scholarly journals Structural instability of mutant β-cell glucokinase: implications for the molecular pathogenesis of maturity-onset diabetes of the young (type-2)

1997 ◽  
Vol 322 (1) ◽  
pp. 57-63 ◽  
Author(s):  
Prabakaran KESAVAN ◽  
Liqun WANG ◽  
Elizabeth DAVIS ◽  
Antonio CUESTA ◽  
Ian SWEET ◽  
...  
Keyword(s):  
Structural Instability ◽  
Pancreatic Β Cell ◽  
Maturity Onset Diabetes ◽  
Wild Type ◽  
Β Cell ◽  
Catalytic Function ◽  
Onset Diabetes ◽  
Impaired Insulin ◽  
Thermal Stability Of

The catalytic function and thermal stability of wild-type and mutant recombinant human pancreatic β-cell glucokinase was investigated. The mutants E70K and E300K, which are thought to be the cause of impaired insulin production by the pancreatic β-cell and decreased glucose uptake by the liver of patients with maturity-onset diabetes of the young, were found to be functionally indistinguishable from the wild-type, i.e. their kcat,S0.5, inflection point and hwere normal. However, these two mutants showed markedly reduced stability under a variety of test conditions. Glucokinase instability, not low enzyme catalytic activity, may be the cause of diabetes mellitus with E70K and E300K mutants.

scholarly journals Islet Inflammation Impairs the Pancreatic β-Cell in Type 2 Diabetes

Physiology ◽  
2009 ◽  
Vol 24 (6) ◽  
pp. 325-331 ◽  
Author(s):  
Marc Y. Donath ◽  
Marianne Böni-Schnetzler ◽  
Helga Ellingsgaard ◽  
Jan A. Ehses
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Metabolic Stress ◽  
Innate Immune ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Amyloid Deposits ◽  
Impaired Insulin ◽  
Islet Inflammation

Onset of Type 2 diabetes occurs when the pancreatic β-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, β-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in β-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.

scholarly journals Cell-biological assessment of human glucokinase mutants causing maturity-onset diabetes of the young type 2 (MODY-2) or glucokinase-linked hyperinsulinaemia (GK-HI)

1999 ◽  
Vol 342 (2) ◽  
pp. 345-352 ◽  
Author(s):  
Charlotte V. BURKE ◽  
Carol W. BUETTGER ◽  
Elizabeth A. DAVIS ◽  
Steven J. MCCLANE ◽  
Franz M. MATSCHINSKY ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Human Islet ◽  
Biological Assessment ◽  
Hill Coefficient ◽  
Published Data ◽  
Mrna Levels ◽  
Maturity Onset Diabetes ◽  
Wild Type ◽  
Onset Diabetes

Mutations in the glucokinase (GK) gene cause type-2 maturity-onset diabetes of the young type 2 (MODY-2) and GK-linked hyperinsulinaemia (GK-HI). Recombinant adenoviruses expressing the human wild-type islet GK or one of four mutant forms of GK, (the MODY-2 mutants E70K, E300K and V203A and the GK-HI mutant V455M) were transduced into glucose-responsive insulin-secreting β-HC9 cells and tested functionally in order to initiate the first analysis in vivoof recombinant wild-type and mutant human islet GK. Kinetic analysis of wild-type human GK showed that the glucose S0.5 and Hill coefficient were similar to previously published data in vitro (S0.5 is the glucose level at the half-maximal rate). E70K had half the glucose affinity of wild-type, but similar enzyme activity. V203A demonstrated decreased catalytic activity and an 8-fold increase in glucose S0.5 when compared with wild-type human islet GK. E300K had a glucose S0.5 similar to wild-type but a 10-fold reduction in enzyme activity. E300K mRNA levels were comparable with wild-type GK mRNA levels, but Western-blot analyses demonstrated markedly reduced levels of immunologically detectable protein, consistent with an instability mutation. V455M was just as active as wild-type GK, but with a markedly reduced S0.5. The effects of the different GK mutants on glucose-stimulated insulin release support the kinetic and expression data. These experiments show the utility of a combined genetic, biochemical and cell-biological approach to the quantification of functional and structural changes of human GK that result from MODY-2 and GK-HI mutations.

Phenotypic and pathomorphological characteristics of a novel mutant mouse model for maturity-onset diabetes of the young type 2 (MODY 2)

2010 ◽  
Vol 298 (3) ◽  
pp. E512-E523 ◽  
Author(s):  
L. van Bürck ◽  
A. Blutke ◽  
S. Kautz ◽  
B. Rathkolb ◽  
M. Klaften ◽  
...  
Keyword(s):  
Mutant Mouse ◽  
Cell Mass ◽  
Mutant Mice ◽  
Maturity Onset Diabetes ◽  
Β Cell ◽  
Onset Diabetes ◽  
Homozygous Mutant ◽  
The Impact ◽  
Cell Volumes

Several mutant mouse models for human diseases such as diabetes mellitus have been generated in the large-scale Munich ENU ( N-ethyl- N-nitrosourea) mouse mutagenesis project. The aim of this study was to identify the causal mutation of one of these strains and to characterize the resulting diabetic phenotype. Mutants exhibit a T to G transversion mutation at nt 629 in the glucokinase ( Gck) gene, leading to an amino acid exchange from methionine to arginine at position 210. Adult Munich GckM210R mutant mice demonstrated a significant reduction of hepatic glucokinase enzyme activity but equal glucokinase mRNA and protein abundances. While homozygous mutant mice exhibited growth retardation and died soon after birth in consequence of severe hyperglycemia, heterozygous mutant mice displayed only slightly elevated blood glucose levels, present from birth, with development of disturbed glucose tolerance and glucose-induced insulin secretion. Additionally, insulin sensitivity and fasting serum insulin levels were slightly reduced in male mutant mice from an age of 90 days onward. While β-cell mass was unaltered in neonate heterozygous and homozygous mutant mice, the total islet and β-cell volumes and the total volume of isolated β-cells were significantly decreased in 210-day-old male, but not female heterozygous mutant mice despite undetectable apoptosis. These findings indicate that reduced total islet and β-cell volumes of male mutants might emerge from disturbed postnatal islet neogenesis. Considering the lack of knowledge about the pathomorphology of maturity-onset diabetes of the young type 2 (MODY 2), this glucokinase mutant model of reduced total islet and total β-cell volume provides the opportunity to elucidate the impact of a defective glucokinase on development and maintenance of β-cell mass and its relevance in MODY 2 patients.

INCRETIN AND DIABETES

2011 ◽  
pp. 5-10
Author(s):  
Huu Dang Tran
Keyword(s):  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Glycaemic Control ◽  
Animal Studies ◽  
Dipeptidyl Peptidase ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Glucose Sensitivity ◽  
Cell Glucose

The incretins are peptide hormones secreted from the gut in response to food. They increase the secretion of insulin. The incretin response is reduced in patients with type 2 diabetes so drugs acting on incretins may improve glycaemic control. Incretins are metabolised by dipeptidyl peptidase, so selectively inhibiting this enzyme increases the concentration of circulating incretins. A similar effect results from giving an incretin analogue that cannot be cleaved by dipeptidyl peptidase. Studies have identified other actions including improvement in pancreatic β cell glucose sensitivity and, in animal studies, promotion of pancreatic β cell proliferation and reduction in β cell apoptosis.

scholarly journals Visceral Adiposity Index is associated with Insulin Resistance, impaired Insulin Secretion, and β-cell dysfunction in subjects at risk for Type 2 Diabetes

2021 ◽  
pp. 100013
Author(s):  
Froylan David Martínez-Sánchez ◽  
Valerie Paola Vargas-Abonce ◽  
Andrea Rocha-Haro ◽  
Romina Flores-Cardenas ◽  
Milagros Fernández-Barrio ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
At Risk ◽  
Insulin Secretion ◽  
Visceral Adiposity ◽  
Visceral Adiposity Index ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin

scholarly journals Childhood obesity complicating the differential diagnosis of maturity-onset diabetes of the young and type 2 diabetes

2007 ◽  
Vol 0 (0) ◽  
pp. 071127170524002-??? ◽  
Author(s):  
Naomi Weintrob ◽  
Eti Stern ◽  
Yaffa Klipper-Aurbach ◽  
Moshe Phillip ◽  
Galia Gat-Yablonski
Keyword(s):  
Type 2 Diabetes ◽  
Differential Diagnosis ◽  
Childhood Obesity ◽  
Maturity Onset Diabetes ◽  
Onset Diabetes

Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes

Diabetes ◽  
2008 ◽  
Vol 57 (6) ◽  
pp. 1738-1744 ◽  
Author(s):  
J. Holmkvist ◽  
P. Almgren ◽  
V. Lyssenko ◽  
C. M. Lindgren ◽  
K.-F. Eriksson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Maturity Onset Diabetes ◽  
Common Variants ◽  
Onset Diabetes ◽  
Future Risk

Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

2007 ◽  
Vol 292 (6) ◽  
pp. E1694-E1701 ◽  
Author(s):  
Jane J. Kim ◽  
Yoshiaki Kido ◽  
Philipp E. Scherer ◽  
Morris F. White ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Response ◽  
Cell Mass ◽  
Comprehensive Treatment ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

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