scholarly journals GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1-Alpha Mutation Carriers

2020 ◽  
Author(s):  
Ada Admin ◽  
Alexander S. Christensen ◽  
Sofie Hædersdal ◽  
Heidi Storgaard ◽  
Kathrine Rose ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucagon Secretion ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Mutation Carriers ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
Nuclear Factor 1 ◽  
Double Blinded ◽  
Insulinotropic Peptide

Sulfonylureas (SUs) provide an efficacious first-line treatment in patients with hepatocyte nuclear factor 1-alpha (HNF1A)-diabetes, but SUs have limitations due to risk of hypoglycemia. Treatment based on the incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like-peptide 1 (GLP-1), are characterized by their glucose-dependent insulinotropic actions without risk of hypoglycemia. The effect of SUs together with GIP or GLP-1, respectively, on insulin and glucagon secretion in patients with HNF1A-diabetes is currently unknown. To investigate this, ten <i>HNF1A </i>mutation carriers and ten non-diabetic controls were recruited for a double-blinded, placebo-controlled, crossover study including six experimental days in a randomized order involving 2h euglycemic-hyperglycemic clamps with co-administration of 1) SU (glimepiride 1 mg) or placebo, combined with 2) infusions of either GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min) or saline (NaCl). In <i>HNF1A </i>mutation carriers we observed: 1) hypoinsulinemia, 2) insulinotropic effects of both GIP and GLP-1, 3) <a>additive to supra-additive effects on insulin secretion when combining SU+GIP and SU+GLP1, respectively, </a>and 4) increased fasting and arginine-induced glucagon levels compared to non-diabetic controls. Our study suggests that a combination of SU and incretin-based treatment may be efficacious in patients with HNF1A-diabetes via potentiation of glucose-stimulated insulin secretion.

scholarly journals GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1-Alpha Mutation Carriers

2020 ◽  
Author(s):  
Ada Admin ◽  
Alexander S. Christensen ◽  
Sofie Hædersdal ◽  
Heidi Storgaard ◽  
Kathrine Rose ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucagon Secretion ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Mutation Carriers ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
Nuclear Factor 1 ◽  
Double Blinded ◽  
Insulinotropic Peptide

Sulfonylureas (SUs) provide an efficacious first-line treatment in patients with hepatocyte nuclear factor 1-alpha (HNF1A)-diabetes, but SUs have limitations due to risk of hypoglycemia. Treatment based on the incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like-peptide 1 (GLP-1), are characterized by their glucose-dependent insulinotropic actions without risk of hypoglycemia. The effect of SUs together with GIP or GLP-1, respectively, on insulin and glucagon secretion in patients with HNF1A-diabetes is currently unknown. To investigate this, ten <i>HNF1A </i>mutation carriers and ten non-diabetic controls were recruited for a double-blinded, placebo-controlled, crossover study including six experimental days in a randomized order involving 2h euglycemic-hyperglycemic clamps with co-administration of 1) SU (glimepiride 1 mg) or placebo, combined with 2) infusions of either GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min) or saline (NaCl). In <i>HNF1A </i>mutation carriers we observed: 1) hypoinsulinemia, 2) insulinotropic effects of both GIP and GLP-1, 3) <a>additive to supra-additive effects on insulin secretion when combining SU+GIP and SU+GLP1, respectively, </a>and 4) increased fasting and arginine-induced glucagon levels compared to non-diabetic controls. Our study suggests that a combination of SU and incretin-based treatment may be efficacious in patients with HNF1A-diabetes via potentiation of glucose-stimulated insulin secretion.

scholarly journals GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1α Mutation Carriers

Diabetes ◽  
2020 ◽  
Vol 69 (9) ◽  
pp. 1989-2002 ◽  
Author(s):  
Alexander S. Christensen ◽  
Sofie Hædersdal ◽  
Heidi Storgaard ◽  
Kathrine Rose ◽  
Nina L. Hansen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Mutation Carriers ◽  
Hepatocyte Nuclear Factor 1Α

scholarly journals Hepatocyte Nuclear Factor-4α Is Essential for Glucose-stimulated Insulin Secretion by Pancreatic β-Cells

2005 ◽  
Vol 281 (8) ◽  
pp. 5246-5257 ◽  
Author(s):  
Atsuko Miura ◽  
Kazuya Yamagata ◽  
Masafumi Kakei ◽  
Hiroyasu Hatakeyama ◽  
Noriko Takahashi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Glucose Stimulated Insulin Secretion

scholarly journals  -Cell Dysfunction, Insulin Sensitivity, and Glycosuria Precede Diabetes in Hepatocyte Nuclear Factor-1  Mutation Carriers

Diabetes Care ◽  
2005 ◽  
Vol 28 (7) ◽  
pp. 1751-1756 ◽  
Author(s):  
A. Stride ◽  
S. Ellard ◽  
P. Clark ◽  
L. Shakespeare ◽  
M. Salzmann ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Cell Dysfunction ◽  
Mutation Carriers ◽  
Nuclear Factor 1

The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element

1993 ◽  
Vol 13 (2) ◽  
pp. 1183-1193
Author(s):  
J Dalmon ◽  
M Laurent ◽  
G Courtois
Keyword(s):  
Binding Site ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Constitutive Expression ◽  
Nuclear Proteins ◽  
Functional Coupling ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Tissue Specific ◽  
Nuclear Factor 1

Acute-phase reactants are liver proteins whose synthesis is positively or negatively regulated during inflammation. The main mediators of this phenomenon are glucocorticoids and interleukin-6 (IL-6), a pleiotropic cytokine that also controls hematopoiesis. Functional analysis of several acute-phase reactant promoter regions has identified two major DNA motifs used by IL-6-regulated genes. The first one corresponds to a CTGG(G/A)AA sequence, and the other is a binding site for members of the C/EBP family of nuclear proteins. We have previously shown that the human beta fibrinogen (beta Fg) promoter contains an IL-6-responsive region, located between bp -150 and -67 (P. Huber, M. Laurent, and J. Dalmon, J. Biol. Chem. 265:5695-5701, 1990). In this study, using DNase I footprinting, mobility shift assays, and mutagenesis, we demonstrate that at least three subdomains of this region are necessary to observe a full response to IL-6. The most distal contains a CTGGGAA motif, and its mutation inhibits IL-6 stimulation. Another, which is able to interact with several distinct nuclear proteins, among them members of the C/EBP family, is dispensable for IL-6 induction but plays an important role in the constitutive expression of beta Fg. Finally, a proximal hepatocyte nuclear factor 1 binding site, already described as the major determinant of beta Fg tissue-specific expression, is also required for IL-6 stimulation. These results indicate a complex interplay between nuclear proteins within the beta Fg IL-6-responsive region and suggest a tight functional coupling between the tissue-specific and inducible elements.

Sign in / Sign up

Export Citation Format

Share Document