The document summarizes research findings from multiple studies conducted by Dr. PM Piatti and colleagues on the relationship between endothelin-1, insulin, triglycerides, and endothelial function. Several key findings are reported: 1) Subjects with metabolic syndrome showed higher endothelin-1 levels than normal subjects, which could be reproduced in normal subjects by increasing insulin and triglyceride levels simultaneously. 2) Low-dose heparin infusion decreased endothelin-1 levels in humans by increasing nitric oxide, an effect reversed by insulin. 3) Glycosylated hemoglobin and triglycerides were independently correlated with endothelin-1 levels in patients with insulin resistance syndrome. 4) Asymmetric dimethylarginine levels were increased in patients

1. Research Findings
Dr. PM PiattiDr. PM Piatti
Scientific InstituteScientific Institute
San RaffaeleSan Raffaele
MilanoMilano

2. PIATTI PM, MONTI LD, CONTI M,
BARUFFALDI L, GALLI L, PHAN VC,
GUAZZINI B, PONTIROLI AE, POZZA
G
Hypertriglyceridemia and
hyperinsulinemia are potent inducers of
endothelin-1 release in man.
Diabetes, 45:316-321, 1996.

3. The purpose of the study was to evaluate
fasting endothelin-1 levels in subjects with
syndrome X, in subjects with insulinoma,
and in normal subjects.
The single and synergistic contributions of
insulin and triglyceride levels to
endothelin-1 release were studied in
normal subjects.
Piatti et al Diabetes 1996; 45: 316-321

4. Subjects with metabolic syndrome X
showed higher endothelin-1 levels than
normal subjects and subjects with
insulinoma.
These levels were reproduced in normal
subjects by a simultaneous increase in
insulin and triglyceride levels.
Piatti et al Diabetes 1996; 45: 316-321

5. PIATTI PM, MONTI LD, VALSECCHI
G, CONTI M, NASSER R, GUAZZINI
B, FOCHESATO E, PHAN VC,
PONTIROLI AE, POZZA G
Effects of low dose heparin infusion on
arterial endothelin-1 release in man.
Circulation, 94:2703-2707, 1996.

6. The aim of this study was to evaluate the
effect of low-dose heparin infusion on
arterialized endothelin-1 (ET-1) release
in the presence of fasting or high insulin
levels in healthy humans.
Piatti et al Circulation 1996; 94:2703-07

7. Piatti et al Circulation 1996; 94:2703-07
The present study showed that it is
possible to decrease ET-1 levels by use of
low-dose heparin infusion in humans. This
effect seems mediated by a simultaneous
increase in nitric oxide levels and is
completely reversed by a mild increase in
insulin concentrations.

8. PIATTI PM, MONTI LD, GALLI L,
FRAGASSO G, VALSECCHI G,
PONTIROLI AE
Relationship between endothelin-1
concentrations and the metabolic
alterations typical of the Insulin
Resistance Syndrome.
Metabolism 49:748-752, 2000

9. The purpose of the study was to examine the
relationship between the endothelin-1 (ET-1)
concentration and the metabolic variables
characteristic of the insulin resistance syndrome
([IRS] hyperinsulinemia, insulin resistance,
hypertriglyceridemia, low high-density
lipoprotein [HDL] cholesterol, visceral obesity,
and glycemic abnormalities). The measurement
of circulating ET-1 is a well-recognized marker
of endothelial atherosclerotic and cardiovascular
disease.
Piatti et al. Metabolism 2000, 49:748-52

10. Piatti et al. Metabolism 2000, 49:748-52
At simple regression analysis, ET-1 levels
significantly correlated with insulin, glycosylated
hemoglobin, body weight, waist to hip ratio, and
triglyceride values. At multiple regression
analysis, only triglycerides (p<0.009) and
glycosylated hemoglobin (p<0.001) remained
independently correlated with ET-1.
This cross-sectional study indicates that
glycosylated hemoglobin and triglycerides are
independently correlated with ET-1 levels in
patients with IRS.

11. PIATTI PM, MONTI LD, ZAVARONI
I, VALSECCHI G, SOLERTE SB,
POZZA G, PONTIROLI AE, REAVEN
G
Alterations in Nitric Oxide/Cyclic-GMP
Pathway in Non Diabetic Siblings of
Patients with type 2 Diabetes
J Clin Endocrinol Metab 85:2416-2420,
2000

12. In this study, we have compared
resistance to insulin-mediated glucose
disposal and plasma concentrations of
nitric oxide (NO) and cyclic-GMP in
healthy volunteers with or without at
least one sibling and one parent with
type 2 diabetes.
Piatti et al. JCEM 2000, 85:2416-2420

13. Piatti et al. JCEM 2000, 85:2416-2420
We demonstrated that alterations of
the NO/cyclic-GMP pathway seem to
be an early event in nondiabetic
individuals with a family history of
type 2 diabetes and these changes are
correlated with the degree of insulin
resistance.

14. PIATTI PM, MONTI LD,
VALSECCHI G, MAGNI F, SETOLA
E, MARCHESI F, GALLI-KIENLE M,
POZZA G, ALBERTI KGMM
Long-term oral L-arginine
administration improves peripheral
and hepatic insulin sensitivity in type 2
diabetic patients.
Diabetes Care 24: 875-880, 2001

15. Piatti et al. Diabetes Care 2001, 24:875-880
The aim of this study was to evaluate
whether long-term administration of
arginine acting through a normalization
of NO/cyclic-guanosine-3' 5'-cyclic
monophosphate (cGMP) pathway was
able to ameliorate peripheral and
hepatic insulin sensitivity in 12 lean type
2 diabetic patients.

16. Piatti et al. Diabetes Care 2001, 24:875-880
We found that, in lean type 2 diabetic
patients, treated with diet alone, L-
Arginine treatment significantly
improved peripheral and hepatic
insulin sensitivity.

17. FRAGASSO G, PIATTI PM, MONTI LD,
CHUNZENG L, VALSECCHI G, SETOLA
E, PALLOSHI A, POZZA G,
MARGONATO A, CHIERCHIA S
Acute effects of heparin administration on
the ischemic threshold of patients with
coronary artery disease: Evaluation of the
protective role of the metabolic modulator
trimetazidine.
J.Am.Coll.Cardiol. 39:413-419, 2002

18. Fragasso, Piatti et al. J Am Coll Cardiol 2002, 39:413-419
We sought to assess the effects of heparin
and the potential protective effects of
trimetazidine (TMZ) on exercise
performance, plasma nitric oxide (NO),
endothelin-1 (ET-1) and free fatty acid
(FFA) release in patients with stable
coronary artery disease (CAD).

19. Fragasso, Piatti et al. J Am Coll Cardiol 2002, 39:413-419
In patients with CAD, heparin reduces the
ischemic threshold. Trimetazidine reduces the
effects of heparin, probably by inhibiting FFA
oxidation and enhancing glucose metabolism.
The concomitant novel observation of reduced
ET-1 release is likely to be also dependent on
TMZ-induced improvement of endothelial
metabolism or reduction of myocardial
ischemia.

20. MONTI LD, ALLIBARDI S, PIATTI PM,
VALSECCHI G, COSTA S, POZZA G,
CHIERCHIA S, SAMAJA M
Triglycerides impair post-ischemic recovery
in isolated hearts: roles of endothelin-1 and
trimetazidine.
Am J Physiol Heart Circ Physiol 281:H1122-
30, 2001

21. Monti, Piatti et al. Am J Physiol Heart Circ Physiol 2001:281:H1122-30
There is growing evidence that
hypertriglyceridemia exacerbates
ischemic injury. We tested the
hypothesis that triglycerides impair
myocardial recovery from low-flow
ischemia in an ex vivo model and that
such an effect is related to endothelin-1.

22. Monti, Piatti et al. Am J Physiol Heart Circ Physiol 2001:281:H1122-30
We conclude that high triglyceride
levels impair myocardial recovery
after low-flow ischemia in association
with endothelin-1 release. The
endothelium-mediated effect of
triglycerides on both contractile
recovery and endothelin-1 release is
prevented by 1 microM trimetazidine.

23. PIATTI PM, FRAGASSO G, MONTI LD,
CAUMO A, PHAN CV, VALSECCHI G,
COSTA S, FOCHESATO E, POZZA G,
PONTIROLI AE, CHIERCHIA S
Endothelial and metabolic characteristics of
patients with angina and angiographically
normal coronary arteries. Comparison with
subjects with insulin resistance syndrome
and normal controls.
J.Am.Coll.Cardiol. 34:1452-1460, 1999

24. This study was performed to
characterize the endothelial and
metabolic alterations of patients with
angina and angiographically normal
coronary arteries ("cardiac" syndrome
X [CSX]) compared with subjects with
insulin resistance syndrome
("metabolic" syndrome X [MSX]) and
normal controls.
Piatti et al. J Am Coll Cardiol 1999, 34:1452-60

25. Piatti et al. J Am Coll Cardiol 1999, 34:1452-60
We observed that blunted nitric oxide
and endothelin responsiveness to
intravenously infused insulin is a typical
feature of patients with angina pectoris
and angiographically normal coronary
arteries and may contribute to the
microvascular dysfunction observed in
these subjects.

26. PIATTI PM, FRAGASSO G, MONTI LD,
SETOLA E, LUCOTTI P, FERMO I, PARONI
R, GALLUCCIO E, POZZA G, CHIERCHIA
S, MARGONATO A
Acute Intravenous L-Arginine Infusion
Decreases Endothelin-1 Levels and Improves
Endothelial Function in Patients with Angina
Pectoris and Normal Coronary Arteriograms:
Correlation with ADMA Levels.
Circulation 2003:107:429-36.

27. We tested the hypothesis that
asymmetric dimethylarginine (ADMA)
levels could be elevated and influence
endothelin-1 and nitric oxide release
and action in patients with cardiac
syndrome X (CSX). In addition, we
evaluated whether an intravenous
infusion of L-arginine would improve
endothelial function in these subjects.
Piatti et al. Circulation 2003, 107:429-36

28. We demonstrated that ADMA levels are
increased in patients with CSX and positively
correlated with basal endothelin-1 levels and
negatively with insulin-induced incremental
levels of NOx.
An increment in nitric oxide availability by an
acute L-arginine infusion, decreases endothelin-
1 levels and therefore, improves endothelial
function in patients with CSX.
These data suggest that increased ADMA levels
play a role in the abnormal vascular reactivity
that is observed in patients with CSX.