Tyrosine Hydroxylase Knockdown at the Hypothalamic Supramammillary Nucleus Area Induces Obesity and Glucose Intolerance.

Introduction: The supramammillary nucleus (SuMN) exerts influences on a wide range of brain functions including feeding and feeding-independent fuel metabolism. However, which specific neuronal type(s) within the SuMN manifest this influence has not been delineated. This study investigated the effect of SuMN tyrosine hydroxylase (TH) (rate-limiting enzyme in dopamine synthesis) knockdown (THx) on peripheral fuel metabolism.

Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects.

Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state.

Time-of-Day-Dependent Effects of Bromocriptine to Ameliorate Vascular Pathology and Metabolic Syndrome in SHR Rats Held on High Fat Diet.

The treatment of type 2 diabetes patients with bromocriptine-QR, a unique, quick release micronized formulation of bromocriptine, improves glycemic control and reduces adverse cardiovascular events. While the improvement of glycemic control is largely the result of improved postprandial hepatic glucose metabolism and insulin action, the mechanisms underlying the drug's cardioprotective effects are less well defined. Bromocriptine is a sympatholytic dopamine agonist and reduces the elevated sympathetic tone, characteristic of metabolic syndrome and type 2 diabetes, which potentiates elevations of vascular oxidative/nitrosative stress, known to precipitate cardiovascular disease.

Activation State of the Supramammillary Nucleus Regulates Body Composition and Peripheral Fuel Metabolism.

Whole body fuel metabolism and energy balance are controlled by an interactive brain neuronal circuitry involving multiple brain centers regulating cognition, circadian rhythms, reward, feeding and peripheral biochemical metabolism. The hypothalamic supramammillary nucleus (SuMN) comprises an integral node having connections with these metabolically relevant centers, and thus could be a key central coordination center for regulating peripheral energy balance. This study investigated the effect of chronically diminishing or increasing SuMN neuronal activity on body composition and peripheral fuel metabolism.

Experimental dopaminergic neuron lesion at the area of the biological clock pacemaker, suprachiasmatic nuclei (SCN) induces metabolic syndrome in rats.

Background: The daily peak in dopaminergic neuronal activity at the area of the biological clock (hypothalamic suprachiasmatic nuclei [SCN]) is diminished in obese/insulin resistant vs lean/insulin sensitive animals. The impact of targeted lesioning of dopamine (DA) neurons specifically at the area surrounding (and that communicate with) the SCN (but not within the SCN itself) upon glucose metabolism, adipose and liver lipid gene expression, and cardiovascular biology in normal laboratory animals has not been investigated and was the focus of this study.

Methods: Female Sprague-Dawley rats received either DA neuron neurotoxic lesion by bilateral intra-cannula injection of 6-hydroxydopamine (2-4 μg/side) or vehicle treatment at the area surrounding the SCN at 20 min post protriptyline ip injection (20 mg/kg) to protect against damage to noradrenergic and serotonergic neurons.

Bromocriptine mesylate improves glucose tolerance and disposal in a high-fat-fed canine model.

Bromocriptine mesylate treatment was examined in dogs fed a high fat diet (HFD) for 8 wk. After 4 wk on HFD, daily bromocriptine (Bromo; = 6) or vehicle (CTR; = 5) injections were administered. Oral glucose tolerance tests were performed before beginning HFD (OGTT1), 4 wk after HFD began (Bromo only), and after 7.

Circadian-timed quick-release bromocriptine lowers elevated resting heart rate in patients with type 2 diabetes mellitus.

Objective: Sympathetic nervous system (SNS) overactivity is a risk factor for insulin resistance and cardiovascular disease (CVD). We evaluated the impact of bromocriptine-QR, a dopamine-agonist antidiabetes medication, on elevated resting heart rate (RHR) (a marker of SNS overactivity in metabolic syndrome), blood pressure (BP) and the relationship between bromocriptine-QR's effects on RHR and HbA1c in type 2 diabetes subjects.

Design And Subjects: RHR and BP changes were evaluated in this post hoc analysis of data from a randomized controlled trial in 1014 type 2 diabetes subjects randomized to bromocriptine-QR vs placebo added to standard therapy (diet ± ≤2 oral antidiabetes medications) for 24 weeks without concomitant antihypertensive or antidiabetes medication changes, stratified by baseline RHR (bRHR).

Impact of bromocriptine-QR therapy on cardiovascular outcomes in type 2 diabetes mellitus subjects on metformin.

Objectives: Type 2 diabetes mellitus (T2DM) is associated with a substantially increased risk of cardiovascular disease (CVD). Bromocriptine-QR (B-QR), a quick release sympatholytic dopamine D receptor agonist, is a FDA-approved therapy for T2DM which may provide CVD risk reduction. Metformin is considered to be an agent with a potential cardioprotective benefit.

Erratum: Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats.

[This corrects the article DOI: 10.1186/1758-5996-6-104.].

Timed Bromocriptine-QR Therapy Reduces Progression of Cardiovascular Disease and Dysglycemia in Subjects with Well-Controlled Type 2 Diabetes Mellitus.

Background: Type 2 diabetes (T2DM) patients, including those in good glycemic control, have an increased risk of cardiovascular disease (CVD). Maintaining good glycemic control may reduce long-term CVD risk. However, other risk factors such as elevated vascular sympathetic tone and/or endothelial dysfunction may be stronger potentiators of CVD.

Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats.

Background: The hypertensive, pro-inflammatory, obese state is strongly coupled to peripheral and hepatic insulin resistance (in composite termed metabolic syndrome [MS]). Hepatic pro-inflammatory pathways have been demonstrated to initiate or exacerbate hepatic insulin resistance and contribute to fatty liver, a correlate of MS. Previous studies in seasonally obese animals have implicated an important role for circadian phase-dependent increases in hypothalamic dopaminergic tone in the maintenance of the lean, insulin sensitive condition.

Effect of bromocriptine-QR on glycemic control in subjects with uncontrolled hyperglycemia on one or two oral anti-diabetes agents.

Objective: To investigate the effect of Bromocriptine-QR on glycemic control in patients with type 2 diabetes whose glycemia is poorly controlled on one or two oral anti-diabetes agents.

Methods: Five hundred fifteen Type 2 Diabetes Mellitus (T2DM) subjects (ages 18 to 80 and average body mass index [BMI] of 32.7) with baseline HbA1c ≥ 7.

Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes.

Objective: Quick-release bromocriptine (bromocriptine-QR), a D2 dopamine receptor agonist, is indicated as a treatment for type 2 diabetes. The Cycloset Safety Trial, a 52-week, randomized, double-blind, multicenter trial, evaluated the overall safety and cardiovascular safety of this novel therapy for type 2 diabetes.

Research Design And Methods: A total of 3,095 patients with type 2 diabetes were randomized 2:1 to bromocriptine-QR or placebo in conjunction with the patient's usual diabetes therapy (diet controlled only or up to two antidiabetes medications, including insulin).

A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset or placebo.

Background: Cycloset is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.

Developmental changes in the Sciara II/9A initiation zone for DNA replication.

Developmentally regulated initiation of DNA synthesis was studied in the fly Sciara at locus II/9A. PCR analysis of nascent strands revealed an initiation zone that spans approximately 8 kb in mitotic embryonic cells and endoreplicating salivary glands but contracts to 1.2 to 2.