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We determined the effect of 48-h elevation of plasma free fatty acids (FFA) on insulin secretion during hyperglycemic clamps in control female Wistar rats (group a) and in the following female rat models of progressive [beta]-cell dysfunction: lean Zucker diabetic fatty (ZDF) rats, both wild-type (group b) and heterozygous for the fa mutation in the leptin receptor gene (group c); obese (fa/fa) Zucker rats (nonprediabetic; group d); obese prediabetic (fa/fa) ZDF rats (group e); and obese (fa/fa) diabetic ZDF rats (group f). FFA induced insulin resistance in all groups but increased C-peptide levels (index of absolute insulin secretion) only in obese prediabetic ZDF rats. Insulin secretion corrected for insulin sensitivity using a hyperbolic or power relationship (disposition index or compensation index, respectively, both indexes of [beta]-cell function) was decreased by FFA. The decrease was greater in normoglycemic heterozygous lean ZDF rats than in Wistar controls. In obese 'prediabetic' ZDF rats with mild hyperglycemia, the FFA-induced decrease in [beta]-cell function was no greater than that in obese Zucker rats. However, in overtly diabetic obese ZDF rats, FFA further impaired [beta]-cell function. In conclusion, 1) the FFA-induced impairment in [beta]-cell function is accentuated in the presence of a single copy of a mutated leptin receptor gene, independent of hyperglycemia. 2) In prediabetic ZDF rats with mild hyperglycemia, lipotoxicity is not accentuated, as the [beta]-cell mounts a partial compensatory response for FFA-induced insulin resistance. 3) This compensation is lost in diabetic rats with more marked hyperglycemia and loss of glucose sensing. free fatty acid; obesity; insulin secretion: hyperglycemic clamp: Zucker diabetic fatty rat

We tested the hypothesis that, due to greater hepatic free fatty acid (FFA) load, portal delivery of FFAs, as in visceral obesity, induces hyperinsulinemia and increases endogenous glucose production to a greater extent than peripheral FFA delivery. For 5 h, 10 [micro]eq*[kg.sup.-1]*[min.sup.-] portal oleate (n = 6), equidose peripheral oleate (n = 5), or saline (n = 6) were given intravenously to conscious dogs infused with a combination of portal and peripheral insulin to enable calculation of hepatic insulin clearance during a pancreatic euglycemic clamp. Peripheral FFAs were similar with both oleate treatments and were threefold greater than in controls. Portal FFAs were 1.5-to 2-fold greater with portal than with peripheral oleate. Peripheral insulin concentrations were greatest with portal oleate, intermediate with peripheral oleate (P < 0.001 vs. portal oleate or controls), and lowest in controls, consistent with corresponding reductions in plasma insulin clearance and hepatic insulin clearance. Although endogenous glucose production did not differ between the two routes of oleate delivery, total glucose output (endogenous glucose production plus glucose cycling) was greater with portal than with peripheral oleate (P < 0.001) despite the higher insulin levels. In conclusion, during euglycemic clamps in dogs, the main effect of short-term elevation in portal FFA is to generate peripheral hyperinsulinemia. This may, in the long term, contribute to the metabolic and cardiovascular risk of visceral obesity. insulin resistance; hepatic glucose production; visceral obesity

Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake [tracer-determined disappearance rate ([R.sub.d]), control 41.2 [+ or -] 1.7 vs. HG 32.4 [+ or -] 1.9 mg * [kg.sup.-1] * [min.sup.-1], P < 0.05], which was prevented by NAC (HG + NAC 45.9 [+ or -] 3.5 mg * [kg.sup.-1] * [min.sup.-1]). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered [R.sub.d]. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance. euglycemic clamp; insulin resistance; protein carbonyls; protein kinase C; antioxidants

In our previous studies in nondiabetic dogs and humans, insulin suppressed glucose production (GP) by both an indirect extrahepatic and a direct hepatic effect. However, insulin had no direct effect on GP in diabetic depancreatized dogs under conditions of moderate hyperglycemia. The present study was designed to investigate whether insulin can inhibit GP by a direct effect in this model under conditions of euglycemia. Depancreatized dogs were made euglycemic (~6 mmol/l), rather than moderately hyperglycemic (~10 mmol/l) as in our previous studies, by basal portal insulin infusion. After ~100 min of euglycemia, a hyperinsulinemic euglycemic clamp was performed by giving an additional infusion of insulin either portally (POR) or peripherally at about one-half the rate (1/2 PER) to match the peripheral venous insulin concentrations. The greater hepatic insulin load in POR resulted in greater suppression of GP (from 16.5 [+ or -] 1.8 to 12.2 [+ or -] 1.6 [micro]mol*[kg.sup.-1]*[min.sup.-1]) than 1/2 PER (from 17.8 [+ or -] 1.9 to 15.6 [+ or -] 2.0 [micro]mol*[kg.sup.-1]*[min.sup-1], P < 0.001 vs. POR), consistent with insulin having a direct hepatic effect in suppressing GP. We conclude that the direct effect of insulin to inhibit GP is present in diabetic depancreatized dogs under conditions of acutely induced euglycemia. These results suggest that, in diabetes, the prevailing glycemic level is a determinant of the balance between insulin's direct and indirect effects on GP. peripheral and hepatic effects of insulin; direct and indirect effects of insulin; hyperglycemia; free fatty acids

Prasugrel results in greater platelet inhibition compared to clopidogrel which may prolong the time to platelet P2Y12 receptor function recovery following drug cessation after loading dose (LD) administration. This randomized study assessed the time to recovery of platelet function in patients with coronary artery disease after a LD of prasugrel or clopidogrel. Enrolled patients ( n = 21) received either prasugrel (30 mg or 60 mg) or clopidogrel (600 mg) in preparation for coronary angiography. Platelet function was assessed by the VerifyNow P2Y12 assay, Multiplate and LTA at baseline and over time (1, 3, 5, 7, 9, and 11 days) post-LD treatment. Recovery of platelet function was defined as occurring on the first day that P2Y12 reaction units were ≤60 below pre-drug values and remained in this range. The relationship between platelet inhibition at 24 h post-LD to time of recovery was also evaluated. Recovery of platelet function occurred from days 3-7 for clopidogrel-treated subjects, by day 7 for patients treated with prasugrel 30 mg and from days 7-9 for patients treated with prasugrel 60 mg. Time for platelet function to return to baseline was independent of treatment assignment, reflecting instead the extent of platelet inhibition at 24 h post-LD (correlation coefficient = 0.81, p < 0.001), which was greater following a prasugrel LD. Conclusions: Prasugrel-treated subjects require a longer time for recovery compared with clopidogrel due to greater post-LD platelet inhibition. Platelet function testing after cessation of P2Y12 receptor blockers may prove useful to guide the timing of surgical procedures (clinicaltrials.gov identifier: NCT01107899). [ABSTRACT FROM AUTHOR]

The similarity in lifestyle risk factors for the development of colorectal cancer (CRC) and type 2 diabetes suggests that there are common underlying pathogenic mechanisms. High-risk lifestyle factors may lead to insulin resistance that, through increased circulating levels of energy substrates, insulin, and insulin-like growth factor-1, may promote the development of CRC. The objective was to determine the extent to which direct and surrogate measures of insulin resistance correlate with multiplicity of aberrant crypt foci, which are putative precursors of CRC. Rats were initiated with the carcinogen azoxymethane, then fed low, intermediate, or high saturated fat diets. Metabolic parameters were assessed at 50 days and ACF at 100 days after initiation. Results indicate that CRC promotion was most strongly correlated with direct measures of insulin sensitivity as assessed with the hyperinsulinemic-euglycemic clamp (r = -0.52, P < 0.009). Practical surrogate measures of insulin resistance such as insulin levels at 180 min after an oral glucose load were strongly correlated with direct measures of insulin sensitivity (r = -0.61, P < 0.001) and with CRC promotion (r = 0.42, P = 0.044) in this animal model. Fasting levels of glucose, insulin, total insulin-like growth factor-1, nonesterified fatty acids, and triglyceride, as well as body weight and insulin sensitivity indices (such as fasting insulin resistance index, quantitative insulin sensitivity check index, homeostasis model assessment formula, insulin sensitivity index of glycemia, oral glucose insulin sensitivity, and composite insulin sensitivity index for the hepatic and peripheral tissues) were all less strongly correlated with direct measures of insulin sensitivity and all poorly correlated with CRC promotion in this animal model. These correlations do not prove causality, however, they suggest possible mechanisms linking diet, insulin resistance with its related parameters, and promotion of CRC.