Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice.
Mutations in the gene for the transcription factor hepatocyte nuclear factor (HNF) 1alpha cause maturity-onset diabetes of the young (MODY) 3, a form of diabetes that results from defects in insulin secretion. Since the nature of these defects has not been defined, we compared insulin secretory function in heterozygous [HNF-1alpha (+/-)] or homozygous [HNF-1alpha (-/-)] mice with null mutations in the HNF-1alpha gene with their wild-type littermates [HNF-1alpha (+/+)]. Blood glucose concentrations were similar in HNF-1alpha (+/+) and (+/-) mice (7.8+/-0.2 and 7.9+/-0.3 mM), but were significantly higher in the HNF-1alpha (-/-) mice (13.1+/-0.7 mM, P < 0.001). Insulin secretory responses to glucose and arginine in the perfused pancreas and perifused islets from HNF-1alpha (-/-) mice were < 15% of the values in the other two groups and were associated with similar reductions in intracellular Ca2+ responses. These defects were not due to a decrease in glucokinase or insulin gene transcription. beta cell mass adjusted for body weight was not reduced in the (-/-) animals, although pancreatic insulin content adjusted for pancreas weight was slightly lower (0.06+/-0.01 vs. 0.10+/-0.01 microg/mg, P < 0.01) than in the (+/+) animals. In summary, a null mutation in the HNF-1alpha gene in homozygous mice leads to diabetes due to alterations in the pathways that regulate beta cell responses to secretagogues including glucose and arginine. These results provide further evidence in support of a key role for HNF-1alpha in the maintenance of normal beta cell function.
Pontoglio
M
M
Department des Biotechnologies, Unité de Recherche Associée 1644 du Centre National de la Recherche Scientifique, Institut Pasteur, 75015 Paris, France.
Sreenan
S
S
Roe
M
M
Pugh
W
W
Ostrega
D
D
Doyen
A
A
Pick
A J
AJ
Baldwin
A
A
Velho
G
G
Froguel
P
P
Levisetti
M
M
Bonner-Weir
S
S
Bell
G I
GI
Yaniv
M
M
Polonsky
K S
KS
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D002118:Calcium / Q000032:analysis; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000235:genetics; D005947:Glucose / Q000494:pharmacology; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006579:Heterozygote; D006720:Homozygote; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins; D009929:Organ Size; D010179:Pancreas / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D001786:Blood Glucose; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D007328:Insulin; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D001120:Arginine; D005947:Glucose; D002118:Calcium