Hepatic Insulin Sensitizing Substance Action 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.

Obesity as an Early Symptom of the AMIS Syndrome.

We review evidence that the AMIS (Absence of Meal-induced Insulin Sensitization) syndrome describes a paradigm fundamental to development of obesity. The hypoglycemic response to a pulse of insulin is doubled after a meal as a result of Hepatic Insulin Sensitizing Substance (HISS), released from the liver to act selectively on muscle, heart and kidney. In the absence of HISS action, the hypoglycemic response to insulin is the same as in the fasted state, and only half of what it should be. Postprandial hyperglycemia ensues, with compensatory hyperinsulinemia, resultant hyperlipidemia and elevated free radical stress. Storage of nutrient energy shifts from glycogen in muscle to fat. Chronic AMIS results in adiposity, occurs with age, is accelerated with sucrose supplement, and prevented by a synergistic antioxidant. Exercise reverses AMIS, as do pharmaceuticals that mimic the “feeding signals”. The AMIS syndrome develops as a sequence of pathologies based on the consequences of absence of HISS action, including adiposity as the earliest symptom. Cardiac dysfunction, hypertension, hypercholesterolemia, and fatty liver are related to lack of HISS action. The AMIS syndrome hypothesis is mechanistic-based and accounts for the major pathologies associated with prediabetes, obesity, diabetes and metabolic syndrome. AMIS can be diagnosed, prevented and treated.

Interaction of antioxidants and exercise on insulin sensitivity in healthy and prediabetic rats

Meal-induced insulin sensitization (MIS) describes the augmented postprandial response to insulin through action of the hepatic insulin sensitizing substance (HISS). HISS-action is impaired in insulin resistance associated with aging and type 2 diabetes, but could be preserved by the antioxidant cocktail SAMEC, along with voluntary exercise. In this study, we tested whether antioxidant supplementation during voluntary training would interact with the effects of exercise on HISS-mediated glucose uptake in healthy and prediabetic rats. The 7-day voluntary running-wheel training was used as an exercise intervention. SAMEC supplementation was provided only during the 7-day training session. The rapid insulin sensitivity test (RIST) was conducted to determine insulin- and HISS-dependent glucose uptake in 14-week-old healthy rats, and sucrose-induced insulin-resistant rats, with or without exercise in the presence or absence of SAMEC supplementation. The postprandial insulin sensitivity was increased by exercise, primarily through enhancement of the HISS-dependent glucose uptake, which remained unaffected by SAMEC. SAMEC supplementation did not either harm or add benefit to the positive effects of exercise on insulin sensitivity in healthy or prediabetic rats. While SAMEC alone was a demonstrated preventive against the progressive loss of HISS action in previous studies, short-term supplementation in this study did not reverse the established disease state.

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.

Loss of Postprandial Insulin Sensitization During Aging

With aging, there is a decrease in parasympathetic nervous activity. Since the hepatic parasympathetic nerves (HPNs) are essential to the disposal of nutrients, through the hepatic insulin sensitizing substance (HISS), we tested the hypothesis that aging leads to a lowering of postprandial glucose disposal by a decrease of the HISS-dependent component of insulin action. Insulin sensitivity was quantified in fed or fasted, male and female Wistar rats (from 6 to 52 weeks), using a euglycemic clamp. The HISS-dependent component was quantified by administration of the muscarinic antagonist atropine. Total insulin action decreased gradually up to 52 weeks of age: The HISS-independent component of insulin action decreased until 9 weeks of age and remained unchanged thereafter; the HISS-dependent component decreased from 9 weeks of age throughout aging. The continuous decrease of HISS action, uncovered by blocking the HPN, is the key phenomenon for the gradual decrease of insulin sensitivity with aging.

HISS-dependent insulin resistance (HDIR) in aged rats is associated with adiposity, progresses to syndrome X, and is attenuated by a unique antioxidant cocktail

The hypotheses were: HISS-dependent insulin resistance (HDIR) accounts for insulin resistance that occurs with aging; HDIR is the initiating metabolic defect that leads progressively to type 2 diabetes and the metabolic syndrome; a synergistic antioxidant cocktail in chow confers protection against HDIR, subsequent symptoms of diabetes, and the metabolic syndrome. Male Sprague Dawley rats were tested at 9, 26, and 52 weeks to determine their dynamic response to insulin, the HISS (hepatic insulin sensitizing substance)-dependent component of insulin action, and the HISS-independent (direct) insulin action using a dynamic insulin sensitivity test. In young rats, the HISS component accounted for 52.3 ± 2.1% of the response to a bolus of insulin (50 mU/kg) which decreased to 29.8 ± 3.4% at 6 months and 17.0 ± 2.7% at 12 months. HISS action correlated negatively with whole body adiposity and all regional fat depots ( r 2 = 0.67–0.87). The antioxidants (vitamin C, vitamin E, and S-adenosylmethionine) conferred protection of HISS action, fat mass at all sites, blood pressure, postprandial insulin and glucose. Data are consistent with the hypotheses. Early detection and therapy directed towards treatment of HDIR offers a novel therapeutic target.

Hepatic parasympathetic role in insulin resistance on an animal model of hypertension

The hepatic insulin sensitizing substance (HISS) pathway, which includes the hepatic parasympathetic nerves and hepatic nitric oxide (HNO), has been shown to be crucial to the action of insulin on glucose metabolism. Insulin resistance in essential hypertension has been related to parasympathetic dysfunction; thus, we tested the hypothesis that the HISS pathway is impaired in spontaneously hypertensive rats (SHR) when compared with their normotensive controls, Wistar (WIS) and Wistar Kyoto (WKY) rats. A modified euglycemic clamp quantified insulin sensitivity. Differentiation of the HISS-dependent and HISS-independent components of insulin action was achieved by administration of a muscarinic receptor antagonist (atropine, 3 mg/kg) or of a nitric oxide synthase inhibitor ( N g-methyl-arginine, 0.73 mg/kg). Both SHR and WKY had lower postprandial total insulin action when compared with WIS (209.1 ± 13.6 for WKY and 217.8 ± 19.8 for SHR vs 296.1 ± 16.9 mg glucose/kg body weight for WIS, P < .05). Furthermore, we observed that this is due to a decrease of the HISS-dependent component of insulin action (154.8 ± 16.4 for WIS vs 87.1 ± 14.5 for WKY and 55.9 ± 15.6 mg glucose/kg body weight for SHR; P < .05 and P < .001, respectively; data concerning the atropine protocol). Blockade of HISS action by inhibition of hepatic nitric oxide synthase with N g-methyl-arginine showed similar results to those obtained with atropine, suggesting that they indeed act through the same pathway. In conclusion, our results support our hypothesis that impairment of the HISS pathway is responsible for the development of insulin resistance between WIS and SHR.

Hemorrhage Results in Hepatic Insulin-Sensitizing Substance-Dependent Insulin Resistance Mediated by Somatostatin in Rats

Background/Aims: Acute hemorrhage results in hyperglycemia regulated in a redundant manner by adrenal catecholamines and hepatic sympathetic nerves. In addition, insulin secretion is suppressed and insulin resistance is accounted for completely by elimination of the hepatic insulin-sensitizing substance (HISS) component of insulin action. Blockade of HISS action secondary to blood loss leads to a state known as HISS-dependent insulin resistance (HDIR) which results in a decrease in the glucose disposal action of insulin by 33 ± 3%. Methods: This paper describes nine studies that have explored the neuroendocrine control of HDIR that is produced in response to the stress of blood loss. The rapid insulin sensitivity test (RIST), a transient euglycemic clamp, was used to measure insulin sensitivity. To test the role of the adrenergic system, α- and β-adrenergic receptor antagonists, phentolamine and propranolol, were tested for the ability to block HDIR produced by hemorrhage. Results: Neither intervention was effective (32 ± 6 and 36 ± 3%, respectively). Exogenous somatostatin was shown to produce HDIR that could be blocked by the somatostatin receptor antagonist, cyclosomatostatin. Cyclosomatostatin completely blocked the development of HDIR that occurred following hemorrhage (RIST index 214 ± 9 control, 218 ± 9 mg glucose/kg body weight after cyclosomatostatin plus hemorrhage). Conclusions: The adrenergic system is not involved in producing HDIR in response to hemorrhage. Somatostatin appears to be the hormonal regulator of this response and it is suggested that the somatostatin derives from a neural origin within the liver.

Alcohol Suppresses Meal-Induced Insulin Sensitization

In the fed state, the glucose disposal action of insulin can be attributed in approximately equal part to the direct action of insulin and to a hepatic insulin sensitizing substance (HISS) that acts selectively on skeletal muscle. HISS action is absent in the 24-hour fasted state. The objective of this study was to determine whether alcohol administered with a meal affected meal-induced insulin sensitization (MIS). Rats were fasted for 24 hours and anesthetized, and insulin sensitivity was evaluated using the rapid insulin sensitivity test (RIST). A liquid mixed meal was injected into the stomach along with diluted alcohol equivalent to 1, 0.25, and 0.125 mL/kg of ethanol. After 90 minutes, a second RIST was carried out, atropine administered, and a third RIST done. A control fed group received no ethanol and a RIST was determined at 90 minutes; then 1 mL/kg ethanol or water was administered and the RIST was tested 1 hour later. Ethanol co-administered with a meal produced a dose-dependent suppression of MIS. MIS was blocked back to fasting levels by atropine. MIS developed to a maximal level by 90 minutes and was maintained for at least 1 hour more. Ethanol (1 mL/kg) administered after MIS was fully developed resulted in complete suppression of insulin sensitivity back to a fasting level. MIS can be demonstrated in response to gastric administration of a liquid mixed meal in anesthetized rats. Alcohol produces a dose-related suppression of MIS and can completely reverse MIS once it has been developed. The concentrations of alcohol reached were well within levels attained by social drinkers. MIS was confirmed to act through HISS action, and neither MIS nor alcohol affected the HISS-independent component of insulin action.

Pattern of insulin delivery affects hepatic insulin sensitizing substance (HISS) action and insulin resistance

Hepatic insulin sensitizing substance (HISS) action accounts for 55% of the glucose disposal effect of a bolus of insulin in the fed state. To determine the effect of continuous versus pulsatile insulin delivery on HISS action in male Sprague-Dawley rats, insulin sensitivity was assessed using the rapid insulin sensitivity test (RIST) before and after a continuous, pulsatile, or bolus insulin (60 mU/kg i.v.) delivery. There was a significant difference in the RIST index after a continuous insulin infusion (247.9 mg/kg before, 73.2 mg/kg after) but not after 3 pulses where insulin action returned to baseline between pulses (211.6 mg/kg before, 191.0 mg/kg after) or single bolus (205.8 mg/kg before, 189.9 mg/kg after) insulin infusion. If a 3-pulse infusion was timed so that insulin action did not return to baseline between pulses, HISS action was suppressed. Continuous insulin infusion (10-30 min) showed progressive postinfusion blockade of HISS action. To maintain HISS-dependent insulin action, continuous insulin infusions should be avoided.

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.

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.