Despite various efficient pharmaceuticals which are already used to manage diabetes, new drugs are needed to preserve and restore the function of pancreatic β-cells (pβCs) including cell-specific gene expression and insulin production and secretion. Newly developed small molecules (SMs) with potential anti-diabetic activity need to be preliminarily tested. Mice insulinoma MIN6 cells can be utilized as an in vitro screening model. These cells have pβC characteristics and can secrete insulin in response to glucose level changes. As well, the β-cell-specific gene expression pattern of these cells is similar to that of mouse pancreatic islet cells. It is possible to use this cell line as a research tool to study the function of pβCs. To date, approximately 60 genes have been identified which are effective in the pβC embryonic development and insulin production and secretion during puberty, including pancreas/duodenum homeobox protein 1 (Pdx1), neuronal differentiation 1 (Neurod1), neurogenin3 (Ngn3), and insulin-1 precursor (Ins1). In this study, a family of new SMs that are structurally similar to glinides was synthesized through 3 different synthetic methods and categorized into 3 categories (C1–C3). Then, these novel SMs were characterized by testing their effects on cell viability, pβC-specific gene expression, and insulin secretion in MIN6 in 4 different concentrations and at 3 time points (24, 48, and 72 h). According to our results, SMs of C1 (1j, 1k, and 1l) and 2 SMs of C3 (1f, 1i), at 200 μM concentration, were able to increase the expression levels of Pdx1, Neurod1, Ngn3, and Ins1 as well as the insulin secretion after 24 h. However, C2 (1a, 1b, 1c, and 1d) did not show significant bioactivity of MIN6 cells. These investigated molecules can provide a tool for exploring pseudo-islet functionality in MIN6 cells or provide a possible basis for future therapeutic interventions for diabetes.

1.
Ball
AJ
,
McCluskey
JT
,
Flatt
PR
,
McClenaghan
NH
.
Chronic exposure to tolbutamide and glibenclamide impairs insulin secretion but not transcription of K(ATP) channel components
.
Pharmacol Res
.
2004
;
50
(
1
):
41
6
.
2.
Bastidas-Ponce
A
,
Roscioni
SS
,
Burtscher
I
,
Bader
E
,
Sterr
M
,
Bakhti
M
,
.
Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells
.
Mol Metab
.
2017
;
6
(
6
):
524
34
.
3.
Cai
J
,
Yu
C
,
Liu
Y
,
Chen
S
,
Guo
Y
,
Yong
J
,
.
Generation of homogeneous PDX1+ pancreatic progenitors from human ES cell-derived endoderm cells
.
J Mol Cell Biol
.
2010
;
2
(
1
):
50
60
.
4.
Cerasi
EJQ
.
Insulin secretion: mechanism of the stimulation by glucose
.
Q Rev Biophys
.
1975
;
8
(
1
):
1
41
.
5.
Chen
C
,
Cohrs
CM
,
Stertmann
J
,
Bozsak
R
,
Speier
S
.
Human beta cell mass and function in diabetes: recent advances in knowledge and technologies to understand disease pathogenesis
.
Mol Metab
.
2017
;
6
(
9
):
943
57
.
6.
Desgraz
R
,
Bonal
C
,
Herrera
PL
.
.
β-cell regeneration: the pancreatic intrinsic faculty
.
Trends Endocrinol Metab
.
2011
;
22
(
1
):
34
43
.
7.
Dioum
EM
,
Osborne
JK
,
Goetsch
S
,
Russell
J
,
Schneider
JW
,
Cobb
MH
.
A small molecule differentiation inducer increases insulin production by pancreatic β cells
.
Proc Natl Acad Sci U S A
.
2011
;
108
(
51
):
20713
8
.
8.
Farhadi
A
,
Vosough
M
,
Zhang
J-S
,
Tahamtani
Y
,
Shahpasand
K
.
A possible neurodegeneration mechanism triggered by diabetes
.
Trends Endocrinol Metab
.
2019
;
30
(
10
):
692
700
.
9.
Fu
Z
,
Gilbert
ER
,
Liu
D
.
Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes
.
Curr Diabetes Rev
.
2013
;
9
(
1
):
25
53
.
10.
Hohmeier
HE
,
Zhang
L
,
Taylor
B
,
Stephens
S
,
Lu
D
,
McNamara
P
,
.
Identification of a small molecule that stimulates human β-cell proliferation and insulin secretion, and protects against cytotoxic stress in rat insulinoma cells
.
PLoS One
.
2020
;
15
(
3
):
e0224344
.
11.
Kasabri
V
,
Abu-Dahab
R
,
Afifi
FU
,
Naffa
R
,
Majdalawi
L
.
Modulation of pancreatic MIN6 insulin secretion and proliferation and extrapancreatic glucose absorption with Achillea santolina, Eryngium creticum and Pistacia atlantica extracts: in vitro evaluation
.
J Exp Integr Med
.
2012
;
2
(
3
):
245
54
.
12.
Kerru
N
,
Singh-Pillay
A
,
Awolade
P
,
Singh
P
.
Current anti-diabetic agents and their molecular targets: A review
.
Eur J Med Chem
.
2018
;
152
:
436
88
.
13.
Kondo
Y
,
Toyoda
T
,
Ito
R
,
Funato
M
,
Hosokawa
Y
,
Matsui
S
,
.
Identification of a small molecule that facilitates the differentiation of human iPSCs/ESCs and mouse embryonic pancreatic explants into pancreatic endocrine cells
.
Diabetologia
.
2017
;
60
(
8
):
1454
66
.
14.
Kunisada
Y
,
Tsubooka-Yamazoe
N
,
Shoji
M
,
Hosoya
M
.
Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells
.
Stem Cell Res
.
2012
;
8
(
2
):
274
84
.
15.
Lee
M
,
Maji
B
,
Manna
D
,
Kahraman
S
,
Elgamal
RM
,
Small
J
,
.
Native zinc catalyzes selective and traceless release of small molecules in β-cells
.
J Am Chem Soc
.
2020
;
142
(
14
):
6477
82
.
16.
Lenci
E
,
Trabocchi
A
.
Synthetic Approaches toward Small Molecule Libraries
. In:
Trabocchi
A
,
Lenci
E
, editors. Small Molecule Drug Discovery.
Elsevier
;
2020
. p.
1
34
.
17.
Leslie
RD
,
Palmer
J
,
Schloot
NC
,
Lernmark
A
.
Diabetes at the crossroads: relevance of disease classification to pathophysiology and treatment
.
Diabetologia
.
2016
;
59
(
1
):
13
20
.
18.
Li
X
,
Wang
X
,
Snyder
M
.
Systematic investigation of protein-small molecule interactions
.
IUBMB Life
.
2013
;
65
(
1
):
2
8
.
19.
Lo
KW
,
Ashe
KM
,
Kan
HM
,
Laurencin
CT
.
The role of small molecules in musculoskeletal regeneration
.
Regen Med
.
2012
;
7
(
4
):
535
49
.
20.
Ma
X
,
Zhu
S
.
Chemical strategies for pancreatic β cell differentiation, reprogramming, and regeneration
.
Acta Biochim Biophys Sin (Shanghai)
.
2017
;
49
(
4
):
289
301
.
21.
Makurvet
FD
.
Biologics vs. small molecules: drug costs and patient access
.
Medicine in Drug Discovery
.
2021
;
9
:
100075
.
22.
Migliorini
A
,
Bader
E
,
Lickert
H
.
Islet cell plasticity and regeneration
.
Mol Metab
.
2014
;
3
(
3
):
268
74
.
23.
Miyazaki
J
,
Araki
K
,
Yamato
E
,
Ikegami
H
,
Asano
T
,
Shibasaki
Y
,
.
Establishment of a pancreatic β cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms
.
Endocrinology
.
1990
;
127
(
1
):
126
32
.
24.
Muoio
DM
,
Newgard
CB
.
Mechanisms of disease: Molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes
.
Nat Rev Mol Cell Biol
.
2008
;
9
(
3
):
193
205
.
25.
Nolan
CJ
,
Prentki
M
.
Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: time for a conceptual framework shift
.
Diab Vasc Dis Res
.
2019
;
16
(
2
):
118
27
.
26.
Pagliuca
FW
,
Melton
DA
.
How to make a functional β-cell
.
Development
.
2013
;
140
(
12
):
2472
83
.
27.
Pagliuca
FW
,
Millman
JR
,
Gürtler
M
,
Segel
M
,
Van Dervort
A
,
Ryu
JH
,
.
Generation of functional human pancreatic β cells in vitro
.
2014
;
159
(
2
):
428
39
.
28.
Ramezanpour
S
,
Panahi
A
,
Rominger
F
.
Diastereoselective synthesis of peptidomimetics in one-pot Ugi reaction using trans-4-isopropylcyclohexanecarboxylic acid
.
Monatsh Chem
.
2018
;
149
:
625
33
.
29.
Romer
AI
,
Sussel
L
.
Pancreatic islet cell development and regeneration
.
Curr Opin Endocrinol Diabetes Obes
.
2015
;
22
(
4
):
255
64
.
30.
Saberzadeh-Ardestani
B
,
Karamzadeh
R
,
Basiri
M
,
Hajizadeh-Saffar
E
,
Farhadi
A
,
Shapiro
AJ
,
.
Type 1 diabetes mellitus: cellular and molecular pathophysiology at a glance
.
Cell J
.
2018
;
20
(
3
):
294
301
.
31.
Salinno
C
,
Cota
P
,
Bastidas-Ponce
A
,
Tarquis-Medina
M
,
Lickert
H
,
Bakhti
M
.
β-Cell Maturation and Identity in Health and Disease
.
Int J Mol Sci
.
2019
;
20
(
21
):
5417
.
32.
Shen
W
,
Tremblay
MS
,
Deshmukh
VA
,
Wang
W
,
Filippi
CM
,
Harb
G
,
.
Small-molecule inducer of β cell proliferation identified by high-throughput screening
.
J Am Chem Soc
.
2013
;
135
(
5
):
1669
72
.
33.
Takahashi
H
,
Hidaka
S
,
Seki
C
,
Yokoi
N
,
Seino
S
.
Characteristics of repaglinide effects on insulin secretion
.
Eur J Pharmacol
.
2018
;
828
:
52
9
.
34.
Thakur
G
,
Lee
HJ
,
Jeon
RH
,
Lee
SL
,
Rho
GJ
.
Small molecule-induced pancreatic β-like cell development: mechanistic approaches and available strategies
.
Int J Mol Sci
.
2020
;
21
(
7
):
2388
.
35.
Vakilian
M
,
Tahamtani
Y
,
Ghaedi
K
.
A review on insulin trafficking and exocytosis
.
Gene
.
2019
;
706
:
52
61
.
36.
Vetere
A
,
Wagner
BK
.
Chemical methods to induce beta-cell proliferation
.
Int J Endocrinol
.
2012
;
2012
:
925143
.
37.
Wang
W
,
Walker
JR
,
Wang
X
,
Tremblay
MS
,
Lee
JW
,
Wu
X
,
.
Identification of small-molecule inducers of pancreatic β-cell expansion
.
Proc Natl Acad Sci U S A
.
2009
;
106
(
5
):
1427
32
.
38.
Yaney
GC
,
Corkey
BE
.
Fatty acid metabolism and insulin secretion in pancreatic beta cells
.
Diabetologia
.
2003
;
46
(
10
):
1297
312
.
39.
Yuan
Y
,
Hartland
K
,
Boskovic
Z
,
Wang
Y
,
Walpita
D
,
Lysy
PA
,
.
A small-molecule inducer of PDX1 expression identified by high-throughput screening
.
Chem Biol
.
2013
;
20
(
12
):
1513
22
.
40.
Zhang
D
,
Jiang
W
,
Liu
M
,
Sui
X
,
Yin
X
,
Chen
S
,
.
Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells
.
Cell Res
.
2009
;
19
(
4
):
429
38
.
41.
Zhong
F
,
Jiang
YJF
.
Endogenous pancreatic β cell regeneration: a potential strategy for the recovery of β cell deficiency in diabetes
.
Front Endocrinol (Lausanne)
.
2019
;
10
:
101
.
42.
Zhu
Y
,
Liu
Q
,
Zhou
Z
,
Ikeda
YJS
,
therapy. PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration
.
Stem Cell Res Ther
.
2017
;
8
(
1
):
240
.
You do not currently have access to this content.