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The objective of this study was to develop a Rapid Insulin Sensitivity Test (RIST) in humans, a test already used in animal studies. Insulin sensitivity was assessed using a rapid modified euglycemic clamp, the RIST. In this test, glucose disposition was determined after an intravenous (i.v.) bolus (50mU/kg bw administered over 30 seconds) of insulin, before and after feeding a standardized test meal, in healthy male subjects (aged 27.8 +/- 2.4 years, BMI 23.5 +/- 1.2 kg/m2). The RIST uses as the index of insulin sensitivity, the total amount of glucose required to be infused to maintain euglycemia during insulin action following an i.v. bolus of insulin. During the RIST, glucose levels are determined at 2-min intervals in order to clamp the glycemia at baseline values. Following a 24 hr fasting period, the RIST index was 225.6 +/- 25.1 mg glucose/kg bw. The volunteers were then fed a standardized test meal, a new stable glucose level was obtained 100 min after the meal, and a second RIST was performed. The glucose requirement (RIST index) increased to 647.9 +/- 73.5 mg glucose/kg bw following the standardized test meal (n = 5, p < 0.001). This report describes a new technique to evaluate insulin sensitivity in healthy humans. The RIST is a powerful research tool to assess the glucose utilization action of an insulin bolus in fasted and fed states both evaluated in the same day.

Normal postprandial insulin sensitivity depends on the action of the hepatic insulin sensitizing substance (HISS), which requires hepatic parasympathetic nerve activation. Since HISS action is impaired in several pathological models, including the genetically-modified obese Zucker rat (OZR), we compared the HISS-dependent and HISS-independent components of insulin action between the OZR model, and the high-fat diet (HFD)-fed rats. We hypothesize that both models present an impaired HISS action, accounting for the decrease in insulin sensitivity. Male Sprague-Dawley rats fed a HFD for 1 week (n = 5) and OZR (n = 5) were used as obese models. Standard diet-fed (STD, n = 5) and lean Zucker rats (LZR, n = 6) were the HFD and OZR non-obese controls, respectively. Rats were 9-weeks-old when tested. Insulin sensitivity was measured in the fed state, before and after atropine blockade of HISS release), using the Rapid Insulin Sensitivity Test (RIST, mg glucose/kg bw). HISS-dependent action was the difference between control and post-atropine RISTs. HISS action was impaired in both the obese groups (HFD vs STD: 40.1 +/- 5.0 vs 117.0 +/- 3.8 mg glucose/kg bw, p < 0.001; OZR vs LZR: 34.4 +/- 12.8 vs 115.9 +/- 19.4 mg glucose/kg bw, p < 0.01), whereas the HISS-independent component (post-atropine RIST), i.e., insulin action per se, was decreased only in the OZR (OZR vs LZR: 39.3 +/- 3.5 vs 173.3 +/- 20.5 mg glucose/kg bw, p < 0.001). According to our data, the insulin resistance mechanisms are different in the two obesity models studied: in the HFD-fed rats, only the HISS-dependent component is impaired, whereas in the OZR both components of nsulin action are equally impaired.

Peripheral insulin sensitivity is dependent on the action of Hepatic Insulin Sensitizing Substance (HISS), in which hepatic NO (HNO) plays an important role. Insulin resistance has been associated with hypertension. NO action is known to be impaired in Spontaneously Hypertensive Rat (SHR) hypertension models. We tested the hypothesis that the HNO pathway is compromised in SHR, resulting in HISS-dependent insulin resistance. Wistar rats (Wis) were the normotensive controls. Insulin sensitivity was evaluated through the Rapid Insulin Sensitivity Test (RIST), a modified euglycemic clamp. A clamp was performed in basal state (control RIST), followed by ipv administration of the NO synthase (NOS) competitive antagonist L-NMMA (0.73 mg/kg) and a RIST post L-NMMA. HISS-dependent insulin sensitivity was assessed by subtracting the RIST post-L-NMMA from the control RIST and is represented as the resultant insulin sensitivity inhibition. In SHR ipv L-NMMA induced 26+/-5% insulin sensitivity inhibition (187.5+/-15.3 mg glucose/kg, n=6; P<0.05), whereas in Wis, ipv L-NMMA induced 53.8+/-5.9% insulin sensitivity inhibition (138.2+/-14.7 mg glucose/kg, n=6, P<0.05), significantly higher than in SHR (P<0.01). Our results suggest that functional HNO is essential to achieve maximal insulin sensitivity and that HNO action is compromised in hypertension, resulting in HISS-dependent insulin resistance.