Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway.

OBJECTIVES: Insulin's ability to counterbalance catecholamine-induced lipolysis defines insulin action in adipose tissue. Insulin suppresses lipolysis directly at the level of the adipocyte and indirectly through signaling in the brain. Here, we further characterized the role of brain insulin signaling in regulating lipolysis and defined the intracellular insulin signaling pathway required for brain insulin to suppress lipolysis. METHODS: We used hyperinsulinemic clamp studies coupled with tracer dilution techniques to assess insulin's ability to suppress lipolysis in two different mouse models with inducible insulin receptor depletion in all tissues (IRΔWB) or restricted to peripheral tissues excluding the brain (IRΔPER). To identify the underlying signaling pathway required for brain insulin to inhibit lipolysis, we continuously infused insulin +/- a PI3K or MAPK inhibitor into the mediobasal hypothalamus of male Sprague Dawley rats and assessed lipolysis during clamps. RESULTS: Genetic insulin receptor deletion induced marked hyperglycemia and insulin resistance in both IRΔPER and IRΔWB mice. However, the ability of insulin to suppress lipolysis was largely preserved in IRΔPER, but completely obliterated in IRΔWB mice indicating that insulin is still able to suppress lipolysis as long as brain insulin receptors are present. Blocking the MAPK, but not the PI3K pathway impaired the inhibition of lipolysis by brain insulin signaling. CONCLUSION: Brain insulin is required for insulin to suppress adipose tissue lipolysis and depends on intact hypothalamic MAPK signaling.

Infiltrative thyrotoxicosis: an unusual case of diffuse large B cell lymphoma.

Thyrotoxicosis is most commonly caused by Graves' disease, toxic multinodular goitre, a functioning thyroid adenoma, or thyroiditis. Extrinsic infiltrative conditions affecting the thyroid gland are typically destructive, and associated with thyroid hypofunction. We describe the case of a 61-year-old woman who presented to our hospital with symptoms of thyrotoxicosis, neck swelling and thyroid function tests consistent with hyperthyroidism. An ultrasound revealed a multinodular goitre with retrosternal extension, but CT imaging suggested thyroid gland infiltration, with cervical lymphadenopathy. An excisional lymph node biopsy confirmed the diagnosis of diffuse large B cell lymphoma causing infiltrative thyrotoxicosis. Treatment with six cycles of Rituximab-CHOP lead to rapid normalization of symptoms, imaging, and thyroid function.

Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain.

Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis.

Brain-liver connections: role of the preautonomic PVN neurons.

Diabetes mellitus and the coexisting conditions and complications, including hypo- and hyperglycemic events, obesity, high cholesterol levels, and many more, are devastating problems. Undoubtedly, there is a huge demand for treatment and prevention of these conditions that justifies the search for new approaches and concepts for better management of whole body metabolism. Emerging evidence demonstrates that the autonomic nervous system is largely involved in the regulation of glucose homeostasis; however, the underlying mechanisms are still under investigation. Within the hypothalamus, the paraventricular nucleus (PVN) is in a unique position to integrate neural and hormonal signals to command both the autonomic and neuroendocrine outflow. This minireview will provide a brief overview on the role of preautonomic PVN neurons and the importance of the PVN-liver pathway in the regulation of glucose homeostasis.

Short term voluntary overfeeding disrupts brain insulin control of adipose tissue lipolysis.

Insulin controls fatty acid (FA) release from white adipose tissue (WAT) through direct effects on adipocytes and indirectly through hypothalamic signaling by reducing sympathetic nervous system outflow to WAT. Uncontrolled FA release from WAT promotes lipotoxicity, which is characterized by inflammation and insulin resistance that leads to and worsens type 2 diabetes. Here we tested whether early diet-induced insulin resistance impairs the ability of hypothalamic insulin to regulate WAT lipolysis and thus contributes to adipose tissue dysfunction. To this end we fed male Sprague-Dawley rats a 10% lard diet (high fat diet (HFD)) for 3 consecutive days, which is known to induce systemic insulin resistance. Rats were studied by euglycemic pancreatic clamps and concomitant infusion of either insulin or vehicle into the mediobasal hypothalamus. Short term HFD feeding led to a 37% increase in caloric intake and elevated base-line free FAs and insulin levels compared with rats fed regular chow. Overfeeding did not impair insulin signaling in WAT, but it abolished the ability of mediobasal hypothalamus insulin to suppress WAT lipolysis and hepatic glucose production as assessed by glycerol and glucose flux. HFD feeding also increased hypothalamic levels of the endocannabinoid 2-arachidonoylglycerol after only 3 days. In summary, overfeeding impairs hypothalamic insulin action, which may contribute to unrestrained lipolysis seen in human obesity and type 2 diabetes.

Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice.

BACKGROUND & AIMS: Obesity-related insulin resistance contributes to cardiovascular disease. Cannabinoid receptor-1 (CB(1)) blockade improves insulin sensitivity in obese animals and people, suggesting endocannabinoid involvement. We explored the role of hepatic CB(1) in insulin resistance and inhibition of insulin signaling pathways. METHODS: Wild-type mice and mice with disruption of CB(1) (CB(1)(-/-) mice) or with hepatocyte-specific deletion or transgenic overexpression of CB(1) were maintained on regular chow or a high-fat diet (HFD) to induce obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp analysis was used to analyze the role of the liver and hepatic CB(1) in HFD-induced insulin resistance. The cellular mechanisms of insulin resistance were analyzed in mouse and human isolated hepatocytes using small interfering or short hairpin RNAs and lentiviral knockdown of gene expression. RESULTS: The HFD induced hepatic insulin resistance in wild-type mice, but not in CB(1)(-/-) mice or mice with hepatocyte-specific deletion of CB(1). CB(1)(-/-) mice that overexpressed CB(1) specifically in hepatocytes became hyperinsulinemic as a result of reduced insulin clearance due to down-regulation of the insulin-degrading enzyme. However, they had increased hepatic glucose production due to increased glycogenolysis, indicating hepatic insulin resistance; this was further increased by the HFD. In mice with hepatocytes that express CB(1), the HFD or CB(1) activation induced the endoplasmic reticulum stress response via activation of the Bip-PERK-eIF2α protein translation pathway. In hepatocytes isolated from human or mouse liver, CB(1) activation caused endoplasmic reticulum stress-dependent suppression of insulin-induced phosphorylation of akt-2 via phosphorylation of IRS1 at serine-307 and by inducing the expression of the serine and threonine phosphatase Phlpp1. Expression of CB(1) was up-regulated in samples from patients with nonalcoholic fatty liver disease. CONCLUSIONS: Endocannabinoids contribute to diet-induced insulin resistance in mice via hepatic CB(1)-mediated inhibition of insulin signaling and clearance.

Central endocannabinoid signaling regulates hepatic glucose production and systemic lipolysis.

OBJECTIVE: The endocannabinoid (EC) system has been implicated as an important regulator of energy homeostasis. In obesity and type 2 diabetes, EC tone is elevated in peripheral tissues including liver, muscle, fat, and also centrally, particularly in the hypothalamus. Cannabinoid receptor type 1 (CB1) blockade with the centrally and peripherally acting rimonabant induces weight loss and improves glucose homeostasis while also causing psychiatric adverse effects. The relative contributions of peripheral versus central EC signaling on glucose homeostasis remain to be elucidated. The aim of this study was to test whether the central EC system regulates systemic glucose fluxes. RESEARCH DESIGN AND METHODS: We determined glucose and lipid fluxes in male Sprague-Dawley rats during intracerebroventricular infusions of either WIN55,212-2 (WIN) or arachidonoyl-2'-chloroethylamide (ACEA) while controlling circulating insulin and glucose levels through hyperinsulinemic, euglycemic clamp studies. Conversely, we fed rats a high-fat diet for 3 days and then blocked central EC signaling with an intracerebroventricular infusion of rimonabant while assessing glucose fluxes during a clamp. RESULTS: Central CB1 activation is sufficient to impair glucose homeostasis. Either WIN or ACEA infusions acutely impaired insulin action in both liver and adipose tissue. Conversely, in a model of overfeeding-induced insulin resistance, CB1 antagonism restored hepatic insulin sensitivity. CONCLUSIONS: Thus central EC tone plays an important role in regulating hepatic and adipose tissue insulin action. These results indicate that peripherally restricted CB1 antagonists, which may lack psychiatric side effects, are also likely to be less effective than brain-permeable CB1 antagonists in ameliorating insulin resistance.

Brain insulin controls adipose tissue lipolysis and lipogenesis.

White adipose tissue (WAT) dysfunction plays a key role in the pathogenesis of type 2 diabetes (DM2). Unrestrained WAT lipolysis results in increased fatty acid release, leading to insulin resistance and lipotoxicity, while impaired de novo lipogenesis in WAT decreases the synthesis of insulin-sensitizing fatty acid species like palmitoleate. Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis. Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality.

Hepatic muscarinic acetylcholine receptors are not critically involved in maintaining glucose homeostasis in mice.

OBJECTIVE: An increase in the rate of hepatic glucose production is the major determinant of fasting hyperglycemia in type 2 diabetes. A better understanding of the signaling pathways and molecules that regulate hepatic glucose metabolism is therefore of great clinical importance. Recent studies suggest that an increase in vagal outflow to the liver leads to decreased hepatic glucose production and reduced blood glucose levels. Since acetylcholine (ACh) is the major neurotransmitter of the vagus nerve and exerts its parasympathetic actions via activation of muscarinic ACh receptors (mAChRs), we examined the potential metabolic relevance of hepatocyte mAChRs. RESEARCH DESIGN AND METHODS: We initially demonstrated that the M(3) mAChR is the only mAChR subtype expressed by mouse liver/hepatocytes. To assess the physiological role of this receptor subtype in regulating hepatic glucose fluxes and glucose homeostasis in vivo, we used gene targeting and transgenic techniques to generate mutant mice lacking or overexpressing M(3) receptors in hepatocytes only. RESULTS: Strikingly, detailed in vivo phenotyping studies failed to reveal any significant metabolic differences between the M(3) receptor mutant mice and their control littermates, independent of whether the mice were fed regular or a high-fat diet. Moreover, the expression levels of genes for various key transcription factors, signaling molecules, and enzymes regulating hepatic glucose fluxes were not significantly altered in the M(3) receptor mutant mice. CONCLUSIONS: This rather surprising finding suggests that the pronounced metabolic effects mediated by activation of hepatic vagal nerves are mediated by noncholinergic signaling pathways.

Anatomy of the ward round.

The ward round has been a central activity of hospital life for hundreds of years. It is hardly mentioned in textbooks. The ward round is a parade through the hospital of professionals where most decision making concerning patient care is made. However the traditional format may be intimidating for patients and inadequate for communication. The round provides an opportunity for the multi-disciplinary team to listen to the patient's narrative and jointly interpret his concerns. From this unfolds diagnosis, management plans, prognosis formation and the opportunity to explore social, psychological, rehabilitation and placement issues. Physical examination of the patient at the bedside still remains important. It has been a tradition to discuss the patient at the bedside but sensitive matters especially of uncertainty may better be discussed elsewhere. The senior doctor as round leader must seek the input of nursing whose observations may be under-appreciated due to traditional professional hierarchy. Reductions in the working hours of junior doctors and shortened length of stay have reduced continuity of patient care. This increases the importance of senior staff in ensuring continuity of care and the need for the joint round as the focus of optimal decision making. The traditional round incorporates teaching but patient's right to privacy and their preferences must be respected. The quality and form of the clinical note is underreported but the electronic record is slow to being accepted. The traditional multi-disciplinary round is disappearing in some centres. This may be regrettable. The anatomy and optimal functioning of the ward round deserves scientific scrutiny and experimentation.

[Political issues in internal medicine in Europe. A position paper]. / Pozycja i przyszlosc medycyny wewn trznej w Europie. Prezentacja naszego stanowiska.

What will be the future of internal medicine in Europe? Because of rapidly growing concerns regarding the position of internal medicine in many European countries, the European Federation of Internal Medicine (EFIM) has established a working group to analyze the situation. Being well aware of the variation in working practices in the different countries, the members of the group used an "all-European" approach to answer the following questions: Are there problems for internal medicine? If so, what are these problems and why? Why do the health care systems in the European countries need internal medicine? Why do patients need internal medicine? What needs to be done? Internal medicine is the modern, clinical, and scientific medical discipline that is responsible for the care of adult patients with one or more complex, acute, or chronic illnesses. Internal medicine is the cornerstone of an integrated health care delivery service that is needed today. Decision-makers in politics and hospitals, insurers, journalists, and the general public need a better understanding of what internal medicine can offer to the health care system and to the individual patient.

Political issues in internal medicine in Europe.

What will be the future of Internal Medicine in Europe? Because of rapidly growing concerns regarding the position of Internal Medicine in many European countries, the European Federation of Internal Medicine has established a working group to analyze the situation. Being well aware of the variation of working practices in the different countries, the members of the group used an "all-European" approach to answer the following questions: Are there problems for Internal Medicine, what problems and why? Why do the health care systems of the European countries need Internal Medicine? Why do the patients need Internal Medicine? What needs to be done? Internal Medicine is the modern, clinical and scientific medical discipline taking care of adult patients with one or more complex, acute or chronic illnesses. Internal Medicine is the cornerstone of integrated health care delivery service that is needed today. Decision-makers in politics and hospitals, insurers, journalists and the general public need a better understanding of what Internal Medicine can offer to the health care system and to the individual patient.

Political issues in internal medicine in Europe. A position paper.

What will be the future of internal medicine in Europe? Because of rapidly growing concerns regarding the position of internal medicine in many European countries, the European Federation of Internal Medicine (EFIM) has established a working group to analyze the situation. Being well aware of the variation in working practices in the different countries, the members of the group used an "all-European" approach to answer the following questions: Internal medicine is the modern, clinical, and scientific medical discipline that is responsible for the care of adult patients with one or more complex, acute, or chronic illnesses. Internal medicine is the cornerstone of an integrated health care delivery service that is needed today. Decision-makers in politics and hospitals, insurers, journalists, and the general public need a better understanding of what internal medicine can offer to the health care system and to the individual patient.

Anomalous origin of the left coronary artery from the pulmonary artery treated by palliative Vineberg operation in an infant.

Anomalous origin of the left coronary artery from the pulmonary artery was diagnosed in an infant girl who had evidence of transmural myocardial infarction of the free wall of the left ventricle. At age 13 months, she underwent a palliative left Vineberg implant, and remained asymptomatic until she was 8 years of age. At that time, she underwent suturing of the left coronary ostium for obliteration of the left coronary shunt at the pulmonary artery. At age 13, she underwent aortocoronary bypass to the left main coronary artery, with end-to-end anastomosis. The patient remains asymptomatic to date. We believe that this is the first reported case of a Vineberg operation performed in an infant for palliation of an anomalous left coronary artery originating from the pulmonary artery. This method allows time for the development of collateral circulation to the left coronary artery before definitive surgery is performed.

SURGICAL CORRECTION OF COMBINED DOUBLE-OUTLET RIGHT VENTRICLE AND TAUSSIG-BING SYNDROME.

Total surgical correction of a Taussig-Bing type double outlet right ventricle (DORV) was successfully performed in a severely cyanotic 3-year-old girl. The malformation was associated with bilateral conus, d-transposition of the great arteries, d-loop, and a subpulmonary ventricular septal defect (VSD) without significant pulmonary stenosis in situs solitus. It was impossible to create a tunnel repair by resecting the markedly hypertrophied muscular conus that separated the aortic valve from the subpulmonary ventricular septal defect. Therefore, the VSD was repaired with a Dacron patch, transforming the double outlet right ventricle into a transposition, after which total correction was achieved by means of a Mustard procedure.

SIGNIFICANCE OF ANGIOGRAPHIC ABSENCE OF LEFT ANTERIOR DESCENDING CORONARY ARTERY IN A LEFT VENTRICLE WITH INTACT ANTERIOR WALL.

Fifteen patients having total occlusion of the proximal left anterior descending coronary artery were studied. All fifteen had normal left ventricular anterior walls. The electrocardiogram was normal in eight patients; old inferior wall infarction was evident in one; anterior ischemia in five; and left anterior hemiblock in one. Collateral circulation was found in twelve patients (80%). These findings suggest that an angiographically non-visualized left anterior descending (LAD) vessel is patent and bypassable in patients where the anterior ventricular wall is intact, thus representing an additional criterion for aortocoronary bypass surgery.

A SECOND CASE OF LATE EMBOLIZATION OF PROSTHETIC MITRAL VALVE OCCLUDER WITH SURVIVAL FOLLOWING REOPERATION.

A 51-year-old male with acute fulminating pulmonary edema and cardiogenic shock secondary to severe mitral insufficiency from dislodgment of the disc occluder in a Wada-Cutter valve was treated by immediate open heart procedure with a Bjork-Shiley mitral valve replacement. The patient survived and remains well. This is the second patient reported to survive operation and replacement of a malfunctioning prosthetic mitral valve from which the poppet escaped and embolized. The first case was reported by Hughes et al(1) in February, 1975. Some striking similarities, as well as differences, in these two cases are discussed.