Is human Type 2 diabetes maternally inherited? Insights from an animal model

Gill-Randall, R.; Adams, David Monk; Ollerton, Richard L.; Alcolado, John

doi:10.1111/j.1464-5491.2004.01225.x

Cited by 14 publications

(10 citation statements)

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“…Our results confirm the importance of genetic factors in crosses are more hyperglycaemic than those of Wistar female/GK male crosses and this has also been taken as evidence of the diabetogenic effects of being exposed to diabetes in-utero [17]. However, these maternal effects have not been confirmed in other studies [18,19] and the experiments are hampered by the fact that the offspring also share the maternal (non-diabetogenic) genes. Our embryo-transfer model removes this potential confounding factor, since offspring have not inherited genetic material from their surrogate mothers.…”

Section: Discussionsupporting

confidence: 32%

Type�2 diabetes mellitus ? genes or intrauterine environment? An embryo transfer paradigm in rats

et al. 2004

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Section: Discussionsupporting

confidence: 32%

Type�2 diabetes mellitus ? genes or intrauterine environment? An embryo transfer paradigm in rats

et al. 2004

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“…Animal studies demonstrate that metabolic imprinting caused by the diabetic intrauterine environment can be transmitted across generations (7)(8)(9). In humans, excess maternal transmission of type 2 diabetes (10,11) supports the hypothesis that the intrauterine environment, independent of genetic transmission, contributes to increased risk of type 2 diabetes in offspring.…”

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confidence: 61%

Association Between Maternal Diabetes in Utero and Age at Offspring's Diagnosis of Type 2 Diabetes

et al. 2008

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OBJECTIVE—The purpose of this study was to examine age of diabetes diagnosis in youth who have a parent with diabetes by diabetes type and whether the parent's diabetes was diagnosed before or after the youth's birth. RESEARCH DESIGN AND METHODS—The cohort comprised SEARCH for Diabetes in Youth Study participants (diabetes diagnosis 2001–2005) with a diabetic parent. SEARCH is a multicenter survey of youth with diabetes diagnosed before age 20 years. RESULTS—Youth with type 2 diabetes were more likely to have a parent with either type 1 or type 2 diabetes (mother 39.3%; father 21.2%) than youth with type 1 diabetes (5.3 and 6.7%, respectively, P < 0.001 for each). Type 2 diabetes was diagnosed 1.68 years earlier among those exposed to diabetes in utero (n = 174) than among those whose mothers’ diabetes was diagnosed later (P = 0.018, controlled for maternal diagnosis age, paternal diabetes, sex, and race/ethnicity). Age at diagnosis of type 1 diabetes for 269 youth with and without in utero exposure did not differ significantly (difference 0.96 year, P = 0.403 after adjustment). Controlled for the father's age of diagnosis, father's diabetes before the child's birth was not associated with age at diagnosis (P = 0.078 for type 1 diabetes; P = 0.140 for type 2 diabetes). CONCLUSIONS—Type 2 diabetes was diagnosed at younger ages among those exposed to hyperglycemia in utero. Among youth with type 1 diabetes, the effect of the intrauterine exposure was not significant when controlled for mother's age of diagnosis. This study helps explain why other studies have found higher age-specific rates of type 2 diabetes among offspring of women with diabetes.

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“…For example, in the Goto Kakizaki-Wistar rat model of type 2 diabetes, studies in reciprocal F 1 populations with identical nuclear genomes but different mitochondrial genomes failed to show any consistent effects on glucose metabolism that might be attributed to sequence variants in the mitochondrial genome (Gill-Randall et al 2004). In a study of reciprocal F 1 populations derived by crossing a glucose-intolerant strain of BHE/Cdb rats with Sprague-Dawley rats, Mathews et al (1999) reported that impaired glucose tolerance was associated with inheritance of a point mutation in the mitochondrial gene encoding ATP synthase subunit 6.…”

Section: Discussionmentioning

confidence: 99%

Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strains

Pravenec¹,

Hyakukoku

Houštěk³

et al. 2007

Genome Res.

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Recently, the relationship of mitochondrial DNA (mtDNA) variants to metabolic risk factors for diabetes and other common diseases has begun to attract increasing attention. However, progress in this area has been limited because (1) the phenotypic effects of variation in the mitochondrial genome are difficult to isolate owing to confounding variation in the nuclear genome, imprinting phenomena, and environmental factors; and (2) few animal models have been available for directly investigating the effects of mtDNA variants on complex metabolic phenotypes in vivo. Substitution of different mitochondrial genomes on the same nuclear genetic background in conplastic strains provides a way to unambiguously isolate effects of the mitochondrial genome on complex traits. Here we show that conplastic strains of rats with identical nuclear genomes but divergent mitochondrial genomes that encode amino acid differences in proteins of oxidative phosphorylation exhibit differences in major metabolic risk factors for type 2 diabetes. These results (1) provide the first direct evidence linking naturally occurring variation in the mitochondrial genome, independent of variation in the nuclear genome and other confounding factors, to inherited variation in known risk factors for type 2 diabetes; and (2) establish that spontaneous variation in the mitochondrial genome per se can promote systemic metabolic disturbances relevant to the pathogenesis of common diseases.[Supplemental material is available online at www.genome.org.]Recently, the potential role of the mitochondrial genome in the pathogenesis of type 2 diabetes and other common diseases has begun to attract increasing attention (Wallace 2005). Mitochondrial DNA is exclusively of maternal origin, and some studies have indicated that the inheritance of type 2 diabetes may be biased toward the maternal lineage (Alcolado et al. 2002). Sun et al. (2003) have estimated that mitochondrial DNA mutations might be involved in >20% of cases of type 2 diabetes. In addition, Wilson et al. (2004) have identified a homoplasmic mitochondrial DNA variant associated with the maternal transmission of hypercholesterolemia, hypomagnesemia, and hypertension through four generations of a large, carefully analyzed kindred. Rare forms of maternally transmitted diabetes associated with heteroplasmic mitochondrial DNA variants have also been reported (Mathews and Berdanier 1998;Maassen et al. 2005). These observations provide indirect evidence that sequence variation in the mitochondrial genome might contribute to inherited variation in the risk for type 2 diabetes and related metabolic disorders.Notwithstanding recent advances in mitochondrial genome research, multiple confounding factors have made it difficult to unequivocally establish a role for mitochondrial DNA variation in the regulation of risk factors for diabetes or other complex metabolic phenotypes. For example, effects of maternal environment or imprinting may contribute to matrilineal transmission patterns of the phenotypes of interest....

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Is human Type 2 diabetes maternally inherited? Insights from an animal model

Cited by 14 publications

References 14 publications

Type�2 diabetes mellitus ? genes or intrauterine environment? An embryo transfer paradigm in rats

Type�2 diabetes mellitus ? genes or intrauterine environment? An embryo transfer paradigm in rats

Association Between Maternal Diabetes in Utero and Age at Offspring's Diagnosis of Type 2 Diabetes

Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strains

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