Hepatalin: the missing link in prediabetes, obesity, and type 2 diabetes.

Hepatalin is a hormone secreted by the liver in response to pulses of insulin after a mixed nutrient meal, but only if the liver receives two permissive synergistic feeding signals from the stomach. Hepatalin stimulates glucose uptake and storage as glycogen in skeletal muscle, heart, and kidney but not liver, intestines, or adipocytes. Insulin acts primarily on liver and fat. Reduced hepatalin action results in postprandial hyperglycemia, compensatory elevation of insulin secretion, and a resultant shift in partitioning of nutrient energy storage from glycogen in muscle, to fat. Chronic hepatalin suppression leads to a predictable chronology of dysfunctions, first diagnosable as Absence of Meal-induced Insulin Sensitization (AMIS) which progresses to prediabetes, adiposity, and type 2 diabetes. The focus on nutrient partitioning and the role of hepatalin allows AMIS to be diagnosed, prevented, and treated, including through the use of lifestyle interventions.

An animal model of gestational obesity and prediabetes: HISS-dependent insulin resistance induced by a high-sucrose diet in Sprague Dawley rats.

This study developed an animal model of gestational obesity and prediabetes in Sprague Dawley rats using 35% sucrose supplementation (SS). Postprandially, insulin stimulates glucose uptake and nutrient partitioning via insulin-dependent action as well as hepatic insulin sensitizing substance (HISS) - dependent action. HISS is glycogenic in heart, kidney, and skeletal muscle (contrasting insulin's lipogenic actions in liver and adipose tissue) and is responsible for the vasodilatory action of insulin. Postprandial insulin sensitivity was quantified using the rapid insulin sensitivity test (RIST). Animals at 15-day gestation and virgin animals received SS for 8 weeks (with a 2-week recovery), 10 weeks, or 22 weeks. SS in pregnant and virgin rats eliminated HISS-dependent glucose uptake, resulting in compensatory hyperinsulinemia and resultant hypertriglyceridemia and obesity. In groups with SS for 8 weeks followed by a 2-week recovery, there was spontaneous partial recovery of HISS-dependent glucose uptake in virgins and complete recovery in pregnancy. The 10-week SS resulted in complete absence of HISS-dependent glucose uptake and produced a model of gestational obesity and prediabetes. The 22-week SS did not produce hyperglycemia or worsen hyperinsulinemia but did increase hypertriglyceridemia above 10-week SS. This substantiates the use of 10-week SS as a model of gestational obesity and (or) prediabetes, allowing further studies into treatments of gestational obesity and insulin resistance.

Gestational postprandial insulin sensitivity in the Sprague Dawley rat: the putative role of hepatic insulin sensitizing substance in glucose partitioning in pregnancy.

Pregnancy requires adaptation of maternal insulin sensitivity. In the fed state, a pulse of insulin stimulates glucose uptake and nutrient energy storage via insulin-dependent as well as hepatic insulin sensitizing substance (HISS)-dependent action. HISS is released by the liver in the fed state in the presence of signals integrated through the liver and a pulse of insulin. HISS promotes glucose storage as glycogen in heart, kidney, and skeletal muscle but not in gut, liver, or adipose tissue. HISS is also responsible for the vasodilatory action previously attributed to insulin. The rapid insulin sensitivity test (RIST), a dynamic euglycemic clamp, can quantitate both HISS-dependent and insulin-dependent glucose uptake. The RIST was used to characterize postprandial insulin sensitivity in the Sprague Dawley rat and the changes in the partitioning of nutrient energy throughout gestation. Early pregnancy demonstrated increased insulin sensitivity attributable to HISS-dependent glucose uptake with unchanged insulin-dependent glucose uptake, preserved plasma insulin concentration, and reduced plasma triglyceride concentration compared to the virgin. In late pregnancy, there was reduced HISS-dependent and insulin-dependent glucose uptake accompanied by increased plasma insulin and triglyceride concentration compared to the virgin. These results suggest an important role for HISS in glucose partitioning in pregnancy.

Postprandial insulin action relies on meal composition and hepatic parasympathetics: dependency on glucose and amino acids: Meal, parasympathetics & insulin action.

Insulin sensitivity (IS) increases following a meal. Meal composition affects postprandial glucose disposal but still remains unclear which nutrients and mechanisms are involved. We hypothesized that gut-absorbed glucose and amino acids stimulate hepatic parasympathetic nerves, potentiating insulin action. Male Sprague-Dawley rats were 24 h fasted and anesthetized. Two series of experiments were performed. (A) IS was assessed before and after liquid test meal administration (10 ml.kg(-1), intraenteric): glucose + amino acids + lipids (GAL, n=6); glucose (n=5); amino acids (n=5); lipids (n=3); glucose + amino acids (GA, n=9); amino acids + lipids (n=3); and glucose + lipids (n=4). (B) Separately, fasted animals were submitted to hepatic parasympathetic denervation (DEN); IS was assessed before and after GAL (n=4) or GA administration (n=4). (A) Both GAL and GA induced significant insulin sensitization. GAL increased IS from 97.9±6.2 mg glucose/kg bw (fasting) to 225.4±18.3 mg glucose/kg bw (P<0.001; 143.6±26.0% potentiation of IS); GA increased IS from 109.0±6.6 to 240.4±18.0 mg glucose/kg bw (P<0.001; 123.1±13.4% potentiation). None of the other meals potentiated IS. (B) GAL and GA did not induce a significant insulin sensitization in DEN animal. To achieve maximal insulin sensitization following a meal, it is required that gut-absorbed glucose and amino acids trigger a vagal reflex that involves hepatic parasympathetic nerves.

Acute glucagon induces postprandial peripheral insulin resistance.

Glucagon levels are often moderately elevated in diabetes. It is known that glucagon leads to a decrease in hepatic glutathione (GSH) synthesis that in turn is associated with decreased postprandial insulin sensitivity. Given that cAMP pathway controls GSH levels we tested whether insulin sensitivity decreases after intraportal (ipv) administration of a cAMP analog (DBcAMP), and investigated whether glucagon promotes insulin resistance through decreasing hepatic GSH levels.Insulin sensitivity was determined in fed male Sprague-Dawley rats using a modified euglycemic hyperinsulinemic clamp in the postprandial state upon ipv administration of DBcAMP as well as glucagon infusion. Glucagon effects on insulin sensitivity was assessed in the presence or absence of postprandial insulin sensitivity inhibition by administration of L-NMMA. Hepatic GSH and NO content and plasma levels of NO were measured after acute ipv glucagon infusion. Insulin sensitivity was assessed in the fed state and after ipv glucagon infusion in the presence of GSH-E. We founf that DBcAMP and glucagon produce a decrease of insulin sensitivity, in a dose-dependent manner. Glucagon-induced decrease of postprandial insulin sensitivity correlated with decreased hepatic GSH content and was restored by administration of GSH-E. Furthermore, inhibition of postprandial decrease of insulin sensitivity L-NMMA was not overcome by glucagon, but glucagon did not affect hepatic and plasma levels of NO. These results show that glucagon decreases postprandial insulin sensitivity through reducing hepatic GSH levels, an effect that is mimicked by increasing cAMP hepatic levels and requires physiological NO levels. These observations support the hypothesis that glucagon acts via adenylate cyclase to decrease hepatic GSH levels and induce insulin resistance. We suggest that the glucagon-cAMP-GSH axis is a potential therapeutic target to address insulin resistance in pathological conditions.

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.

Fatty Liver and Fatty Heart-Where do They Stand in the AMIS Syndrome?

Meal-induced insulin sensitization (MIS) refers to the augmented glucose uptake response to insulin following a meal. Absence of MIS (AMIS) causes significant decrease in post-meal glucose disposal leading to postprandial hyperglycemia, hyperinsulinemia, hyperlipidemia, adiposity, increased free radical stress, and a cluster of progressive metabolic, vascular, and cardiac dysfunctions referred to as the AMIS syndrome. We tested the hypothesis that fat accumulation in the liver and heart is part of the AMIS syndrome. Questions examined in the study: (1) Is prediabetic fat accumulation in the heart and liver a component of the AMIS syndrome? (2) Is fatty liver a cause or consequence of peripheral insulin resistance? (3) Is early cardiac dysfunction in the AMIS syndrome attributable to fat accumulation in the heart? and (4) Can the synergistic antioxidant cocktail SAMEC (S-adenosylmethionine, vitamin E, and vitamin C), known to benefit MIS, affect cardiac and hepatic triglyceride levels? Four animal models of AMIS were used in aged male Sprague-Dawley rats (52 weeks ± sucrose ± SAMEC), compared with young controls (nine weeks). Fat accumulation in the heart was not significant and therefore cannot account for the early cardiac dysfunction. Hepatic triglycerides increased only in the most severe AMIS model but the small changes correlated with the much more rapidly developing peripheral adiposity. Systemic adiposity represents an early stage, whereas accumulation of cardiac and hepatic triglycerides represents a late stage of the prediabetic AMIS syndrome. Fat accumulation in the liver is a consequence, not a cause, of AMIS. SAMEC protected against the sucrose effects on whole body adiposity and hepatic lipid accumulation.

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.

Exercise enhancement of hepatic insulin-sensitising substance-mediated glucose uptake in diet-induced prediabetic rats.

The sensitisation of insulin action in response to a meal (i.e. meal-induced insulin sensitisation, MIS) represents one of the major means of increased glucose disposal in peripheral tissues during the postprandial state. MIS occurs when the release of hepatic insulin-sensitising substance (HISS) stimulates skeletal muscle glucose uptake. Our previous study had demonstrated that the HISS pathway is impaired in age-associated insulin resistance, and in the rats which were part of that study, voluntary exercise improved the response to insulin by restoring HISS action. The present study tests the hypothesis that voluntary exercise would reverse insulin resistance in diet-induced models of insulin resistance, and that the benefits are attributed through the improvement in HISS action. In this study, two experimental diets, a high-fat diet (for 4 weeks) and 35 % sucrose solution (for 9 and 16 weeks), were used to induce insulin resistance in rats. These rats were assigned to the exercise/no-exercise intervention. The effect of 7 d voluntary running-wheel exercise was determined by measuring insulin- and HISS action in the exercised rats and comparing them with the non-exercised controls. Voluntary exercise reversed insulin resistance, caused by dietary manipulation, through restoration of the HISS action. The direct insulin action was not changed by either diet or exercise. The metabolic improvements and reduced adiposity correlated with the extent of reversal of HISS action induced by exercise. Exercise improves insulin sensitivity in diet-induced insulin resistance primarily by restoration of HISS-mediated glucose uptake.

Postprandial but not fasting insulin resistance is an early identifier of dysmetabolism in overweight subjects.

The dynamic response to insulin is highly potentiated after meal ingestion, and this meal-induced insulin sensitization (MIS) in healthy subjects is dependent on cholinergic mechanisms. The main objective of this study was to test the hypothesis that the reduced response to insulin observed in moderately overweight subjects, in comparison with control lean subjects, is due to MIS impairment and not to a reduction in the direct hypoglycemic action of insulin. Both lean and overweight male subjects were recruited. Insulin sensitivity (IS) was assessed by the rapid insulin sensitivity test (RIST) performed after a 24 h fast, as well as after a standardized meal. Fasting glucose disposal was similar between lean and overweight subjects. Following the meal, glucose disposal increased more extensively in lean than overweight subjects. The insulin profiles, in both fasted and fed states, were superimposable, suggesting that the absence of a factor other than insulin is responsible for the decreased postprandial insulin sensitivity observed in overweight subjects. Our data suggest that in overweight subjects, MIS contribution is decreased, which is responsible for the postprandial impaired IS observed and is suggested to be the cause, not effect, of mild adiposity.

Absence of meal-induced insulin sensitization (AMIS) in aging rats is associated with cardiac dysfunction that is protected by antioxidants.

We have previously demonstrated that progressive development of absence of meal-induced insulin sensitization (AMIS) leads to postprandial hyperglycemia, compensatory hyperinsulinemia, resultant hyperlipidemia, increased oxidative stress, and obesity, progressing to syndrome X in aging rats. The present study tested the hypothesis that progressive development of AMIS in aging rats further resulted in deterioration in cardiac performance. Anesthetized male Sprague-Dawley rats were tested at 9, 26, and 52 wk to determine their dynamic response to insulin and cardiac function. Dynamic insulin sensitivity was determined before and after atropine to quantitate hepatic insulin sensitizing substance (HISS)-dependent and -independent insulin action. Cardiac performance was evaluated using a Millar pressure-volume conductance catheter system. AMIS developed with age, as demonstrated by significant decrease in HISS-dependent insulin action, and this syndrome was increased by sucrose supplementation and inhibited by the antioxidant treatment. Associated with progressive development of AMIS, aging rats showed impaired cardiac performance, including the reduction in cardiac index, heart rate, dP/dt(max), dP/dt(min), ejection fraction and decreased slope of left ventricular end-systolic pressure-volume relationship, and increased relaxation time constant of left ventricular pressure as well as increased left ventricular end-diastolic pressure. Total peripheral vascular resistance also increased with age. Sucrose supplementation and antioxidant treatment, respectively, potentiated and attenuated cardiac dysfunction associated with age. In addition, poor cardiac performance correlated closely with the development of AMIS. These results indicate that AMIS is the first metabolic defect that leads to homeostatic disturbances and dysfunctions, including cardiovascular diseases.

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 5 min) was quantified using the rapid insulin sensitivity test (RIST). Gastric injection of a liquid test meal or i.v. administration of N-acetylcysteine in 24 h 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 24 h 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.

HISS, not insulin, causes vasodilation in response to administered insulin.

Meal-induced sensitization to the dynamic actions of insulin results from the peripheral actions of a hormone released by the liver (hepatic insulin sensitizing substance or HISS). Absence of meal-induced insulin sensitization results in the pathologies associated with cardiometabolic risk. Using three protocols that have previously demonstrated HISS metabolic action, we tested the hypothesis that HISS accounts for the vasodilation that has been associated with insulin. The dynamic metabolic actions of insulin and HISS were determined using a euglycemic clamp in response to a bolus of 100 mU/kg insulin in pentobarbital-anesthetized Sprague-Dawley rats. Hindlimb blood flow was measured with an ultrasound flow probe on the aorta above the bifurcation of the iliac arteries. Fed rats showed tightly coupled metabolic and vascular responses, which were completed by 35 min after insulin administration. Blocking HISS release, with the use of atropine or hepatic surgical denervation, eliminated the HISS-dependent metabolic and vascular responses to insulin administration. Physiological suppression of HISS release occurs with fasting. In 24-h fasted rats, HISS metabolic and vascular actions were absent, and atropine had no effect on either action. Fed rats with liver denervation did not release HISS, but intraportal venous infusion of acetylcholine, to mimic the permissive parasympathetic nerve signal, restored the ability of insulin to cause HISS release and restored both the metabolic and vascular actions. These studies report vascular actions of HISS for the first time and demonstrate that HISS, not insulin action, results in the peripheral vasodilation generally attributed to insulin.

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.

Caffeine-induced natriuresis and diuresis via blockade of hepatic adenosine-mediated sensory nerves and a hepatorenal reflex.

The hepatorenal reflex, activated by intrahepatic adenosine, is involved in the regulation of urine production in healthy rats and renal pathogenesis secondary to liver injury. Hepatic adenosine A1 receptors regulate the hepatorenal reflex. The aim of the present study was to evaluate whether caffeine mediates renal natriuresis and diuresis in healthy and diseased liver through this mechanism. Rats were anesthetized and instrumented to monitor systemic, hepatic, and renal circulation and urine production. Intrahepatic (intraportal but not intravenous) caffeine (5 mg·kg-1) increased urine flow (~82%) in healthy rats. This effect was abolished by liver denervation. Intraportal infusion of adenosine decreased urine production, and this response was abolished by intraportal but not intravenous caffeine. Liver injury was induced by intraperitoneal injection of thioacetamide (500 mg·kg-1), and functional assessment was performed 24 h later. Liver injury was associated with lower (~30%) glomerular filtration rate, lower (~18%) renal arterial blood flow, and lower urine production. Intraportal but not intravenous caffeine improved basal urine production and renal ability to increase urine production in response to saline overload. The liver-dependent diuretic effect of caffeine is consistent with the hypothesis for the adenosine-mediated mechanism of hepatorenal syndrome.

High-fat diet results in postprandial insulin resistance that involves parasympathetic dysfunction.

Different diets have distinct impacts on glucose homoeostasis, for which insulin sensitivity (IS) after a meal (postprandial IS) is highly relevant. Postprandial IS depends upon hepatic parasympathetic activation and glutathione content elevation. We tested the hypothesis that postprandial IS is compromised in high-fat diet (HFD)-induced obesity. Sprague-Dawley rats were fed a standard diet (STD, n 10), 1-week HFD (n 9) or 4-week HFD (n 8). IS was tested in postprandial state using the rapid IS test (RIST) before and after the blockade of the parasympathetic nerves (atropine, 1 mg/kg); parasympathetic-dependent IS was obtained from the difference between control and post-atropine RIST. Fasting IS was also assessed in the STD-fed rats (n 4) and 4-week HFD-fed rats (n 3) using the RIST. Whole-body fat and regional fat pads were heavier in the 1-week HFD-fed rats (79.8 (SE 7.9) and 23.7 (SE 1.0) g, respectively) or 4-week HFD-fed rats (106.5 (SE 6.1) and 30.1 (SE 1.4) g, respectively) than in the STD-fed rats (32.5 (SE 3.7) and 13.7 (SE 1.0) g, respectively; P < 0.001). Fasted-state IS was similar between the groups studied. Postprandial IS was higher in the STD-fed rats (185.8 (SE 5.6) mg glucose/kg body weight (bw)) than in both the 1-week HFD-fed rats (108.8 (SE 2.9) mg glucose/kg bw; P < 0.001) and 4-week HFD-fed rats (69.3 (SE 2.6) mg glucose/kg bw; P < 0.001). Parasympathetic-dependent IS was impaired in both HFD-fed groups (STD, 108.9 (SE 3.9) mg glucose/kg bw; 1-week HFD, 38.6 (SE 4.2) mg glucose/kg bw; 4-week HFD, 5.4 (SE 1.7) mg glucose/kg bw; P < 0.001). Total (postprandial) and parasympathetic-dependent IS correlated negatively with whole-body fat (R² 0.81 and 0.87) and regional adiposity (R² 0.85 and 0.79). In conclusion, fat accumulation induced by HFD is associated with postprandial insulin resistance, but not with fasting insulin resistance. HFD-associated postprandial insulin resistance is largely mediated by impairment of parasympathetic-dependent insulin action, which correlates with adiposity.

Attenuation of age- and sucrose-induced insulin resistance and syndrome X by a synergistic antioxidant cocktail: the AMIS syndrome and HISS hypothesis.

Absence of meal-induced insulin sensitization (AMIS) results in a predictable progression of dysfunctions, including postprandial hyperglycemia, compensatory hyperinsulinemia, resultant hyperlipidemia, increased oxidative stress, and obesity, progressing to syndrome X and diabetes. To one year of age, rats show a slow development of AMIS, but this can be potentiated by addition of a low-dose sucrose supplement to the diet. Provision of a synergistic antioxidant cocktail consisting of S-adenosylmethionine, vitamin E, and vitamin C (Samec) attenuates the rate and extent of development of AMIS in both normal aging animals and in aging animals on the sucrose diet. Adiposity, assessed from weighed regional fat masses and from bioelectrical impedance to estimate whole-body adiposity, correlated strongly with AMIS (r2 = 0.7-0.8). Rats given the sucrose supplement had accelerated AMIS and developed fasting hyperinsulinemia and postprandial hyperglycemia, hyperlipidemia, hyperinsulinemia, and adiposity. Samec completely compensated for the negative impact of this sucrose supplement and attenuated development of the associated dysfunctions. AMIS is explained by the HISS (hepatic insulin-sensitizing substance) hypothesis, which is outlined in the paper.

Acetylcholinesterase antagonist potentiated insulin action in fed but not fasted state.

The glucose disposal effect of insulin is doubled in response to a meal. This meal-induced insulin sensitization results from insulin acting on the liver, in the presence of a permissive hepatic parasympathetic feeding signal and elevated hepatic glutathione (GSH), to release hepatic insulin-sensitizing substance (HISS), a hormone that acts selectively on skeletal muscle to stimulate insulin-mediated glucose uptake. Blockade of the parasympathetic feeding signal to the liver, either through surgical denervation or atropine-mediated antagonism of hepatic muscarinic receptors, eliminates the HISS response, resulting in HISS-dependent insulin resistance (HDIR) and decreasing the response to insulin by approximately 55% in the fed state. Insulin action in Sprague-Dawley rats, as determined with a rapidly sampled, transient euglycemic clamp in response to insulin (50 mU/kg), is decreased in a dose-dependent manner by atropine. In this study, we have used the ED75 atropine-induced model of HDIR. After a submaximal dose of atropine, potentiation of the remaining parasympathetic effect with the acetylcholinesterase antagonist neostigmine significantly restored postprandial insulin sensitization in a dose-dependent manner with peak effect at 0.1 microg/kg/min. Neostigmine reversed the insulin resistance induced by partial fasting and partial muscarinic inhibition (hepatic GSH levels are at fed levels), but not that induced by surgical hepatic denervation (GSH normal, no nerve signal) or 24-h fasting (low GSH). No potentiation of the response to insulin by neostigmine occurred in normal, fed rats. The data suggest the use of either direct or indirectly acting cholinergic agonists for the treatment of impaired postprandial insulin sensitization.