Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.
OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
Ingelsson
Erik
E
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. erik.ingelsson@ki.se
Langenberg
Claudia
C
Hivert
Marie-France
MF
Prokopenko
Inga
I
Lyssenko
Valeriya
V
Dupuis
Josée
J
Mägi
Reedik
R
Sharp
Stephen
S
Jackson
Anne U
AU
Assimes
Themistocles L
TL
Shrader
Peter
P
Knowles
Joshua W
JW
Zethelius
Björn
B
Abbasi
Fahim A
FA
Bergman
Richard N
RN
Bergmann
Antje
A
Berne
Christian
C
Boehnke
Michael
M
Bonnycastle
Lori L
LL
Bornstein
Stefan R
SR
Buchanan
Thomas A
TA
Bumpstead
Suzannah J
SJ
Böttcher
Yvonne
Y
Chines
Peter
P
Collins
Francis S
FS
Cooper
Cyrus C
CC
Dennison
Elaine M
EM
Erdos
Michael R
MR
Ferrannini
Ele
E
Fox
Caroline S
CS
Graessler
Jürgen
J
Hao
Ke
K
Isomaa
Bo
B
Jameson
Karen A
KA
Kovacs
Peter
P
Kuusisto
Johanna
J
Laakso
Markku
M
Ladenvall
Claes
C
Mohlke
Karen L
KL
Morken
Mario A
MA
Narisu
Narisu
N
Nathan
David M
DM
Pascoe
Laura
L
Payne
Felicity
F
Petrie
John R
JR
Sayer
Avan A
AA
Schwarz
Peter E H
PE
Scott
Laura J
LJ
Stringham
Heather M
HM
Stumvoll
Michael
M
Swift
Amy J
AJ
Syvänen
Ann-Christine
AC
Tuomi
Tiinamaija
T
Tuomilehto
Jaakko
J
Tönjes
Anke
A
Valle
Timo T
TT
Williams
Gordon H
GH
Lind
Lars
L
Barroso
Inês
I
Quertermous
Thomas
T
Walker
Mark
M
Wareham
Nicholas J
NJ
Meigs
James B
JB
McCarthy
Mark I
MI
Groop
Leif
L
Watanabe
Richard M
RM
Florez
Jose C
JC
D000483:Alleles; D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics / Q000502:physiology*; D055106:Genome-Wide Association Study; D000081410:Germinal Center Kinases; D005947:Glucose / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics; D051820:TCF Transcription Factors / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000098551:Prospero-Related Homeobox 1 Protein
D000090943:Delta-5 Fatty Acid Desaturase; D000081410:Germinal Center Kinases; D018398:Homeodomain Proteins; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C041086:gastric inhibitory polypeptide receptor; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human; D017346:Protein Serine-Threonine Kinases; D005947:Glucose