The aetiology of Type 2 diabetes [NIDDM] is assumed to involve a multiplicity of causal factors involving both genetic and environmental, including intrauterine, components. Aim: To identify the relationship of various aspects of family history and hence the possible role of genetic influence in the development of Type 2 DM in the Maltese population. Methods: The family history details of a study population undergoing an oGTT during pregnancy was assessed during pregnancy and at follow-up eight years postpartum. The findings were related to previous national epidemiological studies. Results: The study showed a definite statistical correlation between a maternal and sibling family history of diabetes with the onset of GDM/GIGT and later Type 2 DM. No such correlation was shown with a paternal or grandparent family history. Conclusions: The findings suggest that genetic factors are poor determinants for adult-onset GDM or Type 2 DM, the major role player being apparently alterations in the intrauterine environment of the fetus.peer-reviewe

Chircop, Marcelle

Savona-Ventura, Charles

Schranz, Antoine G.

English

OAR@UM

Malta Medical Journal    Volume 15   Issue 02   November 2003 25Family History in the Aetiology of GestationalDiabetes Mellitus and Type 2 DiabetesOriginal ArticleCharles Savona-Ventura, Antoine G Schranz,  Marcelle ChircopAbstractThe aetiology of Type 2 diabetes [NIDDM] is assumed toinvolve a multiplicity of causal factors involving both geneticand environmental, including intrauterine, components.Aim: To identify the relationship of various aspects of familyhistory and hence the possible role of genetic influence in thedevelopment of Type 2 DM in the Maltese population.Methods: The family history details of a study populationundergoing an oGTT during pregnancy was assessed duringpregnancy and at follow-up eight years postpartum. The find-ings were related to previous national epidemiological studies.Results: The study showed a definite statistical correla-tion between a maternal and sibling family history of diabeteswith the onset of GDM/GIGT and later Type 2 DM. No suchcorrelation was shown with a paternal or grandparent familyhistory.Conclusions: The findings suggest that genetic factors arepoor determinants for adult-onset GDM or Type 2 DM, themajor role player being apparently alterations in the intrauter-ine environment of the fetus.IntroductionEthnic susceptibility to diabetes varies tremendously, avariation in liability that must depend both upon the widelydiffering conditions in which the human species exists andupon the diversity of the genetic endowment. The diabetic statemust be considered as the outcome of a multiplicity of causalfactors, potentially varying in both the genetic and the envi-ronmental components of the mix. The contribution of theintrauterine milieu interior of the fetus to the later develop-ment of Type 2 diabetes mellitus (Type 2 DM) and gestationaldiabetes mellitus (GDM) has been repeatedly demonstratedin both experimental animal models and human epidemio-logical studies with prenatal hyperglycaemia/hyperinsulinismand prenatal nutritional deprivation both being implicated 1,2.The genetics of Type 2 DM and the genetic influence towardsthe development of adult-onset diabetes are not well under-stood. The present study was set up to investigate the familyhistory correlates to the development of gestational diabetesin the Maltese population known to have a high prevalence ofType 2 DM3.MethodsThe first and second-degree parental family history dataof randomly chosen two hundred and sixty-seven (267) womenwho had had their glucose tolerance assessed during theirpregnancy was established. One hundred and sixteen of thesesubjects were traced and recalled for reassessment eight yearslater when first degree parental and sibling family history wasassessed. The family history characteristics of those womenwho were identified as having GIGT/GDM (defined as a two-hour blood glucose value >7.8 mmol/l after a 75 g oGTT) orlater Type 2 DM/IGT (defined similarly as a two-hour bloodglucose value >7.8 mmol/l) was compared to the characteris-tics of women found to have normal glucose tolerance. Theseobservations were compared to previous national epidemio-logical studies conducted on female subjects belonging to thesame population and using similar diagnostic criteria4. Re-cruitment of the original study population was carried out byinviting all pregnant women (excluding only non-Maltese orpreviously known diabetics) seen at the antenatal clinics atSt. Luke’s Hospital or the Government Peripheral Health Cen-tres over a period of three months. Statistical analyses weremade using using a standard statistical package Statcalc (WHOCharles Savona-Ventura MD, DScMedDiabetic Pregnancy Joint ClinicDepartment of Obstetrics - GynaecologySt Luke’s Teaching Hospital, Gwardamangia, MaltaEmail: charles.savona-ventura@gov.mtAntoine G Schranz MD, DScDiabetic Clinic, Department of MedicineSt Luke’s Teaching Hospital, Gwardamangia, MaltaEmail: antoine.schranz@gov.mtMarcelle Chircop MD, MRCOGDiabetic Pregnancy Joint ClinicDepartment of Obstetrics - GynaecologySt Luke’s Teaching Hospital, Gwardamangia, MaltaKeywordsType 2 diabetes mellitus, gestational diabetes, familyhistory, genetics, environment26 Malta Medical Journal    Volume 15   Issue 02   November 2003FAMILY Epidemiological National Study [Phase V] - female dataNGT AbGT P valueMaternal 172 29.2%  [n=589] 47 51.6%  [n=91] 0.000021Paternal 86 15.3%  [n=563] 16 17.9%  [n=89] 0.62051Sibling - brother 105 7.3%  [n=1434] 49 21.3%  [n=230] <0.0000011Sibling - sister 89 5.9% [n=1501] 51 23.2% [n=220] <0.000001Table 2: Family history in Epidemiological studies4(NGT - Normal glucose tolerance;  AbGT - Abnormal glucose tolerance) (Statistical analysis: 1 = Yates Chi Square test)HISTORYEpiInfo 2000) utilising the Yates modification of the Chi Squaretest and the Fisher exact test  when an expected cell was <5.Significance was assumed with a probability value <0.05.ResultsTable 1 suggests that a positive maternal family history ofdiabetes was a statistically significant correlate to the develop-ment of GIGT/GDM or later Type 2 DM/IGT in the femalepopulation. Similarly a positive sibling family history was a sta-tistically significant correlate to later development of Type 2DM/IGT. There did not appear to be any significant correla-tions shown with the development of GIGT/GDM or Type 2DM/IGT with a family history of diabetes in the father or grand-parents. These findings conform to the results of the nationalepidemiological study conducted on female subjects who simi-larly confirmed that a statistically significant relationship ex-isted between the development of Type 2 DM and a family his-tory in the mother or siblings. No such relationship was notedwith a paternal family history (Table 2).DiscussionThe genetics of Type 2 DM are not well understood sincemarkers such as the HLA system, associated to Type 1 diabe-tes, are not available. The National Diabetes Programme con-ducted in Malta showed no significant associations betweenHLA type and persons suffering from DM and IGT3. The re-ported increased prevalence of Type 2 DM in Mediterraneancountries with a high population density - notably Malta,Cyprus, Spain, Israel and Lebanon - may be considered to re-flect a genetic predisposition exhibited through increased in-terbreeding. On the other hand, a high population density in-creases the degree of urbanisation, a factor that has also beencorrelated to an increased prevalence of Type 2 DM5. Evidencefor a genetic susceptibility to developing Type 2 DM has beenpresented, and defects in both insulin production and actionare suspect. Five genes have been associated with the autoso-mal dominant maturity-onset diabetes of the young [MODY]subtype: glucokinase, and 4 transcription factors that play akey role in the development of the endocrine pancreas or inthe expression of glucose metabolism genes. Apart from themonogenic forms of type 2 diabetes, little is known about thenature of the genetic factors involved. Minor contributors in-clude insulin, sulfamide receptor and some others. Genomescans of diabetic families have revealed susceptibility loci onchromosome 1q, 2p, 2q (where the gene calpain 10 was re-cently cloned), 3q, 12q and 206. Other receptor genes such asthe B3-adrenergic receptor gene have been suggested as fac-tors towards the development of weight gain, insulin resis-tance and the earlier onset of Type 2 DM. This gene polymor-phism is predominantly expressed in adipose tissue and regu-FAMILY Pregnant population Follow-up populationNGT AbGT      P value NGT AbGT P valuen=237 n=30 n=93 N=23Maternal 28 1.8% 9 30.0%     0.0122 22 23.7% 14 60.9% 0.0011Paternal 23 9.7% 5 16.7%     0.1902 20 21.5% 5 21.7% 0.5892Sibling N/A N/A 3 3.2% 4 17.4% 0.0282Grandparent 38 16.0% 2 6.7%     0.1362 N/A N/ATable 1: Family history in cases of present or past GIGT/GDM[NGT - Normal glucose tolerance;  AbGT - Abnormal glucose tolerance; N/A - not assessed][Statistical analysis: 1 = Yates Chi Square test; 2 = Fisher 1-tailed test]HISTORYMalta Medical Journal    Volume 15   Issue 02   November 2003 27lates lipid metabolism and thermogenesis, so its impairmentmay lead to obesity through its effect on the energy expendi-ture of fat tissue. The reported data so far remains conflict-ing7. Recent studies have further suggested that variationwithin the TH-INS-IGF2 locus, most plausibly at the VNTR,may influence Type 2 DM susceptibility. This locus may bemediated exclusively by the paternally derived allele8.The present study, carried out on the Type 2 DM high-prevalence Maltese population, has shown that a maternal orsibling family history is a significant risk factor. No such sta-tistically significant correlation has been identified with a pa-ternal or grandparent family history. The present cohort com-pliments earlier family history studies in general diabetes clin-ics9 and in the Pima Indian population10, which showed a highermaternal than paternal transmission of diabetes. The mater-nal, but not paternal, association suggests that whereas a fa-milial tendency definitely exists, this is probably not a geneticinfluence unless it involves transmission through maternalmitrochondrial genetic material. Siblings can be assumed tohave been influenced in a similar fashion as the subject understudy. The familial association is more likely the product ofthe minor alterations that occur in the intrauterine milieu in-terior of the infant of the mother with abnormal carbohydratemetabolism. The role of the altered intrauterine environmentin the aetiology of Type 2 DM has been previously suggestedby epidemiological studies in other populations. Most convinc-ing are the studies on Pima Indians that have shown that, be-sides a genetic transmission, the diabetic intrauterine envi-ronment can also induce a diabetogenic tendency in the off-spring. These studies have shown that impaired glucose toler-ance was more frequent in children of mothers who had dia-betes during pregnancy than in children of mothers who de-veloped diabetes after pregnancy10 . In the Pima populationtoday over 70% of persons with prenatal exposure to diabeteshave Type 2 DM diabetes by 25-34 years of age, while prenatalexposure to maternal hyperglycaemia is believed to be respon-sible for 40% of all Type 2 DM in 5-19 year old children11. Therelationship has also been shown by experimental animalmodels. These studies showed that adult offspring (second gen-eration) of streptozotocin-injected rats (first generation) de-veloped gestational diabetes, while their fetuses (third gen-eration) showed islet cell hyperplasia and beta cell degranula-tion to the same degree as second generation fetuses of dia-betic mothers12. These observations suggests that the main fac-tor in the development of adult-onset GDM or Type 2 DM isprobably not purely a genetic one unless determined by ma-ternal mitrochondrial genetic transmission.  The study sup-ports other previous epidemiological and animal observationsthat link Type 2 DM with alterations in the intrauterine milieuReferences1 Van Assche FA, Aerts L, Holemans K. The effects of maternaldiabetes on the offspring. Bailliere’s Clinical Obstetrics andGynaecology 1991; 5:485-492.2 Phillips DIW. Birth weight and the future development ofdiabetes. Diabetologia 1998; 36:62-67.3 Katona G, Aganovic I, Vuscan V, Skrabalo Z. The NationalDiabetes Programme in Malta - Final Report Phases I & II.WHO.NCD/OND/DIAB/83.2, WHO, Geneva, 1983, pp.+115.4 Schranz AG. Abnormal glucose tolerance in the Maltese. Apopulation-based longitudinal study of the natural history ofNIDDM and IGT in Malta. Diabetes Research and ClinicalPractice 1989; 7:7-16.5 Arab M, Abdel-Rehim AA. Socioeconomic background for theepidemiology of diabetes mellitus in Mediterranean countries.Proceedings IV Meeting Mediterranean Group for the Study ofDiabetes, Medicographia 1994; 16(suppl.1):84-90.6 Froguel P, Velho G. Genetic determinants of type 2 diabetes.Recent Prog Horm Res 2001; 56:91-1057 Bouchard C, Perusse L. Current status of the human obesity genemap. Obesity Res 1996; 4:81-908 Huxtable SJ, Saker PJ, Haddad L, et al. Analysis of parent-offspring trios provides evidence for linkage and associationbetween the insulin gene and type 2 diabetes mediated exclusivelythrough paternally transmitted class III variable number tandemrepeat alleles.—Diabetes  2000; 49(1):126-1309 Alcolado JC, Alcolado R. Importance of maternal history of non-insulin-dependent diabetic patients. Br Med J 1991; 302:1178-118010 Pettitt DJ, Aleck KA, Baird HR, et al. Congenital susceptibility toNIDDM. Role of intrauterine environment, Diabetes 1988; 37622-62811 Dabelea D, Knowler WC, Pettitt DJ. Effect of diabetes in preg-nancy on offspring: follow-up research in the Pima Indians.Journal of Maternal-Fetal Medicine 2000; 9(1):83-8812 Aerts L, Van Assche A. Is gestational diabetes an acquiredcondition? Journal of  Developmental Physiology 1979; 1:219-225interior of the infant of the mother with abnormal carbohydratemetabolism. In the light of this observation and the risk of highantenatal glucose levels to the developing fetus, it may be pru-dent to advise all pregnant women belonging to an ethnic groupknown to have a high prevalence of Type 2 DM to avoid takinghigh doses of refined sugars irrespective of their identified car-bohydrate metabolism status. Furthermore, it may be oppor-tune to investigate seriously the role of using oral hypoglycaemicagents during the third trimester in those pregnant women whoare shown to suffer from GDM but are not identified as requir-ing insulin therapy thus ensuring optimum glucose control.

Abnormal glucose tolerance in the Maltese. A population-based longitudinal study of the natural history

Analysis of parentoffspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles.—Diabetes

Birth weight and the future development of diabetes. Diabetologia

Congenital susceptibility to NIDDM. Role of intrauterine environment,

Current status of the human obesity gene map. Obesity Res

Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians.

Genetic determinants of type 2 diabetes. Recent Prog Horm Res

Importance of maternal history of noninsulin-dependent diabetic patients.

Is gestational diabetes an acquired condition?

Socioeconomic background for the epidemiology of diabetes mellitus in Mediterranean countries.

The effects of maternal diabetes on the offspring. Bailliere’s Clinical Obstetrics and Gynaecology

Family history in the Aetiology of Gestational Diabetes Mellitus and Type 2 Diabetes

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Family history in the Aetiology of Gestational Diabetes Mellitus and Type 2 Diabetes

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