Hepatic Insulin Sensitizing Substance Release Research Articles

A synergistic, balanced antioxidant cocktail, protects aging rats from insulin resistance and absence of meal-induced insulin sensitization (AMIS) syndrome.

A series of in vivo and in vitro studies using animal and human models in the past 15 years have demonstrated that approximately 55% (~66% in humans) of the glucose disposal effect of an i.v. injection of insulin in the fed state is dependent on the action of a second hormone, hepatic insulin sensitizing substance (HISS), which is released from the liver and stimulates glucose uptake in muscle, heart and kidneys. Sensitization of the insulin response by a meal through release of HISS is called meal-induced insulin sensitization (MIS). Absence of HISS action results in postprandial hyperglycemia, hyperinsulinemia, hyperlipidemia, adiposity, increased free radical stress and a cluster of progressive metabolic and cardiovascular dysfunctions referred to as the AMIS (absence of meal-induced insulin sensitization) syndrome. Reduced HISS release accounts for the insulin resistance that occurs with aging and is made worse by physical inactivity and diets high in sucrose or fat. This brief review provides an update of major metabolic disturbances associated with aging due to reduction of HISS release, and the protection against these pathological changes in aging animals using a balanced synergistic antioxidant cocktail SAMEC (S-adenosylmethionine, vitamins E and C). The synergy amongst the components is consistent with the known benefits of antioxidants supplied by a mixed diet and acting through diverse mechanisms. Using only three constituents, SAMEC appears suitable as an antioxidant specifically targeting the AMIS syndrome.

Lifestyle impact on meal-induced insulin sensitization in health and prediabetes: A focus on diet, antioxidants, and exercise interventions

The augmented whole-body glucose uptake response to insulin during the postprandial state is described as meal-induced insulin sensitization (MIS). MIS occurs when the presence of food in the upper gastrointestinal tract activates 2 feeding signals (activation of hepatic parasympathetic nerves and elevation of hepatic glutathione level), and causes insulin to release hepatic insulin sensitizing substance (HISS), which stimulates glucose uptake in skeletal muscle, heart, and kidneys. HISS action results in nutrient storage, primarily as glycogen. Impairment of HISS release results in the absence of meal-induced insulin sensitization (AMIS), which causes postprandial hyperglycemia and hyperinsulinemia, and chronically leads to the progression to a cluster of metabolic, vascular, and cardiac dysfunctions, which we refer to as components of the AMIS syndrome. Manipulation of the MIS process in health and in disease, by pharmacological and nonpharmacological interventions, is outlined in this review. High fat or sugar supplemented diet reduces MIS; exercise elevates MIS; and antioxidants protect MIS against reductions associated with diet and age.

Bethanechol and N-acetylcysteine mimic feeding signals and reverse insulin resistance in fasted and sucrose-induced diabetic rats

Meal-induced insulin sensitization (MIS) is explained by the HISS (hepatic insulin sensitizing substance) hypothesis. In the presence of two "feeding signals," a pulse of insulin results in the release of HISS from the liver. HISS acts selectively on skeletal muscle and doubles the response to insulin. HISS is not released in the fasted state or in the sucrose-supplemented diabetes model. We tested the hypothesis that provision of both feeding signals allows insulin to cause HISS release in both the normal fasted and the diabetic model. The dynamic response to insulin (50 mU/kg over 5min) was quantified using the rapid insulin sensitivity test (RIST). Gastric injection of a liquid test meal or i.v. administration of N-acetylcysteine in 24h fasted rats raised hepatic glutathione to a similar degree (by 46%-47%). Hepatic denervation in fed rats eliminated the parasympathetic signal and eliminated MIS, and bethanechol completely restored MIS. Both compounds administered together allowed insulin to stimulate HISS release in 24h fasted rats and in a diabetic model (9-week, 35% liquid sucrose supplement). Neither was effective alone. Both "feeding signals" are necessary and sufficient for insulin to stimulate HISS release.

Insulin sensitization by voluntary exercise in aging rats is mediated through hepatic insulin sensitizing substance (HISS)

Background Food in the upper gastrointestinal tract potentiates the glucose uptake response to insulin. Meal-induced insulin sensitization (MIS) occurs as a result of insulin-mediated release of hepatic insulin sensitizing substance (HISS) that increases glucose uptake in peripheral tissues. HISS release decreases with age, and exercise causes metabolic improvements in aging, therefore it is important to analyze the effect of exercise on age-associated decline in HISS-action. Objectives The aim of this study is to test the hypothesis that improved insulin sensitivity, by voluntary running-wheel exercise in aging rats, is attained by preserving the HISS response. We also investigate the possible association of exercise-mediated beneficial changes in metabolic conditions and body composition with improved HISS-action. Methods We measured insulin- and HISS-sensitivity in 9, 14 and 21-week old rats with/without exercise. Metabolic markers were also determined in age-matched control and exercised rats. Results Exercise significantly improved HISS-dependent glucose uptake in all age groups. The direct action of insulin was minimally altered by age or exercise. Body composition and metabolic conditions were beneficially changed with exercise-induced improvements in the HISS response. Conclusion The therapeutic efficacy of voluntary exercise against insulin resistance in aging rats is achieved mainly through restoration of HISS-action.

Synergistic protection by S-adenosylmethionine with vitamins C and E on liver injury induced by thioacetamide in rats

Free radicals are involved in the pathogenesis of acute liver injury induced by thioacetamide (TAA). We investigated the effects of S-adenosylmethionine (SAMe) combined with/without vitamins C and E on TAA-induced acute liver injury in rats. TAA was given intraperitoneally (200 mg kg −1). Antioxidant treatments (SAMe, 25 mg kg −1; vitamin C, 100 mg kg −1; vitamin E, 200 mg kg −1, intraperitoneal) were given 1 h later. Liver histology, enzymology, and ability to release hepatic insulin-sensitizing substance (HISS) were assessed. TAA caused liver tissue injury, increased liver enzymes, and decreased insulin sensitivity ( p < 0.01). Blockade of HISS release by atropine did not further decrease insulin sensitivity in rats with TAA insult, indicating that the decrease in insulin sensitivity was HISS dependent. Treatment with SAMe alone or vitamins C+E slightly improved liver histology but not the changes in liver enzymes and insulin sensitivity. Combined treatment with SAMe plus vitamins C+E greatly protected the liver from tissue injury, the increase in liver enzymes, and the decrease in insulin sensitivity. In conclusion, acute liver injury causes HISS-dependent insulin resistance (HDIR). There are synergistic antioxidative effects among the antioxidants, SAMe and vitamins C and E, that protect the liver from TAA-induced HDIR, suggesting that antioxidant treatment may best be done using a balanced “cocktail.”

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

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.

Increased incidence of hepatic insulin-sensitizing substance (HISS)-dependent insulin resistance in female rats prenatally exposed to ethanol

Insulin causes the release of the hepatic insulin-sensitizing substance (HISS) from the liver. Hepatic parasympathetic nerves play a permissive role in the release of HISS. HISS-dependent insulin resistance (HDIR) occurs in the absence of HISS. Fetal ethanol exposure has been shown to cause dose-dependent HDIR in adult male rat offspring. Since female offspring are more severely affected by in utero ethanol toxicity, we hypothesized that fetal alcohol exposure causes higher incidence and more severe HDIR in adult female offspring. Adult female rat offspring prenatally exposed to different concentrations of ethanol (0%, 15%, and 20%) were tested for insulin sensitivity using the rapid insulin sensitivity test (RIST). The RIST index was significantly reduced in the 15% (134.1 +/- 16.1 mg/kg) and the 20% (98.7 +/- 9.7 mg/kg) group compared with the 0% (220.9 +/- 27.6 mg/kg) group. Administration of atropine produced significant additional HDIR in the 15% group (82.9 +/- 14.5 mg/kg) but not the 20% group (83.8 +/- 20.5 mg/kg) indicating complete HDIR had been produced in this group, contrary to the adult male offspring in a previous study. The results are consistent with the hypothesis that adult-female offspring are more severely affected by in utero ethanol exposure compared with adult-male offspring.

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

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 i.v.) or by blockade of NOS [NG-nitro-L-arginine methyl ester (L-NAME), 1 mg/kg intraportally (i.p.v.)]. After the blockade, HISS action was tentatively restored using a NOdonor [3-morpholynosydnonimine (SIN-1), 5-10 mg/kg i.p.v.] or ACh (2.5-5 microg.kg(-1).min(-1) .i.p.v.). 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 i.p.v.), 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.

A New Paradigm for Diabetes and Obesity: the Hepatic Insulin Sensitizing Substance (HISS) Hypothesis

The glucose disposal effect of insulin after a meal is accounted for in approximately equal measure by the direct action of insulin and the action of HISS (hepatic insulin sensitizing substance) released from the liver and acting on skeletal muscle to stimulate glucose storage as glycogen. The ability of insulin to cause HISS release is determined by hepatic parasympathetic nerves. Eliminating the parasympathetic signal by surgical denervation of the liver or by blockade of hepatic muscarinic receptors, hepatic nitric oxide synthase, or hepatic cyclooxygenase results in insulin resistance that can be accounted for by the absence of HISS action and is referred to as HISS-dependent insulin resistance (HDIR). Animal models in which the insulin resistance has been shown to be HDIR includes the spontaneously hypertensive rat, sucrose fed rats, animals with liver disease, adult offspring of fetal alcohol exposure, acute stress, and ageing. We suggest that HDIR accounts for the major metabolic disturbances in type 2 diabetes, including the postprandial hyperglycemia that results in the majority of pathologies related to diabetes. The observation of meal-induced insulin sensitization (MIS) and the role of HISS allows for consideration of a new paradigm relating meal processing, diabetes, obesity, and insulin resistance. New diagnostic approaches and therapeutic targets are described.

A Proposed New Paradigm for Insulin Resistance

The perspective presented here is a working hypothesis suggesting a new paradigm for insulin resistance where, analogous to the cause of type 1 diabetes being attributed to lack of insulin, type 2 diabetes is due to lack of action of a hepatic insulin sensitizing substance (HISS). In both cases, the major metabolic dysfunction is with post-meal nutrient processing. In the immediate postprandial state, insulin causes the release of the putative hormone, HISS, from the liver. HISS stimulates glucose uptake in skeletal muscle. The hepatic parasympathetic nerves determine, in a permissive manner, the ability of insulin to cause HISS release maximally in the postprandial state. HISS release in response to insulin is progressively reduced with fasting. The glucose disposal effect of insulin in the fed state is decreased by approximately 55% by blocking HISS release. HISS release is blocked by fasting, surgical parasympathetic denervation of the liver, blockade of hepatic cholinergic muscarinic receptors, blockade of hepatic nitric oxide production, or blockade of hepatic cyclooxygenase, and results in a condition referred to as HISS-dependent insulin resistance (HDIR). HDIR is physiologically and appropriately produced in the fasted state and, pathologically, in chronic liver disease, sucrose fed, fetal alcohol exposed, spontaneously hypertensive, and aging rats. Therapeutic approaches to correct the metabolic imbalance in processing the meal nutrients that occur in type 2 diabetes can be approached through this paradigm.

Practice and Principles of Pharmacodynamic Determination of HISS‐Dependent and HISS‐Independent Insulin Action: Methods to Quantitate Mechanisms of Insulin Resistance

AbstractFor Abstract see ChemInform Abstract in Full Text.

Practice and principles of pharmacodynamic determination of HISS-dependent and HISS-independent insulin action: methods to quantitate mechanisms of insulin resistance.

Injection of insulin causes release of HISS (hepatic insulin sensitizing substance) from the liver in the fed state. HISS action accounts for 50-60% of the glucose disposal produced by a wide range of insulin doses (5-100 mU/kg). Although the chemical nature of HISS is unknown, precluding pharmacokinetic studies, the pharmacodynamics of HISS has advanced because of the use of the rapid insulin sensitivity test (RIST) which is a transient euglycemic clamp used following a bolus of insulin. HISS action can be blocked by hepatic denervation and restored by intraportal but not intravenous infusion of acetylcholine or a nitric oxide donor. HISS release is prevented by blockade of hepatic muscarinic receptors, nitric oxide synthase blockers, indomethacin, and animal models of insulin resistance, including chronic liver disease, sucrose feeding, hypertension, aging, obesity, and fetal alcohol exposure. HISS acts on skeletal muscle but not liver, gut, or adipose tissue. HISS is released by insulin in the fed state but decreases to insignificance after 24-hr fasting in rats. Cats and dogs appear to require a longer period of fasting to prevent HISS action. Lack of HISS action is suggested to be the cause of post-meal hyperglycemia and hyperlipidemia in type 2 diabetes and other disease states with similar metabolic dysfunction. The RIST can be carried out up to six times in the same animal, is not affected by pentobarbital anesthesia, and can readily differentiate HISS-dependent and HISS-independent insulin action.

Insulin sensitivity regulated by feeding in the conscious unrestrained rat.

Hepatic insulin sensitizing substance (HISS), a putative hormone released from the liver in response to insulin in fed animals, accounts for 50-60% of insulin action. HISS release is regulated by permissive control of the hepatic parasympathetic nerves. The objectives were to develop the rapid insulin sensitivity test (RIST) in conscious rats, and to assess the effects of anesthesia, atropine, feeding, and fasting on insulin action. The RIST index, expressed as milligrams glucose per kilogram body weight required to maintain euglycemia after a 50 mU/kg bolus of insulin, was similar in conscious and anesthetized rats (238.6+/-42.5 vs. 225.3+/-30.4 mg/kg). Atropine produced a 56% inhibition of insulin action in fed rats. After a 24 h fast, full HISS-dependent insulin resistance had developed as shown by a low RIST index that was not reduced further by atropine. Fasting caused a 10.5% decrease in insulin action per hour over six hours. HISS-dependent insulin resistance in 24-h fasted rats was reversed 4 h after re-feeding (90.9+/-12.3 vs. 204.5+/-30.5 mg/kg). We conclude that HISS-dependent and HISS-independent insulin action, as assessed by the RIST, is similar in conscious and pentobarbital-anesthetized rats. Pharmacological blockade of HISS-dependent insulin action and physiological regulation of HISS action by feeding-fasting is confirmed. Re-feeding fasted rats reversed HISS-dependent insulin resistance. Merits of use of the RIST in conscious versus anesthetized rats are discussed.

Hepatic parasympathetic (HISS) control of insulin sensitivity determined by 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.

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

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.

Blockade of hepatic nitric oxide synthase causes 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 of L-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 of L-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 by L-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.

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

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.