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Parental transmission of type 2 diabetes: the Framingham Offspring Study
Open accessAbstract
Study of parental transmission of diabetes provides insight into the relative contributions of underlying maternal and paternal influences. We estimated risk for type 2 diabetes and milder degrees of glucose intolerance associated with parental diabetes among subjects of the population-based Framingham Offspring Study, in which participants are primarily Caucasian and at relatively low risk for diabetes and for which both parental and offspring phenotypes were ascertained by direct examination. Parental diabetes, assessed over 40 years of biennial follow-up, was defined by use of hypoglycemic drug therapy or a casual plasma glucose level > or = 11.1 mmol/l at any examination. Offspring glucose tolerance, assessed over 20 years of quadrennial follow-up, was defined by fasting plasma glucose levels > or = 7.8 mmol/l at any two examinations, use of hypoglycemic drug therapy at any examination, or with a 75-g oral glucose tolerance test (1980 World Health Organization criteria) at the most recent examination. We calculated odds ratios (ORs) and 95% CIs for offspring glucose tolerance status using generalized estimating equations to account for differential correlations within and between families. The 2,527 offspring came from 1,303 nuclear families, of which 77.6% had two or more siblings per family and in which the prevalence of parental diabetes was 24.6%. The mean offspring age was 54 years (range 26-82), 53% were women, 8.6% had diabetes, 11.4% had impaired glucose tolerance, 76.3% had no parental diabetes, 10.5% had maternal diabetes, 11.5% had paternal diabetes, and 1.7% had bilineal diabetes. Relative to individuals without parental diabetes, the age-adjusted ORs (95% CI) for offspring type 2 diabetes or abnormal glucose tolerance (fasting plasma glucose > or = 6.1 mmol/l or 2-h postchallenge glucose tolerance > or = 7.8 mmol/l) among individuals with maternal diabetes were 3.4 (2.3-4.9) and 2.7 (2.0-3.7), respectively; among individuals with paternal diabetes were 3.5 (2.3-5.2) and 1.7 (1.2-2.4), respectively; and among individuals with bilineal diabetes were 6.1 (2.9-13.0) and 5.2 (2.6-10.5), respectively. Although maternal and paternal diabetes conferred equivalent risk for offspring type 2 diabetes, offspring with maternal diabetes were slightly more likely to have abnormal glucose tolerance compared with those with paternal diabetes (OR 1.6, 95% CI 1.1-2.4). Offspring with maternal diabetes and an age of onset of <50 years had marked increased risk for both type 2 diabetes (9.7, 4.3-22.0) and abnormal glucose tolerance (9.0, 4.2-19.7). We conclude that risk ratios for offspring type 2 diabetes are consistent with a simple additive risk model, where risk when both parents are affected equals the sum of risk when either parent is affected. For maternal diabetes to confer excess risk for mild but not overt glucose intolerance, offspring of diabetic fathers may transit abnormal to impaired glucose tolerance relatively quickly, or diabetic mothers may transmit risk for a mild slowly progressive form of abnormal glucose tolerance in addition to overt diabetes. Very high risk for abnormal glucose homeostasis among offspring with young age-of-onset maternal diabetes is consistent with hypotheses that perinatal exposures increase diabetes risk. Given equivalent risk ratios for type 2 diabetes, fathers may transmit unique paternal genetic factors of similar strength to maternal environmental factors.
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“Diabetes during pregnancy also predisposes offspring for the development of obesity, T2D and cardiometabolic disease risk factors [33,70,71,72,73,74,75,76,77] (Figure 1).”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [33]
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“Powerful evidence for a genetic component to T2D ( 1 ) has driven extensive efforts to identify genetic variants contributing to risk.”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [1]
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“maternal diabetes conferred a greater risk of abnormal glucose tolerance in the offspring, when compared to paternal diabetes [33].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [33]
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“maternal and paternal diabetes conferred equivalent risk for offspring T2D”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [33]
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Metadata
- Authors
- Meigs, J. B., Cupples, L. A., & Wilson, P. W.
- Affiliations
- Harvard University (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2000-12-01
- Volume
- 49
- Issue
- 12
- Pages
- 2201-2207
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W1989797259
- Cited by
- 666
- References
- 37
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 27 · 2023: 29 · 2022: 44 · 2021: 40 · 2020: 37 · 2019: 37 · 2018: 31 · 2017: 32 · 2016: 26 · 2015: 41 · 2014: 36 · 2013: 44 · 2012: 28
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (N01-HC-38083)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 2 diabetes, parental diabetes, familial aggregation, maternal diabetes, paternal diabetes, impaired glucose tolerance, diabetes risk, Framingham Offspring Study
- MeSH terms
- Adult, Aged, Aged, 80 and over, Blood Glucose, Diabetes Mellitus, Type 2, Fathers, Female, Glucose Tolerance Test, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Middle Aged, Mothers, Cohort Studies, Prevalence, Odds Ratio, Randomized Controlled Trials as Topic, Genetic Predisposition to Disease
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