The primary objective of this study is to determine whether glucagon-mediated activation of the calcineurin-pathway is associated with LVH in severely insulin-resistant diabetic subjects.
ID
Source
Brief title
Condition
- Myocardial disorders
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint of this investigation will be a significant (P < 0.05)
difference in glucagon levels and calcineurin activation between the two groups
(LVH vs. no LVH).
Secondary outcome
Secondary endpoint will be a significant (P < 0.05) difference in NT-proBNP and
galectin-3 levels between the two groups (left ventricular hypertrophy vs. no
left ventricular hypertrophy).
Background summary
Diabetes mellitus is a complex, multifactorial syndrome characterized by
defective insulin secretion and insulin resistance. Fasting and postprandial
hyperglycemia are the result of dysregulated hepatic glucose production and
reduced glucose uptake, which is generally attributed to reduced activity of
insulin.
Wang et al. recently demonstrated that glucagon promotes CRTC2
dephosphorylation during fasting by triggering increases in cytoplasmatic
calcium via phosphorylation of the inositol-1,4,5-triphosphate receptors
(InsP3Rs) that lead to calcineurin activation and consequently an increase in
gluconeogenic gene expression. They found that, in diabetes, InsP3Rs and
calcineurin activity was increased, leading to upregulation of the
gluconeogenic programme. Knockdown of either calcineurin or InsP3Rs in db/db
mice reduced gluconeogenetic gene expression and hepatic gluconeogenesis.(1)
This suggests that agents that can selectively block the activity of the
InsP3Rs and calcineurin might lower CRTC2 dephosphorylation and hepatic
gluconeogenesis in diabetic subjects.
Interestingly, besides its involvement in diabetes, increased calcineurin
activity is also associated with induction of LVH.(2) In this study, we aim to
investigate whether glucagon-mediated activation of calcineurin is associated
with LVH in severely insulin-resistant diabetic subjects.
Study objective
The primary objective of this study is to determine whether glucagon-mediated
activation of the calcineurin-pathway is associated with LVH in severely
insulin-resistant diabetic subjects.
Study design
Prospective single-center case-control proof of principle study.
Study burden and risks
Echocardiography: no risk and low burden
MRI of the heart: Side-effects of gadolinium contrast are very rare (0.066% in
all investigations with gadolinium) but can cause headache, nausea, rash and
pruritus. In severe cases, an allergic reaction or shock is seen. MRI of the
heart has a low burden.
Blood drawing: low risk and low burden
Participating in this trial encompasses no burden or risk associated with being
either in the LVH or no LVH group.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
1. Patient is * 18 years-old.
2. Insulin-resistance requiring insulin injection of more than 1,5 IU/kg/day
3. Written informed consent to participate in this study prior to any study procedures
Exclusion criteria
1. Any (known) cardiac history
2. Patients treated with any dose of glucagon-lowering medication as DPP-4 inhibitors (Saxagliptin, Sitagliptin and Vildagliptin) and incretin-mimetics (Exenatide and Liraglutide).
3. Patients treated with immunosuppressive medication as cyclosporine A, tacrolimus or pimecrolimus.
4. Patients with current uncontrolled hypertension or uncontrolled hypertension in the past two years (Office measurement of systolic blood pressure >165 mmHg or office diastolic blood pressure >105 mmHg at any moment in the past two years)
5. Presence of any cardiac abnormalities on study-related echocardiographic examination (clinically relevant valvular disease, severe congenital abnormalities, asymmetric hypertrophy with one wall exceeding 15mm while other areas are below 10mm thickness, dilated cardiomyopathies)
6. Patients with contraindications for MRI or gadolinium contrast (claustrophobia, implanted electronic devices, creatinine > 200 µmol/L determined within 3 months prior to inclusion, proven gadolinium contrast allergy)
7. Presence of a glucagonoma
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL41800.018.12 |