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Biomedical subjects

Jean-François Gautier

Publications and source records attributed to Jean-François Gautier.

16 recordsLinked to original sources
PubMed2006

Consequences of fetal exposure to maternal diabetes in offspring.

CONTEXT: Type 2 diabetes is the result of both genetic and environmental factors. Fetal exposure to maternal diabetes is associated with a higher risk of abnormal glucose homeostasis in offspring beyond that attributable to genetic factors, and therefore, may participate in the excess of maternal transmission of type 2 diabetes. EVIDENCE ACQUISITION: A MEDLINE search covered the period from 1960-2005. EVIDENCE SYNTHESIS: Human studies performed in children and adolescents suggest that offspring who had been exposed to maternal diabetes during fetal life exhibit higher prevalence of impaired glucose tolerance and markers of insulin resistance. Recent studies that directly measured insulin sensitivity and insulin secretion have shown an insulin secretory defect even in the absence of impaired glucose tolerance in adult offspring. In animal models, exposure to a hyperglycemic intrauterine environment also led to the impairment of glucose tolerance in the adult offspring. These metabolic abnormalities were transmitted to the next generations, suggesting that in utero exposure to maternal diabetes has an epigenetic impact. At the cellular level, some findings suggest an impaired pancreatic beta-cell mass and function. Several mechanisms such as defects in pancreatic angiogenesis and innervation, or modification of parental imprinting, may be implicated, acting either independently or in combination. CONCLUSION: Thus, fetal exposure to maternal diabetes may contribute to the worldwide diabetes epidemic. Public health interventions targeting high-risk populations should focus on long-term follow-up of subjects who have been exposed in utero to a diabetic environment and on a better glycemic control during pregnancy.

Adult↗
PubMed2006

How do different GLP-1 mimetics differ in their actions?

Glucagon-like peptide-1 (GLP-1) mimetics have been developed to overcome the pharmacokinetic limitations of GLP-1 for the treatment of type 2 diabetes. Their mechanisms of action and clinical effects appear particularly interesting because they target the main pathophysiologic mechanisms involved in type 2 diabetes. GLP-1 receptor agonists are more powerful and are particularly advantageous by their weight loss-inducing capacity, whereas dipeptidyl peptidase IV inhibitors exhibit a better tolerance profile. However, their ultimate role is still to be defined in the therapeutic strategy of type 2 diabetes.

Adamantane↗
PubMed2005

High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes.

CONTEXT: Ketosis-prone diabetes (KPD) is mostly observed in males of West African descent and is characterized by phasic or permanent insulin dependence without apparent autoimmune process. OBJECTIVE: KPD subjects display a propensity to hyperglycemia-induced acute insulin deficiency, suggesting that they exhibit a propensity to oxidative stress in beta-cells. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a defense mechanism against oxidative stress, and G6PD deficiency, an X-linked genetic disorder with male predominance, is frequent in West Africans. We hypothesized that mutations in the G6PD gene could predispose to KPD. DESIGN: We studied G6PD erythrocyte enzyme activity and the insulin secretory reserve (glucagon-stimulated C peptide) in a cohort of hospitalized West Africans with KPD (n = 59) or type 2 diabetes (T2DM; n = 59) and in normoglycemic controls (n = 55). We also studied the G6PD gene in an extended population of KPD patients (n = 100), T2DM patients (n = 59), and controls (n = 85). RESULTS: The prevalence of G6PD deficiency was higher in KPD than in T2DM and controls (42.3%; 16.9%; 16.4%; P = 0.01). In KPD, but not in T2DM, insulin deficiency was proportional to the decreased G6PD activity (r = 0.33; P = 0.04). We found no increase in the prevalence of G6PD gene mutations in KPD compared with T2DM and controls. Rather, we found a 20.3% prevalence of G6PD deficiency in KPD without gene mutation. CONCLUSIONS: This study suggests that 1) G6PD deficiency alone is not causative of KPD; and 2) alterations in genes controlling both insulin secretion and G6PD-mediated antioxidant defenses may contribute to the predisposition to KPD in West Africans.

Africa, Western↗
PubMed2005

Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5.

Maturity-onset diabetes of the young (MODY) 5 is caused by mutations in the TCF2 gene encoding the transcription factor hepatocyte nuclear factor-1beta. However, in 60% of the patients with a phenotype suggesting MODY5, no point mutation is detected in TCF2. We have hypothesized that large genomic rearrangements of TCF2 that are missed by conventional screening methods may account for this observation. In 40 unrelated patients presenting with MODY5 phenotype, TCF2 was screened for mutations by sequencing. Patients without mutations were then screened for TCF2 rearrangements by the quantitative multiplex PCR of short fluorescent fragments (QMPSF). Among the 40 patients, the overall detection rate was 70%: 18 had point mutations, 9 had whole-gene deletions, and 1 had a deletion of a single exon. Similar phenotypes were observed in patients with mutations and in subjects with large deletions. These results suggest that MODY5 is more prevalent than previously reported, with one-third of the cases resulting from large deletions of TCF2. Because QMPSF is more rapid and cost effective than sequencing, we propose that patients whose phenotype is consistent with MODY5 should be screened first with the QMPSF assay. In addition, other MODY genes should be screened for large genomic rearrangements.

Adolescent↗
PubMed2004

PAX4 gene variations predispose to ketosis-prone diabetes.

Ketosis-prone diabetes (KPD) is a rare form of type 2 diabetes, mostly observed in subjects of west African origin (west Africans and African-Americans), characterized by fulminant and phasic insulin dependence, but lacking markers of autoimmunity observed in type 1 diabetes. PAX4 is a transcription factor essential for the development of insulin-producing pancreatic beta-cells. Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects. The phenotype similarities between KPD and Japanese carriers of Arg121Trp have prompted us to investigate the role of PAX4 in KPD. We have screened 101 KPD subjects and we have found a new variant in the PAX4 gene (Arg133Trp), specific to the population of west African ancestry, and which predisposes to KPD under a recessive model. Homozygous Arg133Trp PAX4 carriers were found in 4% of subjects with KPD but not in 355 controls or 147 subjects with common type 2 or type 1 diabetes. In vitro, the Arg133Trp variant showed a decreased transcriptional repression of target gene promoters in an alpha-TC1.6 cell line. In addition, one KPD patient was heterozygous for a rare PAX4 variant (Arg37Trp) that was not found in controls and that showed a more severe biochemical phenotype than Arg133Trp. Clinical investigation of the homozygous Arg133Trp carriers and of the Arg37Trp carrier demonstrated a more severe alteration in insulin secretory reserve, during a glucagon-stimulation test, compared to other KPD subjects. Together these data provide the first evidence that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggest that KPD, like maturity onset diabetes of the young, is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes.

Africa, Western↗
PubMed2004

Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations.

BACKGROUND: Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations. OBJECTIVE: To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations. DESIGN: Multicenter, descriptive study. SETTING: 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology. PARTICIPANTS: 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring. MEASUREMENTS: Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results. RESULTS: All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients. LIMITATIONS: Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations. CONCLUSIONS: Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1beta is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present.

Adult↗
PubMed2004

Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin: clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance.

Nonautoimmune ketosis-prone diabetic syndromes are increasingly frequent in nonwhite populations. We have characterized a cohort of patients of sub-Saharan African origin who had ketosis-prone type 2 diabetes (n = 111), type 1 diabetes (n = 21), and type 2 diabetes (n = 88) and were admitted to a hospital for management of uncontrolled diabetes. We compared epidemiological, clinical, and metabolic features at diabetes onset and measured insulin secretion (glucagon-stimulated C-peptide) and insulin action (short intravenous insulin tolerance test) during a 10-year follow-up. Ketosis-prone type 2 diabetes shows a strong male predominance, stronger family history, higher age and BMI, and more severe metabolic decompensation than type 1 diabetes. In ketosis-prone type 2 diabetes, discontinuation of insulin therapy with development of remission of insulin dependence is achieved in 76% of patients (non-insulin dependent), whereas only 24% of patients remain insulin dependent. During evolution, ketosis-prone type 2 diabetes exhibit specific beta-cell dysfunction features that distinguish it from type 1 and type 2 diabetes. The clinical course of non-insulin-dependent ketosis-prone type 2 diabetes is characterized by ketotic relapses followed or not by a new remission. Progressive hyperglycemia precedes and is a strong risk factor for ketotic relapses (hazard ratio 38). The probability for non-insulin-dependent ketosis-prone type 2 diabetes to relapse is 90% within 10 years, of whom approximately 50% will become definitively insulin dependent. Insulin sensitivity is decreased in equal proportion in both ketosis-prone type 2 diabetes and type 2 diabetes, but improves significantly in non-insulin-dependent ketosis-prone type 2 diabetes, only after correction of hyperglycemia. In conclusion, ketosis-prone type 2 diabetes can be distinguished from type 1 diabetes and classical type 2 diabetes by specific features of clinical pathophysiology and also by the natural history of beta-cell dysfunction and insulin resistance reflecting a propensity to glucose toxicity.

Adult↗
PubMed2003

Effect of a diabetic environment in utero on predisposition to type 2 diabetes.

BACKGROUND: Type 2 diabetes is affected by genetics and environmental factors. We aimed to assess the effect of an in-utero diabetic environment independently of the genetic background for type 2 diabetes. METHODS: We measured insulin sensitivity and insulin secretion in response to oral and intravenous glucose in 15 non-diabetic adult offspring of mothers with type 1 diabetes (exposed participants) and 16 offspring of type 1 diabetic fathers (controls). No participants had type 1 diabetes-associated autoantibodies. We also measured pancreatic polypeptide, a marker of parasympathetic drive to the pancreas. FINDINGS: There was no difference between the groups with respect to percent body fat and insulin sensitivity. Five of the 15 exposed participants, but none of the controls had impaired glucose tolerance (p=0.02). Early insulin secretion after an oral glucose tolerance test was lower in exposed participants than in controls: 8.6 IU/mmol (SD 5.4) in exposed participants with impaired glucose tolerance, 14.2 IU/mmol (6.5) in those with normal glucose tolerance and 17.7 IU/mmol (10.9) in controls (p=0.04). Mean insulin secretion rate during glucose infusion study was 4.7 pmol/kg per min (3.6) in people with impaired glucose tolerance, 5.5 pmol/kg per min (4.5) in exposed participants with normal glucose tolerance and 7.5 pmol/kg per min (6.1) in controls (p<0.0001). The area under the curve of pancreatic polypeptide 120 min after oral glucose ingestion was 1007 (429) in people with impaired glucose tolerance, 2829 (1701) in those with normal glucose tolerance, and 3224 (1352) in controls (p=0.04). INTERPRETATION: Exposure to a diabetic environment in utero is associated with increased occurrence of impaired glucose tolerance and a defective insulin secretory response in adult offspring, independent of genetic predisposition to type 2 diabetes. This insulin secretory defect could be related to low parasympathetic tone. Epidemiological studies are needed to confirm our observations before therapeutic strategies can be devised.

Adult↗
PubMed2002

[Cushing's syndrome during pregnancy].

The rare association of Cushing's syndrome and pregnancy is explained by the amenorrhea and sterility inherent to the syndrome. In the literature, 125 cases have been reported: 30 cases of early diagnosis and 95 others diagnosed in the second half of pregnancy. AT THE START OF PREGNANCY: When hypercorticism exists before pregnancy it is hardly secretory. Its diagnosis, at an early stage, is not hindered by the hormone modifications of pregnancy. Its aetiological treatment raises the problem of the compatibility in pursuing the latter. IN THE SECOND HALF OF PREGNANCY: The positive and aetiological diagnoses of Cushing's syndrome are difficult and its prevalence may therefore be underestimated. The evocative clinical signs are unspecific: excessive weight gain, hypertension of pregnancy and gestational diabetes. The 24-hour free hypercortisoluria and the absence of dexamethasone inhibition are of little diagnostic value after the 14th week of amenorrhea. The positive diagnosis therefore relies essentially on the abolition of the circadian rhythm of cortisol. The biological hyperandrogenia commonly observed is not discriminating. Adrenal aetiologies are frequent. Imaging must be performed to eliminate an adrenocortical tumor. PROGNOSIS: The maternal prognosis depends on the hypertension, preeclampsia, diabetes and the complications of Cushing's syndrome. It depends on the activity of the hypercorticism and its early aetiological treatment, which must not be delayed after pregnancy. The foetal prognosis depends on the maternal prognosis. It is represented by preterm delivery, hypotrophy and death of the foetus in utero. The therapeutic management must be symptomatic and aetiologic, maternal and obstetrical.

Adrenal Cortex Neoplasms↗
PubMed2002

Tasting a liquid meal after a prolonged fast is associated with preferential activation of the left hemisphere.

We used positron emission tomographic scanning of the brain and measures of regional cerebral blood flow to investigate the response of 44 right-handed people to the oral administration of 2 ml of a liquid formula meal after a 36 h fast (and shortly before the administration of a satiating amount of the same meal). Several areas of the left hemisphere were significantly more activated than the contralateral, including the frontal operculum, ventral insula, and piriform cortex. In contrast with reports of right-hemisphere dominance in chemosensory perception in non-hungry individuals, our study reveals a preferential activation of the left hemisphere when people who are very hungry are briefly exposed to the chemical and physical properties of a liquid meal. This raises the possibility that the physiological context in which perception takes place (i.e. extreme vs moderate vs no hunger) may importantly affect the brain representation of chemosensory stimuli.

Adult↗
PubMed2002

Sex differences in the human brain's response to hunger and satiation.

BACKGROUND: Sex differences in eating behavior are well documented, but it is not known whether these differences have neuroanatomical correlates. Recent neuroimaging studies have provided functional maps of the human cerebral areas activated in response to hunger and satiation. OBJECTIVE: The objective of this study was to assess whether the brain's response to a meal is sex-specific. DESIGN: Using positron emission tomography, we measured regional cerebral blood flow, a marker of neuronal activity, to investigate the functional neuroanatomy of hunger (36-h fast) and satiation (in response to a liquid meal) in 22 women and 22 men. RESULTS: We observed extensive similarities, as well as some differences, between the sexes. In response to hunger, the men tended to have greater activation in the frontotemporal and paralimbic areas than did the women (P < 0.005). In response to satiation, the women tended to have greater activation in the occipital and parietal sensory association areas and in the dorsolateral prefrontal cortex than did the men (P < 0.005); in contrast, the men tended to have greater activation in the ventromedial prefrontal cortex than did the women (P < 0.005). CONCLUSIONS: Despite extensive similarities in the brain responses to hunger and satiation between the men and women, our study showed sex-specific brain responses to a meal that indicate possible differences between men and women in the cognitive and emotional processing of hunger and satiation. This study provides a foundation for investigating the brain regions and cognitive processes that distinguish normal and abnormal eating behavior in men and women.

Adult↗