The HISS story overview: a novel hepatic neurohumoral regulation of peripheral insulin sensitivity in health and diabetes

1999 ◽  
Vol 77 (8) ◽  
pp. 553-562 ◽  
Author(s):  
W Wayne Lautt
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Nitric Oxide Donor ◽  
Severe Insulin Resistance ◽  
Parasympathetic Nerves ◽  
Neurohumoral Regulation ◽  
Duct Ligation ◽  
Oxide Synthase

Data are reviewed that are consistent with the following working hypothesis that proposes a novel mechanism regulating insulin sensitivity, which when nonfunctional, leads to severe insulin resistance. Postprandial elevation in insulin levels activates a hepatic parasympathetic reflex release of a putative hepatic insulin-sensitizing substance (HISS), which activates glucose uptake at skeletal muscle. Insulin causes HISS release in fed but not fasted animals. The reflex is mediated by acetylcholine and involves release of nitric oxide in the liver. Interruption of the release of HISS is achieved by surgical denervation of the anterior hepatic nerve plexus, muscarinic receptor blockade, or nitric oxide synthase antagonism and leads to immediate severe insulin resistance. The nitric oxide donor, SIN-1, reverses L-NAME-induced insulin resistance. Denervation-induced insulin resistance is reversed by intraportal but not intravenous administration of acetylcholine or SIN-1. Liver disease is often associated with insulin resistance; the bile duct ligation model of liver disease results in parasympathetic neuropathy and insulin resistance that is reversed by intraportal acetylcholine. Possible relevance of this HISS-dependent control of insulin action to insulin resistance in diabetes, liver disease, and obesity is discussed.Key words: insulin resistance, parasympathetic nerves, liver, obesity, nitric oxide.

Hepatic parasympathetic (HISS) control of insulin sensitivity determined by feeding and fasting

2001 ◽  
Vol 281 (1) ◽  
pp. G29-G36 ◽  
Author(s):  
W. W. Lautt ◽  
M. P. Macedo ◽  
P. Sadri ◽  
S. Takayama ◽  
F. Duarte Ramos ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Dynamic Control ◽  
Hormone Action ◽  
Parasympathetic Nerves ◽  
Oxide Synthase ◽  
Similar Dynamic ◽  
Feeding And Fasting

In response to insulin, a hormone [hepatic insulin sensitizing substance (HISS)] is released from the liver to stimulate glucose uptake in skeletal muscle but not liver or gut. The aim was to characterize dynamic control of HISS action in response to insulin and regulation of release by hepatic parasympathetic nerves. Insulin action was assessed by the rapid insulin sensitivity test, where the index is the glucose required (mg/kg) to maintain euglycemia after a bolus of insulin. Blocking HISS release by interruption of the hepatic parasympathetic nerves by surgical denervation, atropine, or blockade of hepatic nitric oxide synthase produced similar degrees of insulin resistance and revealed a similar dynamic pattern of hormone action that began 3–4 min after, and continued for 9–10 min beyond, insulin action (50 mU/kg). HISS action accounted for 56.5 ± 3.5% of insulin action at insulin doses from 5 to 100 mU/kg (fed). We also tested the hypothesis that HISS release is controlled by the feed/fast status. Feeding resulted in maximal HISS action, which decreased progressively with the duration of fasting.

Insulin sensitivity is mediated by the activation of the ACh/NO/cGMP pathway in rat liver

2004 ◽  
Vol 287 (3) ◽  
pp. G527-G532 ◽  
Author(s):  
Maria P. Guarino ◽  
Nina C. Correia ◽  
W. Wayne Lautt ◽  
M. Paula Macedo
Keyword(s):  
Nitric Oxide ◽  
Insulin Sensitivity ◽  
Muscarinic Receptors ◽  
Wistar Rats ◽  
No Donor ◽  
Parasympathetic Nerves ◽  
Cgmp Pathway ◽  
Male Wistar Rats ◽  
Oxide Synthase

The hepatic parasympathetic nerves and hepatic nitric oxide synthase (NOS) are involved in the secretion of a hepatic insulin sensitizing substance (HISS), which mediates peripheral insulin sensitivity. We tested whether binding of ACh to hepatic muscarinic receptors is an upstream event to the synthesis of nitric oxide (NO), which, along with the activation of hepatic guanylate cyclase (GC), permits HISS release. Male Wistar rats (8–9 wk) were anesthetized with pentobarbital sodium (65 mg/kg). Insulin sensitivity was assessed using a euglycemic clamp [the rapid insulin sensitivity test (RIST)]. HISS inhibition was induced by antagonism of muscarinic receptors (atropine, 3 mg/kg iv) or by blockade of NOS [ NG-nitro-l-arginine methyl ester (l-NAME), 1 mg/kg intraportally (ipv)]. After the blockade, HISS action was tentatively restored using a NO donor [3-morpholynosydnonimine (SIN-1), 5–10 mg/kg ipv] or ACh (2.5–5 μg·kg−1·min−1 ipv). SIN-1 (10 mg/kg) reversed the inhibition caused by atropine (RIST postatropine 137.7 ± 8.3 mg glucose/kg; reversed to 288.3 ± 15.5 mg glucose/kg, n = 6) and by l-NAME (RIST post-l-NAME 152.2 ± 21.3 mg glucose/kg; reversed to 321.7 ± 44.7 mg glucose/kg, n = 5). ACh did not reverse HISS inhibition induced by l-NAME. The role of GC in HISS release was assessed using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 nmol/kg ipv), a GC inhibitor that decreased HISS action (control RIST 237.6 ± 18.6 mg glucose/kg; RIST post-ODQ 111.7 ± 6.2 mg glucose/kg, n = 5). We propose that hepatic parasympathetic nerves release ACh, leading to hepatic NO synthesis, which activates GC, triggering HISS action.

Blockade of hepatic nitric oxide synthase causes insulin resistance

1999 ◽  
Vol 277 (1) ◽  
pp. G101-G108 ◽  
Author(s):  
Parissa Sadri ◽  
W. Wayne Lautt
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Methyl Ester ◽  
Nitric Oxide Synthase ◽  
Insulin Response ◽  
No Donor ◽  
Peripheral Insulin Resistance ◽  
Oxide Synthase ◽  
Liver Insulin Resistance

The hypothesis was tested that insulin sensitivity, previously shown to depend on a functional hepatic parasympathetic reflex, was mediated by hepatic production of nitric oxide (NO). Insulin sensitivity was measured using the rapid insulin sensitivity test. N-nitro-l-arginine methyl ester (l-NAME, 2.5 and 5.0 mg/kg iv) and N-monomethyl-l-arginine (l-NMMA, 0.73 mg/kg), nitric oxide synthase (NOS) antagonists, caused insulin resistance in rats. Intraportal administration ofl-NAME at a dose of 1.0 mg/kg significantly reduced the response to insulin (54.9 ± 5.2%); however, administration of the same dose ofl-NAME intravenously did not cause a significant decrease in insulin response. Intraportal, but not intravenous, administration of 3-morpholinosydnonimine (SIN-1, 5.0 mg/kg), a NO donor, partially reversed the insulin resistance caused byl-NMMA. Intraportal administration of SIN-1 (10.0 mg/kg) completely restored insulin sensitivity after l-NMMA or surgical denervation of the liver. Insulin resistance produced by denervation was not further increased by NOS blockade. These results suggest that blockade of NOS causes peripheral insulin resistance secondary to blockade of the hepatic parasympathetic reflex release of hepatic insulin-sensitizing substance in response to insulin.

Low-dose dexamethasone in the rat: a model to study insulin resistance

2002 ◽  
Vol 283 (2) ◽  
pp. E367-E373 ◽  
Author(s):  
C. Severino ◽  
P. Brizzi ◽  
A. Solinas ◽  
G. Secchi ◽  
M. Maioli ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Isosorbide Dinitrate ◽  
Low Dose ◽  
Tap Water ◽  
Nitric Oxide Donor ◽  
Concomitant Treatment ◽  
Set Up

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 · kg−1 · day−1 os), and 4) dexamethasone plus metformin. In experiment 2the 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.

Insulin Sensitivity in Skeletal Muscle Regulated by a Hepatic Hormone, HISS

2005 ◽  
Vol 30 (3) ◽  
pp. 304-312 ◽  
Author(s):  
W. Wayne Lautt
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Physiological State ◽  
Nitric Oxide Donor ◽  
Fed State ◽  
Spontaneously Hypertensive ◽  
Parasympathetic Nerves ◽  
Key Words Insulin ◽  
The Impact

The current state of the HISS (hepatic insulin sensitizing substance) hypothesis is briefly outlined. In the postmeal absorptive state, 50-60% of the glucose storage action of insulin is accounted for by the actions of HISS released from the liver and acting on skeletal muscle. Hepatic parasympathetic nerves permissively regulate the ability of a pulse of insulin to release HISS, thereby potentiating the impact of insulin in the fed state. HISS release in response to insulin decreases progressively with fasting to create a physiological state of HISS-dependent insulin resistance. HISS release is regulated by parasympathetic nerves via muscarinic receptors and nitric oxide, and insulin resistance of skeletal muscle produced by hepatic denervation is reversed by intraportal but not intravenous acetylcholine or a nitric oxide donor. It is suggested that HISS-dependent insulin resistance occurs in animal models including sucrose-fed rats, spontaneously hypertensive rats, chronic liver disease, fetal alcohol effect in the adult offspring, and type 2 diabetes. Key words: insulin resistance, RIST, parasympathetic nerves, liver, diabetes

scholarly journals Obesity, insulin resistance, and skeletal muscle nitric oxide synthase

2012 ◽  
Vol 113 (5) ◽  
pp. 758-765 ◽  
Author(s):  
Raymond M. Kraus ◽  
Joseph A. Houmard ◽  
William E. Kraus ◽  
Charles J. Tanner ◽  
Joseph R. Pierce ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Body Mass Index ◽  
Insulin Sensitivity ◽  
Nitric Oxide Synthase ◽  
Body Mass ◽  
Inos Protein ◽  
Oxide Synthase ◽  
Nonobese Group

The molecular mechanisms responsible for impaired insulin action have yet to be fully identified. Rodent models demonstrate a strong relationship between insulin resistance and an elevation in skeletal muscle inducible nitric oxide synthase (iNOS) expression; the purpose of this investigation was to explore this potential relationship in humans. Sedentary men and women were recruited to participate (means ± SE: nonobese, body mass index = 25.5 ± 0.3 kg/m2, n = 13; obese, body mass index = 36.6 ± 0.4 kg/m2, n = 14). Insulin sensitivity was measured using an intravenous glucose tolerance test with the subsequent modeling of an insulin sensitivity index (SI). Skeletal muscle was obtained from the vastus lateralis, and iNOS, endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) content were determined by Western blot. SI was significantly lower in the obese compared with the nonobese group (∼43%; P < 0.05), yet skeletal muscle iNOS protein expression was not different between nonobese and obese groups. Skeletal muscle eNOS protein was significantly higher in the nonobese than the obese group, and skeletal muscle nNOS protein tended to be higher ( P = 0.054) in the obese compared with the nonobese group. Alternative analysis based on SI (high and low tertile) indicated that the most insulin-resistant group did not have significantly more skeletal muscle iNOS protein than the most insulin-sensitive group. In conclusion, human insulin resistance does not appear to be associated with an elevation in skeletal muscle iNOS protein in middle-aged individuals under fasting conditions.

scholarly journals Defective Allele of the Neuronal Nitric Oxide Synthase Gene Increases Insulin Resistance During Acute Phase of Myocardial Infarction.

2021 ◽  
Author(s):  
Otávio T Nóbrega ◽  
Alessandra M. Campos-Staffico ◽  
Elayne Kelen Oliveira ◽  
Daniel B Munhoz ◽  
Filipe A. Moura ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Nitric Oxide Synthase ◽  
Acute Phase ◽  
Neuronal Nitric Oxide Synthase ◽  
No Production ◽  
Defective Allele ◽  
Oxide Synthase

Abstract Background: glycemia disorders are a strong predictor of mortality in ST-Elevation Myocardial Infarction (STEMI) patients. Disruption in nitric oxide (NO) production is associated with insulin-resistant states. We evaluated whether NO production in carriers of a defective allele of the neuronal nitric oxide synthase (nNOS or NOS1), whose in vivo expression is reduced by up to 50%, might influence the insulin response during acute phase of STEMI. Methods and Results: Consecutive patients with STEMI (n = 354) underwent clinical evaluations and genotyping for the promoter variation rs41279104. Blood tests were performed at admission (D1) and after five days (D5) of in-hospital follow up, with the disposition index assessed in the period. Flow-mediated dilation (FMD) was assessed by reactive hyperemia on the 30th day. Homozygotes for the defective allele (A) showed lower glycemia and insulin sensitivity at D1 while showing the highest b-cells function and no changes in the circulating NO pool, what is compatible with hyperresponsive b-cells to counteract the inherent glucose-resistant state of AA patients. At D5, glycemic scores shifted to indicate greater insulin sensitivity among A homozygotes, paralleled by a slight yet poor increase in NO bioavailability than that among G carriers. All in all, defective homozygotes showed greater insulin resistance expressed by the disposition index at admission, which was compensated 5 days after STEMI even though FMD of A carriers was lower compared to G homozygotes. Conclusion: a defective nNOS allele seems to elicit endocrine adaptation and to associate with insulin resistance during the acute phase of STEMI.

scholarly journals Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance

2011 ◽  
Vol 301 (5) ◽  
pp. H2093-H2101 ◽  
Author(s):  
Baptiste Kurtz ◽  
Helene B. Thibault ◽  
Michael J. Raher ◽  
John R. Popovich ◽  
Sharon Cawley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Insulin Resistance ◽  
Mitochondrial Respiration ◽  
Pressure Overload ◽  
Lv Remodeling ◽  
Stress Levels ◽  
Nitric Oxide Synthase 3 ◽  
And Function ◽  
Oxide Synthase

Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3−/−) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2′,7′-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3−/− mice than in SD-fed WT mice. In contrast, HFD-fed NOS3−/− developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3−/− than in those from HFD-fed WT. Nω-nitro-l-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3−/− mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.

Inhibition of tetrahydrobiopterin biosynthesis impairs endothelium-dependent relaxations in canine basilar artery

1997 ◽  
Vol 273 (2) ◽  
pp. H718-H724 ◽  
Author(s):  
H. Kinoshita ◽  
S. Milstien ◽  
C. Wambi ◽  
Z. S. Katusic
Keyword(s):  
Nitric Oxide ◽  
Superoxide Dismutase ◽  
Nitric Oxide Synthase ◽  
Endothelial Function ◽  
Isometric Force ◽  
Cerebral Arteries ◽  
Calcium Ionophore ◽  
Nitric Oxide Donor ◽  
Ionophore A23187 ◽  
Oxide Synthase

Tetrahydrobiopterin is an essential cofactor in biosynthesis of nitric oxide. The present study was designed to determine the effect of decreased intracellular tetrahydrobiopterin levels on endothelial function of isolated cerebral arteries. Blood vessels were incubated for 6 h in minimum essential medium (MEM) in the presence or absence of a GTP cyclohydrolase I inhibitor, 2,4-diamino-6-hydroxypyrimidine (DAHP, 10(-2) M). Rings with and without endothelium were suspended for isometric force recording in the presence of a cyclooxygenase inhibitor, indomethacin (10(-5) M). In arteries with endothelium, DAHP significantly reduced intracellular levels of tetrahydrobiopterin. DAHP in combination with a precursor of the salvage pathway of tetrahydrobiopterin biosynthesis, sepiapterin (10(-4) M), not only restored but increased levels of tetrahydrobiopterin above control values. In DAHP-treated arteries, endothelium-dependent relaxations to bradykinin (10(-10)-10(-6) M) or calcium ionophore A23187 (10(-9)-10(-6) M) were significantly reduced, whereas endothelium-independent relaxations to a nitric oxide donor, 3-morpholinosydnonimine (10(-9)-10(-4) M), were not affected. When DAHP-treated arteries with endothelium were incubated with sepiapterin (10(-4) M) or superoxide dismutase (150 U/ml), relaxations to bradykinin and A23187 were restored to control levels. In contrast, superoxide dismutase did not affect endothelium-dependent relaxations in arteries incubated in MEM. A nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (10(-4) M), abolished relaxations to bradykinin or A23187 in control arteries and in DAHP-treated arteries. These studies demonstrate that in cerebral arteries, decreased intracellular levels of tetrahydrobiopterin can reduce endothelium-dependent relaxations. Production of superoxide anions during activation of dysfunctional endothelial nitric oxide synthase appears to be responsible for the impairment of endothelial function.

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