Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.
We report the design, synthesis, and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid receptor type 1 (CBR) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB receptor (CBR) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CBR antagonist activities and iNOS inhibitory activities. Some key compounds displayed high CBR binding affinities. Compound 7 demonstrated potent in vivo pharmacological activities such as reduction of food intake mediated by the antagonism of the CBRs and antifibrotic effect in the animal models of fibrosis mediated by iNOS inhibition and CBR antagonism.
In the present report, we describe
the synthesis and structure–activity
relationships of novel “four-arm” dihydropyrazoline
compounds designed as peripherally restricted antagonists of cannabinoid-1
receptor (CB1R). A series of racemic 3,4-diarylpyrazolines
were synthesized and evaluated initially in CB1 receptor
binding assays. The novel compounds, designed to limit brain penetrance
and decreased lipophilicity, showed high affinity for CB1R and potent in vitro CB1R antagonist
activities. Promising compounds with potent CB1R activity
were evaluated in tissue distribution studies. Compounds 6a, 6f, and 7c showed limited brain penetrance
attesting to its peripheral restriction. The 4S-enantiomer
of these compounds further showed a stereoselective affinity for the
CB1 receptor and behaved as inverse agonists. In
vivo studies on food intake and body weight reduction in
diet-induced obese (DIO) mice showed that these compounds could serve
as potential leads for the development of selective CB1R antagonists with improved potency and peripheral restriction.
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