scholarly journals Functional characterization of naturally occurring transglutaminase 2 mutants implicated in early-onset type 2 diabetes

2012 ◽  
Vol 48 (3) ◽  
pp. 203-216 ◽  
Author(s):  
Neil W Salter ◽  
Sudharsana R Ande ◽  
Hoa K Nguyen ◽  
B L Grégoire Nyomba ◽  
Suresh Mishra

Transglutaminase 2 (TG2) is an enzyme with diverse biological functions. TG2 catalyzes transamidation reactions, has intrinsic kinase activity, and acts as a G-protein in intracellular signaling. TG2 (Tgm2)-null mice are glucose intolerant and have impaired glucose-stimulated insulin secretion (GSIS). Furthermore, three naturally occurring missense mutations in the human TGM2 gene, corresponding to amino acid substitutions of Met330Arg, Ile331Asn, and Asn333Ser in the TG2 protein, have been reported and found to be associated with early-onset type 2 diabetes. However, their effect on TG2 function is not fully understood. To determine this, we have reproduced naturally occurring mutations in TG2 using site-directed mutagenesis. Overexpression of Myc-TG2 mutants in INS-1E cells resulted in a reduction of GSIS in comparison with cells overexpressing wild-type Myc-TG2 (WT-TG2). The maximum reduction was found in cells overexpressing Ile331Asn-TG2 (32%) followed by Met330Arg-TG2 (20%), and the least in Asn333Ser-TG2 (7%). Enzymatic analysis revealed that TG2 mutants have impaired transamidation and kinase activities in comparison with WT-TG2. GTP-binding assays showed that TG2 mutants also have altered GTP-binding ability, which is found to be modulated in response to glucose stimulation. Collectively, these data suggest that naturally occurring mutations in TG2 affect transamidation, kinase, and GTP-binding functions of TG2. While reduced insulin secretion, as a result of naturally occurring mutations in TG2, is due to the impairment of more than one biological function of TG2, it is the transamidation function that appears to be impaired during the first phase, whereas the GTP-binding function affects the second phase of insulin secretion.

2007 ◽  
Vol 28 (11) ◽  
pp. 1150-1150 ◽  
Author(s):  
O. Porzio ◽  
O. Massa ◽  
V. Cunsolo ◽  
C. Colombo ◽  
M. Malaponti ◽  
...  

Diabetes ◽  
2006 ◽  
Vol 55 (12) ◽  
pp. 3625-3629 ◽  
Author(s):  
Y. Guo ◽  
M. Traurig ◽  
L. Ma ◽  
S. Kobes ◽  
I. Harper ◽  
...  

Diabetologia ◽  
2021 ◽  
Author(s):  
Amélie Keller ◽  
Fanney Thorsteinsdottir ◽  
Maria Stougaard ◽  
Isabel Cardoso ◽  
Peder Frederiksen ◽  
...  

2007 ◽  
Vol 292 (6) ◽  
pp. E1775-E1781 ◽  
Author(s):  
Kenneth Cusi ◽  
Sangeeta Kashyap ◽  
Amalia Gastaldelli ◽  
Mandeep Bajaj ◽  
Eugenio Cersosimo

Elevated plasma FFA cause β-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% ( P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or ΔC-peptide/Δglucose AUC (+177%, P = 0.02), an index of improved β-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 ± 5% ( P < 0.04). First- (+19 ± 6%, P = 0.1) and second-phase (+31 ± 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 ± 7 ( P < 0.05) and 41 ± 8% ( P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR ( r2 = 0.31, P < 0.02) and acute (2–4 min) glucose-induced insulin release after acipimox ( r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.


2013 ◽  
Vol 72 (1) ◽  
pp. 21190 ◽  
Author(s):  
Julia D. Rempel ◽  
Juliet Packiasamy ◽  
Heather J. Dean ◽  
Jonathon McGavock ◽  
Alyssa Janke ◽  
...  

2017 ◽  
Vol 15 (9) ◽  
pp. 458-464 ◽  
Author(s):  
Gadadharan Vijayakumar ◽  
Ganapathy K. Sreehari ◽  
Aswathi Vijayakumar ◽  
Abdul Jaleel

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