Synergistic effects of genetic beta cell dysfunction and maternal glucose intolerance on offspring metabolic phenotype in mice

Lau, Sue Mei; Lin, Shu; Stokes, Rebecca; Cheng, Kui; Baldock, Paul A.; Enriquez, Ronaldo F.; McLean, Mark; Cheung, N. Wah; Sainsbury, Amanda; Gonzalez, Frank J.; Herzog, Herbert; Gunton, Jenny E.

doi:10.1007/s00125-010-1998-z

Cited by 17 publications

(25 citation statements)

References 38 publications

(47 reference statements)

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“…Those data in adults fit well with findings that offspring of diabetic mothers are prone to develop obesity during childhood (12, 23). The current findings also align with evidence from a mouse model of beta cell dysfunction that causes females to develop diabetes during pregnancy (24). The offspring of those diabetic dams had lower energy expenditure and higher respiratory exchange ratio while young.…”

Section: Discussionsupporting

confidence: 85%

“…The offspring of those diabetic dams had lower energy expenditure and higher respiratory exchange ratio while young. Furthermore, the altered fuel metabolism preceded the divergence in growth curves and the higher accrual of body fat in the diabetic offspring compared with control animals, suggesting that reduced REE and fat oxidation contribute to future obesity (24). …”

Section: Discussionmentioning

confidence: 99%

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Lower Resting Energy Expenditure and Fat Oxidation in Native American and Hispanic Infants Born to Mothers with Diabetes

Short

Teague

Fields

et al. 2015

The Journal of Pediatrics

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Objective To determine whether exposure to diabetes in utero affects resting energy expenditure (REE) and fuel oxidation in infants. Study design At 35 ± 5 days after birth, body composition and REE were measured in full-term offspring of Native American and Hispanic women with either well-controlled diabetes (13 girls, 11 boys) or normal healthy pregnancies (18 girls, 17 boys). Results Control of dysglycemia during gestation in the women with diabetes mellitus met current clinical standards shown by average glycated hemoglobin (5.9 ± 0.2%; 40.6 ± 2.3 mmol/mol). Infant body mass (offspring of women with diabetes: 4.78 ± 0.13, control offspring: 4.56 ± 0.08 kg) and body fatness (offspring of women with diabetes: 25.2 ± 0.6, control offspring: 24.2 ± 0.5 %) did not differ between groups. REE, adjusted for lean body mass, was 14% lower in offspring of women with diabetes (41.7 ± 2.3 kJ/h) than control offspring (48.6 ± 2.0, p=0.025). Fat oxidation was 26% lower in offspring of women with diabetes (0.54 ± 0.05 g/h) than control offspring (0.76 ± 0.04, p < 0.01) but carbohydrate oxidation did not differ. Thus, fat oxidation accounted for a lower fraction of REE in the offspring of women with diabetes (49 ± 4%) than control offspring (60 ± 3%, p = 0.022). Mothers with diabetes were older and had higher pre-pregnancy BMI than control mothers. Conclusion Well-controlled maternal diabetes did not significantly affect body mass or composition of offspring at 1-month old. However, infants with diabetic mothers had reduced REE and fat oxidation, which could contribute to adiposity, and future disease risk. Further studies are needed to assess the impact differences in age and higher prepregnancy BMI.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Lower Resting Energy Expenditure and Fat Oxidation in Native American and Hispanic Infants Born to Mothers with Diabetes

Short

Teague

Fields

et al. 2015

The Journal of Pediatrics

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“…Thus, the molecular basis for the metabolic abnormalities in wildtype offspring of Akita parents an area of important future investigation. The impaired glucose tolerance may be the result of low insulin production, as shown in other models [19], [8] or of insulin resistance. To investigate this hypothesis further, we assessed fasted insulin levels.…”

Section: Discussionmentioning

confidence: 94%

“…Researchers have used different types of high-fat or high sucrose diets (cafeteria diet), [15] [16] [17] [18], models of induced gestational diabetes [19], hyperglycemia via continuous glucose infusion [6] [8], streptozotocin induced diabetes models [18] [20] and other models of obesity and type 2 diabetes to investigate phenotypic outcome in offspring of these pregnancies.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of neuroregulation was also supported by data from Lau et al indicating that a modulation of metabolic phenotype in offspring of diabetic mothers may stem from dysregulation of hypothalamic POMC and NPY gene expression in offspring. These authors postulate an additional effect of maternal hyperglycemia on genetic beta- cell dysfunction in offspring [19].…”

Section: Discussionmentioning

confidence: 99%

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Parental Diabetes: The Akita Mouse as a Model of the Effects of Maternal and Paternal Hyperglycemia in Wildtype Offspring

et al. 2012

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Aim/HypothesisMaternal diabetes and high-fat feeding during pregnancy have been linked to later life outcomes in offspring. To investigate the effects of both maternal and paternal hyperglycemia on offspring phenotypes, we utilized an autosomal dominant mouse model of diabetes (hypoinsulinemic hyperglycemia in Akita mice). We determined metabolic and skeletal phenotypes in wildtype offspring of Akita mothers and fathers.ResultsBoth maternal and paternal diabetes resulted in phenotypic changes in wildtype offspring. Phenotypic changes were more pronounced in male offspring than in female offspring. Maternal hyperglycemia resulted in metabolic and skeletal phenotypes in male wildtype offspring. Decreased bodyweight and impaired glucose tolerance were observed as were reduced whole body bone mineral density and reduced trabecular bone mass.Phenotypic changes in offspring of diabetic fathers differed in effect size from changes in offspring of diabetic mothers. Male wildtype offspring developed a milder metabolic phenotype, but a more severe skeletal phenotype. Female wildtype offspring of diabetic fathers were least affected.ConclusionsBoth maternal and paternal diabetes led to the development of metabolic and skeletal changes in wildtype offspring, with a greater effect of maternal diabetes on metabolic parameters and of paternal diabetes on skeletal development. The observed changes are unlikely to derive from Mendelian inheritance, since the investigated offspring did not inherit the Akita mutation. While fetal programming may explain the phenotypic changes in offspring exposed to maternal diabetes in-utero, the mechanism underlying the effect of paternal diabetes on wildtype offspring is unclear.

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Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function

Girgis

Minn

et al. 2019

J cachexia sarcopenia muscle

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BackgroundIt has long been recognized that vitamin D deficiency is associated with muscle weakness and falls. Vitamin D receptor (VDR) is present at very low levels in normal muscle. Whether vitamin D plays a direct role in muscle function is unknown and is a subject of hot debate. Myocyte‐specific deletion of VDR would provide a strategy to answer this question.MethodsMyocyte‐specific vitamin D receptor (mVDR) null mice were generated by crossing human skeletal actin‐Cre mice with floxed VDR mice. The effects of gene deletion on the muscle phenotype were studied in terms of body tissue composition, muscle tissue histology, and gene expression by real‐time PCR.ResultsUnlike whole‐body VDR knockout mice, mVDR mice showed a normal body size. The mVDR showed a distinct muscle phenotype featuring reduced proportional lean mass (70% vs. 78% of lean mass), reduced voluntary wheel‐running distance (22% decrease, P = 0.009), reduced average running speed, and reduced grip strength (7–16% reduction depending on age at testing). With their decreased voluntary exercise, and decreased lean mass, mVDR have increased proportional fat mass at 20% compared with 13%.Surprisingly, their muscle fibres showed slightly increased diameter, as well as the presence of angular fibres and central nuclei suggesting ongoing remodelling. There were, however, no clear changes in fibre type and there was no increase in muscle fibrosis. VDR is a transcriptional regulator, and changes in the expression of candidate genes was examined in RNA extracted from skeletal muscle. Alterations were seen in myogenic gene expression, and there was decreased expression of cell cycle genes cyclin D1, D2, and D3 and cyclin‐dependent kinases Cdk‐2 and Cdk‐4. Expression of calcium handling genes sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) Serca2b and Serca3 was decreased and Calbindin mRNA was lower in mVDR muscle.ConclusionsThis study demonstrates that vitamin D signalling is needed for myocyte function. Despite the low level of VDR protein normally found muscle, deleting myocyte VDR had important effects on muscle size and strength. Maintenance of normal vitamin D signalling is a useful strategy to prevent loss of muscle function and size.

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Synergistic effects of genetic beta cell dysfunction and maternal glucose intolerance on offspring metabolic phenotype in mice

Cited by 17 publications

References 38 publications

Lower Resting Energy Expenditure and Fat Oxidation in Native American and Hispanic Infants Born to Mothers with Diabetes

Lower Resting Energy Expenditure and Fat Oxidation in Native American and Hispanic Infants Born to Mothers with Diabetes

Parental Diabetes: The Akita Mouse as a Model of the Effects of Maternal and Paternal Hyperglycemia in Wildtype Offspring

Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function

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