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Limited evidence suggests that GLP-I may also preserve ventricular function and improve outcomes in human subjects with heart failure or myocardial infarction (11,12). [...] both exenatide and liraglutide reduce blood pressure, body weight, and plasma lipid profiles in subjects with type 2 diabetes (13), raising the hope that longterm treatment with these agents may reduce the incidence of cardiovascular events. However, two safety issues have been raised - pancreatitis and medullary carcinoma of the thyroid.

Abstract 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. Design A hyperinsulinemic-hypoglycemic clamp was performed in conjunction with positron emission tomographic imaging. Participants Nine lean healthy volunteers were studied during the hyperinsulinemic-hypoglycemic clamp. Design Participants received intravenous injections of (S,S)-[11C]O-methylreboxetine ([11C]MRB), a highly selective NE transporter (NET) ligand, at baseline and during hypoglycemia. Results Hypoglycemia increased plasma epinephrine, glucagon, cortisol, and growth hormone and decreased [11C]MRB binding potential (BPND) by 24% ± 12% in the raphe nucleus (P < 0.01). In contrast, changes in [11C]MRB BPND in the hypothalamus positively correlated with increments in epinephrine and glucagon levels and negatively correlated with glucose infusion rate (all P < 0.05). Furthermore, in rat hypothalamus studies, hypoglycemia induced NET translocation from the cytosol to the plasma membrane. Conclusions Insulin-induced hypoglycemia initiated a complex brain NA response in humans. Raphe nuclei, a region involved in regulating autonomic output, motor activity, and hunger, had increased NA activity, whereas the hypothalamus showed a NET-binding pattern that was associated with the individual’s CR response magnitude. These findings suggest that NA output most likely is important for modulating brain responses to hypoglycemia in humans. Hypoglycemia increases noradrenergic activity in the raphe nuclei, whereas changes in hypothalamic noradrenergic activity correlate with the counterregulatory response to hypoglycemia in humans.

The prevalence and magnitude of childhood obesity are increasing dramatically. These investigators examined the effect of the degree of obesity on the prevalence of the metabolic syndrome and the relation of the syndrome to insulin resistance and C-reactive protein and adiponectin levels in a large multiracial, multiethnic cohort of children and adolescents. The relation of the syndrome to insulin resistance and C-reactive protein and adiponectin levels. In 1988, Reaven and colleagues 1 described “the metabolic syndrome” as a link between insulin resistance and hypertension, dyslipidemia, type 2 diabetes, and other metabolic abnormalities associated with an increased risk of atherosclerotic cardiovascular disease 2 in adults. Recent studies suggest that the metabolic syndrome may originate in utero. 2 , 3 Obesity, which is the most common cause of insulin resistance in children, 4 is also associated with dyslipidemia, 5 type 2 diabetes, 6 and long-term vascular complications. 7 – 9 In a sample of adolescents in the United States who were included in the third National Health and Nutrition Examination Survey (NHANES III), conducted between 1988 and . . .

Medium-Chain Fatty Acids Improve Cognitive Function in Intensively Treated Type 1 Diabetic Patients and Support In Vitro Synaptic Transmission During Acute Hypoglycemia Kathleen A. Page 1 , Anne Williamson 2 , Namyi Yu 3 , Ewan C. McNay 4 , James Dzuira 5 , Rory J. McCrimmon 1 and Robert S. Sherwin 1 1 Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut; 2 Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; 3 Winthrop University Hospital, Long Island, New York; 4 Department of Psychology, State University of New York, University at Albany, Albany, New York; and 5 Yale Center for Clinical Investigation, New Haven, Connecticut. Corresponding author: Kathleen A. Page, kathleen.page{at}yale.edu . Abstract OBJECTIVE We examined whether ingestion of medium-chain triglycerides could improve cognition during hypoglycemia in subjects with intensively treated type 1 diabetes and assessed potential underlying mechanisms by testing the effect of β-hydroxybutyrate and octanoate on rat hippocampal synaptic transmission during exposure to low glucose. RESEARCH DESIGN AND METHODS A total of 11 intensively treated type 1 diabetic subjects participated in stepped hyperinsulinemic- (2 mU · kg −1 · min −1 ) euglycemic- (glucose ∼5.5 mmol/l) hypoglycemic (glucose ∼2.8 mmol/l) clamp studies. During two separate sessions, they randomly received either medium-chain triglycerides or placebo drinks and performed a battery of cognitive tests. In vitro rat hippocampal slice preparations were used to assess the ability of β-hydroxybutyrate and octanoate to support neuronal activity when glucose levels are reduced. RESULTS Hypoglycemia impaired cognitive performance in tests of verbal memory, digit symbol coding, digit span backwards, and map searching. Ingestion of medium-chain triglycerides reversed these effects. Medium-chain triglycerides also produced higher free fatty acids and β-hydroxybutyrate levels compared with placebo. However, the increase in catecholamines and symptoms during hypoglycemia was not altered. In hippocampal slices β-hydroxybutyrate supported synaptic transmission under low-glucose conditions, whereas octanoate could not. Nevertheless, octanoate improved the rate of recovery of synaptic function upon restoration of control glucose concentrations. CONCLUSIONS Medium-chain triglyceride ingestion improves cognition without adversely affecting adrenergic or symptomatic responses to hypoglycemia in intensively treated type 1 diabetic subjects. Medium-chain triglycerides offer the therapeutic advantage of preserving brain function under hypoglycemic conditions without causing deleterious hyperglycemia. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received November 10, 2008. Accepted February 4, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia Rory J. McCrimmon , Margaret Shaw , Xiaoning Fan , Haiying Cheng , Yuyan Ding , Monica C. Vella , Ligang Zhou , Ewan C. McNay and Robert S. Sherwin Yale University School of Medicine, Department of Internal Medicine and Endocrinology, New Haven, Connecticut Address correspondence and reprint requests to Rory J. McCrimmon, MD, FRCP, Yale University School of Medicine, P.O. Box 208020, New Haven, CT 06520-8020. E-mail: rory.mccrimmon{at}yale.edu Abstract OBJECTIVE —To examine in vivo in a rodent model the potential role of AMP-activated protein kinase (AMPK) within the ventromedial hypothalamus (VMH) in glucose sensing during hypoglycemia. RESEARCH DESIGN AND METHODS —Using gene silencing technology to selectively downregulate AMPK in the VMH, a key hypothalamic glucose-sensing region, we demonstrate a key role for AMPK in the detection of hypoglycemia. In vivo hyperinsulinemic-hypoglycemic (50 mg dl −1 ) clamp studies were performed in awake, chronically catheterized Sprague-Dawley rats that had been microinjected bilaterally to the VMH with an adeno-associated viral (AAV) vector expressing a short hairpin RNA for AMPKα. RESULTS —In comparison with control studies, VMH AMPK downregulation resulted in suppressed glucagon (∼60%) and epinephrine (∼40%) responses to acute hypoglycemia. Rats with VMH AMPK downregulation also required more exogenous glucose to maintain the hypoglycemia plateau and showed significant reductions in endogenous glucose production and whole-body glucose uptake. CONCLUSIONS —We conclude that AMPK in the VMH plays a key role in the detection of acute hypoglycemia and initiation of the glucose counterregulatory response. ACTH, adrenocorticotrophin hormone AAV vector, adeno-associated viral vector AICAR, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside AMPK, AMP-activated protein kinase Arc, Arcuate nucleus CAG, chicken β-actin promoter CRH, corticotrophin-releasing hormone CRR, counterregulatory response DMH, dorsomedial hypothalamus GFP, green fluorescent protein GIR, glucose infusion rate NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases PBT, 0.04% Triton X-100 in PBS PVN, paraventricular nucleus Ra, rate of endogenous glucose production Rd, rate of whole-body glucose uptake VMH, ventromedial hypothalamus VMN, ventromedial nucleus WPRE, woodchuck posttranscriptional regulatory element Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 31 October 2007. DOI: 10.2337/db07-0837. R.J.M. and M.S. contributed equally to this article. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 26, 2007. Received June 20, 2007. DIABETES

Implementation of a Safe and Effective Insulin Infusion Protocol in a Medical Intensive Care Unit Philip A. Goldberg , MD 1 , Mark D. Siegel , MD 2 , Robert S. Sherwin , MD 1 , Joshua I. Halickman 1 , Michelle Lee , MD 1 , Valerie A. Bailey , MSN, RN 3 , Sandy L. Lee , MSN, RN 3 , James D. Dziura , PHD 4 and Silvio E. Inzucchi , MD 1 1 Department of Internal Medicine, Section of Endocrinology, Yale New Haven Hospital, Yale University School of Medicine, New Haven, Connecticut 2 Department of Internal Medicine, Section of Pulmonary & Critical Care, Yale New Haven Hospital, Yale University School of Medicine, New Haven, Connecticut 3 Department of Nursing, Yale New Haven Hospital, Yale University School of Medicine, New Haven, Connecticut 4 General Clinical Research Center, Yale New Haven Hospital, Yale University School of Medicine, New Haven, CT. Address correspondence and reprint requests to Silvio E. Inzucchi, MD, Section of Endocrinology, Yale University School of Medicine, 333 Cedar St., TMP 534, P.O. Box 208020, New Haven, CT 06520-8020. E-mail: silvio.inzucchi{at}yale.edu Abstract OBJECTIVE —In a recent randomized controlled trial, lowering blood glucose levels to 80–110 mg/dl improved clinical outcomes in critically ill patients. In that study, the insulin infusion protocol (IIP) used to normalize blood glucose levels provided valuable guidelines for adjusting insulin therapy. In our hands, however, ongoing expert supervision was required to effectively manage the insulin infusions. This work describes our early experience with a safe, effective, nurse-implemented IIP that provides detailed insulin dosing instructions and requires minimal physician input. RESEARCH DESIGN AND METHODS —We collected data from 52 medical intensive care unit (MICU) patients who were placed on the IIP. Blood glucose levels were the primary outcome measurement. Relevant clinical variables and insulin requirements were also recorded. MICU nurses were surveyed regarding their experience with the IIP. RESULTS —To date, our IIP has been employed 69 times in 52 patients admitted to an MICU. Using the IIP, the median time to reach target blood glucose levels (100–139 mg/dl) was 9 h. Once blood glucose levels fell below 140 mg/dl, 52% of 5,808 subsequent hourly blood glucose values fell within our narrow target range; 66% within a “clinically desirable” range of 80–139 mg/dl; and 93% within a “clinically acceptable” range of 80–199 mg/dl. Only 20 (0.3%) blood glucose values were <60 mg/dl, none of which resulted in clinically significant adverse events. In general, the IIP was readily accepted by our MICU nursing staff, most of whom rated the protocol as both clinically effective and easy to use. CONCLUSIONS —Our nurse-implemented IIP is safe and effective in improving glycemic control in critically ill patients. APACHE II, Acute Physiology And Chronic Health Evaluation II ICU, intensive care unit IIP, insulin infusion protocol MICU, medical ICU Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted October 21, 2003. Received August 4, 2003. DIABETES CARE

Increased GABAergic Tone in the Ventromedial Hypothalamus Contributes to Suppression of Counterregulatory Reponses After Antecedent Hypoglycemia Owen Chan 1 , Haiying Cheng 1 , Raimund Herzog 1 , Daniel Czyzyk 2 , Wanling Zhu 1 , Ajin Wang 1 , Rory J. McCrimmon 1 , Margretta R. Seashore 2 and Robert S. Sherwin 1 1 Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 2 Department of Genetics, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut Corresponding author: Dr. Robert S. Sherwin, Yale University School of Medicine, Department of Internal Medicine, Section of Endocrinology, 300 Cedar St., TAC S141, New Haven, CT 06520. E-mail: robert.sherwin{at}yale.edu Abstract OBJECTIVE— We have previously demonstrated that modulation of γ-aminobutyric acid (GABA) inhibitory tone in the ventromedial hypothalamus (VMH), an important glucose-sensing region in the brain, modulates the magnitude of glucagon and sympathoadrenal responses to hypoglycemia. In the current study, we examined whether increased VMH GABAergic tone may contribute to suppression of counterregulatory responses after recurrent hypoglycemia. RESEARCH DESIGN AND METHODS— To test this hypothesis, we quantified expression of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), in the VMH of control and recurrently hypoglycemic rats. Subsequently, we used microdialysis and microinjection techniques to assess changes in VMH GABA levels and the effects of GABA A receptor blockade on counterregulatory responses to a standardized hypoglycemic stimulus. RESULTS— Quantitative RT-PCR and immunoblots in recurrently hypoglycemic animals revealed that GAD 65 mRNA and protein were increased 33 and 580%, respectively. Basal VMH GABA concentrations were more than threefold higher in recurrently hypoglycemic animals. Furthermore, whereas VMH GABA levels decreased in both control and recurrently hypoglycemic animals with the onset of hypoglycemia, the fall was not significant in recurrently hypoglycemic rats. During hypoglycemia, recurrently hypoglycemic rats exhibited a 49–63% reduction in glucagon and epinephrine release. These changes were reversed by delivery of a GABA A receptor antagonist to the VMH. CONCLUSIONS— Our data suggest that recurrent hypoglycemia increases GABAergic inhibitory tone in the VMH and that this, in turn, suppresses glucagon and sympathoadrenal responses to subsequent bouts of acute hypoglycemia. Thus, hypoglycemia-associated autonomic failure may be due in part to a relative excess of the inhibitory neurotransmitter, GABA, within the VMH. ECF, extracellular fluid GABA, γ-aminobutyric acid GAD, glutamic acid decarboxylase HAAF, hypoglycemia-associated autonomic failure VMH, ventromedial hypothalamus Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 28 March 2008. DOI: 10.2337/db07-1559. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 27, 2008. Received November 3, 2007. DIABETES

Insulin released by the beta-cell is thought to act locally to regulate glucagon secretion. The possibility that insulin might also act centrally to modulate islet glucagon secretion has received little attention. Initially the counterregulatory response to identical hypoglycemia was compared during intravenous insulin and phloridzin infusion in awake chronically catheterized nondiabetic rats. To explore whether the disparate glucagon responses seen were in part due to changes in ventromedial hypothalamus (VMH) exposure to insulin, bilateral guide cannulas were inserted to the level of the VMH and 8 days later rats received a VMH microinjection of either 1) anti-insulin affibody, 2) control affibody, 3) artificial extracellular fluid, 4) insulin (50 microU), 5) insulin receptor antagonist (S961), or 6) anti-insulin affibody plus a gamma-aminobutyric acid A (GABA(A)) receptor agonist muscimol, prior to a hypoglycemic clamp or under baseline conditions. As expected, insulin-induced hypoglycemia produced a threefold increase in plasma glucagon. However, the glucagon response was fourfold to fivefold greater when circulating insulin did not increase, despite equivalent hypoglycemia and C-peptide suppression. In contrast, epinephrine responses were not altered. The phloridzin-hypoglycemia induced glucagon increase was attenuated (40%) by VMH insulin microinjection. Conversely, local VMH blockade of insulin amplified glucagon twofold to threefold during insulin-induced hypoglycemia. Furthermore, local blockade of basal insulin levels or insulin receptors within the VMH caused an immediate twofold increase in fasting glucagon levels that was prevented by coinjection to the VMH of a GABA(A) receptor agonist. Together, these data suggest that insulin's inhibitory effect on alpha-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions.