Insulin Sensitivity In Adulthood Research Articles

MiR-222 exerts negative regulation on insulin signaling pathway in 3T3-L1 adipocytes.

Increased miR-222 levels are associated with metabolic syndrome, insulin resistance, and diabetes. Moreover, rats fed an obesogenic diet during lactation have higher miR-222 content in breast milk and the offspring display greater body fat mass and impaired insulin sensitivity in adulthood. In order to investigate the molecular mechanisms involved and to dissect the specific effects of miR-222 on adipocytes, transfection with a mimic or an inhibitor of miR-222 has been conducted on 3T3-L1 preadipocytes. 3T3-L1 cells were transfected with either a mimic or an inhibitor of miR-222 and collected after 2 days (preadipocytes) or 8 days (mature adipocytes) for transcriptomic analysis. Results showed a relevant impact on pathways associated with insulin signaling, lipid metabolism and adipogenesis. Outcomes in key genes and proteins were further analyzed with quantitative reverse transcription polymerase chain reaction and Western Blotting, respectively, which displayed a general inhibition in important effectors of the identified routes under miR-222 mimic treatment in preadipocytes. Although to a lesser extent, this overall signature was maintained in differentiated adipocytes. Altogether, miR-222 exerts a direct effect in metabolic pathways of 3T3-L1 adipocytes that are relevant to adipocyte function, limiting adipogenesis and insulin signaling pathways, offering a mechanistic explanation for its reported association with metabolic diseases.

Four weeks of exercise early in life reprograms adult skeletal muscle insulin resistance caused by a paternal high-fat diet.

A paternal high-fat diet/obesity before mating can negatively influence the metabolism of offspring. Exercise only early in life has a remarkable effect with respect to reprogramming adult rat offspring exposed to detrimental insults before conception. Exercise only early in life normalized adult whole body and muscle insulin resistance as a result of having a high-fat fed/obese father. Unlike the effects on the muscle, early exercise did not normalize the reduced adult pancreatic beta cell mass as a result of having a high-fat fed/obese father. Early-life exercise training may be able to reprogram an individual whose father was obese, inducing long-lasting beneficial effects on health. A paternal high-fat diet (HFD) impairs female rat offspring glucose tolerance, pancreatic morphology and insulin secretion. We examined whether only 4weeks of exercise early in life could reprogram these negative effects. Male Sprague-Dawley rats consumed a HFD for 10weeks before mating with chow-fed dams. Female offspring remained sedentary or performed moderate intensity treadmill exercise (5daysweek-1 , 60minday-1 , 20mmin-1 ) from 5 to 9weeks of age. Paternal HFD impaired (P< 0.05) adult offspring whole body insulin sensitivity (i.p. insulin sensitivity test), as well as skeletal muscle ex vivo insulin sensitivity and TBC1D4 phosphorylation. It also lowered β-cell mass and reduced in vivo insulin secretion in response to an i.p. glucose tolerance test. Early-life exercise in offspring reprogrammed the negative effects of a paternal HFD on whole body insulin sensitivity, skeletal muscle ex vivo insulin-stimulated glucose uptake and TBC1D4 phosphorylation and also increased glucose transporter 4 protein. However, early exercise did not normalize the reduced pancreatic β-cell mass or insulin secretion. In conclusion, only 4weeks of exercise early in life in female rat offspring reprograms reductions in insulin sensitivity in adulthood caused by a paternal HFD without affecting pancreatic β-cell mass or insulin secretion.

Differential Pathways to Adult Metabolic Dysfunction following Poor Nutrition at Two Critical Developmental Periods in Sheep

Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1–31 days gestation) or 50% nutritional requirements (104–127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk.

The influence of parental history of diabetes and offspring birthweight on offspring glucose metabolism in adulthood

Links are well established between both family history of diabetes and reduced birthweight and increased risk of diabetes in adulthood. 1) To investigate the influence of parental history of type 2 diabetes (T2DM) on offspring birthweight and adult offspring glucose tolerance status in non-diabetic offspring of patients with T2DM and 2) to study the associations of birthweight with measures of pancreatic beta-cell function and insulin sensitivity. Family cohort study. Offspring of patients with verified T2DM diagnosed after age 40 years with a spouse without known diabetes. Oral glucose tolerance tests and frequently sampled intravenous glucose tolerance tests (FSIGT) in non-diabetic offspring. Birthweight and length obtained from birth records. Among 122 offspring with maternal history of T2DM, 14.8% had diabetes compared to 8.0% in 137 offspring with paternal history of diabetes, p=0.09. Offspring with maternal history of T2DM had a mean birthweight 196 g higher than offspring with paternal T2DM (3,651 ± 640 g (mean ± SD) vs. 3,456 ± 472g (p=0.01)). Non-diabetic offspring with birthweights in the lowest tertile had significantly higher plasma glucose levels after an oral glucose tolerance test (OGTT) [Area under the curve(glucOGTT) , mean (95%CI), 1 795 (1 725-1 866) vs. 1 683 (1 613-1 753) mmol/L/min, p=0.02], and lower insulin sensitivity index calculated from a frequently sampled intravenous glucose tolerance test - Si 9.60 [10(-5) (min*pmol/L)(-1) ] (8.23-10.97) vs. 11.79 (10.41-13.18), p=0.02 - in adulthood compared to offspring with birthweights in the upper tertile. Offspring with a family history of maternal T2DM have higher birthweights than those with paternal T2DM. Low birthweight associates with elevated plasma glucose levels after an oral glucose load and decreased insulin sensitivity in adulthood.

Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats

In insulin resistance and type II diabetes, there is an elevation of hepatic gluconeogenesis, which contributes to hyperglycaemia. Studies in experimental animals have provided evidence that consumption of high fat (HF) diets by female rats programs the progeny for glucose intolerance in adulthood, but the mechanisms behind the in utero programming remain poorly understood. The present study analysed the effect of a maternal HF diet on fetal gluconeogenic gene expression and potential regulation mechanism related to histone modifications. Dams were fed either a Control (C, 16% kcal fat) or a high-fat (HF, 45% kcal fat) diet throughout gestation. Livers of the offspring were collected on gestational day 21 and analysed to determine the consequences of a maternal HF diet on molecular markers of fetal liver gluconeogenesis. We demonstrated that offspring of HF-fed dams were significantly heavier and had significantly higher blood glucose levels at the time of delivery than offspring of dams fed the C diet. While maternal gluconeogenesis and plasma glucose were not affected by the HF diet, offspring of HF-fed dams had significantly higher mRNA contents of gluconeogenic genes in addition to the elevated plasma glucose. In addition to increased transcription rate, a gestational HF diet resulted in modifications of the Pck1 histone code in livers of offspring. Our results demonstrate that in utero exposure to HF diet has the potential to program the gluconeogenic capacity of offspring through epigenetic modifications, which could potentially lead to excessive glucose production and altered insulin sensitivity in adulthood.

Gestational High Fat Diet Programs Hepatic Gluconeogenic Gene Expression And Histone Modification In Offspring Rats

According to current CDC figures, diabetes rates continue to rise, but the mechanisms behind the in-utero programming of diabetes development are unclear. It has been reported that a maternal high-fat (HF) diet affects fetal liver development, which can lead to altered glucose metabolism in adulthood. In the current study, Obesity Resistant (OR) dams were fed a control (C) or a high-fat (HF) diet during gestation. After cesarean delivery, offspring livers were analyzed to determine the consequences of a maternal HF diet on molecular markers of gluconeogenesis. We demonstrated that while HF-fed dams were not heavier at the end of gestation and did not gain more gestational weight than C dams, HF offspring were heavier and had higher blood glucose at birth than C offspring. Liver mRNA analysis demonstrated that while maternal gluconeogenic genes were not affected by the HF diet, offspring of HF-fed dams had significantly higher expression of hepatic G6Pase, Srebp1c, Cebpα, Pgc1a, and Pck1, which also had an increased transcription rate. Pck1 ChIP analysis showed that a gestational HF diet resulted in epigenetic modifications of the histone code in offspring livers. Our results demonstrate that in-utero exposure to HF diet has the potential to program the gluconeogenic capacity of offspring through epigenetic modifications, which could inevitably lead to altered insulin sensitivity in adulthood. Grant Funding Source: USDA

Prematurity Is Not Associated with Reduced Insulin Sensitivity in Adulthood

In 2005, 12.7% of all babies were born preterm, and the incidence is rising. Nowadays, due to improved survival, an increasing number of children born preterm reach young adulthood. A recent report suggested lower insulin sensitivity in children born preterm, which may put them at risk for the development of type 2 diabetes. It is, however, still unknown whether this reduced insulin sensitivity persists into adulthood. We determined insulin sensitivity and beta-cell function with frequently sampled iv glucose tolerance tests in 305 young adults (aged 18-24 yr; 169 preterm and 136 term). Adult body composition was measured by dual energy x-ray absorptiometry. We investigated the effect of gestational age, size at birth, and adult body composition on insulin sensitivity. In contrast to previous reports, we found no evidence that preterm birth has a deleterious effect on insulin sensitivity in young adulthood. Adult trunk fat and the use of oral contraceptives in women were the most important determinants of insulin insensitivity, independently of size at birth and duration of pregnancy. Contrary to our hypothesis, preterm birth was not associated with reduced insulin sensitivity in young adulthood.

Insulin sensitivity is normalized in the third generation (F3) offspring of developmentally programmed insulin resistant (F2) rats fed an energy-restricted diet

Background/AimsThe offspring and grandoffspring of female rats fed low protein diets during pregnancy and lactation, but fed nutritionally adequate diets thereafter, have been shown to exhibit altered insulin sensitivity in adulthood. The current study investigates the insulin sensitivity of the offspring and grandoffspring of female rats fed low protein diets during pregnancy, and then maintained on energy-restricted diets post weaning over three generations.MethodsFemale Sprague Dawley rats (F0) were mated with control males and protein malnourished during pregnancy/lactation. F1 offspring were then weaned to adequate but energy-restricted diets into adulthood. F1 dams were fed energy-restricted diets throughout pregnancy/lactation. F2 offspring were also fed energy-restricted diets post weaning. F2 pregnant dams were maintained as described above. Their F3 offspring were split into two groups; one was maintained on the energy-restricted diet, the other was maintained on an adequate diet consumed ad libitum post weaning.ResultsF2 animals fed energy-restricted diets were insulin resistant (p < 0.05), while the insulin sensitivity of their F3 offspring equaled and surpassed that of controls on both the energy-restricted and adequate ad libitum postweaning diets (p < 0.05).ConclusionMaternal energy-restriction did not consistently program reduced insulin sensitivity in offspring over three consecutive generations. The reasons for this remain unclear. It is possible that the intergenerational transmission of developmentally programmed insulin resistance is determined in part by the relative insulin sensitivity of the mother during pregnancy/lactation.

Maternal protein restriction during early lactation induces GLUT4 translocation and mTOR/Akt activation in adipocytes of adult rats

Epidemiological and experimental studies have demonstrated that early postnatal nutrition has been associated with long-term effects on glucose homeostasis in adulthood. Recently, our group demonstrated that undernutrition during early lactation affects the expression and activation of key proteins of the insulin signaling cascade in rat skeletal muscle during postnatal development. To elucidate the molecular mechanisms by which undernutrition during early life leads to changes in insulin sensitivity in peripheral tissues, we investigated the insulin signaling in adipose tissue. Adipocytes were isolated from epididymal fat pads of adult male rats that were the offspring of dams fed either a normal or a protein-free diet during the first 10 days of lactation. The cells were incubated with 100 nM insulin before the assays for immunoblotting analysis, 2-deoxyglucose uptake, immunocytochemistry for GLUT4, and/or actin filaments. Following insulin stimulation, adipocytes isolated from undernourished rats presented reduced tyrosine phosphorylation of IR and IRS-1 and increased basal phosphorylation of IRS-2, Akt, and mTOR compared with controls. Basal glucose uptake was increased in adipocytes from the undernourished group, and the treatment with LY294002 induced only a partial inhibition both in basal and in insulin-stimulated glucose uptake, suggesting an involvement of phosphoinositide 3-kinase activity. These alterations were accompanied by higher GLUT4 content in the plasma membrane and alterations in the actin cytoskeleton dynamics. These data suggest that early postnatal undernutrition impairs insulin sensitivity in adulthood by promoting changes in critical steps of insulin signaling in adipose tissue, which may contribute to permanent changes in glucose homeostasis.

Effect of fetal dexamethasone exposure on the development of adult insulin sensitivity in a rat model

Objective. A rat model was designed to determine if fetal dexamethasone exposure is associated with decreased insulin sensitivity in adulthood, manifested as decreased binding of p85 to phosphorylated insulin receptor substrate-1 (IRS-1) within the phosphatidylinositol 3-kinase (PI 3-kinase) pathway of insulin signaling. Additionally, the study investigated whether a differential effect exists in male and female rodent offspring, such that females demonstrate decreased binding of p85 to IRS-1 after exposure to dexamethasone in utero.Methods. Timed-pregnant Sprague-Dawley rats received either tap water or dexamethasone in drinking water from day 13 of gestation until delivery. Fasting male and female offspring from each group were sacrificed on day 50 of life, and half of these rats were given insulin subcutaneously prior to sacrifice. Adipocyte, skeletal muscle, and liver cell lysates were analyzed by immunoprecipitation and Western blotting of IRS-1 and IRS-1-associated p85.Results. In all tissues examined, a significant inverse relationship was found between dexamethasone treatment in utero and association of p85 with IRS-1 in adulthood. p85 association with IRS-1 was similar in tissues from fasting and insulin-stimulated states. Furthermore, tissues of male and female rats demonstrated similar binding of p85 to IRS-1.Conclusions. In a rat model, fetal exposure to dexamethasone was associated with decreased insulin signaling at the level of p85 binding to IRS-1, a proximal step in insulin signaling within the PI 3-kinase pathway. This effect did not appear to be enhanced by administration of insulin prior to sacrifice, nor was a sex-dependent differential effect noted.

Up-regulation of phosphatidylinositol 3-kinase and glucose transporter 4 in muscle of rats subjected to maternal undernutrition

Early postnatal nutrition has been associated with the long-term effects on glucose homeostasis in adulthood. To elucidate the molecular mechanisms by which undernutrition during early life leads to changes in insulin sensitivity, we investigated the insulin signaling in skeletal muscle of rats during development. Offspring of dams fed with either protein-free or normal diets during the first 10 days of lactation were studied from lactation period until adulthood. Early maternal undernutrition impaired secretion of insulin but maintained normal blood glucose levels until adulthood. Insulin receptor (IR) activation after insulin stimulation was decreased during the period of protein restriction. In addition, glucose uptake, insulin receptor substrate 1 (IRS-1) phosphorylation and glucose transporter 4 (GLUT-4) translocation in muscle were reduced in response to insulin during suckling. In contrast, non- or insulin-stimulated glucose uptake and GLUT-4 translocation were found significantly increased in muscle of adult offspring. Finally, basal association of phosphatidylinositol 3-kinase (PI3-kinase) with IRS-1 was increased and was highly stimulated by insulin in muscle from adult rats. Our findings suggest that early postnatal undernutrition increases insulin sensitivity in adulthood, which appears to be directly related to changes in critical steps required for glucose metabolism.