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Hannelore Daniel
Type 2 diabetes metabolic footprint and biomarkers
Hannelore Daniel
Hannelore Daniel
SOME BASICS
glycerol
free fatty acids
free fatty acids
acylcarnitines
ketones
GLUCAGON
CATCHOLAMINES
Insulin
Insulin
GLUCAGON
CATCHOLAMINES
GLUCAGON
CATCHOLAMINES
free fatty acids
Catabolic state
Insulin
+
+
+
amino acids
amino acids
glucose
Hannelore Daniel
SOME BASICS
GLUCAGON
CATCHOLAMINES
Insulin
Insulin
GLUCAGON
CATCHOLAMINES
GLUCAGON
CATCHOLAMINES
Insulin
+
+
+
glycerol
free fatty acids
free fatty acids
acylcarnitines
ketones
free fatty acids
amino acids
amino acids
glucose
GLUCOSEAMINO ACIDSLIPIDS
Catabolic state
Hannelore Daniel
SOME BASICS
GLUCAGON
CATCHOLAMINES
Insulin
Insulin
GLUCAGON
CATCHOLAMINES
GLUCAGON
CATCHOLAMINES
Anabolic state
Insulin +
+
+
glycerol
free fatty acids
free fatty acids
acylcarnitines
ketones
free fatty acids
amino acids
amino acids
glucose
GLUCOSEAMINO ACIDSLIPIDS
Hannelore Daniel
SOME BASICS
GLUCAGON
CATCHOLAMINES
Insulin
Insulin
GLUCAGON
CATCHOLAMINES
GLUCAGON
CATCHOLAMINES
Anabolic state
Insulin +
+
+amino acids
glucose
amino acids
glucose
lipids
glucose
Hannelore Daniel
SOME BASICS
Hannelore Daniel
Hannelore Daniel
Obesity and the cause of the metabolic syndrome
Hannelore Daniel
Hannelore Daniel
Metabolomic (bio)markers of obesity, IR and type 2 diabetes
Hannelore Daniel
Insights gained in groups of monocygotic twins
Hannelore Daniel
monozygotic twinsdiscordant for obesity
Cell Metab. 2009 April; 9(4): 311–326.
Plasma Amino Acid Levels and Insulin Secretion in ObesityPhilip Felig, Errol Marliss and George F. Cahill, Jr.
N Engl J Med 1969; 281:811-816October 9, 1969
Metabolite markers of obesity
n=67n=74
Hannelore Daniel
The relationships between the mean expression of the BCAA catabolism pathway enzymes and markers of obesity in twins discordant for obesity
Pietiläinen KH, Naukkarinen J, Rissanen A, Saharinen J, et al. (2008) Global Transcript Profiles of Fat in Monozygotic Twins Discordant for BMI: Pathways behind Acquired Obesity . PLoS Med 5(3): e51. doi:10.1371/journal.pmed.0050051
18 monozygotic twinsdiscordant for obesity
Metabolite markers of obesity
Hannelore Daniel
Pietiläinen KH, Naukkarinen J, Rissanen A, Saharinen J, et al. (2008) Global Transcript Profiles of Fat in Monozygotic Twins Discordant for BMI: Pathways behind Acquired Obesity . PLoS Med 5(3): e51. doi:10.1371/journal.pmed.0050051
The relationships between the mean expression of the BCAA catabolism
pathway enzymes and markers of obesity in twins discordant for obesity
Metabolite markers of obesity
18 monozygotic twinsdiscordant for obesity
Hannelore Daniel
Samples derived from body mass index-(BMI) and age-matched
overweight to obese type 2 diabetic (n = 44) and non-diabetic (n = 12)
Gullah-speaking African-American women
Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic
and type 2 diabetic obese African-American women.
Urinary metabolic signatures of human adiposity. Elliott P, et al. Nicholson JK. Sci Transl Med. 2015 Apr 29;7(285):285
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discovery 1880 validation 444
NMR-based analysis in urine in reference in BMI
Hannelore Daniel
Biomarker discovery approaches in type 2 diabetes
Hannelore Daniel
An amino acid profile to predict diabetes?
Among 2.422 normoglycemic individuals followed for 12 years, 201 developed
diabetes
Hannelore Daniel
PLoS One. 2010 May 28;5(5):e10883.
Metabolite profiling in non-diabetic human volunteers with insulin resistance α-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population.
Hannelore Daniel
Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach
Diabetes. 2012 Oct 4. , Mol Syst Biol. 2012 Sep 25;8:615
from 866 to 238 with impaired glucose tolerance to 91 people with type 2 diabetes
Hannelore Daniel
Targeted High Performance Liquid Chromatography Tandem Mass Spectrometry-based Metabolomics differentiates metabolic syndrome from
obesity. Zhong F et al. Exp Biol Med (Maywood). 2017 Apr;242(7):773-780.
43 obese 26 obese/metS
Hannelore Daniel
A systems view of type 2 diabetes-associated metabolic perturbations in saliva, blood and urine at different timescales of glycaemic control.
Yousri NA, et al. Suhre K. Diabetologia. 2015 Aug;58(8):1855-67.
Selected gaussian graphical networks across biofluids
188 controls 181 type2 diabetics
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HUMAN GENETICS for identification of causes
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Manhattan plot of the association of genetic variants with the levels of branched-chain amino acids.
Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.
Lotta LA et. Al. Langenberg C. PLoS Med. 2016 Nov 29;13(11):e1002179.
meta-analysis of 1.992 incident type 2 diabetes and 4.319 non-cases
Hannelore Daniel
Schematic representation of the branched-chain amino acid pathway and associations with type 2 diabetes. BCKD, branched-chain alphaketoacid dehydrogenase.
Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.
Lotta LA et. Al. Langenberg C. PLoS Med. 2016 Nov 29;13(11):e1002179.
meta-analysis of 1.992 incident type 2 diabetes and 4.319 non-cases
Hannelore Daniel
Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.
Lotta LA et. Al. Langenberg C. PLoS Med. 2016 Nov 29;13(11):e1002179.
meta-analysis of 1.992 incident type 2 diabetes and 4.319 non-cases
Hannelore Daniel
Heritability was estimated using multilevel mixed-effects linear regression adjusting for gestationalage, gender, weight and age.The highest heritability was for short-chainacylcarnitines (mainly C4 and C5). There is directevidence for a strong genetic contribution. To themetabolic profile at birth and that newbornscreening data can be utilized for studying thegenetic regulation of many clinically relevantmetabolites.
The heritability of metabolomic profiles in newborn twins
Heritability of analyzed metabolites and analyte ratios. The y-axis is the negative log10 of the P-value for additive genetic component and the heritabilityestimate is on the x-axis. Confidence intervals around the heritability point estimates are in light gray bars. IRT, TSH, 17-OHP and GALT are represented asdark gray squares, amino acids are represented as medium gray circles and acylcarnitines are represented as light gray triangles.
Heredity (Edinb). 2013 Mar; 110(3): 253–258.
after bariatric surgery
BC
CA
tra
nsa
min
ase
pro
tein
(arb
irar
y u
nit
s)
before bariatric surgery
Hannelore Daniel
Selective down-regulation of BCATm in human obesity
Am J Physiol Endocrinol Metab. 2007 December; 293(6): E1552–E1563.
Effects of bariatric surgery
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How good are marker-metabolites for diagnosis ?
Hannelore Daniel
Diabetes. 2013 Feb; 62(2): 639–648.
from 866 to 238 with impaired glucose tolerance to 91 people with type 2 diabetes
Hannelore Daniel
Validation of a metabolite panel for early diagnosis of type 2 diabetes. Carter TC, et al. Metabolism. 2016 Sep;65(9):1399-408.
78 controls 61 type2 diabetics
Hannelore Daniel
Using animals to identify the origins of changes
Hannelore Daniel
Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes.
Giesbertz P, et al. Daniel H. Diabetologia. 2015;58(9):2133-43.
Hannelore Daniel
C0
C2
C5.OH
C3.0
X2.M.C3.0
C4.0
C5.1
C4.1.DC
C3.DC
C4.DC
C6.0
C3.DC.M
C5.DC
C5.1.DC
C5.M.DC
C7.DC
C8.0
C10.0
C12.0
C16.2
C14.0
C16.OH
C18.1.OH
C16.1
C18.2
C16.0C18.1
C12.DC
C18.0
X2.M.C4.0
X3.M.C4.0
C5.0
C4.OH.a
C4.OH.b
X2.M.C3.OH iso.C15.0
C15.0
iso.C17.0
C17.0
iso.C13.0
C13.0
C7.0
C6.OH.a..7.30.
C6.OH.b..7.55.
C0
C3.1
C2
C5.OH
C3.0
X2.M.C3.0
C4.0
C5.1
C4.1.DC
C3.DC
C4.DC
C6.0
C3.DC.M
C5.DC
C5.M.DC
C7.DC
C8.0
C9.0
C14.2.OH
C10.0
C12.1
C14.2
C12.0
C14.1
C16.2
C14.0
C16.OH
C18.1.OH
C16.1
C18.2
C16.0
C18.1
C12.DC
C18.0
X2.M.C4.0
X3.M.C4.0
C5.0
C4.1
X2.M.C3.1C4.OH.a
C4.OH.b
X2.M.C3.OH
C6.DC
iso.C15.0
C15.0
iso.C17.0
C17.0
iso.C13.0
C13.0
iso.C11.0
C11.0
iso.C7.0
C7.0
C6.OH.a..7.30.
C6.OH.b..7.55.
X3.M.C4.1
X3.OH.3.M.C4.0
C0
C3.1
C2
C5.OH
C3.0
X2.M.C3.0
C4.0
C5.1
C3.DC
C4.DC
C6.0
C3.DC.M
C5.DC
C10.2
C8.0C10.1
C9.0
C14.2.OH
C10.0
C12.1
C16.2.OH
C14.2
C12.0
C14.1
C16.2
C14.0C16.OH
C18.1.OH
C16.1
C18.2
C16.0
C18.1
C12.DC
C18.0
X2.M.C4.0X3.M.C4.0
C5.0
C4.1
X2.M.C3.1
C4.OH.a
C4.OH.b
C6.DC
iso.C15.0C15.0
iso.C17.0
C17.0
iso.C13.0
C13.0
iso.C11.0
C11.0
iso.C7.0
C7.0
C6.OH.a..7.30.
C6.OH.b..7.55.
C0
C3.OH
C5.OH
X2.M.C3.0
C4.0
C5.1
C4.1.DCC3.DC
C4.DC
C6.0
C3.DC.M
C5.DC
C5.M.DC
C8.1
C7.DC
C10.2
C8.0
C9.0
C14.2.OH
C10.0
C12.1
C16.2.OH
C14.2
C12.0
C16.2
C14.0
C16.OH
C18.1.OH
C16.1
C18.2
C16.0
C18.1
C12.DCC18.0
X2.M.C4.0X3.M.C4.0
C5.0
C4.1
X2.M.C3.1
C4.OH.a
C4.OH.b
X2.M.C3.OH
C6.DC
iso.C15.0C15.0iso.C17.0
C17.0
iso.C13.0
C13.0
iso.C11.0
C11.0
iso.C7.0
C7.0
C6.OH.a..7.30.
C6.OH.b..7.55.
Plasma
Liver
Muscle
Kidney
Plasma
Liver
Muscle
Kidney
The correlation network shows the strongest correlations between individual
concentrations of acylcarnitines in plasma and tissues.
Hannelore Daniel
Branched-chain amino acids as biomarkers in diabetes. Giesbertz P, Daniel H. Curr Opin Clin Nutr Metab Care. 2016 Jan;19(1):48-54.
A working hypothesis for explaining the characteristic alterations of plasma metabolites in obesity, insulin-resistance and diabetes
Hannelore Daniel
Selective down-regulation of BCATm in rodent obesity models
Am J Physiol Endocrinol Metab. 2007 December; 293(6): E1552–E1563.
Hannelore Daniel
Identified plasma (bio)markers of insulin resistance & diabetes in humans
For insulin resistance and type 2 diabetes numerous studies have identified in plasma metabolomics approaches aminoacids and derivatives, novel ketone bodies and selected lipids (mainly lyso-PC´s) as biomarkers with predictive quality.
Leucine
Isoleucine
Valine
Glucose
α-keto-Isovalerate
Propionyl-carnitine
free fatty acids
Carnitine
acetyl-Carnitine
C4-Carnitine
LyoPC17:0
lysoPC18:0
lysoPC 18:1
lysoPC 18:2C5- Carnitine
PLASMA
PC aa 32:1
ether PC´s
Sphingomyelins
Tyr/Phe
Glycine
Methionine
Threonine
α-Aminobutyrate
2-OH-Butyrate
3-OH-Butyrate
2-AminoadipateLysine
3-methyl-2-oxovalerate
Mannose
Glyoxylate
Glucosamine
Hannelore Daniel
Metabolite-markers of obesity, insulin resistance and T2DM observed in human samples are mainly products of impaired amino
acid metabolism (in particular of branched chain amino acids, glycine, threonine and lysine) followed by entities from fatty and
carbohydrate metabolism.
The key determinant for most changes is likely the disbalance in insulin (sensitivity) to catabolic hormones signalling.
This „metabolic signature“ (footprint) however seems not o improve significantly diagnosis of insulin resistance or T2DM.
Take home message
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