Low-calorie diet-induced weight loss is associated with altered brain connectivity and food desire in obesity.

Objective: The main objective of this study is to better understand the effects of diet-induced weight loss on brain connectivity in response to changes in glucose levels in individuals with obesity.

Methods: A total of 25 individuals with obesity, among whom 9 had a diagnosis of type 2 diabetes, underwent functional magnetic resonance imaging (fMRI) scans before and after an 8-week low-calorie diet. We used a two-step hypereuglycemia clamp approach to mimic the changes in glucose levels observed in the postprandial period in combination with task-mediated fMRI intrinsic connectivity distribution (ICD) analysis.

Deficits in brain glucose transport among younger adults with obesity.

Objective: Obesity is associated with alterations in eating behavior and neurocognitive function. In this study, we investigate the effect of obesity on brain energy utilization, including brain glucose transport and metabolism.

Methods: A total of 11 lean participants and 7 young healthy participants with obesity (mean age, 27 years) underwent magnetic resonance spectroscopy scanning coupled with a hyperglycemic clamp (target, ~180 mg/dL) using [1-C] glucose to measure brain glucose uptake and metabolism, as well as peripheral markers of insulin resistance.

Approach to the Patient With Nonalcoholic Fatty Liver Disease.

Context: Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes (T2D), causing substantial burden from hepatic and extrahepatic complications. However, endocrinologists often follow people who are at the highest risk of its more severe form with nonalcoholic steatohepatitis or NASH (i.e.

Stress-level glucocorticoids increase fasting hunger and decrease cerebral blood flow in regions regulating eating.

Context: The neural regulation of appetite and energy homeostasis significantly overlaps with the neurobiology of stress. Frequent exposure to repeated acute stressors may cause increased allostatic load and subsequent dysregulation of the cortico-limbic striatal system leading to inefficient integration of postprandial homeostatic and hedonic signals. It is therefore important to understand the neural mechanisms by which stress generates alterations in appetite that may drive weight gain.

PPAR-γ-induced changes in visceral fat and adiponectin levels are associated with improvement of steatohepatitis in patients with NASH.

Background And Aims: Peroxisome proliferator-activated receptor (PPAR)-γ agonists decrease hepatic/visceral fat (VF) and improve necroinflammation despite subcutaneous (SC) fat weight-gain. Understanding the impact of changes in VF, VF-to-SC fat distribution (VF/SC) and adiponectin (ADPN) levels in relation to histological improvement after weight-loss or pioglitazone is relevant as novel PPAR-γ agonists are being developed for treating non-alcoholic steatohepatitis (NASH).

Methods: Fifty-five patients with NASH received a -500 kcal/d hypocaloric diet and were randomized (double-blind) to pioglitazone (45 mg/d) or placebo for 6-months.

Implementing a pharmacist-led transition of care model for posttransplant hyperglycemia.

Purpose: The implementation of a pharmacist-managed transition of care program for kidney transplant recipients with posttransplant hyperglycemia (PTHG) is described.

Methods: In September 2015, a collaborative practice agreement between pharmacists and transplant providers at an academic medical center for management of PTHG was developed. The goal of the pharmacist-run service was to reduce hospitalizations by providing care to patients in the acute phase of hyperglycemia while they transitioned back to their primary care provider or endocrinologist.

Metabolic Disorders with Kidney Transplant.

Metabolic disorders are highly prevalent in kidney transplant candidates and recipients and can adversely affect post-transplant graft outcomes. Management of diabetes, hyperparathyroidism, and obesity presents distinct opportunities to optimize patients both before and after transplant as well as the ability to track objective data over time to assess a patient's ability to partner effectively with the health care team and adhere to complex treatment regimens. Optimization of these particular disorders can most dramatically decrease the risk of surgical and cardiovascular complications post-transplant.

Norepinephrine transporter availability in brown fat is reduced in obesity: a human PET study with [C] MRB.

The energy-dissipating properties of brown adipose tissue (BAT) have been proposed as therapeutic targets for obesity and diabetes. Little is known about basal BAT activity. Capitalizing on the dense sympathetic innervation of BAT, we have previously shown that BAT can be detected in humans under resting room temperature (RT) conditions by using (S,S)-C-O-methylreboxetine (MRB), a selective ligand for the norepinephrine transporter (NET).

CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation.

Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity.

In a Free-Living Setting, Obesity Is Associated With Greater Food Intake in Response to a Similar Premeal Glucose Nadir.

Purpose: Changes in blood glucose levels have been shown to influence eating in healthy individuals; however, less is known about effects of glucose on food intake in individuals who are obese (OB). The goal of this study was to determine the predictive effect of circulating glucose levels on eating in free-living OB and normal weight (NW) individuals.

Methods: Interstitial glucose levels, measured with a continuous glucose monitor (CGM) system, were obtained from 15 OB and 16 NW volunteers (age: 40 ± 14 and 37 ± 12 years; weight: 91 ± 13 and 68 ± 12 kg; hemoglobin A1c: 5.

Food Cues and Obesity: Overpowering Hormones and Energy Balance Regulation.

Purpose Of Review: In the modern obesogenic environment, food cues play a crucial role in the development of obesity by disrupting hormone and energy balance mechanisms. Thus, it is critical to understand the neurobiology of feeding behaviors and obesity in the context of ubiquitous food cues. The current paper reviews the physiology of feeding, hormonal regulation of energy balance, and food cue responses and discusses their contributions to obesity.

Noradrenergic Activity in the Human Brain: A Mechanism Supporting the Defense Against Hypoglycemia.

Context: Hypoglycemia, one of the major factors limiting optimal glycemic control in insulin-treated patients with diabetes, elicits a brain response to restore normoglycemia by activating counterregulation. Animal data indicate that local release of norepinephrine (NE) in the hypothalamus is important for triggering hypoglycemia-induced counterregulatory (CR) hormonal responses.

Objective: To examine the potential role of brain noradrenergic (NA) activation in humans during hypoglycemia.

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia.

Background: Among nondiabetic individuals, mild glucose decrements alter brain activity in regions linked to reward, motivation, and executive control. Whether these effects differ in type 1 diabetes mellitus (T1DM) patients with and without hypoglycemia awareness remains unclear.

Methods: Forty-two individuals (13 healthy control [HC] subjects, 16 T1DM individuals with hypoglycemia awareness [T1DM-Aware], and 13 T1DM individuals with hypoglycemia unawareness [T1DM-Unaware]) underwent blood oxygen level-dependent functional MRI brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dl)-hypoglycemic (60 mg/dl) clamp for assessment of neural responses to mild hypoglycemia.

Humans with obesity have disordered brain responses to food images during physiological hyperglycemia.

Blood glucose levels influence brain regulation of food intake. This study assessed the effect of mild physiological hyperglycemia on brain response to food cues in individuals with obesity (OB) versus normal weight individuals (NW). Brain responses in 10 OB and 10 NW nondiabetic healthy adults [body mass index: 34 (3) vs.

Blunted rise in brain glucose levels during hyperglycemia in adults with obesity and T2DM.

In rodent models, obesity and hyperglycemia alter cerebral glucose metabolism and glucose transport into the brain, resulting in disordered cerebral function as well as inappropriate responses to homeostatic and hedonic inputs. Whether similar findings are seen in the human brain remains unclear. In this study, 25 participants (9 healthy participants; 10 obese nondiabetic participants; and 6 poorly controlled, insulin- and metformin-treated type 2 diabetes mellitus (T2DM) participants) underwent 1H magnetic resonance spectroscopy scanning in the occipital lobe to measure the change in intracerebral glucose levels during a 2-hour hyperglycemic clamp (glucose ~220 mg/dl).

The human brain produces fructose from glucose.

Fructose has been implicated in the pathogenesis of obesity and type 2 diabetes. In contrast to glucose, CNS delivery of fructose in rodents promotes feeding behavior. However, because circulating plasma fructose levels are exceedingly low, it remains unclear to what extent fructose crosses the blood-brain barrier to exert CNS effects.

Evaluation of the counter-regulatory responses to hypoglycaemia in patients with type 1 diabetes during opiate receptor blockade with naltrexone.

Aims: Hypoglycaemia is the major limiting factor in achieving optimal glycaemic control in people with type 1 diabetes (T1DM), especially intensively treated patients with impaired glucose counter-regulation during hypoglycaemia. Naloxone, an opiate receptor blocker, has been reported to enhance the acute counter-regulatory response to hypoglycaemia when administered intravenously in humans. The current study was undertaken to investigate the oral formulation of the long-acting opiate antagonist, naltrexone, and determine if it could have a similar effect, and thus might be useful therapeutically in treatment of T1DM patients with a high risk of hypoglycaemia.

Inhaled Formoterol Diminishes Insulin-Induced Hypoglycemia in Type 1 Diabetes.

Objective: Hypoglycemia is one of the major factors limiting implementation of tight glycemic control in patients with type 1 diabetes and is associated with increased morbidity and mortality during intensive insulin treatment. β-2 Adrenergic receptor (AR) agonists have been reported to diminish nocturnal hypoglycemia; however, whether long-acting inhaled β-2 AR agonists could potentially be used to treat or prevent hypoglycemia has not been established.

Research Design And Methods: Seven patients with type 1 diabetes and seven healthy control subjects received inhaled formoterol (48 μg), a highly specific β-2 AR agonist, or a placebo during a hyperinsulinemic-hypoglycemic clamp study to evaluate its capacity to antagonize the effect of insulin.

Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women.

Background: Fructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000 th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS) fructose production from glucose via the polyol pathway (glucose → sorbitol → fructose) contributes to brain exposure to fructose.

Imaging human brown adipose tissue under room temperature conditions with (11)C-MRB, a selective norepinephrine transporter PET ligand.

Introduction: Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET).

Increased brain transport and metabolism of acetate in hypoglycemia unawareness.

Context: Intensive insulin therapy reduces the risk for long-term complications in patients with type 1 diabetes mellitus (T1DM) but increases the risk for hypoglycemia-associated autonomic failure (HAAF), a syndrome that includes hypoglycemia unawareness and defective glucose counterregulation (reduced epinephrine and glucagon responses to hypoglycemia).

Objective: The objective of the study was to address mechanisms underlying HAAF, we investigated whether nonglucose fuels such as acetate, a monocarboxylic acid (MCA), can support cerebral energetics during hypoglycemia in T1DM individuals with hypoglycemia unawareness.

Design: Magnetic resonance spectroscopy was used to measure brain transport and metabolism of [2-(13)C]acetate under hypoglycemic conditions.

LRP6 enhances glucose metabolism by promoting TCF7L2-dependent insulin receptor expression and IGF receptor stabilization in humans.

Common genetic variations in Wnt signaling genes have been associated with metabolic syndrome and diabetes by mechanisms that are poorly understood. A rare nonconservative mutation in Wnt coreceptor LRP6 (LRP6(R611C)) has been shown to underlie autosomal dominant early onset coronary artery disease, type 2 diabetes, and metabolic syndrome. We examined the interplay between Wnt and insulin signaling pathways in skeletal muscle and skin fibroblasts of healthy nondiabetic LRP6(R611C) mutation carriers.

Circulating glucose levels modulate neural control of desire for high-calorie foods in humans.

Obesity is a worldwide epidemic resulting in part from the ubiquity of high-calorie foods and food images. Whether obese and nonobese individuals regulate their desire to consume high-calorie foods differently is not clear. We set out to investigate the hypothesis that circulating levels of glucose, the primary fuel source for the brain, influence brain regions that regulate the motivation to consume high-calorie foods.