PMID- 8349822
OWN - NLM
STAT- MEDLINE
DCOM- 19930915
LR  - 20181217
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 92
IP  - 2
DP  - 1993 Aug
TI  - Small elevations of glucose concentration redirect and amplify the synthesis of 
      guanosine 5'-triphosphate in rat islets.
PG  - 872-82
AB  - Recent studies suggest a permissive requirement for guanosine 5'-triphosphate 
      (GTP) in insulin release, based on the use of GTP synthesis inhibitors (such as 
      myocophenolic acid) acting at inosine monophosphate (IMP) dehydrogenase; herein, 
      we examine the glucose dependency of GTP synthesis. Mycophenolic acid inhibited 
      insulin secretion equally well after islet culture at 7.8 or 11.1 mM glucose (51% 
      inhibition) but its effect was dramatically attenuated when provided at < or = 
      6.4 mM glucose (13% inhibition; P < 0.001). These observations were explicable by 
      a stimulation of islet GTP synthesis derived from IMP since, at high glucose: (a) 
      total GTP content was augmented; (b) a greater decrement in GTP (1.75 vs. 1.05 
      pmol/islet) was induced by mycophenolic acid; and (c) a smaller "pool" of 
      residual GTP persisted after drug treatment. Glucose also accelerated GTP 
      synthesis from exogenous guanine ("salvage" pathway) and increased content of a 
      pyrimidine, uridine 5'-triphosphate (UTP), suggesting that glucose augments 
      production of a common regulatory intermediate (probably 
      5-phosphoribosyl-1-pyrophosphate). Pathway-specific radiolabeling studies 
      confirmed that glucose tripled both salvage and de novo synthesis of nucleotides. 
      We conclude that steep changes in the biosynthesis of cytosolic pools of GTP 
      occur at modest changes in glucose concentrations, a finding which may have 
      relevance to the adaptive (patho) physiologic responses of islets to changes in 
      ambient glucose levels.
FAU - Metz, S A
AU  - Metz SA
AD  - Department of Medicine, University of Wisconsin, Madison 53792.
FAU - Meredith, M
AU  - Meredith M
FAU - Rabaglia, M E
AU  - Rabaglia ME
FAU - Kowluru, A
AU  - Kowluru A
LA  - eng
GR  - DK 37312/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Hypoxanthines)
RN  - 0 (Insulin)
RN  - 2TN51YD919 (Hypoxanthine)
RN  - 5Z93L87A1R (Guanine)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - IY9XDZ35W2 (Glucose)
RN  - TE7660XO1C (Glycine)
RN  - UT0S826Z60 (Uridine Triphosphate)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Chromatography, High Pressure Liquid
MH  - Glucose/*pharmacology
MH  - Glycine/metabolism
MH  - Guanine/metabolism/pharmacology
MH  - Guanosine Triphosphate/*biosynthesis
MH  - Hypoxanthine
MH  - Hypoxanthines/metabolism
MH  - Insulin/*metabolism
MH  - Insulin Secretion
MH  - Islets of Langerhans/drug effects/*metabolism
MH  - Kinetics
MH  - Male
MH  - Mycophenolic Acid/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Uridine Triphosphate/metabolism
PMC - PMC294926
EDAT- 1993/08/01 00:00
MHDA- 1993/08/01 00:01
PMCR- 1993/08/01
CRDT- 1993/08/01 00:00
PHST- 1993/08/01 00:00 [pubmed]
PHST- 1993/08/01 00:01 [medline]
PHST- 1993/08/01 00:00 [entrez]
PHST- 1993/08/01 00:00 [pmc-release]
AID - 10.1172/JCI116662 [doi]
PST - ppublish
SO  - J Clin Invest. 1993 Aug;92(2):872-82. doi: 10.1172/JCI116662.