DESIGN AND METHODS: A total of 522 Mexican American subjects participated in this study. Each subject received a 75-g oral glucose tolerance test (OGTT) after a 10- to 12-h overnight fast. Insulin sensitivity was assessed with the Matsuda index. Insulin secretory rate was quantitated from deconvolution of the plasma C-peptide concentration. ß-Cell function was assessed with the insulin secretion/insulin resistance (IS/IR) (disposition) index and was related to the level of HbA(1c). RESULTS: At HbA(1c) levels <5.5%, both the Matsuda index of insulin sensitivity and IS/IR index were constant. However, as the HbA(1c) increased >5.5%, there was a precipitous decrease in both the Matsuda index and the IS/IR index. Subjects with HbA(1c) = 6.0-6.4% had a 44 and 74% decrease in the Matsuda index and the IS/IR index, respectively, compared with subjects with HbA(1c) <5.5% (P < 0.01 for both indices). Subjects with normal glucose tolerance and HbA(1c) <5.7% had ß-cell function comparable to that of subjects with normal glucose tolerance with HbA(1c) = 5.7-6.4%. However, subjects with impaired fasting glucose or impaired glucose tolerance had a marked decrease in ß-cell function independent of their HbA(1c) level. CONCLUSIONS: The results of the current study demonstrate that in Mexican Americans, as HbA(1c) increases >6.0%, both insulin sensitivity and ß-cell function decrease markedly. Performing an OGTT is pivotal for accurate identification of subjects with impaired ß-cell function.
Subject(s)
Glycated Hemoglobin/metabolism , Insulin-Secreting Cells/metabolism , Female , Glucose Tolerance Test , Humans , Insulin/blood , Insulin Resistance/physiology , Male , Middle Aged , United StatesABSTRACT
BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has recently come to be performed as a sole bariatric operation. The postoperative morbidity and mortality are cause for concern, and possibly are related to non-standardized surgical technique. METHODS: The following is the surgical LSG technique used in 25 morbidly obese patients. Five trocars are used. Division of the vascular supply of the greater gastric curvature is begun at 6-7 cm proximal to the pylorus, proceeding to the angle of His. A 50-Fr calibrating bougie is positioned against the lesser curvature. The LSG is created using a linear stapler-cutter device with one 4.1-mm green load for the antrum, followed by five to seven sequential 3.5-mm blue loads for the remaining gastric corpus and fundus. The staple-line is inverted by placing a sero-serosal continuous absorbable suture over the bougie from the angle of His. The resected stomach is removed through the 12-mm trocar, and a Jackson-Pratt drain is left along the suture-line. RESULTS: The mean operative time was 120 minutes, and length of hospital stay was 4 +/- 2 days. There were no conversions to open procedures. There were no postoperative complications (no hemorrhage from the staple-line, no anastomotic leakage, no stricture) and no mortality. In 1 patient, cholecystectomy was also done, and in 4, a gastric band was removed. During a median follow-up of 4 months, BMI decreased from 43 +/- 5 kg/m2 to 34 +/- 6 kg/m2, and the % excess BMI loss was 49 +/- 25%. CONCLUSIONS: The proposed surgical technique appears to be a safe and effective procedure for morbid obesity.
