Introduction
Methods
Participants
Characteristic | Discordant monozygotic twin study | Non-diabetic twin study | ||
---|---|---|---|---|
Diabetic twins | Non-diabetic co-twins |
p value | ||
n (female/male) | 11 (6/5) | 11 (6/5) | 164 (76/88) | |
n (NGT/IGT/T2D) | 11 (0/0/11) | 11 (2/9/0) | — | |
Zygosity (MZ/DZ) | — | — | 90/74 | |
Age (years) | 68 ± 8 | 68 ± 8 | 42.9 ± 17.1 | |
Birthweight (g) | — | — | 2,671 ± 468 | |
BMI (kg/m2) | 32.5 ± 6.7 | 30.4 ± 6.5 | 0.04 | 25.3 ± 4 |
Fasting glucose (mmol/l) | 10.6 ± 2.1 | 6.3 ± 0.5 | <0.001 | 5.4 ± 0.7 |
Glu120 (mmol/l) | 19.5 ± 3.5 | 9.0 ± 1.7 | <0.0001 | 6.5 ± 1.7 |
GIR (mg m−2 min−1)a
| 153.8 ± 63.2 | 288.1 ± 175.4 | 0.05 | — |
HbA1c (%)b
| 7.7 ± 1.5 | 5.9 ± 0.5 | <0.003 | — |
HbA1c (mmol/mol) | 61 ± 16.4 | 41 ± 5.5 | — | |
Total fat (%) | — | — | 24.7 ± 9 | |
R
d (mg kgFFM
−1 min−1) | — | — | 10.9 ± 3.4 | |
\( \overset{\cdot }{V}{\mathrm{O}}_{2 \max } \) (ml kg−2 min−1) | — | — | 33.9 ± 10.1 |
Clinical examination
LNA arrays
Familiar relationships and target analysis
Statistical methods
Human myocytes
Rat protocol
L6 cells
Gene expression
Protein levels
Results
Differentially expressed miRNAs in MZ twins discordant for type 2 diabetes
miRNA | Family | C | FC |
p
|
p
(FDR)
|
r
Glu120
|
p-r
Glu120
|
\( {r}_{{\mathrm{HbA}}_{1\mathrm{c}}} \)
|
p-
\( {r}_{{\mathrm{HbA}}_{1\mathrm{c}}} \)
|
---|---|---|---|---|---|---|---|---|---|
hsa-miR-15b | miR-15 | a | −2.0 | 2.4 × 10−8
| 8.0 × 10−6
| −0.64 | 0.04 | −0.77 | 0.01 |
hsa-miR-16 | miR-15 | a | −1.7 | 5.7 × 10−6
| 9.4 × 10−4
| −0.41 | 0.21 | −0.63 | 0.05 |
hsa-miR-17 | miR-17 | b | −1.7 | 7.3 × 10−5
| 0.007 | −0.53 | 0.1 | −0.66 | 0.04 |
hsa-miR-451 | −1.8 | 9.0 × 10−5
| 0.007 | −0.55 | 0.08 | −0.76 | 0.01 | ||
hsa-miR-106b | miR-17 | c | −1.5 | 2.2 × 10−4
| 0.01 | −0.57 | 0.07 | −0.64 | 0.05 |
hsa-miR-103 | miR-103 | −1.5 | 5.3 × 10−4
| 0.03 | −0.4 | 0.1 | −0.67 | 0.03 | |
hsa-miR-425 | −1.6 | 6.2 × 10−4
| 0.03 | −0.52 | 0.22 | −0.52 | 0.12 | ||
hsa-miR-106a | miR-17 | d | −1.7 | 8.9 × 10−4
| 0.04 | −0.52 | 0.1 | −0.67 | 0.03 |
hsa-miR-10b | −1.5 | 1.0 × 10−3
| 0.04 | 0.1 | 0.77 | −0.1 | 0.77 | ||
hsa-miR-25 | miR-25 | c | −1.7 | 1.3 × 10−3
| 0.04 | −0.4 | 0.11 | −0.64 | 0.05 |
hsa-miR-93 | miR-17 | c | −1.5 | 1.5 × 10−3
| 0.04 | −0.51 | 0.23 | −0.55 | 0.1 |
hsa-miR-363 | d | −1.7 | 1.6 × 10−3
| 0.04 | −0.43 | 0.19 | −0.76 | 0.01 | |
hsa-miR-107 | miR-103 | −1.6 | 1.8 × 10−3
| 0.05 | −0.56 | 0.07 | −0.57 | 0.08 | |
hsa-miR-191 | −1.4 | 1.9 × 10−3
| 0.05 | −0.56 | 0.07 | −0.56 | 0.09 | ||
hsa-miR-30e* | −1.6 | 2.2 × 10−3
| 0.05 | −0.2 | 0.56 | −0.1 | 0.78 | ||
hsa-let-7i | −1.4 | 3.2 × 10−3
| 0.07 | −0.25 | 0.46 | −0.37 | 0.3 | ||
hsa-miR-20a | miR-17 | b | −1.7 | 3.4 × 10−3
| 0.07 | −0.41 | 0.2 | −0.52 | 0.12 |
hsa-miR-223 | −1.6 | 4.1 × 10−3
| 0.08 | −0.55 | 0.08 | −0.65 | 0.04 | ||
hsa-miR-92a | miR-25 | bd | −1.4 | 4.9 × 10−3
| 0.09 | −0.54 | 0.04 | −0.59 | 0.08 |
hsa-miR-20b | miR-17 | d | −1.5 | 5.6 × 10−3
| 0.09 | −0.39 | 0.21 | −0.61 | 0.06 |
The diabetes-dysregulated miR-15 family is involved in insulin signalling
Ingenuity canonical pathways |
p
(FDR)
|
---|---|
INSR signalling | 0.0039 |
AMPK signalling | 0.0045 |
PPARα/RXRα activation | 0.0045 |
TGF-β signalling | 0.0068 |
Wnt/β-catenin signalling | 0.0126 |
IGF-1 signalling | 0.0126 |
Molecular mechanisms of cancer | 0.0126 |
mTOR signalling | 0.0126 |
EIF2 signalling | 0.0126 |
PI3K/Akt signalling | 0.0126 |
BMP signalling pathway | 0.0155 |
14-3-3-mediated signalling | 0.0158 |
PTEN signalling | 0.0245 |
Protein ubiquitination pathway | 0.0339 |
Cell cycle regulation by BTG family proteins | 0.0339 |
Axonal guidance signalling | 0.0339 |
Ceramide signalling | 0.0339 |
Mitotic roles of polo-like kinase | 0.0355 |
Myc-mediated apoptosis signalling | 0.0417 |
Cell cycle: G1/S checkpoint regulation | 0.0417 |
miR-15b and miR-16 regulate protein levels of insulin signalling molecules
Target | Effect | CI 95% | Change |
p
|
---|---|---|---|---|
INSR protein | ||||
miR-15b | 0.91 | (0.86, 0.97) | 9%↓ | 0.004 |
miR-16 | 0.93 | (0.86, 1.00) | 7%↓ | 0.06 |
INSR mRNA | ||||
miR-15b | 0.94 | (0.87, 1.02) | 0.1 | |
miR-16 | 1.00 | (0.92, 1.09) | 1.0 | |
IRS-1 protein | ||||
miR-15b | 0.82 | (0.75, 0.88) | 18%↓ | <0.0001 |
miR-16 | 0.95 | (0.87, 1.03) | 0.2 | |
IRS-1 mRNA | ||||
miR-15b | 0.92 | (0.86, 0.99) | 8%↓ | 0.03 |
miR-16 | 0.95 | (0.88, 1.02) | 0.2 | |
PIK3R1 protein | ||||
miR-15b | 0.97 | (0.93, 1.02) | 0.2 | |
miR-16 | 1.04 | (1.00, 1.08) | 4%↑ | 0.07 |
PIK3R1 mRNA | ||||
miR-15b | 0.92 | (0.85, 1.01) | 8%↓ | 0.07 |
miR-16 | 0.98 | (0.90, 1.07) | 0.6 |
Effects of high glucose and insulin levels on miRNA expressions in cell culture
Implications for intrauterine-dependent regulation of the miR-15 family
Effect | 95% CI | Change |
p
| |
---|---|---|---|---|
miR-15b | ||||
Age | 0.97 | (0.72, 1.28) | 0.8 | |
Sex | 0.81 | (0.62, 1.05) | 0.1 | |
\( \dot{V}{\mathrm{O}}_{2 \max } \)
| 0.99 | (0.88, 1.11) | 0.9 | |
Birthweight | 0.87 | (0.79, 0.96) | 13%↓ | 0.005 |
Total fat percentage | 1.11 | (0.93, 1.34) | 0.3 | |
miR-16 | ||||
Age | 1.28 | (0.99, 1.64) | 0.06 | |
Sex | 1.06 | (0.83, 1.35) | 0.6 | |
\( \dot{V}{\mathrm{O}}_{2 \max } \)
| 1.08 | (0.97, 1.19) | 0.2 | |
Birthweight | 0.87 | (0.80, 0.95) | 13%↓ | 0.002 |
Total fat percentage | 1.27 | (1.08, 1.48) | 27%↑ | 0.003 |