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Recent studies in animal and human models have revealed that free fatty acid (FFA) release from adipose tissue is oscillatory. We have shown in our laboratory that these oscillations are controlled by the sympathetic nervous system (SNS). Although FFAs have been shown to directly stimulate glucose production [endogenous glucose production (EGP)] by the liver and to reduce peripheral glucose utilization, whether the specific pattern of FFA release affects glucose metabolism is unknown. The aim of this study was to examine the effects of pulsatile vs. constant infusion of FFA on glucose homeostasis in the canine model. Euglycemic clamps with basal insulin replacement (0.1 mU x [kg.sup.-1] x [min.sup.-1] insulin) were performed in dogs (n = 8) during infusion of saline (SAL) or the medium-chain fatty acid octanoate, which was given by either pulsatile infusion (PUL: 10 mmol over 2 rain every 10 min) or continuous infusion (C-INF: 1 mmol/min) designed to achieve equivalent total FFA mass. Endogenous lipolytic pulses were suppressed with the [[beta].sub.3]-specific adrenergic receptor antagonist bupranolol. PUL infusion elicited a pulsatile pattern of FFA in circulation with average maximum pulse height of 0.82 [+ or -] 0.04 mM, whereas C-INF FFA levels reached 0.47 [+ or -] 0.03 mM (fasting levels) and were maintained throughout. Glucose uptake was not affected by PUL; however, C-INF significantly reduced glucose uptake compared with both SAL and PUL. Steady-state EGP increased by >90% from basal steady state during PUL but did not change during either SAL or C-INF. Thus, pulsatile FFA infusion led to an increase in EGP while preserving glucose disposal. These data suggest that the pattern of FFA may have a role in regulation of glucose homeostasis, which may have consequences in the obese or insulin-resistant state where the SNS is known to be altered. octanoate; oscillations; lipolysis; sympathetic nervous system doi: 10.1152/ajpendo.00427.2009.

The full impact of the liver, through both glucose production and uptake, on systemic glucose appearance cannot be readily studied in a classical glucose clamp because hepatic glucose metabolism is regulated not only by portal insulin and glucose levels but also portal glucose delivery (the portal signal). In the present study, we modified the classical glucose clamp by giving exogenous glucose through portal vein, the 'portal glucose infusion (PoG)-glucose clamp', to determine the net hepatic effect on postprandial systemic glucose supply along with the measurement of whole body glucose disposal. By comparing systemic rate of glucose appearance (Ra) with portal glucose infusion rate ([PoG.sub.inf]), we quantified 'net hepatic glucose addition (NHGA)' in the place of endogenous glucose production determined in a regular clamp. When PoG-glucose clamps (n = 6) were performed in dogs at basal insulinemia and hyperglycemia (~150 mg/dl, portal and systemic), we measured consistently higher Ra than [PoG.sub.inf] (4.2 [+ or -] 0.6 vs. 2.9 [+ or -] 0.6 mg * [kg.sup.-1] * [min.sup.-1] at steady state, P < 0.001) and thus positive NHGA at 1.3 [+ or -] 0.1 mg * [kg.sup.-1] * [min.sup.-1], identifying net hepatic addition of glucose to portal exogenous glucose. In contrast, when PoG-glucose clamps (n = 6) were performed at hyperinsulinemia (~250 pmol/l) and systemic euglycemia (portal hyperglycemia due to portal glucose infusion), we measured consistently lower [R.sub.a] than [PoG.sub.inf] (13.1 [+ or -] 2.4 vs. 14.3 [+ or -] 2.4 mg * [kg.sup.-1] * [min.sup.-1], P < 0.001), and therefore negative NHGA at - 1.1 [+ or -] 0.1 mg * [kg.sup.-1] * [min.sup.-l], identifying a switch of the liver from net production to net uptake of portal exogenous glucose. Steady-state whole body glucose disposal was 4.1 [+ or -] 0.5 and 13.0 [+ or -] 2.4 mg * [kg.sup.-1] * [min.sup.-1], respectively, determined as in a classical glucose clamp. We conclude that the PoG-glucose clamp, simulating postprandial glucose entry and metabolism, enables simultaneous assessment of the net hepatic effect on postprandial systemic glucose supply as well as whole body glucose disposal in various animal models (rodents, dogs, and pigs) with established portal vein catheterization. net hepatic glucose addition doi: 10.1152/ajpendo.00280.2009

Am J Physiol Endocrinol Metab 298: E38-E48, 2010. First published October 20, 2009; doi:10.1152/ajpendo.00466.2009.--Human type 2 diabetes mellitus (T2DM) is often characterized by obesity-associated insulin resistance (IR) and [beta]-cell function deficiency. Development of relevant large animal models to study T2DM is important and timely, because most existing models have dramatic reductions in pancreatic function and no associated obesity and IR, features that resemble more T1DM than T2DM. Our goal was to create a canine model of T2DM in which obesity-associated IR occurs first, followed by moderate reduction in [beta]-cell function, leading to mild diabetes or impaired glucose tolerance. Lean dogs (n = 12) received a high-fat diet that increased visceral (52%, P < 0.001) and subcutaneous (130%, P < 0.001) fat and resulted in a 31% reduction in insulin sensitivity ([S.sub.1]) (5.8 [+ or -] 0.7 X [10.sup.-4] to 4.1 [+ or -] 0.5 x [10.sup.-4] [micro]U x [ml.sup.-1] x [min.sup.-1], P < 0.05). Animals then received a single low dose of streptozotocin (STZ; range 30-15 mg/kg). The decrease in [beta]-cell function was dose dependent and resulted in three diabetes models: 1) frank hyperglycemia (high STZ dose); 2) mild T2DM with normal or impaired fasting glucose (FG), 2-h glucose >200 mg/dl during OGTT and 77-93% [AIR.sub.g] reduction (intermediate dose); and 3) prediabetes with normal FG, normal 2-h glucose during OGTT and 17-74% [AIR.sub.g] reduction (low dose). Twelve weeks after STZ, animals without frank diabetes had 58% more body fat, decreased [beta]-cell function (17-93%), and 40% lower [S.sub.I]. We conclude that high-fat feeding and variable-dose STZ in dog result in stable models of obesity, insulin resistance, and 1) overt diabetes, 2) mild T2DM, or 3) impaired glucose tolerance. These models open new avenues for studying the mechanism of compensatory changes that occur in T2DM and for evaluating new therapeutic strategies to prevent progression or to treat overt diabetes. obesity; animal models; streptozotocin; insulin secretion

We investigated whether rimonabant, a type 1 cannabinoid receptor antagonist, reduces visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in dogs maintained on a hypercaloric high-fat diet (HHFD). To determine whether energy expenditure contributed to body weight changes, we also calculated resting metabolic rate. Twenty male dogs received either rimonabant (1.25 mg x [kg.sup.-1] x [day.sup.-1], orally; n = 11) or placebo (n = 9) for 16 wk, concomitant with a HHFD. VAT, SAT, and nonfat tissue were measured by magnetic resonance imaging. Resting metabolic rate was assessed by indirect calorimetry. By week 16 of treatment, rimonabant dogs lost 2.5% of their body weight (P = 0.029), whereas in placebo dogs body weight increased by 6.2% (P < 0.001). Rimonabant reduced food intake (P = 0.027), concomitant with a reduction of SAT by 19.5% (P < 0.001). In contrast with the VAT increase with placebo (P < 0.01), VAT did not change with rimonabant. Nonfat tissue remained unchanged in both groups. Body weight loss was not associated with either resting metabolic rate ([r.sup.2] = 0.24; P = 0.154) or food intake ([r.sup.2] = 0.24; P = 0.166). In conclusion, rimonabant reduced body weight together with a reduction in abdominal fat, mainly because of SAT loss. Body weight changes were not associated with either resting metabolic rate or food intake. The findings provide evidence of a peripheral effect of rimonabant to reduce adiposity and body weight, possibly through a direct effect on adipose tissue. adipose tissue; body weight; energy expenditure; magnetic resonance; resting metabolic rate

The effects of insulin on the suppression of lipolysis are neither fully understood nor quantified. We examined a variety of mathematical models analogous to the minimal model of glucose disposal (MMG) to quantify the combined influence of insulin on lipolysis and glucose disposal during an insulin-modified frequently sampled intravenous glucose tolerance test. The tested models, which include two previously published ones, consisted of separate compartments for plasma free fatty acids (FFA), glucose, and insulin. They differed in the number of compartments and in the action of insulin to suppress lipolysis that decreased the plasma FFA level. In one category of models, a single insulin compartment acted on both glucose and FFA simultaneously. In a second category, there were two insulin compartments, each acting on FFA and glucose independently. For each of these two categories, we tested 11 variations of how insulin suppressed lipolysis. We also tested a model with an additional glucose compartment that acted on FFA. These 23 models were fit to the plasma FFA and glucose concentrations of I02 subjects individually. Using Bayesian model comparison methods, we selected the model that best balanced fit and minimized model complexity. In the best model, insulin suppressed lipolysis via a Hill function through a remote compartment that acted on both glucose and FFA simultaneously, and glucose dynamics obeyed the classic MMG. free fatty acids; insulin resistance; mathematical model

Exenatide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic used in the treatment of type 2 diabetes. There is increasing evidence that GLP-1 can influence glycemia not only via pancreatic (insulinotropic and glucagon suppression) and gastric-emptying effects, but also via an independent mechanism mediated by portal vein receptors. The aim of our study was to investigate whether exenatide has an islet-and gastric-independent glycemia-reducing effect, similar to GLP-1. First, we administered mixed meals, with or without exenatide (20 [micro]g sc) to dogs. Second, to determine whether exenatide-induced reduction in glycemia is independent of slower gastric emptying, in the same animals we infused glucose intraportally (to simulate meal test glucose appearance) with exenatide, exenatide + the intraportal GLP-1 receptor antagonist exendin-(9-39), or saline. Exenatide markedly decreased postprandial glucose: net 0- to 135-rain area under the curve = +526 [+ or -] 315 and -536 [+ or -] 197 mg*[dl.sup.-1]*[min.sup.-1] with saline and exenatide, respectively (P < 0.05). Importantly, the decrease in plasma glucose occurred without a corresponding increase in postprandial insulin but was accompanied by delayed gastric emptying and lower glucagon. Significantly lower glycemia was induced by intraportal glucose infusion with exenatide than with saline (92 [+ or -] 1 vs. 97 [+ or -] 1 mg/dl, P < 0.001) in the absence of hyperinsulinemia or glucagon suppression. The exenatide-induced lower glycemia was partly reversed by intraportal exendin-(9-39): 95 [+ or -] 3 and 92 [+ or -] 3 mg/dl with exenatide + antagonist and exenatide, respectively (P < 0.01). Our results suggest that, similar to GLP-1, exenatide lowers glycemia via a novel mechanism independent of islet hormones and slowing of gastric emptying. We hypothesize that receptors in the portal vein, via a neural mechanism, increase glucose clearance independent of islet hormones. glucagon-like peptide-1; insulin-independent; glucose regulation

Obesity is strongly associated with hyperinsulinemia and insulin resistance, both primary risk factors for type 2 diabetes. It has been thought that increased fasting free fatty acids (FFA) may be responsible for the development of insulin resistance during obesity, causing an increase in plasma glucose levels, which would then signal for compensatory hyperinsulinemia. But when obesity is induced by fat feeding in the dog model, there is development of insulin resistance and a marked increase in fasting insulin despite constant fasting FFA and glucose. We examined the 24-h plasma profiles of FFA, glucose, and other hormones to observe any potential longitudinal postprandial or nocturnal alterations that could lead to both insulin resistance and compensatory hyperinsulinemia induced by a high-fat diet in eight normal dogs. We found that after 6 wk of a high-fat, hypercaloric diet, there was development of significant insulin resistance and hyperinsulinemia as well as accumulation of both subcutaneous and visceral fat without a change in either fasting glucose or postprandial glucose. Moreover, although there was no change in fasting FFA, there was a highly significant increase in the nocturnal levels of FFA that occurred as a result of fat feeding. Thus enhanced nocturnal FFA, but not glucose, may be responsible for development of insulin resistance and fasting hyperinsulinemia in the fat-fed dog model. obesity; diurnal doi: 10.1152/ajpendo.00669.2006

During insulin resistance, glucose homeostasis is maintained by an increase in plasma insulin via increased secretion and/or decreased first-pass hepatic insulin extraction. However, the relative importance of insulin secretion vs. clearance to compensate for insulin resistance in obesity has yet to be determined. This study utilizes the fat-fed dog model to examine longitudinal changes in insulin secretion and first-pass hepatic insulin extraction during development of obesity and insulin resistance. Six dogs were fed an isocaloric diet with an ~8% increase in fat calories for 12 wk and evaluated at weeks 0, 6, and 12 for changes in 1) insulin sensitivity by euglycemic-hyperinsulinemic clamp, 2) first-pass hepatic insulin extraction by direct assessment, and 3) glucose-stimulated insulin secretory response by hyperglycemic clamp. We found that 12 wk of a fat diet increased subcutaneous and visceral fat as assessed by MR imaging. Consistent with increased body fat, the dogs exhibited a ~30% decrease in insulin sensitivity and fasting hyperinsulinemia. Although insulin secretion was substantially increased at week 6, [beta]-cell sensitivity returned to prediet levels by week 12. However, peripheral hyperinsulinemia was maintained because of a significant decrease in first-pass hepatic insulin extraction, thus maintaining hyperinsulinemia, despite changes in insulin release. Our results indicate that when obesity and insulin resistance are induced by an isocaloric, increased-fat diet, an initial increase in insulin secretion by the [beta]-cells is followed by a decrease in first-pass hepatic insulin extraction. This may provide a secondary physiological mechanism to preserve pancreatic [beta]-cell function during insulin resistance. hyperinsulinemia; insulin resistance; obesity; insulin secretion; insulin clearance doi: 10.1152/ajpendo.00351.2006

The insulinotropic intestinal hormone GLP-1 is thought to exert one of its effects by direct action on the pancreatic [beta]-cell receptors. GLP-1 is rapidly degraded in plasma, such that only a small amount of the active form reaches the pancreas, making it questionable whether this amount is sufficient to produce a direct incretin effect. The aim of our study was to assess, in a dog model, the putative incretin action of GLP-1 acting directly on the [beta]-cell in the context of postprandial rises in GLP-1 and glucose. Conscious dogs were fed a high-fat, high-carbohydrate meal, and insulin response was measured. We also infused systemic glucose plus GLP-1, or glucose alone, to simulate the meal test values of these variables and measured insulin response. The results were as follows: during the meal, we measured a robust insulin response (52 [+ or -] 9 to 136 [+ or -] 14 pmol/1, P < 0.05 vs. basal) with increases in portal glucose and GLP-1 but only limited increases in systemic glucose (5.3 [+ or -] 0.1 to 5.7 [+ o r-] 0.1 mmol/1, P = 0.1 vs. basal) and GLP-1 (6 [+ or -] 0 to 9 [+ or -] 1 pmol/1, P = 0.5 vs. basal). Exogenous infusion of systemic glucose and GLP-1 produced a moderate increase in insulin (43 [+ or -] 5 to 84 [+ or -] 15 pmol/1, 43% of the meal insulin). However, infusion of glucose alone, without GLP-1, produced a similar insulin response (37 [+ or -] 6 to 82 [+ or -] 14 pmol, 53% of the meal insulin, P = 0.7 vs. glucose and GLP-1 infusion). In conclusion, in dogs with postprandial rises in systemic glucose and GLP-1, the hormone might not have a direct insulinotropic effect and could regulate glycemia via indirect, portohepatic-initiated neural mechanisms. glucagon-like peptide-1; insulin secretion; portal; meal test; neural mechanism

The mechanism by which increased central adiposity causes hepatic insulin resistance is unclear. The 'portal hypothesis' implicates increased lipolytic activity in the visceral fat and therefore increased delivery of free fatty acids (FFA) to the liver, ultimately leading to liver insulin resistance. To test the portal hypothesis at the transcriptional level, we studied expression of several genes involved in glucose and lipid metabolism in the fat-ted dog model with visceral adiposity vs. controls (n = 6). Tissue samples were obtained from dogs after 12 wk of either moderate fat (42% calories from fat; n = 6) or control diet (35% calories from fat). Northern blot analysis revealed an increase in the ratio of visceral to subcutaneous (v/s ratio) mRNA expression of both lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]). In addition, the ratio for sterol regulatory element-binding transcription factor-1 (SREBP-1) tended to be higher in fat-ted dogs, suggesting enhanced lipid accumulation in the visceral fat depot. The v/s ratio of hormone-sensitive lipase (HSL) increased significantly, implicating a higher rate of lipolysis in visceral adipose despite hyperinsulinemia in obese dogs. In fat-fed dogs, liver SREBP-1 expression was increased significantly, with a tendency for increased fatty acid-binding protein (FABP) expression. In addition, glucose-6-phosphatase (G-6-Pase) and phospboenolpyruvate carboxykinase (PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat-fed animals vs. controls. Moreover, insulin receptor binding was 50% lower in fat-fed dogs. Increased gene expression promoting lipid accumulation and lipolysis in visceral fat, as well as elevated rate-limiting gluconeogenic enzyme expression in the liver, is consistent with the portal theory. Further studies will need to be performed to determine whether FFA are involved directly in this pathway and whether other signals (either humoral and/or neural) may contribute to the development of hepatic insulin resistance observed with visceral obesity. visceral fat; lipolysis; gluconeogenic enzymes; messenger ribonucleic acid; dogs

Research was conducted to investigate the performance of the combined model approach in estimating prehepatic insulin secretion. Equations were developed to represent the extravascular compartments for C-peptides and the exchange rates between the first and second compartments. Results showed systematic patterns at three error levels. They also indicated that residual time course pattern is directly correlated with a structural deficiency in the model.

A radioactive labeling nuclear magnetic resonance technique has been developed to estimate relative cardiac anaplerosis using [13C] glutamate. The technique is not impaired by isotopic biochemical precursor pyruvic acid sources. Mathematical analysis and physiological pathways involving pyruvate and the citric acid cycle are illustrated. The effects of biochemicals malate-aspartate shuttle are assessed.

The effect of insulin on whole body glucose distribution kinetics was investigated in anesthetized dogs. Whole body kinetic analysis of plasma L-glucose was performed using a three- or four-compartment model. Lymph L-glucose data were compared with the results of plasma L-glucose analysis. Data indicated that insulin does not affect whole body glucose distribution. Glucose dynamics were best predicted by a four-compartment model.

A new model is proposed for the estimation of the rate of the flux through the citric acid cycle (CAC) in heart without the use of differential equations. The conventional models require elaborate numerical solutions for differential equations which describe the CAC in the heart. The new model is accurate and also simple in design and usage.

The Modified Minimal Model method, used in longitudinally studying glucoregulation and insulin sensitivity in restricted and control monkeys, reveals that dietary restriction reduces insulin and glucose levels and enhances insulin sensitivity in monkeys. Observations of variation in glucose regulation and insulin sensitivity over a period of 30 months show that variations in adiposity are correlated with insulin variations.

A syntactic modeling approach to biochemical fluxes reveals that 32 glutamate isotopomers are formed into four groups. The four groups possess similar intragroup dynamics, but varying amplitudes. The relative area of multiplets of the nuclear magnetic resonance spectrum may be calculated from the relative abundance of each isotopomer.

Experiments involving the administration of intravenous glucose tolerance test on conscious dogs reveals that transendothelial insulin transport is crucial for insulin action. Interstitial insulin triggers tissue response leading to glucose disappearance. Blood flow changes do not affect insulin transport and the resultant glucose uptake in vivo. The lymph insulin level is correlated to the rate of glucose disappearance.

The measurement error in time courses and other continuous curves is determined by a new technique. The original curve which has no errors is reconstructed in this type of error estimate. The assumption of the measure of the error data is made initially, and optimal segments are used in smoothening the data so that the smoothened curve misses the data points by an amount equal to the assumed measurement error. This new type of measurement error estimation and the reconstruction of error free data curves is applied in data analysis and experimental design.

In a longitudinal study of the effects of moderate (70%) dietary restriction (DR) on aging, plasma glucose and insulin concentrations were measured from semiannual, frequently sampled intravenous glucose tolerance tests (FSIGTT) in 30 adult male rhesus monkeys. FSIGTT data were analyzed with Bergman's minimal model, and analysis of covariance revealed that restricted (R) monkeys exhibited increased insulin sensitivity ([S.sub.I], P [is less than] 0.001) and plasma glucose disappearance rate ([K.sub.G], P = 0.015), and reduced fasting plasma insulin ([I.sub.b], P [is less than] 0.001) and insulin response to glucose ([AIR.sub.G], P = 0.023) compared with control (C; ad libitum-fed) monkeys. DR reduced the baseline fasting hyperinsulinemia of two R monkeys, whereas four C monkeys have maintained from baseline, or subsequently developed, fasting hyperinsulinemia; one has progressed to diabetes. Compared with only the normoinsulinemic C monkeys, R monkeys exhibited similarly improved FSIGTT and minimal-model parameters. Thus chronic DR not only has protected against the development of insulin resistance in aging rhesus monkeys, but has also improved glucoregulatory parameters compared with those of otherwise normoinsulinemic monkeys. glucose metabolism; insulin; minimal model; energy restriction

Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin. Am J Physiol Endocrinol Metab 279: E630-E637, 2000.--We have shown that insulin controls endogenous glucose production (EGP) indirectly, via suppression of adipocyte lipolysis. Free fatty acids (FFA) and EGP are suppressed proportionately, and when the decline in FFA is prevented during insulin infusion, suppression of EGP is also prevented. The present study tested the hypothesis that suppression of lipolysis under conditions of constant insulin would yield a suppression of EGP. [N.sup.6]-cyclohexyladenosine (CHA) was used to selectively suppress adipocyte lipolysis during euglycemic clamps in conscious male dogs. FFA suppression by CHA caused suppression of EGP. Liposyn control experiments, which maintained FFA levels above basal during CHA infusion, completely prevented the decline in EGP, whereas glycerol control experiments, which maintained glycerol levels close to basal, did not prevent a decline in EGP. These controls suggest that the EGP suppression was secondary to the suppression of FFA levels specifically. A difference in the sensitivity of FFA and EGP suppression (FFA were suppressed ~85% whereas EGP only declined ~40%) was possibly caused by confounding effects of CHA, including an increase in catecholamine and glucagons levels during CHA infusion. Thus suppression of lipolysis under constant insulin causes suppression of EGP, despite a significant rise in catecholamines. free fatty acids; hepatic glucose output; catecholamines; adenosine

Richey, Joyce M., Marilyn Ader, Donna Moore, and Richard N. Bergman. Angiotensin II induces insulin resistance independent of changes in interstitial insulin. Am. J. Physiol. 277 (Endocrinol. Metab. 40): E920-E926, 1999.--We set out to examine whether angiotensin-driven hypertension can alter insulin action and whether these changes are reflected as changes in interstitial insulin (the signal to which insulin-sensitive cells respond to increase glucose uptake). To this end, we measured hemodynamic parameters, glucose turnover, and insulin dynamics in both plasma and interstitial fluid (lymph) during hyperinsulinemic euglycemic clamps in anesthetized dogs, with or without simultaneous infusions of angiotensin II (ANG II). Hyperinsulinemia per se failed to alter mean arterial pressure, heart rate, or femoral blood flow. ANG II infusion resulted in increased mean arterial pressure (68 [+ or -] 16 to 94 [+ or -] 14 mmHg, P [is less than] 0.001) with a compensatory decrease in heart rate (110 [+ or -] 7 vs. 86 [+ or -] 4 [+ or -], P [is less than] 0.05). Peripheral resistance was significantly increased by ANG II from 0.434 to 0.507 mmHg [multiplied by] [ml.sup.-1] [multiplied by] min (P [is less than] 0.05). ANG II infusion increased femoral artery blood flow (176 [+ or -] 4 to 187 [+ or -] 5 ml/min, P [is less than] 0.05) and resulted in additional increases in both plasma and lymph insulin (93 [+ or -] 20 to 122 [+ or -] 13 [micro]U/ml and 30 [+ or -] 4 to 45 [+ or -] 8 [micro]U/ml, P [is less than] 0.05). However, glucose uptake was not significantly altered and actually had a tendency to be lower (5.9 [+ or -] 1.2 vs. 5.4 [+ or -] 0.7 mg [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1], P [is less than] 0.10). Mimicking of the ANG II-induced hyperinsulinemia resulted in an additional increase in glucose uptake. These data imply that ANG II induces insulin resistance by an effect independent of a reduction in interstitial insulin. lymph insulin; euglycemic hyperinsulinemia; endogenous glucose production; blood flow

The improvement of hepatic insulin sensitivity by the cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been recently been reported to be due to upregulation of adiponectin. Several studies demonstrated that improvement in insulin clearance accompanies the enhancement of hepatic insulin sensitivity. However, the effects of RIM on hepatic insulin clearance (HIC) have not been fully explored. The aim of this study was to explore the molecular mechanism(s) by which RIM affects HIC, specifically to determine whether upregulation of liver adiponectin receptors (ADRs) and other key genes regulated by adiponectin mediate the effects. To induce insulin resistance in skeletal muscle and liver, dogs were fed a hypercaloric high-fat diet (HFD) for 6 wk. Thereafter, while still maintained on a HFD, animals received RIM (HFD+RIM; n = 11) or placebo (HFD+PL; n = 9) for an additional 16 wk. HIC, calculated as the metabolic clearance rate (MCR), was estimated from the euglycemichyperinsulinemic clamp. The HFD+PL group showed a decrease in MCR; in contrast, the HFD+RIM group increased MCR. Consistently, the expression of genes involved in HIC, CEACAM-1 and IDE, as well as gene expression of liver ADRs, were increased in the HFD+RIM group, but not in the HFD+PL group. We also found a positive correlation between CEACAM-1 and the insulin-degrading enzyme IDE with ADRs. Interestingly, expression of liver genes regulated by adiponectin and involved in lipid oxidation were increased in the HFD+RIM group. We conclude that in fat-fed dogs RIM enhances HIC, which appears to be linked to an upregulation of the adiponectin pathway. [ABSTRACT FROM AUTHOR]

The acute and chronic effects of approximately two-fold elevation of plasma free fatty acids (FFA) vs control on glucose-stimulate insulin secretion was studied in healthy young men. Findings showed that acute and chronic FFA elevation causes insulin resistance. With acute FFA elevation, this insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that the disposition index does not change. Also, chronic FFA elevation disables this beta-cell compensation.

The endocannabinoid system is highly implicated in the development of insulin resistance associated with obesity. It has been shown that antagonism of the CB1 receptor improves insulin sensitivity (SI). However, it is unknown whether this improvement is due to the direct effect of CB1 blockade on peripheral tissues or secondary to decreased fat mass. Here, we examine in the canine dog model the longitudinal changes in SI and fat deposition when obesity was induced with a high-fat diet (HFD) and animals were treated with the CB1 antagonist rimonabant. SI was assessed (n = 20) in animals fed a HFD for 6 wk to establish obesity. Thereafter, while HFD was continued for 16 additional weeks, animals were divided into two groups: rimonabant (1.25 mg.kg-1.day-1 RIM; n = 11) and placebo (n = 9). Euglycemic hyperinsulinemic clamps were performed to evaluate changes in insulin resistance and glucose turnover before HFD (week -6) after HFD but before treatment (week 0) and at weeks 2, 6, 12, and 16 of treatment (or placebo) + HFD. Magnetic resonance imaging was performed to determine adiposity- related changes in SI. Animals developed significant insulin resistance and increased visceral and subcutaneous adiposity after 6 wk of HFD. Treatment with RIM resulted in a modest decrease in total trunk fat with relatively little change in peripheral glucose uptake. However, there was significant improvement in hepatic insulin resistance after only 2 wk of RIM treatment with a concomitant increase in plasma adiponectin levels; both were maintained for the duration of the RIM treatment. CB1 receptor antagonism appears to have a direct effect on hepatic insulin sensitivity that may be mediated by adiponectin and independent of pronounced reductions in body fat. However, the relatively modest effect on peripheral insulin sensitivity suggests that significant improvements may be secondary to reduced fat mass. [ABSTRACT FROM AUTHOR]