A first-in-human pharmacodynamic and pharmacokinetic study of a fully human anti-glucagon receptor monoclonal antibody in normal healthy volunteers.

Aims: Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first-in-human healthy volunteer randomized double-blinded trial.

Methods: Healthy men and women received single ascending doses of REGN1193 ranging from 0.

Glycemic response and attainment of A1C goals following newly initiated insulin therapy for type 2 diabetes.

Objective: To identify the characteristics associated with glycemic response to newly initiated insulin therapy.

Research Design And Methods: We identified 1,139 type 2 diabetic patients who initiated insulin therapy between 1 January 2009 and 30 June 2010. Outcomes of interest were the proportion of patients achieving A1C <7% and mean change in A1C within 3-9 months.

Early treatment-related changes in diabetes and cardiovascular disease risk markers in first episode psychosis subjects.

Objective: To examine prospective changes in cardiovascular disease (CVD) and type-2 diabetes risk factors in young adult first episode psychotic (FEP) patients treated with second generation antipsychotic medications.

Methods: At baseline, fasting serum and anthropometric measures were obtained from 45 FEP patients and 41 healthy adults (controls) of similar age, ethnicity and sex; sixteen of the FEP patients remained on the same antipsychotic medication and were available for a second blood draw at 24 weeks of treatment. Serum was assayed for glucose, insulin, triglycerides, total cholesterol and high and low density lipoproteins (HDL, LDL), adiponectin, leptin, interleukin 6, E-selectin and VCAM-1.

Adipose-specific disruption of signal transducer and activator of transcription 3 increases body weight and adiposity.

To determine the role of STAT3 in adipose tissue, we used Cre-loxP DNA recombination to create mice with an adipocyte-specific disruption of the STAT3 gene (ASKO mice). aP2-Cre-driven disappearance of STAT3 expression occurred on d 6 of adipogenesis, a time point when preadipocytes have already undergone conversion to adipocytes. Thus, this knockout model examined the role of STAT3 in mature but not differentiating adipocytes.

Increased energy expenditure, dietary fat wasting, and resistance to diet-induced obesity in mice lacking renin.

An overactive renin-angiotensin system is associated with obesity and the metabolic syndrome. However, the mechanisms behind it are unclear. Cleaving angiotensinogen to angiotensin I by renin is a rate-limiting step of angiotensin II production, but renin is suggested to have angiotensin-independent effects.

Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus.

Obesity is associated with an impaired immune response, an increased susceptibility to bacterial infection, and a chronic increase in proinflammatory cytokines such as IL-6 and TNFalpha. However, few studies have examined the effect of obesity on the immune response to viral infections. Because infection with influenza is a leading cause of morbidity and mortality worldwide, we investigated the effect of obesity on early immune responses to influenza virus exposure.

Why do obese patients not lose more weight when treated with low-calorie diets? A mechanistic perspective.

Maximal weight loss observed in low-calorie diet (LCD) studies tends to be small, and the mechanisms leading to this low treatment efficacy have not been clarified. Less-than-expected weight loss with LCDs can arise from an increase in fractional energy absorption (FEA), adaptations in energy expenditure, or incomplete patient diet adherence. We systematically reviewed studies of FEA and total energy expenditure (TEE) in obese patients undergoing weight loss with LCDs and in patients with reduced obesity (RO), respectively.

Midkine is an autocrine activator of signal transducer and activator of transcription 3 in 3T3-L1 cells.

Mitotic clonal expansion is believed to be necessary for 3T3-L1 adipocyte formation. Signal transducer and activator of transcription 3 (STAT3), a mitogenic signaling protein, is activated through tyrosine phosphorylation during the proliferative phases of adipogenesis. We hypothesize that this signaling protein plays a key role in mitotic clonal expansion and differentiation.

Protein inhibitor of activated STAT3 inhibits adipogenic gene expression.

Protein inhibitor of activated STAT3 (PIAS3), a cytokine-induced repressor of signal transducer and activator of transcription 3 (STAT3) and a modulator of a broad array of nuclear proteins, is expressed in white adipose tissue, but its role in adipogenesis is not known. Here, we determined that PIAS3 was constitutively expressed in 3T3-L1 cells at all stages of adipogenesis. However, it translocated from the nucleus to the cytoplasm 4 days after induction of differentiation by isobutylmethylxanthine, dexamethasone, and insulin (MDI).

Double-blind, placebo-controlled investigation of amantadine for weight loss in subjects who gained weight with olanzapine.

Objective: This study sought to determine if amantadine affects weight gain in psychiatric patients taking olanzapine.

Method: Twenty-one adults who had gained at least 5 lb with olanzapine were randomly assigned to receive amantadine (N=12) or placebo (N=9) in addition to olanzapine. The length of time taking olanzapine ranged from 1 to 44 months.

Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis.

Objective: Weight gain is a commonly observed adverse effect of atypical antipsychotic medications, but associated changes in energy balance and body composition are not well defined. The authors report here the effect of olanzapine on body weight, body composition, resting energy expenditure, and substrate oxidation as well as leptin, insulin, glucose, and lipid levels in a group of outpatient volunteers with first-episode psychosis.

Method: Nine adults (six men and three women) experiencing their first psychotic episode who had no previous history of antipsychotic drug therapy began a regimen of olanzapine and were studied within 7 weeks and approximately 12 weeks after olanzapine initiation.

New insights into inhibitors of adipogenesis.

Purpose Of Review: Adipose tissue is a dynamic organ that changes mass throughout life in response to the metabolic needs of the animal. In the past three decades, significant advances have been made in delineating key extracellular and intracellular stimulators of fat cell formation or adipogenesis. In this review, the author focuses on new findings of specific inhibitors of adipogenesis.

Interleukin-4 inhibits platelet-derived growth factor-induced preadipocyte proliferation.

Interleukin-4 (IL-4) activates STAT6 in 3T3-L1 preadipocytes but its functional role is not known. In this report, we first assessed interleukin-4 receptor alpha (IL-4Ralpha) expression during adipogenesis. IL-4Ralpha was highly expressed in proliferating 3T3-L1 preadipocytes.

Rb regulates C/EBPbeta-DNA-binding activity during 3T3-L1 adipogenesis.

Two pathways are initiated upon 3T3-L1 preadipocyte differentiation: the reentry of cells into the cell cycle and the initiation of a cascade of transcriptional events that "prime" the cell for differentiation. The "priming" event involves the synthesis of members of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors. However, the relationship between these two pathways is unknown.

Dietary weight loss decreases serum angiotensin-converting enzyme activity in obese adults.

Objective: To study the effect of dietary weight loss, postural change, and an oral glucose load on serum angiotensin-converting enzyme (ACE) activity in obese adults.

Research Methods And Procedures: Sixteen obese adult men and women with a mean body mass index of 35.7 +/- 4.

Genistein inhibits CCAAT/enhancer-binding protein beta (C/EBPbeta) activity and 3T3-L1 adipogenesis by increasing C/EBP homologous protein expression.

The tyrosine kinase inhibitor genistein inhibits 3T3-L1 adipogenesis when present during the first 72 h of differentiation. In this report, we investigated the underlying mechanisms involved in the anti-adipogenic effects of genistein. We found that genistein blocked the DNA binding and transcriptional activity of CCAAT/enhancer-binding protein beta (C/EBPbeta) during differentiation by promoting the expression of C/EBP homologous protein, a dominant-negative member of the C/EBP family.