Dataset Information

Biomarker panels associated with progression of renal disease in type 1 diabetes.

ABSTRACT: AIMS/HYPOTHESIS:We aimed to identify a sparse panel of biomarkers for improving the prediction of renal disease progression in type 1 diabetes. METHODS:We considered 859 individuals recruited from the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) and 315 individuals from the Finnish Diabetic Nephropathy (FinnDiane) study. All had an entry eGFR between 30 and 75 ml min-1[1.73 m]-2, with those from FinnDiane being oversampled for albuminuria. A total of 297 circulating biomarkers (30 proteins, 121 metabolites, 146 tryptic peptides) were measured in non-fasting serum samples using the Luminex platform and LC electrospray tandem MS (LC-MS/MS). We investigated associations with final eGFR adjusted for baseline eGFR and with rapid progression (a loss of more than 3 ml min-1[1.73 m]-2 year-1) using linear and logistic regression models. Panels of biomarkers were identified using a penalised Bayesian approach, and their performance was evaluated through 10-fold cross-validation and compared with using clinical record data alone. RESULTS:For final eGFR, 16 proteins and 30 metabolites or tryptic peptides showed significant association in SDRNT1BIO, and nine proteins and five metabolites or tryptic peptides in FinnDiane, beyond age, sex, diabetes duration, study day eGFR and length of follow-up (all at p?

SUBMITTER: Colombo M

PROVIDER: S-EPMC6677704 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Biomarker panels associated with progression of renal disease in type 1 diabetes.

Colombo Marco M Valo Erkka E McGurnaghan Stuart J SJ Sandholm Niina N Blackbourn Luke A K LAK Dalton R Neil RN Dunger David D Groop Per-Henrik PH McKeigue Paul M PM Forsblom Carol C Colhoun Helen M HM

Diabetologia 20190620 9

<h4>Aims/hypothesis</h4>We aimed to identify a sparse panel of biomarkers for improving the prediction of renal disease progression in type 1 diabetes.<h4>Methods</h4>We considered 859 individuals recruited from the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) and 315 individuals from the Finnish Diabetic Nephropathy (FinnDiane) study. All had an entry eGFR between 30 and 75 ml min<sup>-1</sup>[1.73 m]<sup>-2</sup>, with those from FinnDiane being oversampled for albuminuria ...[more]

PMID: 31222504

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Project description:The goals and objectives: To study Type 2 diabetes progression and the development of insulin resistance in two animal models with and without a high fat diet superimposed on these models. Background: Diabetes is a systemic metabolic imbalance involving multiple tissues/organs, and an early hallmark feature of this disease state is insulin resistance. Multifactorial interactions of genetics, prenatal environmental factors (fetal programming) and postnatal environmental factors (nutrition and activity) likely contribute to the diabetic phenotype.Animal models can serve as a valuable tool for studying diabetes disease progression and for identifying useful biomarkers of type 2 diabetes. Several inbred rodent models are available for diabetes related studies. The GK rat is an obvious choice among available inbred models as the genetic basis for this inheritable form of diabetes is polygenic (5), unlike most other inbred rodent models that exhibit single gene defects. Many of the characteristics of the GK rat mirror human diabetes (hyperglycemia, glucose intolerance, insulin resistance), although hyperlipidemia does not appear to be prominent in the GK rat. Due to its polygenic mode of inheritance and 100% penetrance, the GK rat may be a useful model for human diabetes. Induced animal models can also be useful in diabetes studies. One such model is metabolic syndrome resulting from experimentally induced fetal programming (produced by maternal malnutrition or by exposure to corticosteroids in the third trimester). Both in humans and animals, accumulating evidence suggests that alterations in the human fetal environment can result in permanent physiologic changes that manifest as increased incidence of adult onset pathology. Numerous epidemiological studies have forged a strong link between low birth weight and the development of metabolic syndrome in adulthood. From such observations has arisen the concept of “fetal programming” whereby exposure to some factor(s) during crucial stages in development can permanently alter or “reset” physiologic/metabolic functions. In the rat, exposure to corticosteroids during a “window” in third trimester gestation (CS programming) results in fetal growth retardation and insulin resistance in adult offspring. Genetic factors play a primarily role in the etiology of diabetes in the GK rat, whereas fetal environmental factors are causative in CS programming. (It should be noted that although altered fetal environmental effects, most likely stemming from maternal hyperglycemia, have been implicated to play some role in the decreased pancreatic B cell mass in GK rats, these effects occur earlier in gestation and therefore differ from programming by CS in late gestation.) A comparison of the development of insulin resistance in the GK rat with development in the CS programmed rat will provide insight into genetic and fetal environmental factors in disease development. Superimposing dietary alterations (i.e., high fat feeding) (11) on both animal models may aid in the dissection of multiple interacting factors (genetic, fetal environmental factors, postnatal environmental factors) on the development and progression of insulin resistance and type 2 diabetes. Such studies may also aid in the identification of useful biomarkers for insulin resistance and type 2 diabetes in humans. Proposed research: Experiments are designed to study disease progression and the development of insulin resistance in two animal models: the GK rat and the CS programmed rat, with and without a high fat diet superimposed on these models. Animals will be maintained in our facility from weaning (GK rats) or birth (CS programmed - WKY), and body weights taken weekly. Appropriate diets (normal or high fat) will be introduced at weaning. Groups of animals (N=6) will be sacrificed at 5 different ages: 4, 8, 12, 16, and 20 weeks. Plasma samples will be analyzed for markers of hyperglycemia, hyperinsulinemia, dyslipidimia, and for selected other hormonal factors which may contribute to disease etiology (adiponectin, leptin, corticosterone). At sacrifice, muscle is harvested, flash-frozen in liquid nitrogen, and warehoused in our tissue collection maintained at - 80 degrees C for this and possible future work. Study will initially focus on examination of selected molecular markers of insulin resistance at the mRNA level in rat liver (PEPCK, PDK4). Keywords: Type 2 diabetes, biomarker, rat, liver, time series

Project description:The goals and objectives: To study Type 2 diabetes progression and the development of insulin resistance in two animal models with and without a high fat diet superimposed on these models. Background: Diabetes is a systemic metabolic imbalance involving multiple tissues/organs, and an early hallmark feature of this disease state is insulin resistance. Multifactorial interactions of genetics, prenatal environmental factors (fetal programming) and postnatal environmental factors (nutrition and activity) likely contribute to the diabetic phenotype.Animal models can serve as a valuable tool for studying diabetes disease progression and for identifying useful biomarkers of type 2 diabetes. Several inbred rodent models are available for diabetes related studies. The GK rat is an obvious choice among available inbred models as the genetic basis for this inheritable form of diabetes is polygenic (5), unlike most other inbred rodent models that exhibit single gene defects. Many of the characteristics of the GK rat mirror human diabetes (hyperglycemia, glucose intolerance, insulin resistance), although hyperlipidemia does not appear to be prominent in the GK rat. Due to its polygenic mode of inheritance and 100% penetrance, the GK rat may be a useful model for human diabetes. Induced animal models can also be useful in diabetes studies. One such model is metabolic syndrome resulting from experimentally induced fetal programming (produced by maternal malnutrition or by exposure to corticosteroids in the third trimester). Both in humans and animals, accumulating evidence suggests that alterations in the human fetal environment can result in permanent physiologic changes that manifest as increased incidence of adult onset pathology. Numerous epidemiological studies have forged a strong link between low birth weight and the development of metabolic syndrome in adulthood. From such observations has arisen the concept of “fetal programming” whereby exposure to some factor(s) during crucial stages in development can permanently alter or “reset” physiologic/metabolic functions. In the rat, exposure to corticosteroids during a “window” in third trimester gestation (CS programming) results in fetal growth retardation and insulin resistance in adult offspring. Genetic factors play a primarily role in the etiology of diabetes in the GK rat, whereas fetal environmental factors are causative in CS programming. (It should be noted that although altered fetal environmental effects, most likely stemming from maternal hyperglycemia, have been implicated to play some role in the decreased pancreatic B cell mass in GK rats, these effects occur earlier in gestation and therefore differ from programming by CS in late gestation.) A comparison of the development of insulin resistance in the GK rat with development in the CS programmed rat will provide insight into genetic and fetal environmental factors in disease development. Superimposing dietary alterations (i.e., high fat feeding) (11) on both animal models may aid in the dissection of multiple interacting factors (genetic, fetal environmental factors, postnatal environmental factors) on the development and progression of insulin resistance and type 2 diabetes. Such studies may also aid in the identification of useful biomarkers for insulin resistance and type 2 diabetes in humans. Proposed research: Experiments are designed to study disease progression and the development of insulin resistance in two animal models: the GK rat and the CS programmed rat, with and without a high fat diet superimposed on these models. Animals will be maintained in our facility from weaning (GK rats) or birth (CS programmed - WKY), and body weights taken weekly. Appropriate diets (normal or high fat) will be introduced at weaning. Groups of animals (N=6) will be sacrificed at 5 different ages: 4, 8, 12, 16, and 20 weeks. Plasma samples will be analyzed for markers of hyperglycemia, hyperinsulinemia, dyslipidimia, and for selected other hormonal factors which may contribute to disease etiology (adiponectin, leptin, corticosterone). At sacrifice, muscle is harvested, flash-frozen in liquid nitrogen, and warehoused in our tissue collection maintained at - 80 degrees C for this and possible future work. Study will initially focus on examination of selected molecular markers of insulin resistance at the mRNA level in rat gastrocnemius muscles (IRS-1, PDK4). Keywords: Type 2 diabetes, biomarker, rat, muscle, time series

Project description:The goals and objectives: To study Type 2 diabetes progression and the development of insulin resistance in two animal models with and without a high fat diet superimposed on these models. Background: Diabetes is a systemic metabolic imbalance involving multiple tissues/organs, and an early hallmark feature of this disease state is insulin resistance. Multifactorial interactions of genetics, prenatal environmental factors (fetal programming) and postnatal environmental factors (nutrition and activity) likely contribute to the diabetic phenotype.Animal models can serve as a valuable tool for studying diabetes disease progression and for identifying useful biomarkers of type 2 diabetes. Several inbred rodent models are available for diabetes related studies. The GK rat is an obvious choice among available inbred models as the genetic basis for this inheritable form of diabetes is polygenic (5), unlike most other inbred rodent models that exhibit single gene defects. Many of the characteristics of the GK rat mirror human diabetes (hyperglycemia, glucose intolerance, insulin resistance), although hyperlipidemia does not appear to be prominent in the GK rat. Due to its polygenic mode of inheritance and 100% penetrance, the GK rat may be a useful model for human diabetes. Induced animal models can also be useful in diabetes studies. One such model is metabolic syndrome resulting from experimentally induced fetal programming (produced by maternal malnutrition or by exposure to corticosteroids in the third trimester). Both in humans and animals, accumulating evidence suggests that alterations in the human fetal environment can result in permanent physiologic changes that manifest as increased incidence of adult onset pathology. Numerous epidemiological studies have forged a strong link between low birth weight and the development of metabolic syndrome in adulthood. From such observations has arisen the concept of “fetal programming” whereby exposure to some factor(s) during crucial stages in development can permanently alter or “reset” physiologic/metabolic functions. In the rat, exposure to corticosteroids during a “window” in third trimester gestation (CS programming) results in fetal growth retardation and insulin resistance in adult offspring. Genetic factors play a primarily role in the etiology of diabetes in the GK rat, whereas fetal environmental factors are causative in CS programming. (It should be noted that although altered fetal environmental effects, most likely stemming from maternal hyperglycemia, have been implicated to play some role in the decreased pancreatic B cell mass in GK rats, these effects occur earlier in gestation and therefore differ from programming by CS in late gestation.) A comparison of the development of insulin resistance in the GK rat with development in the CS programmed rat will provide insight into genetic and fetal environmental factors in disease development. Superimposing dietary alterations (i.e., high fat feeding) (11) on both animal models may aid in the dissection of multiple interacting factors (genetic, fetal environmental factors, postnatal environmental factors) on the development and progression of insulin resistance and type 2 diabetes. Such studies may also aid in the identification of useful biomarkers for insulin resistance and type 2 diabetes in humans. Proposed research: Experiments are designed to study disease progression and the development of insulin resistance in two animal models: the GK rat and the CS programmed rat, with and without a high fat diet superimposed on these models. Animals will be maintained in our facility from weaning (GK rats) or birth (CS programmed - WKY), and body weights taken weekly. Appropriate diets (normal or high fat) will be introduced at weaning. Groups of animals (N=6) will be sacrificed at 5 different ages: 4, 8, 12, 16, and 20 weeks. Plasma samples will be analyzed for markers of hyperglycemia, hyperinsulinemia, dyslipidimia, and for selected other hormonal factors which may contribute to disease etiology (adiponectin, leptin, corticosterone). At sacrifice, muscle is harvested, flash-frozen in liquid nitrogen, and warehoused in our tissue collection maintained at - 80 degrees C for this and possible future work. Study will initially focus on examination of selected molecular markers of insulin resistance at the mRNA level in rat abdominal fat (PEPCK, IRS-1). Keywords: Type 2 diabetes, biomarker, adipose tissue, rat, time series

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Dataset Information

Biomarker panels associated with progression of renal disease in type 1 diabetes.

Publications

Biomarker panels associated with progression of renal disease in type 1 diabetes.

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