ObjectiveGhrelin acylation by ghrelin O-acyltransferase (GOAT) has recently been reported to be essential for the prevention of hypoglycemia during prolonged negative energy balance. Using a unique set of four different genetic loss-of-function models for the GOAT/ghrelin/growth hormone secretagogue receptor (GHSR) system, we thoroughly tested the hypothesis that lack-of-ghrelin activation or signaling would lead to hypoglycemia during caloric deprivation.MethodologyMale and female knockout (KO) mice for GOAT, ghrelin, GHSR, or both ghrelin and GHSR (dKO) were subjected to prolonged calorie restriction (40% of ad libitum chow intake). Body weight, fat mass, and glucose levels were recorded daily and compared to wildtype (WT) controls. Forty-eight hour blood glucose profiles were generated for each individual mouse when 2% or less body fat mass was reached. Blood samples were obtained for analysis of circulating levels of acyl- and desacyl-ghrelin, IGF-1, and insulin.Principal FindingsChronic calorie restriction progressively decreased body weight and body fat mass in all mice regardless of genotype. When fat mass was depleted to 2% or less of body weight for 2 consecutive days, random hypoglycemic events occurred in some mice across all genotypes. There was no increase in the incidence of hypoglycemia in any of the four loss-of-function models for ghrelin signaling including GOAT KO mice. Furthermore, no differences in insulin or IGF-1 levels were observed between genotypes.ConclusionThe endogenous GOAT-ghrelin-GHSR system is not essential for the maintenance of euglycemia during prolonged calorie restriction.

In patients with Type 2 DM, home BP monitoring is superior to clinic BP measurement, when compared with 24-h ambulatory BP, and allows better detection of hypertension. It would be a rational addition to the annual review process. Diabet. Med. 18, 431-437 (2001)

Several bariatric operations are currently used to treat obesity and obesity-related comorbidities. These vary in efficacy, but most are more effective than current pharmaceutical treatments. Roux-en-Y gastric bypass (RYGB) produces substantial body weight (BW) loss and enhanced glucose tolerance, and is associated with increased secretion of the gut hormone glucagon-like peptide 1 (GLP-1). Given the success of GLP-1–based agents in lowering blood glucose levels and BW, we hypothesized that an individual sensitivity to GLP-1 receptor agonism could predict metabolic benefits of surgeries associated with increased GLP-1 secretion. One hundred ninety-seven high-fat diet–induced obese male Long-Evans rats were monitored for BW loss during exendin-4 (Ex4) administration. Stable populations of responders and nonresponders were identified based on Ex4-induced BW loss and GLP-1–induced improvements in glucose tolerance. Subpopulations of Ex4 extreme responders and nonresponders underwent RYGB surgery. After RYGB, responders and nonresponders showed similar BW loss compared with sham, but nonresponders retained impaired glucose tolerance. These data indicate that the GLP-1 response tests may predict some but not all of the improvements observed after RYGB. These findings present an opportunity to optimize the use of bariatric surgery based on an improved understanding of GLP-1 biology and suggest an opportunity for a more personalized therapeutic approach to the metabolic syndrome.

A humanized anti‐cocaine monoclonal antibody (mAb), h2E2, has been reported to sequester cocaine in the plasma and decrease cocaine concentrations in the brain in mice and to antagonize cocaine‐induced reinstatement of self‐administration behavior in rats. This predicts that h2E2 will decrease the probability of relapse in cocaine abusers. Many cocaine users also abuse alcohol and when cocaine and ethanol are simultaneously ingested, the active metabolite cocaethylene is formed. This potentially compromises the efficacy of h2E2. However, the mAb h2E2 has high affinity for cocaethyene as well as cocaine. In the present study, the ability of h2E2 to prevent cocaethylene entry into the brain was tested. Mice were infused with h2E2 (1.6 μmol/kg i.v.) or vehicle and after one hour were injected with cocaethylene fumurate at a dose equimolar with the mAb. After 5 min, plasma and brain were collected and cocaethylene concentrations were measured by gas chromatography/mass spectrometry with reference to internal and external standards. The h2E2 produced a >; 90% increase in plasma cocaethylene concentrations and a concomitant >; 90% decrease in brain concentrations. The ability of h2E2 to protect the brain from both cocaine and cocaethylene predicts that the clinical efficacy of h2E2 will be retained in cocaine abusers who also co‐abuse alcohol. Supported by NIH grant DPIDA031386 and 2012 ASPET SURF Program.

Monoclonal antibody (mAb) h2E2 is a further humanized version of the high‐affinity anti‐cocaine mAb 2E2. h2E2 is a potential immunotherapeutic for cocaine abuse that retains the same high‐affinity (4 nM Kd) and specificity as 2E2 for cocaine over its inactive metabolites. Infused h2E2 (1.6 μmol/kg i.v.) in both mice and rats produced dramatic increases in the area under the plasma cocaine concentration‐time curve (AUC) and a concomitant decrease of >;90% in the brain AUC following an i.v. injection of an equimolar cocaine dose. Consequently, h2E2 substantially reduced cocaine's volume of distribution in both species by sequestering cocaine in plasma, indicating potential clinical efficacy. Furthermore, h2E2 did not inhibit the clearance of cocaine in either rats or mice. Interestingly, h2E2 restricted cocaine distribution and metabolism from plasma to a single‐compartment model in mice but cocaine disappearance remained multi‐compartmental in rats. This differential effect of h2E2 on cocaine distribution between species may be related to the metabolism of cocaine predominantly to ecgonine methylester (EME) in mice but to benzoylecgonine (BE) in rats. The metabolism of cocaine to BE and EME in humans is between that in mice and rats. Thus, these studies will help determine whether differences in cocaine metabolism are relevant to h2E2's clinical efficacy.Supported by NIH grant DP1DA031386.