ABSTRACT
Glucagon-like peptide-1 (GLP-1) is an incretin hormone released from intestinal L-cells in response to food entering into the gastrointestinal tract. GLP-1-based pharmaceuticals improve blood glucose regulation and may hold promise for obesity treatment, as GLP-1 drugs reduce food intake and body weight in humans and animals. In an effort to improve GLP-1 pharmacotherapies, we focused our attention on macronutrients that, when present in the gastrointestinal tract, may enhance GLP-1 secretion and improve glycemic regulation and food intake suppression when combined with systemic administration of sitagliptin, a pharmacological inhibitor of DPP-IV (enzyme responsible for GLP-1 degradation). In particular, previous data suggest that specific macronutrient constituents found in dairy foods may act as potent secretagogues for GLP-1 and therefore may potentially serve as an adjunct dietary therapy in combination with sitagliptin. To directly test this hypothesis, rats received intraperitoneal injections of sitagliptin (6 mg/kg) or saline vehicle followed by intraduodenal infusions of either milk protein concentrate (MPC; 80/20% casein/whey; 4 kcal), soy protein (nondairy control infusate; 4 kcal), or 0.9% NaCl. Food intake was assessed 30 min postinfusion. In separate studies, regulation of blood glucose was examined via a 2-h oral glucose tolerance test (2 g/kg) following identical sitagliptin treatment and intraduodenal nutrient infusions. Collectively, results show that intraduodenal MPC, but not soy protein, significantly enhances both the food intake suppression and improved control of blood glucose produced by sitagliptin. These data support the hypothesis that dietary intake of dairy protein may be beneficial as an adjunct behavioral therapy to enhance the glycemic and food intake suppressive effects of GLP-1-based pharmacotherapies.
Subject(s)
Blood Glucose/drug effects , Dipeptidyl Peptidase 4/drug effects , Eating , Glucagon-Like Peptide 1/drug effects , Hypoglycemic Agents/therapeutic use , Milk Proteins/metabolism , Pyrazines/therapeutic use , Triazoles/therapeutic use , Animals , Blood Glucose/metabolism , Dipeptidyl Peptidase 4/metabolism , Eating/drug effects , Eating/physiology , Glucagon-Like Peptide 1/metabolism , Male , Obesity/drug therapy , Rats , Rats, Sprague-Dawley , Sitagliptin PhosphateABSTRACT
Macrosomia, obesity, macrocephaly, and ocular abnormalities syndrome (MOMO syndrome) has been reported in only four patients to date. In these sporadic cases, no chromosomal or molecular abnormality has been identified thus far. Here, we report on the clinical, cytogenetic, and molecular findings in a child of healthy consanguineous parents suffering from MOMO syndrome. Conventional karyotyping revealed an inherited homozygous balanced reciprocal translocation (16;20)(q21;p11.2). Uniparental disomy testing showed bi-parental inheritance for both derivative chromosomes 16 and 20. The patient's oligonucleotide array-comparative genomic hybridization profile revealed no abnormality. From the homozygous balanced reciprocal translocation (16;20)(q21;p11.2), a positional cloning strategy, designed to narrow 16q21 and 20p11.2 breakpoints, revealed the disruption of a novel gene located at 20p11.23. This gene is now named LINC00237, according to the HUGO (Human Genome Organization) nomenclature. The gene apparently leads to the production of a non-coding RNA. We established that LINC00237 was expressed in lymphocytes of control individuals while normal transcripts were absent in lymphocytes of our MOMO patient. LINC00237 was not ubiquitously expressed in control tissues, but it was notably highly expressed in the brain. Our results suggested autosomal recessive inheritance of MOMO syndrome. LINC00237 could play a role in the pathogenesis of this syndrome and could provide new insights into hyperphagia-related obesity and intellectual disability.
Subject(s)
Abnormalities, Multiple/genetics , Coloboma/genetics , Fetal Macrosomia/genetics , Genetic Predisposition to Disease , Homozygote , Intellectual Disability/genetics , Megalencephaly/genetics , Obesity/genetics , RNA, Long Noncoding/genetics , Translocation, Genetic , Abnormalities, Multiple/diagnosis , Amino Acid Sequence , Base Sequence , Child , Chromosome Breakpoints , Coloboma/diagnosis , Fetal Macrosomia/diagnosis , Gene Expression Profiling , Head/abnormalities , Humans , In Situ Hybridization, Fluorescence , Intellectual Disability/diagnosis , Karyotype , Male , Megalencephaly/diagnosis , Molecular Sequence Data , Mutation , Obesity/diagnosis , Open Reading Frames , PhenotypeABSTRACT
OBJECTIVE: To assess the extent to which couples who could benefit from fetal karyotyping during the first or second trimester would agree to delay the examination until the third trimester. METHODS: In this prospective monocentric study, the same physician suggested to some couples to delay fetal karyotyping until the third trimester. RESULTS: 458 couples participated in this study. 230 couples (230/458 = 50.2%) refused to delay the examination until the third trimester of pregnancy (group 1). For these patients, four chromosomal abnormalities led to the termination of pregnancy. Fifty-six couples (56/458 = 12.2%) who initially agreed to delay the fetal karyotyping later changed their minds (group 2). 104 couples (104/458 = 22.7%) agreed to delay the examination (group 3). For these patients, one trisomy 21 was diagnosed and led to the subsequent termination of the pregnancy at 33 weeks of amenorrhea. Sixty-eight couples (68/458 = 14.8%) refused any form of invasive prenatal diagnosis (group 4). There was no difference in the rate of preterm premature rupture of membranes, pregnancy term, premature birth rate and birth weight between the four groups. CONCLUSIONS: Our study reports that about a quarter of couples did indeed agree to delay fetal karyotype assessment until the third trimester of pregnancy.
