1 Servizio Diabetologia, Dipartimento Struttura Clinica Medica e Patologia Speciale Medica, and 2 Dipartimento Scienze Biomediche Sezione di Fisiologia Umana, Universita' di Sassari, 07100 Sassari, Italy
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ABSTRACT |
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The main aim of this study was to set up a
new animal model to study insulin resistance. Wistar rats (6 or 7 per
group) received the following for 4 wk in experiment 1:
1) vehicle, 2) 2 µg/day subcutaneous
dexamethasone, 3) metformin (400 mg · kg1 · day
1 os), and
4) dexamethasone plus metformin. In experiment 2 the rats received the following: 1) vehicle, 2)
dexamethasone, 3) dexamethasone plus arginine (2%; as
substrate of the nitric oxide synthase for nitric oxide production) in
tap water, and 4) dexamethasone plus isosorbide dinitrate
(70 mg/kg; as direct nitric oxide donor) in tap water. Insulin
sensitivity was significantly reduced by dexamethasone already at
week 1, before the increase in blood pressure (day
15) and without significant changes in body weight compared with
vehicle. Dexamethasone-treated rats had significantly higher
triglycerides, hematocrit, and insulin, whereas serum total nitrates/ nitrites were lower compared with vehicle. The
concomitant treatment with metformin minimized all the described
effects of dexamethasone. In experiment 2, only
isosorbide dinitrate was able to prevent the observed
dexamethasone-induced metabolic, hemodynamic, and insulin
sensitivity changes. Chronic low-dose subcutaneous dexamethasone
(2 µg/day) is a useful model to study the relationships between
insulin resistance and blood pressure in the rat, and dexamethasone
might decrease insulin sensitivity and increase blood pressure through
an endothelium-mediated mechanism.
glucocorticoids; metabolic syndrome; metformin; hypertension
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INTRODUCTION |
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THERE IS CONSIDERABLE evidence that abnormalities of glucose, insulin, and lipoprotein metabolism occur more frequently in untreated hypertensive patients than in normotensive subjects. It could be argued that the relationship between high blood pressure and metabolic disorder is incidental, but, on the other hand, there is evidence that changes in glucose, insulin, and lipoprotein metabolism play a role in the etiopathology and/or clinical course of hypertension. In human hypertension, subtle changes in adrenal steroid metabolism have been suggested (28, 29, 36), indicating that glucocorticoids, besides the well-known Cushing syndrome, might have an important role in the development of high blood pressure. Moreover, glucocorticoids have been shown to reduce cellular glucose uptake affecting the glucose transport system per se (7), with no direct effects on the insulin receptor (26). Thus glucocorticoids alter glucose metabolism, and in turn they have a role in the development of peripheral insulin resistance. Insulin resistance may be an impetus for the development of hypertension, impaired carbohydrate tolerance, and lipid alteration, but the underlying mechanisms are still unclear. Similar metabolic abnormalities occur in rodent models of hypertension. For example, endothelial dysfunction precedes hypertension in an experimental model of fructose-induced insulin resistance (9, 24), but fructose-induced insulin resistance is not easily comparable to humans. At the best of our knowledge, there is no established model of insulin resistance induced by dexamethasone without the dramatic catabolic side effects commonly seen with glucocorticoids. We previously showed that it is possible to increase blood pressure for long term in rats with subcutaneous doses of dexamethasone on the order of micrograms per day (31) without appreciable catabolic effects. This animal model is not associated with sodium retention but with sodium shift from the intracellular to the extracellular space (12), and the effects on blood pressure are opposite to those obtained by intracerebroventricular dexamethasone administration (32). The main aim of this study was to establish if our previously described "old model" of glucocorticoid-induced hypertension in the rat is indeed a useful "new" model to study insulin resistance in the metabolic syndrome. To do so we used our previously described animal model (31) to evaluate the effects of metformin, a well-established drug able to ameliorate insulin sensibility in rats (25).
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RESEARCH DESIGN AND METHODS |
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Experiment 1
Animals. Male Wistar rats, with a weight of 400 g, were used through the experiments in groups of 6 or 7 animals each. All rats were housed in an automatically light-controlled animal facility (12 h on, 12 h off) with constant temperature (22 C°) and humidity, with free access to food (Mil mice and rats GLP Diets, Mucedola Srl, Italy) and tap water ad libitum. Two weeks before start of the experiment, animals were accustomed to handling as well as blood pressure and blood glucose measurements (by a vein puncture in the tail). Four groups were thereafter treated for 4 wk: 1) vehicle: tap water and daily subcutaneous injection of 0.9% NaCl (75 µl) at 8:00 AM and 8:00 PM; 2) dexamethasone (Dex): tap water and daily subcutaneous injections of Dex (1 µg in 75 µl 0.9% NaCl) at 8:00 AM and 8:00 PM; 3) metformin (Met): Met in tap water (3.5 mg/ml) and daily subcutaneous injection of 0.9% NaCl (75 µl) at 8:00 AM and 8:00 PM; and 4) Dex + Met: Met dissolved in tap water (3.5 mg/ml) and daily subcutaneous injection of Dex (1 µg in 75 µl 0.9% NaCl) at 8:00 AM and 8:00 PM.
Methods.
Three times a week systolic blood pressure was measured in the morning
(tail cuff method, Letica, Le 5001 pressure meter) in the conscious
lightly restrained animal after the animals were prewarmed at 38 C°
for 10 min as previously described (12, 31, 32); body
weight and tap water consumption were recorded at the same time. At
days +8, +14, and +26 after blood
pressure measurement, in the conscious rats blood from a tail vein was
obtained for glucose measurement with a reflectometer (Lifescan One
Touch Profile, Johnson-Johnson, Minneapolis, MN), immediately before
and 30 min after rats received intraperitoneal fast-acting insulin (1.6 U/kg Actrapid, Novo Nordisk). In this "insulin-tolerance test," the 1.6-U/kg dose and the 30-min values were chosen to calculate the maximum decrease in blood glucose. This method was, in our laboratory, repetitive as shown in Fig. 1, where the
effects of three different doses of intraperitoneal insulin (0, 0.8, and 1.6 U/kg) on blood glucose, over 80 min after insulin injection,
are given. The reflectometer was validated in our laboratory against an
automatic analyzer (Hitachi 912, automatic analyzer, Boehringer
Mannheim, using standard reagents) for values from 30 to 200 mg/dl
(n = 68, r2 = 0.921 P < 0.001).
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Histology. Liver and left kidney tissues after fixation in 10% buffered formalin were dehydrated with ethyl alcohol and then included in paraffin. Sections of 5 µm were obtained by a microtome (Top Rotary S-130, pabish). Periodic acid-Schiff coloration for polysaccharides has been used to evaluate glycogen content in the hepatocytes. Two independent observers not aware of the different treatments gave independent comment on the histological material.
Steady-state glucose concentration.
Steady-state glucose concentration (24) was measured to
confirm the findings of the insulin-tolerance test in the period preceding the rise in blood pressure observed in Dex-treated rats. Steady-state glucose concentration was measured in an additional four
rats after 8 days of Dex treatment alone (before any significant rise
in systolic blood pressure) or with Met following the described protocol of Reaven et al. (24). In brief, under anesthesia
with pentothal sodium (Tiopentale Sodico 0.5 g, Farmaceutici
Gellini), the right femoral vein was cannulated for insulin and glucose infusion at the fixed doses of 2.5 mU · kg1 · min
1 and 8 mg · kg
1 · min
1,
respectively, for 3 h. Tail blood samples for glycemia were taken
at 15-min intervals during the last hour of infusion, and the four
obtained values were used to find the mean.
Experiment 2
Animals and methods. To better characterize the possible endothelial involvement in the development of insulin resistance in this animal model, four additional groups of six animals each were compared in a 28-day experiment. The main reason for this second study was to evaluate if NO production (measured, as said above, as total nitrates and nitrites) was restored giving exogenously the endogenous substrate for NO production, arginine. The arginine effects were compared with those obtained by exogenous direct NO gift through a NO donor, isosorbide dinitrate.
The experimental groups were as follows: 1) vehicle: tap water and daily subcutaneous injection of 0.9% NaCl (75 µl) at 8:00 AM and 8:00 PM; 2) Dex: tap water ad libitum and daily subcutaneous injections of Dex (1 µg in 75 µl of 0.9% NaCl) at 8:00 AM and 8:00 PM; 3) Dex + arginine (Arg): daily subcutaneous injections of Dex (1 µg in 75 µl of 0.9% NaCl) at 8:00 AM and 8:00 PM and 2% Arg in tap water ad libitum; 4) Dex + isosorbide dinitrate (Isn): daily subcutaneous injections of Dex (1 µg in 75 µl of 0.9% NaCl) at 8:00 AM and 8:00 PM and 70 mg/kg Isn in tap water ad libitum. Thus, in this second experiment, Arg was given as substrate of NO synthase for the production of NO, while Isn was given as a direct NO donor to establish the role of endothelium in this animal model. Animals were studied as in experiment 1 including insulin-tolerance test evaluation. After 1 and 4 wk of treatment, immediately after blood pressure measurements, 2 ml of blood were obtained from the tail in the conscious rat for biochemistry determination and hematocrit.Statistical Analysis
Data are presented as means ± SE. After ANOVA measurements, with pairwise Newman-Keuls test for multiple comparisons, parameters found significantly different were subsequently analyzed with the paired (within groups, different times) or unpaired (between groups, same time) two-tailed Student's t-test when appropriate. P < 0.05 was taken as significant. Data were analyzed using the Sigma Stat 3.0 program.Principles of laboratory animal care [Department of Health and Human Services Publication No. (NIH) 85-23, Revised 1985] were followed in these experiments.
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RESULTS |
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Experiment 1
All rats completed the 28 days of experiments. Water consumption was equal in the groups (32-38 ml · day
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Insulin sensitivity as estimated by the 30-min drop of blood glucose after intraperitoneal fast-acting insulin was significantly reduced in Dex-treated rats compared with the other groups at days +8, +12, and +26 (Fig. 2B). Similar results were obtained when insulin sensitivity was estimated by the steady-state plasma glucose during insulin/glucose infusion. Mean steady-state glycemia during the third hour of insulin/glucose infusion was significantly higher in Dex rats compared with Dex + Met rats: 128 ± 6 vs. 84 ± 5 mg/dl (P < 0.02), while serum insulin at the end of the 3-h infusion was comparable in the two groups.
At the end of the study, no significant difference in heart, liver, and
kidney weight (corrected for body weight) was evident in the four
groups of rats. Glycogen content, determined histologically in the
hepatocytes, was reduced in Dex-treated rats compared with vehicle and
Met-treated rats. Moreover, in Dex-treated rats, an increased deposit
of lipids at the liver level was evident (Fig. 3). The addition of Met in Dex rats
partially restored the content of glycogen at the liver level,
dramatically reducing the liver lipids content. No significant
differences in the different groups of rats were evident regarding
kidney structure, although the glomerular apparatus in Dex rats
appeared bigger than in the other groups (data not shown).
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Experiment 2
All animals completed the 28 days of experiment, and water consumption was equal in the groups (30-37 ml · day
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DISCUSSION |
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In this paper we describe for the first time, to the best of our knowledge, a new animal model of glucocorticoid-induced insulin resistance possibly due to endothelial dysfunction. We previously showed that it is possible to increase blood pressure for long term in rats with subcutaneous doses of dexamethasone on the order of micrograms per day without appreciable catabolic effects and a complete inhibition of ACTH secretion (31) and without sodium retention (12). The main aim of this study was to establish if this old model of glucocorticoid-induced hypertension is a useful new model to study insulin resistance. Using our "pure glucocorticoid" model, characterized by the absence of catabolic side effects, we were able to show that dexamethasone-induced insulin resistance (increase in serum insulin concentration, decreased insulin tolerance, and higher state-state glucose concentration during exogenous insulin/glucose infusion) precedes hypertension and is accompanied by other features of the metabolic syndrome (increased serum free fatty acids, cholesterol, and triglycerides and decreased NO production as marker of endothelial dysfunction). Insulin resistance in our animal model clearly precedes the development of hypertension, and we were able to show that dexamethasone treatment reduces total nitrates/nitrites. Indeed, total nitrates/nitrites may be considered a good marker of NO synthase activity (13), suggesting an endothelial dysfunction as primun movens for the development of this dexamethasone-induced insulin resistance. NO undergoes a series of reactions with several molecules present in biological fluids as plasma and urine. The final in vivo products of NO are nitrite and nitrate. Since the relative proportion of nitrite and nitrate may vary, as a better index we measured the sum of the two as previously reported (13). The addition of metformin to dexamethasone treatment restores serum total nitrates/nitrites to the levels observed in the vehicle group, suggesting that metformin might have overcome the dexamethasone-induced endothelial dysfunction, the most probable pathogenetic mechanism of insulin resistance in this animal model. Pharmacological blockade of NO synthase activity has suggested an important role of its product, NO, in regulating insulin sensitivity and carbohydrate metabolism (1, 27). Data obtained in our second experiment confirm this hypothesis. Indeed, arginine did not modify dexamethasone-induced increase in SBP and serum triglycerides; it was not able to restore the circulating levels of nitrite/nitrates to the levels observed with vehicle and did not modify the dexamethasone-induced decrease in insulin sensitivity. When isosorbide dinitrate treatment is added to dexamethasone, serum nitrates/nitrites values higher than in the vehicle, although not significantly, were achieved, and only isosorbide was able to prevent the rise in SBP and in circulating triglycerides and the decrease in insulin sensitivity induced by dexamethasone alone. Mice with gene disruption of endothelial NO synthase show insulin resistance (21), stressing the importance of this system in the modulation of the peripheral insulin sensitivity at least in animals. Our data suggest that an endothelial disruption caused by dexamethasone treatment inactivates the NO synthase that has an important role in this newly described animal model of insulin resistance and metabolic syndrome.
Insulin resistance, before the development of type 2 diabetes and/or
hypertension, may cause endothelial dysfunction with a key role in the
pathogenesis of vascular complications (8, 33). Metformin
is able to increase peripheral insulin sensitivity and insulin-mediated
glucose uptake in the cells, increasing insulin-induced translation of
GLUT4 from an intracellular pool to the plasma membrane and increasing
the functional activity of the glucose carrier without altering the de
novo synthesis of the glucose carrier both in vivo (15)
and in vitro (15). In this way, metformin might reverse
the concomitant endothelial dysfunction. Indeed, recently, the
United Kingdom Prospective Diabetes Study (UKPDS) has shown
that metformin treatment in overweight type 2 patients reduces
significantly the occurrence of myocardial infarction
(35), compared with sulfonylureas or insulin in
normal-weight type 2 patients (34), suggesting additional
effects of metformin (2) in addition to lowering glycemia.
It is well known that glucocorticoids alter insulin sensitivity, and
they have a role in altering glucose metabolism and blood pressure
regulation. Most of the already described glucocorticoid animal models
do not take into account catabolism, with muscle atrophy (6, 17, 37) and increased blood pressure that can affect the measurement of insulin sensitivity by altering peripheral blood flow. Moreover, no
data on the long-term glucocorticoid treatment are available as well
regarding a possible endothelial involvement. We chose metformin as a
well-established (25), both in vivo and in vitro, drug
therapy to ameliorate peripheral insulin resistance in rats as well in
humans. Its wide use in diabetes is mainly due to its effects on
peripheral insulin action to increase glucose uptake and utilization
(30), although recently a direct effect of metformin on
restoring -cell insulin secretion response in vitro has been described. The reduction in blood pressure induced by metformin in
insulin-resistant rats is apparently through a direct mechanism with a
NO-dependent relaxation (10). Indeed, metformin has been shown able to attenuate the development of hypertension in the spontaneously hypertensive rats (19) usually reported to
be insulin resistant (4, 17). These effects of metformin
on blood pressure are not present in other animal models of
hypertension not characterized by insulin resistance (38),
indicating that metformin is not able per se to decrease blood
pressure. An additional alternative "nonesterified fatty acid
hypothesis" may be added to explain glucocorticoid-induced insulin
resistance (17). Our data show that dexamethasone
treatment increases free fatty acids in plasma, and this might have
contributed to insulin resistance, while metformin treatment restores
free fatty acid metabolism (21), as we found in this
experiment. Metformin increases the effects of infused
L-arginine on lowering blood pressure, decreasing platelet
aggregation and blood viscosity in non-insulin-dependent diabetes
mellitus patients. We did not measure blood viscosity in our
experiment, but metformin plus dexamethasone rats showed, compared with
dexamethasone-only rats, lower hematocrit levels, lower triglycerides,
and lower free fatty acids, all features that can explain a decrease in
blood viscosity. Feeding rats with the NO synthase inhibitor
N
-nitro-L-arginine elevates serum
triglycerides and cholesterol and lowers hepatic fatty acid oxidation,
affecting the activity of hepatic carnitine palmitoyltransferase, the
rate-limiting enzyme of fatty acid oxidation, increasing circulating
free fatty acid due to a reduction in fatty acid oxidation
(11). Indeed, raised free fatty acid concentrations have
been associated with the development of hypertension (3),
skeletal muscle insulin resistance (23), decreased insulin
secretion (20), and fatty liver (14), this last being regarded as the hepatic consequence of the metabolic syndrome due to specific hepatic insulin resistance (14).
In our experimental model, dexamethasone, together with the other classic features of metabolic syndrome such as insulin resistance, hypertriglyceridemia, was able also to increase the hepatic fatty accumulation, as observed in humans in whom nonalcoholic fatty liver
disease is a feature of the metabolic syndrome with insulin resistance
(14). Metformin dramatically reversed this fat
accumulation together with the other features of the metabolic
syndrome. Recently (39), metformin has been shown able to
activate AMP-activated protein kinase in hepatocytes, leading to
reduction in acetyl-CoA carboxylase activity, induction of fatty acid
oxidation, and suppression of the expression of lipogenic enzymes.
These new data may provide a unified explanation for the pleiotropic
effects of metformin, in particular regarding modulation in circulating
lipids and reduction in hepatic lipid synthesis and fatty liver, as we
observed in our experiment. The effects on cholesterol, triglycerides,
and free fatty acids were observed with dexamethasone treatment and reversed by the concomitant use of metformin. Thus we postulate that
dexamethasone, by altering NO synthase expression, might alter lipid
metabolism with an increase in free fatty acid and consequently insulin
resistance. Because in human hypertension subtle changes in adrenal
steroid metabolism have been suggested (28, 29, 36),
indicating that glucocorticoids in addition to the well-known Cushing
syndrome might have an important role in the development of high blood
pressure, this animal model is useful to study this aspect of human hypertension.
In conclusion, the two most important findings of this study are as follows: 1) long-term low-dose subcutaneous dexamethasone induces insulin resistance that precedes hypertension, and both conditions are reversed by the concomitant treatment with metformin; and 2) dexamethasone-induced insulin resistance might be due to endothelial dysfunction. Our data indicate that low-dose dexamethasone-induced hypertension in rats, an old model (12, 31, 32) of hypertension, can be revisited as an endothelial dysfunction causing insulin resistance and consequently some of the commonly observed features of the metabolic syndrome (hypertension, lipid-metabolism alteration, fatty liver, etc.). In particular, the presence also of the hepatic consequences of the insulin resistance in humans (fatty liver) appears to complete the picture of metabolic syndrome due to reduced insulin sensitivity. This model would be useful for studying insulin resistance-blood pressure relationships.
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ACKNOWLEDGEMENTS |
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We acknowledge the excellent technical work of Maristella Spissu and Gianluigi Fenu.
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FOOTNOTES |
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C. Severino is at present working in the Servizio Diabetologia, Dipartimento Struttura Clinica Medica e Patologia Speciale Medica, University of Sassari as a postdoctorate fellow.
Address for reprint requests and other correspondence: G. Tonolo, Servizio Diabetologia, Dipartimento Struttura Clinica Medica e Patologia Medica, Istituto di Clinica Medica, Viale S Pietro 8, 07100 Sassari, Italy (E-mail: giantono2001{at}yahoo.it).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
February 5, 2002;10.1152/ajpendo.00185.2001
Received 30 April 2001; accepted in final form 27 January 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Baron, AD,
Zhu JS,
Marshall S,
Irsula O,
Brechtel G,
and
Keech C.
Insulin resistance after hypertension induced by the nitric oxide synthase inhibitor L-NMMA in rats.
Am J Physiol Endocrinol Metab
269:
E709-E715,
1995
2.
Beisswenger, PJ,
Howell SK,
Touchette AD,
Lal S,
and
Szwergold S.
Metformin reduces systemic Methylglyoxal levels in type 2 diabetes.
Diabetes
48:
198-202,
1999[Abstract].
3.
Fagot-Campagna, A,
Balkau B,
Simon D,
Warnet JM,
Claude JR,
Ducimetiere P,
and
Eschwege E.
High free fatty acid concentration: an independent risk factor for hypertension in the Paris Prospective Study.
Int J Epidemiol
27:
808-813,
1998[Abstract].
4.
Finch, D,
Davis G,
Bocur J,
and
Kircher K.
Effects of insulin in renal sodium handling in hypertensive rats.
Hypertension
15:
514-518,
1990[Abstract].
5.
Garay, RP,
and
Meyer P.
A new test showing abnormal net Na+ and K+ fluxes in erythrocytes of essential hypertensive patients.
Lancet
i:
349-353,
1979.
6.
Haber, RS,
and
Weinstein SP.
Role of glucose transporters in glucocorticoid-induced insulin resistance.
Diabetes
41:
728-735,
1992[Abstract].
7.
Horner, HC,
Munck A,
and
Lienhard GE.
Dexamethasone causes translocation of glucose transporters from the plasma membrane to the intracellular site in human fibroblasts.
J Biol Chem
262:
17696-17702,
1987
8.
Jaap, AJ,
Shore AC,
and
Tooke JE.
Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia.
Diabetologia
40:
238-243,
1997[Medline].
9.
Katakam, PV,
Ujhelyi MR,
Hoenig ME,
and
Millar AW.
Endothelial dysfunction precedes hypertension in diet-induced insulin resistance.
Am J Physiol Regulatory Integrative Comp Physiol
275:
R788-R792,
1998
10.
Katakam, PV,
Ujhelyi MR,
Hoenig M,
and
Miller AW.
Metformin improves vascular function in insulin-resistant rats.
Hypertension
35:
108-112,
2000
11.
Khedara, A,
Kawai Y,
Kayashita J,
and
Kato N.
Feeding rats the nitric oxide synthase inhibitor, L-N-(omega)nitroarginine, elevates serum triglyceride and cholesterol and lowers hepatic fatty acid oxidation.
J Nutr
126:
2563-2567,
1996[ISI][Medline].
12.
Kenyon, CJ,
Brown WB,
Fraser R,
Tonolo G,
McPherson F,
and
Davies D.
Effects of dexamethasone on body fluid and electrolyte composition of rats.
Acta Endocrinol
122:
599-604,
1990[ISI][Medline].
13.
Marzining, M,
Nussler AK,
Stadler J,
Marzinzig E,
Barthlen W,
Nussler NC,
Beger HG,
Morris SM,
and
Bruckner UB.
Improved methods to measure end products of nitric oxide in biological fluids: nitrite, nitrate and S-nitrosothiols.
Nitric Oxide
2:
177-189,
1997.
14.
Marchesini, G,
Brizi M,
Bianchi G,
Tomasetti S,
Bugianesi E,
Lenzi M,
McCullough AJ,
Natale S,
Forlani G,
and
Melchionda N.
Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.
Diabetes
50:
1844-1850,
2001
15.
Matthaei, S,
and
Greten H.
Evidence that metformin ameliorates cellular insulin-resistance by potentiating insulin-induced translocation of glucose transporters to the plasma membrane.
Diabetes Metab
17:
150-158,
1991[ISI].
16.
Matthaei, S,
Reibold JP,
Hamann A,
Benecke H,
Haring HU,
Greten H,
and
Klein HH.
In vivo metformin treatment ameliorates insulin resistance: evidence for potentiation of insulin-induced translocation, and increased functional activity of glucose transporters in obese (fa/fa) Zucker rat adipocytes.
Endocrinology
133:
304-311,
1993[Abstract].
17.
Mokuda, O,
and
Sakamoto Y.
Peripheral insulin sensitivity is decreased by elevated nonesterfied fatty acid level in dexamethasone-treated rats.
Diabetes Nutr Metab
12:
252-255,
1999[ISI][Medline].
18.
Mondan, CE,
and
Reaven GM.
Evidence of abnormalities of insulin metabolism in rats with spontaneous hypertension.
Metabolism
37:
303-305,
1988[ISI][Medline].
19.
Morgan, DA,
Ray CA,
Balon TW,
and
Mark AL.
Metformin increases insulin sensitivity and lowers arterial blood pressure in spontaneously hypertensive rats.
Clin Res
22:
214-220,
1992.
20.
Paolisso, G,
and
Howard BV.
Role of non-esterified fatty acids in the pathogenesis of type 2 diabetes mellitus.
Diabetes Med
15:
360-366,
1999[ISI].
21.
Patane, G,
Piro S,
Rabuazzo AM,
Anello M,
Vigneri R,
and
Purrello F.
Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells.
Diabetes
49:
735-740,
2000[Abstract].
23.
Reaven, GM.
Banting lecture: role of insulin resistance in human disease.
Diabetes
37:
1595-1607,
1988[Abstract].
24.
Reaven, GM,
Ho H,
and
Hoffman BB.
Attenuation of fructose-induced hypertension in rats by exercise training.
Hypertension
12:
129-132,
1988[Abstract].
25.
Rossetti, L,
DeFronzo RA,
Gherzi R,
Stein P,
Andraghetti G,
Falzetti G,
Shulman GI,
Klein-Robbenhaar E,
and
Cordera R.
Effects of metformin treatment on insulin action in diabetic rats: in vivo and in vitro correlations.
Metabolism
39:
425-435,
1990[ISI][Medline].
26.
Saad, MJA,
Folli F,
and
Kahn CR.
Modulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats.
J Clin Invest
92:
2065-2072,
1993[ISI][Medline].
27.
Shankar, R,
Zhu JS,
Ladd B,
Henry D,
Shen HQ,
and
Baron AD.
Central nervous system nitric oxide synthase activity regulates insulin secretion and insulin action.
J Clin Invest
102:
1403-1412,
1998
27a.
Shankar, RR,
Wu Y,
Shen HQ,
Zhu JS,
and
Baron A.
Mice with disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance.
Diabetes
49:
684-687,
2000[Abstract].
28.
Soro, A,
Ingram MC,
Tonolo G,
Glorioso N,
and
Fraser R.
Mildly raised corticosterone excretion rates in patients with essential hypertension.
J Hum Hypertens
9:
391-393,
1995[ISI][Medline].
29.
Soro, A,
Ingram MC,
Tonolo G,
Glorioso N,
and
Fraser R.
Evidence of coexisting changes in 11--hydroxysteroid dehydrogenase and 5
-reductase activity in subjects with untreated essential hypertension.
Hypertension
25:
67-70,
1995
30.
Stumvoll, M,
Nurjhan N,
Perriello G,
Dailey G,
and
Gerich JE.
Metabolic effects of metformin in non insulin dependent diabetes mellitus.
N Engl J Med
333:
550-554,
1995
31.
Tonolo, G,
Fraser R,
Connel JMC,
and
Kenyon CJ.
Chronic low-dose infusion of dexamethasone in rats: effects on blood pressure, body weight and plasma atrial natriuretic peptide.
J Hypertens
6:
25-31,
1988[ISI][Medline].
32.
Tonolo, G,
Soro A,
Madeddu P,
Troffa C,
Melis MG,
Patteri G,
Pinna Parpaglia P,
Sabino G,
Maioli M,
and
Glorioso N.
Effect of chronic intracerebroventricular dexamethasone on blood pressure in normotensive rats.
Am J Physiol Endocrinol Metab
264:
E843-E847,
1993
33.
Tooke, JE,
and
Goh KL.
Vascular function in type 2 diabetes mellitus and pre-diabetes: the case for intrinsic endopathy.
Diabetic Med
16:
710-715,
1999[ISI][Medline].
34.
UKPDS Report 33.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes.
Lancet
352:
837-853,
1998[ISI][Medline].
35.
UKPDS Report 34.
Effects of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes.
Lancet
352:
854-865,
1998[ISI][Medline].
36.
Walker, BR,
Stewart PM,
Padfield PL,
and
Edwards CRW
Increased vascular sensitivity to glucocorticoids in essential hypertension: 11 hydroxysteroid dehydrogenase revisited.
J Hypertens
9:
1082-1083,
1991.
37.
Weinstein, SP,
Paquin T,
Pritsker A,
and
Haber RS.
Glucocorticoid-induced insulin resistance: dexamethasone inhibits the activation of glucose transport in rat skeletal muscle by both insulin- and non-insulin-related stimuli.
Diabetes
44:
441-445,
1995[Abstract].
38.
Zhang, HY,
Reddy SR,
and
Kotchen TA.
Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity.
Hypertension
24:
106-110,
1994[Abstract].
39.
Zhou, G,
Myers R,
Li Y,
Chen Y,
Shen X,
Fenyk-Melody J,
Wu M,
Ventre J,
Doebber T,
Fujii N,
Musi N,
Hirshman MF,
Goodyear LJ,
and
Moller DE.
Role of AMP-activated protein kinase in mechanism of metformin action.
J Clin Invest
108:
1167-1174,
2001