PMID- 24666736
OWN - NLM
STAT- MEDLINE
DCOM- 20140908
LR  - 20211021
IS  - 2050-6511 (Electronic)
IS  - 2050-6511 (Linking)
VI  - 15
DP  - 2014 Mar 25
TI  - CNX-011-67, a novel GPR40 agonist, enhances glucose responsiveness, insulin 
      secretion and islet insulin content in n-STZ rats and in islets from type 2 
      diabetic patients.
PG  - 19
LID - 10.1186/2050-6511-15-19 [doi]
AB  - BACKGROUND: GPR40 is a G-protein coupled receptor regulating free fatty acid 
      induced and also glucose induced insulin secretion. We generated 
      neonatally-streptozotocin-treated female rats (n-STZ) and treated them with 
      CNX-011-67, a GPR40 agonist to examine the role of GPR40 in modulation of glucose 
      metabolism, insulin secretion and content. METHODS: Female n-STZ animals were 
      orally administered with CNX-011-67 (15 mg/kg body weight, twice daily) or with 
      vehicle for 8 weeks (n = 8 per group). Glucose tolerance in treated animals and 
      insulin secretion, islet insulin content and gene expression in isolated islets 
      were determined. Islets from type 2 diabetic mellitus (T2DM) patients were 
      treated with different concentrations of glucose in presence or absence of 
      CNX-011-67 and insulin secretion was measured. RESULTS: Treatment of n-STZ rats 
      with GPR40 agonist CNX-011-67 enhanced insulin secretion in response to oral 
      glucose load on day 0 and this response persisted during the treatment period. 
      The treatment also produced a 'memory effect' during which insulin secretion in 
      response to oral glucose load remained enhanced, for a week, even in absence of 
      the agonist. Activation of GPR40 enhanced responsiveness of islets to glucose and 
      increased glucose induced insulin secretion and islet insulin content. An 
      increase in islet mRNA expression of GCK, PDX1, insulin and PC was also observed. 
      Acute treatment of islets from n-STZ rats with GPR40 agonist enhanced cellular 
      ATP content. Activation of GPR40 enhanced mitochondrial calcium level in NIT-1 
      insulinoma cells. CNX-011-67 increased insulin secretion in islets from T2DM 
      patients which were non-responsive to increased glucose concentration 
      CONCLUSIONS: Our data provide evidence that activation of GPR40 with CNX-011-67 
      stimulates glucose metabolism, enhances glucose responsiveness, increases insulin 
      secretion and content and that pharmacological activation of GPR40 will prove 
      beneficial for treatment of T2DM.
FAU - Sunil, Venkategowda
AU  - Sunil V
FAU - Verma, Mahesh Kumar
AU  - Verma MK
FAU - Oommen, Anup M
AU  - Oommen AM
FAU - Sadasivuni, Manojkumar
AU  - Sadasivuni M
FAU - Singh, Jaideep
AU  - Singh J
FAU - Vijayraghav, Dasarahalli N
AU  - Vijayraghav DN
FAU - Chandravanshi, Bhawna
AU  - Chandravanshi B
FAU - Shetty, Jayalaxmi
AU  - Shetty J
FAU - Biswas, Sanghamitra
AU  - Biswas S
FAU - Dandu, Anilkumar
AU  - Dandu A
FAU - Moolemath, Yoganand
AU  - Moolemath Y
FAU - Venkataranganna, Marikunte V
AU  - Venkataranganna MV
FAU - Somesh, Baggavalli P
AU  - Somesh BP
FAU - Jagannath, Madanahalli R
AU  - Jagannath MR
AD  - Connexios Life Sciences Pvt Ltd, #49, "SHILPA VIDYA" 1st Main, 3rd Phase, JP 
      Nagar, Bangalore 560078, India. m.r.jagannath@connexios.com.
LA  - eng
PT  - Journal Article
DEP - 20140325
PL  - England
TA  - BMC Pharmacol Toxicol
JT  - BMC pharmacology & toxicology
JID - 101590449
RN  - 0 (FFAR1 protein, human)
RN  - 0 (G-protein-coupled receptor 40, rat)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - IY9XDZ35W2 (Glucose)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Calcium/metabolism
MH  - Cell Line
MH  - Diabetes Mellitus, Experimental/*metabolism
MH  - Diabetes Mellitus, Type 2/*metabolism
MH  - Female
MH  - Glucose/metabolism
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology
MH  - Insulin/metabolism
MH  - Insulin Secretion
MH  - Insulin-Secreting Cells/drug effects/metabolism
MH  - Islets of Langerhans/drug effects/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, G-Protein-Coupled/*agonists
PMC - PMC3994293
EDAT- 2014/03/29 06:00
MHDA- 2014/09/10 06:00
PMCR- 2014/03/25
CRDT- 2014/03/27 06:00
PHST- 2014/01/09 00:00 [received]
PHST- 2014/03/19 00:00 [accepted]
PHST- 2014/03/27 06:00 [entrez]
PHST- 2014/03/29 06:00 [pubmed]
PHST- 2014/09/10 06:00 [medline]
PHST- 2014/03/25 00:00 [pmc-release]
AID - 2050-6511-15-19 [pii]
AID - 10.1186/2050-6511-15-19 [doi]
PST - epublish
SO  - BMC Pharmacol Toxicol. 2014 Mar 25;15:19. doi: 10.1186/2050-6511-15-19.