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The nervous system is involved in: The secretion of insulin from beta cells. The secretion of glucagon from alpha cells. The release of glucagon from alpha cells in response to hypoglycemia (sympathetic fibers) The steady state release of glucose (glucose homeostasis) from the liver via gluconeogenesis (vagus nerve) and glycogenolysis, through GLP-1 (inhibiting) and epinephrine and norepinephrine (promoting). The rate of absorption of nutrients from the gut through control over gastric motility via the vagus nerve. There are receptors in the hypothalamus for insulin, glucose, FFA, Leptin, and GLP-1. PPARgamma receptors (TZD receptors) are abundant in the pituitary and may exist in the hypothalmus. The nervous system maintains glucose homestasis.
Hypothalamic lesions in rats with long-term streptozotocin-induced diabetes mellitus Journal ActaNeuropathologica Publisher Springer Berlin / Heidelberg ISSN 0001-6322 Issue Volume 52, Number 2 / January, 1980 Category Original Works DOI 10.1007/BF00688009 Pages 119-127 Subject Collection Medicine SpringerLink Date Sunday, December 12, 2004 Hypothalamic lesions in rats with long-term streptozotocin-induced diabetes mellitus A semiquantitative light- and electron-microscopic study G. Bestetti1 and G. L. Rossi1 (1) Institute of Animal Pathology, University of Berne, P. O. Box 2735, CH-3001 Berne, Switzerland Received: 12 May 1980 Accepted: 14 July 1980 Summary: Sixteen male Wistar rats, 1 year after injection of streptozotocin or vehicle, were fixed by whole-body perfusion, the brains were removed and processed for light and electron microscopy. Study of semithin sections from the hypothalamic area revealed changes in the arcuate nucleus and median eminence. The lesions, in comparison with controls, were subjected to a blind semiquantitative evaluation. The following changes were observed by light microscopy in diabetic rats: accumulation of glycogen (P<0.01), degeneration of neurons (P<0.05), hypertrophy of tanycytes (P<0.01), and axonal changes. Electron microscopy of diabetic rats revealed that glycogen was increased in neuronal bodies and processes (axons, synapses), also in tanycytes, and glia cells. In neurons were seen: dilated and fragmented endoplasmic reticulum, degranulatedergastoplasm, loss of organelles, increased number of microtubuli, myelin figures, irregulatities in the form of nuclei, and appearance of chromatin . The tanycytes in diabetic animals were reduced in volume, had an increased nuclear cytoplasmic ratio, a reduced number of organelles, short basal processes, and almost complete loss of the apical processes. These changes demonstrate the existence, under experimental conditions, of an encephalopathy pathogenetically related to streptozotocin-induced diabetes. Key words Hypothalmus - Rat - Streptozotocin - Diabetes - Morphology Supported by the SchweizerNationalfonds grant No. 3. 198-0.77
Transplantation. 1993 Jul;56(1):138-43.Links Reinnervation of transplanted pancreatic islets. A comparison among islets implanted into the kidney, spleen, and liver. Korsgren O, JanssonL, Andersson A, Sundler F. Department of Medical Cell Biology, Uppsala University, Sweden. Islets transplanted beneath the kidney capsule become reinnervated during the first 3-4 months after implantation by both afferent and efferent nerve fibers. To evaluate the importance of the implantation organ for this process, the present study compared both the degree and the types of nerve fibers reinnervating islets transplanted into the liver, kidney, and spleen. For this purpose, 150 syngeneic islets were grafted under the kidney capsule of C57BL/6 mice. In addition, the same animals were injected with 150 islets into the spleen or liver. All animals were killed 14 weeks after transplantation, after which the graft-bearing organs were processed for indirect immunofluorescence for neuropeptides and tyrosine hydroxylase (TH), and with acetyl cholinesterase (AchE) staining to visualize nerve fibers. Both afferent (containing substance P and/or calcitonin gene-related peptide) and parasympathetic (containing vasoactive intestinal peptide or AchE) nerve fibers were absent from islets implanted into the spleen; an occasional CGRP fiber was seen in islets implanted into the liver; and all these fibers were regularly seen in islets implanted beneath the renal capsule. The islets implanted into the liver or spleen contained a dense network of sympathetic (containing neuropeptide Y and TH) nerve fibers that was often more dense than in the islet grafts under the kidney capsule. One-fifth of islets implanted into the liver were, however, completely devoid of demonstrable nerve fibers. In conclusion, there are marked differences with regard to the pattern of reinnervation of islets transplanted to different implantation sites. Reinnervation of transplanted pancreatic islets
Proc NatlAcadSci U S A. 1998 Jun 23;95(13):7784-8. Pancreatic beta cells synthesize and secrete nerve growth factor. Rosenbaum T, Vidaltamayo R, Sánchez-Soto MC, Zentella A, Hiriart M. Department of Biophysics, Instituto de FisiologíaCelular, Universidad NacionalAutónoma de México DF 04510 Mexico. Differentiation and function of pancreatic beta cells are regulated by a variety of hormones and growth factors, including nerve growth factor (NGF). Whether this is an endocrine or autocrine/paracrine role for NGF is not known. We demonstrate that NGF is produced and secreted by adult rat pancreatic beta cells. NGF secretion is increased in response to elevated glucose or potassium, but decreased in response to dibutyrylcAMP. Moreover, steady-state levels of NGF mRNA are down-regulated by dibutyrylcAMP, which is opposite to the effect of cAMP on insulin release. NGF-stimulated changes in morphology and function are mediated by high-affinity Trk A receptors in other mammalian cells. Trk A receptors are present in beta cells and steady-state levels of Trk A mRNA are modulated by NGF and dibutyrylcAMP. Taken together, these findings suggest endocrine and autocrine roles for pancreatic beta-cell NGF, which, in turn, could be related to the pathogenesis of diabetes mellitus where serum NGF levels are diminished. Pancreatic beta cells secrete nerve growth factor
The Source of “Insulin Resistance” must emanate, at least, in part, from a CNS lesion.
Insulin secretion and insulin action in Taiwanese with type 2 diabetes Diabetes Res Clin Pract. 1988 Apr 6;4(4):289-93.Links Shen DC, Kuo SW, Shian LR, Fuh MT, Wu DA, Chen YD, Reaven GM. Department of Medicine, Stanford University School of Medicine, CA. In contrast to the United State, type 2 diabetes appears to be a common occurrence in non-obese Asians. In order to evaluate the possibility that this epidemiologic difference was indicative of a basic metabolic phenomenon, estimates of insulin secretion and insulin action were generated in 32 Chinese males, 16 with type 2 diabetes and 16 with normal glucose tolerance. Half of the individuals in each diagnostic category were obese (body mass index greater than 28 kg/m2) and half were non-obese (less than 26 kg/m2). Plasma glucose responses to a 75-g oral glucose challenge were significantly higher in patients with type 2 diabetes, but did not vary significantly within either group as a function of obesity. Plasma insulin concentrations were lower than normal when patients with type 2 diabetes were compared to their weight-matched controls. In addition, the absolute insulin values also varied as a function of body weight, with higher plasma insulin concentrations observed in the obese individuals. Insulin action was estimated by determination of the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations during the last 60 min of a continuous 180-min intravenous infusion of somatostatin, crystalline insulin, and glucose. Under these conditions endogenous insulin secretion is suppressed, SSPI concentrations are similar in all individuals, and SSPG concentrations provide a quantitative estimate of insulin-stimulated glucose disposal. The results of these studies indicated that patients with type 2 diabetes had significantly elevated SSPG concentrations as compared to normals, and this was true whether the diabetic subjects were obese or non-obese.
Diabetes Nutr Metab. 2002 Oct;15(5):318-22 Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia. Taborsky GJ Jr, Ahren B, Mundinger TO, Mei Q, Havel PJ. Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA. email@example.com In summary, this article briefly reviews the evidence that three separate autonomic inputs to the islet are capable of stimulating glucagon secretion and that each is activated during IIH. We have reviewed our evidence that these autonomic inputs mediate the glucagon response to IIH, both in non-diabetic animals and humans. Finally, we outline our new preliminary data suggesting an eSIN in an autoimmune animal model of T1DM. We conclude that the glucagon response to IIH is autonomically mediated in non-diabetic animals and humans. We further suggest that at least one of these autonomic inputs, the sympathetic innervation of the islet, is diminished in autoimmune T1DM. These data raise the novel possibility that an autonomic defect contributes to the loss of the glucagon response to IIH in T1DM. glucagon response to insulin-induced hypoglycaemia.
Neuroscience. 2007 Dec 12;150(3):592-602. Epub 2007 Oct 11. Pancreatic innervation in mouse development and beta-cell regeneration. Burris RE, Hebrok M. University of California, San Francisco, Diabetes Center, 513 Parnassus Avenue, Room HSW1116 Box 0540, San Francisco, CA 94143-0540, USA. Pancreatic innervation is being viewed with increasing interest with respect to pancreatic disease. At the same time, relatively little is currently known about innervation dynamics during development and disease. The present study employs confocal microscopy to analyze the growth and development of sympathetic and sensory neurons and astroglia during pancreatic organogenesis and maturation. Our research reveals that islet innervation is closely linked to the process of islet maturation-neural cell bodies undergo intrapancreatic migration/shuffling in tandem with endocrine cells, and close neuro-endocrine contacts are established quite early in pancreatic development. In addition, we have assayed the effects of large-scale beta-cell loss and repopulation on the maintenance of islet innervation with respect to particular neuron types. We demonstrate that depletion of the beta-cell population in the rat insulin promoter (RIP)-cmyc(ER) mouse line has cell-type-specific effects on postganglionic sympathetic neurons and pancreatic astroglia. This study contributes to a greater understanding of how cooperating physiological systems develop together and coordinate their functions, and also helps to elucidate how permutation of one organ system through stress or disease can specifically affect parallel systems in an organism. Pancreatic innervation
FEBS Lett. 2004 May 7;565(1-3):133-8. Neuronal traits are required for glucose-induced insulin secretion. Abderrahmani A, Niederhauser G, Plaisance V, Haefliger JA, Regazzi R, Waeber G. Department of Internal Medicine, University of Lausanne, CHUV-1011 Lausanne, Switzerland. The transcriptional repressor RE1 silencer transcription factor (REST) is an important factor that restricts some neuronal traits to neurons. Since these traits are also present in pancreatic beta-cells, we evaluated their role by generating a model of insulin-secreting cells that express REST. The presence of REST led to a decrease in expression of its known target genes, whereas insulin expression and its cellular content were conserved. As a consequence of REST expression, the capacity to secrete insulin in response to mitochondrial fuels, a particularity of mature beta-cells, was impaired. These data provide evidence that REST target genes are required for an appropriate glucose-induced insulin secretion. Pancreatic beta cells resemble neurons
J Biol Chem. 1997 Jan 17;272(3):1929-34. Expression of neuronal traits in pancreatic beta cells. Implication of neuron-restrictive silencing factor/repressor element silencing transcription factor, a neuron-restrictive silencer. Atouf F, Czernichow P, Scharfmann R. INSERM CJF93-13, Hospital R. Debré, 48 Boulevard Sérurier, 75019 Paris, France. Pancreatic beta cells (insulin-producing cells) and neuronal cells share a large number of similarities. Here, we investigate whether the same mechanisms could control the expression of neuronal genes in both neurons and insulin-producing cells. For that purpose, we tested the role of the transcriptional repressor neuron-restrictive silencing factor/repressor element silencing transciption factor (NRSF/REST) in the expression of a battery of neuronal genes in insulin-producing cells. NRSF/REST is a negative regulator of the neuronal fate. It is known to silence neuronal-specific genes in non-neuronal cells. We demonstrate that, as in the case of the neuronal pheochromocytoma cell line PC12, mRNA coding for NRSF/REST is absent from the insulinoma cell line INS-1 and from three other insulin- and glucagon-producing cell lines. NRSF/REST activity is also absent from insulin-producing cell lines. Transient expression of REST in insulin-producing cell lines is sufficient to silence a reporter gene containing a NRSF/REST binding site, demonstrating the role of NRSF/REST in the expression of neuronal markers in insulin-producing cells. Finally, by searching for the expression of NRSF/REST-regulated genes in insulin-producing cells, we increased the list of the genes expressed in both neurons and insulin-producing cells. Pancreatic beta cells resemble neurons 2
Endocrinology. 1997 Oct;138(10) Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. Larsen PJ, Tang-Christensen M, Jessop DS. Department of Medical Anatomy, University of Copenhagen, Denmark. P.Larsen@mai.ku.dk Within the central nervous system, glucagon-like peptide-1-(7-36) amide (GLP-1) acts as a transmitter, inhibiting feeding and drinking behavior. Hypothalamic neuroendocrine neurons are centrally involved in the regulatory mechanisms controlling these behaviors, and high densities of GLP-1 binding sites are present in the rat hypothalamus. In the present study we have, over a period of 4 h, followed the effect of centrally injected GLP-1 on plasma levels of the neurohypophysial hormones vasopressin and oxytocin. Plasma levels of corticosterone and glucose were also followed across time after central administration of GLP-1. In conscious, freely moving, and unstressed rats, central injection of GLP-1 significantly elevated plasma levels of vasopressin 15 and 30 min after administration (basal, 0.8 +/- 0.2 pg/ml; 15 min, 7.5 +/- 2.0 pg/ml; 30 min, 5.6 +/- 1.1 pg/ml; mean +/- SEM) and elevated corticosterone 15 min after administration (52 +/- 13 vs. 447 +/- 108 ng/ml, basal vs. 15 min; mean +/- SEM). In contrast, plasma oxytocin levels were unaffected by intracerebroventricular (icv) injections of GLP-1 over a period of 4 h after the injection. The animals given a central injection of GLP-1 developed transient hypoglycemia 20 min after the injection, which was fully restored to normal levels at 30 min. Furthermore, we used c-fosimmunocytochemistry as an index of stimulated neuronal activity. The distribution and quantity of GLP-1-induced c-fosimmunoreactivity were evaluated in a number of hypothalamic neuroendocrine areas, including the magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei and the parvicellular neurons of the medial parvicellularsubregion of the PVN. The number of c-fos-expressing nuclei in those areas was assessed 30, 60, and 90 min after icv administration of GLP-1. Intracerebroventricular injection of GLP-1 induced c-fos expression in the medial parvicellularsubregion of the PVN as well as in magnocellular ne urons of the PVN and SON. A slight induction of c-fos expression was seen in the arcuate nucleus and the nucleus of the solitary tract, including the area postrema. In contrast, the subfornical organ, which is a rostrally situated circumventricular organ, was free of c-fos-positive cells after central administration of GLP-1. When the GLP-1 antagonist exendin-(9-39) was given before the GLP-1, c-fos expression in these neuroendocrine areas was almost completely abolished, suggesting that the effect of GLP-1 on c-fos expression is mediated via specific receptors. A dual labeling immunocytochemical technique was used to identify the phenotypes of some of the neurons containing c-fos-immunoreactive nuclei. Approximately 80% of the CRH-positive neurons in the hypophysiotropic medial parvicellular part of the PVN coexpressed c-fos 90 min after icv GLP-1 administration. In contrast, very few (approximately 10%) of the vasopressinergicmagnocellular neurons of the PVN/SON contained c-fos- positive nuclei, whereas approximately 38% of the magnocellularoxytocinergic neurons expressed c-fos-positive nuclei in response to GLP-1 administration. This study demonstrates that central administration of the anorectic neuropeptide GLP-1 activates the central CRH-containing neurons of the hypothalamo-pituitary-adrenocortical axis as well as oxytocinergic neurons of the hypothalamo-neurohypophysial tract. Therefore, we conclude that GLP-1 activates the hypothalamo-pituitary-adrenocortical axis primarily through stimulation of CRH neurons, and this activation may also be responsible for the inhibition of feeding behavior. glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons
Diabetes. 1996 Jun;45(6):832-5 Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I. Orskov C, Poulsen SS, Møller M, Holst JJ. Department of Medical Anatomy, The Panum Institute, University of Copenhagen, Denmark. The intestinal incretin hormone glucagon-like peptide I (GLP-I) inhibits gastric motility and secretion in normal, but not in vagotomized subjects, pointing to a centrally mediated effect. Therefore, our aim was to study the availability of rat brain GLP-I receptors to peripherally injected 125I-labeled GLP-I. The specificity of the binding was tested by co-injection of excess amounts of unlabeled GLP-I. Using light microscopical autoradiography of rat brain sections, we found specific 125I-GLP-I binding exclusively in the subfornical organ and the area postrema. This binding was abolished when an excess amount of unlabeled GLP-I was co-injected with the labeled GLP-I. We conclude that cells in the subfornical organ and the area postrema could be responsive to blood-borne GLP-I. The observed binding of peripherally administered GLP-I to the subfornical organ and the area postrema, which both have close neuroanatomical connections with hypothalamic areas involved in water and ap petite homeostasis, is consistent with the potential roles of circulating GLP-I in the central regulation of appetite and autonomic functions. Glucagon-like peptide I receptors in the subfornical organ and the area postrema
Am J PhysiolEndocrinolMetab. 2008 Mar 11 Mechanism of Action of Exenatide to Reduce Postprandial Hyperglycemia In Type 2 Diabetes. Cervera A, Wajcberg E, Sriwijitkamol A, Fernandez M, Zuo P, Triplitt C, Musi N, Defronzo RA, Cersosimo E. Medicine/Diabetes, UTHSCSA, San Antonio, Texas, United States. Aim: To examine the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Experimental Design: 12 subjects with type 2 diabetes (44+/-2y, BMI=34+/-4kg/m(2), HbA1c=7.5+/-1.5%) participated in 3 meal-tolerance tests performed with double tracer technique (i.v. 3-3H-glucose and oral 1-(14)C- glucose): (i) i.v. saline (CON); (ii) i.v. exenatide (EXE); (iii) i.v. exenatide plus glucagon (E+G) studies. Acetaminophen was given with the mixed meal (75g glucose, 25g fat, 20g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen levels and glucose specific activities were measured for 6 hrs. Results: Post-meal hyperglycemia was markedly reduced (p<0.01) in EXE (138+/-16 mg/dl) and in E+G (165+/-12) compared to CON (206+/-15). Baseline plasma glucagon (~90 pg/ml) decreased by 20% to 73+ /-4 in EXE (p<0.01) and was not different from CON in E+G (81+/-2). Endogenous glucose production was suppressed by exenatide (231+/-9 to 108+/-8 mg/min [54%] vs. 254+/-29 to189+/-27 mg/min [26%], p<0.001, EXE vs. CON) and partially reversed by glucagon replacement (247+/-15 to 173+/-18 mg/min [31%]). Oral glucose appearance was 39+/-4 g in CON vs. 23+/-6g in EXE, p<0.001 and 15+/-5g in E+G, p<0.01 vs. CON). The glucose retained within the splanchnic bed increased from ~36g in CON to ~52g in EXE and to ~60g in E+G (p<0.001 vs. CON). Acetaminophen (AUC) was reduced by ~80% in EXE vs. CON (p<0.01). Conclusion: Exenatide infusion attenuates postprandial hyperglycemia by decreasing endogenous glucose production (by ~50%) and by slowing gastric emptying. Key words: Exenatide, Hyperglycemia, Splanchnic Glucose Metabolism, Type 2 Diabetes Mellitus, Insulin Secretion. Mechanism of Action of Exenatide to Reduce Postprandial Hyperglycemia In Type 2 Diabetes
Remission of early onset childhood diabetes mellitus induced with TZD and DPP-IV inhibitor
C-Peptide value is always within the normal limits or elevated in patients with so-called type 2 diabetes. Some of these patients have very high blood sugars when they present initially. If C-Peptide reflects endogenous insulin production then their hyperglycemia cannot be due to a “lack of insulin”. Nor, is it due to “insulin resistance”. This misleading term is addressed elsewhere in this text. What we are left with then is the influence of the central nervous system changing the “set-point” of steady-state blood sugar. This is mediated via the vagus nerve and is the earliest change seen in diabetes. (Diabetes Res Clin Pract. 1988 Apr 6;4(4):289-93 Shen DC, Kuo SW, Shian LR, Fuh MT, Wu DA, Chen YD, Reaven GM. Department of Medicine, Stanford University School of Medicine, CA.).
The appearance of beta cell failure, or severe beta cell mass reduction appears late in the disease in most cases, but may appear earlier where islet-cell destruction occurs as a result of autoimmune disease or direct destruction by a pathogen. T-Lymphoctye infiltration can be seen in the autoimmune cases. Immune system mediated accelerated destruction of islets can be seen in both adults and children. In adults it has been termed LADA (Late autoimmune disease of adulthood?). However, rapid progression of diabetes associated with destruction of islets can be seen in the absence of autoimmunity. The ultimate course is diabetes in any particular individual will be determined by the initiating process or pathogen (there are several), and that individual’s genetic makeup.
Thus, intervention with agents that have CNS receptors which will affect this “set-point” are the agents of choice in early disease. This could be termed the Central Nervous System Phase of Diabetes Mellitus. I have demonstrated that in adults and children that early intervention with thiazolidinediones and DPP-IV inhibitors can rapidly induce euglycemia and, in many instances bring about complete remission.
The CNS and The Etiology of Diabetes Mellitus
Metabolism. 1994 Jul;43(7):860-6. Redundant parasympathetic and sympathoadrenal mediation of increased glucagon secretion during insulin-induced hypoglycemia in conscious rats. Havel PJ, Parry SJ, Stern JS, Akpan JO, Gingerich RL, Taborsky GJ Jr, Curry DL. Department of Anatomy, School of Veterinary Medicine, University of California, Davis 95616. Both the parasympathetic and sympathoadrenal inputs to the pancreas can stimulate glucagon release and are activated during hypoglycemia. However, blockade of only one branch of the autonomic nervous system may not reduce hypoglycemia-induced glucagon secretion, because the unblocked neural input is sufficient to mediate the glucagon response, ie, the neural inputs are redundant. Therefore, to determine if parasympathetic and sympathoadrenal activation redundantly mediate increased glucagon secretion during hypoglycemia, insulin was administered to conscious rats pretreated with a muscarinic antagonist (methylatropine, n = 7), combined alpha- and beta-adrenergic receptor blockade (tolazoline + propranolol, n = 5) or adrenergic blockade + methylatropine (n = 7). Insulin administration produced similar hypoglycemia in control and antagonist-treated rats (25 to 32 mg/dL). In control rats (n = 9), plasma immunoreactive glucagon (IRG) increased from a baseline level of 125 +/- 11 to 1,102 +/- 102 pg/mL during hypoglycemia (delta IRG = +977 +/- 98 pg/mL, P < .0005). The plasma IRG response was not significantly altered either by methylatropine (delta IRG = +677 +/- 141 pg/mL) or by adrenergic blockade (delta IRG = +1,374 +/- 314 pg/mL). However, the IRG response to hypoglycemia was reduced to 25% of the control value by the combination of adrenergic blockade + methylatropine (delta IRG = +250 +/- 83 pg/mL, P < .01 v control rats). These results suggest that the plasma glucagon response to hypoglycemia in conscious rats is predominantly the result of autonomic neural activation, and is redundantly mediated by the parasympathetic and sympathoadrenal divisions of the autonomic nervous system. Glucagon response to hypoglycemia is predominantly the result of autonomic neural activation
Cell Metab. 2005 Jan;1(1):53-61 A brain-liver circuit regulates glucose homeostasis Pocai A, Obici S, Schwartz GJ, Rossetti L. Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA. Increased glucose production (GP) is the major determinant of fasting hyperglycemia in diabetes mellitus. Previous studies suggested that lipid metabolism within specific hypothalamic nuclei is a biochemical sensor for nutrient availability that exerts negative feedback on GP. Here we show that central inhibition of fat oxidation leads to selective activation of brainstem neurons within the nucleus of the solitary tract and the dorsal motor nucleus of the vagus and markedly decreases liver gluconeogenesis, expression of gluconeogenic enzymes, and GP. These effects require central activation of ATP-dependent potassium channels (K(ATP)) and descending fibers within the hepatic branch of the vagus nerve. Thus, hypothalamic lipid sensing potently modulates glucose metabolism via neural circuitry that requires the activation of K(ATP) and selective brainstem neurons and intact vagal input to the liver. This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient production and its disruption may lead to hyperglycemia A brain-liver circuit regulates glucose homeostasis
Nature. 2005 Apr 21;434(7036):1026-31. Hypothalamic K(ATP) channels control hepatic glucose production. Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L. Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA. Obesity is the driving force behind the worldwide increase in the prevalence of type 2 diabetes mellitus. Hyperglycaemia is a hallmark of diabetes and is largely due to increased hepatic gluconeogenesis. The medial hypothalamus is a major integrator of nutritional and hormonal signals, which play pivotal roles not only in the regulation of energy balance but also in the modulation of liver glucose output. Bidirectional changes in hypothalamic insulin signalling therefore result in parallel changes in both energy balance and glucose metabolism. Here we show that activation of ATP-sensitive potassium (K(ATP)) channels in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis. Finally, the infusion of a K(ATP) blocker within the mediobasal hypothalamus, or the surgical resection of the hepatic branch of the vagus nerve, negates the effects of central insulin and halves the effects of systemic insulin on hepatic glucose production. Consistent with these results, mice lacking the SUR1 subunit of the K(ATP) channel are resistant to the inhibitory action of insulin on gluconeogenesis. These findings suggest that activation of hypothalamic K(ATP) channels normally restrains hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycaemia. Hypothalamic K(ATP) channels control hepatic glucose production.
Jpn J Physiol. 1986;36(5):827-41. Neural control of blood glucose level. Niijima A. All of the experimental results described above can be categorized as follows: the relationship between glucose levels and pancreatic and adrenal nerve activities; innervations of the liver and their role in the regulation of blood glucose level; central integration of blood glucose level; glucose-sensitive afferent nerve fibers in the liver and regulation of blood glucose; oral and intestinal inputs involved in reflex control of blood glucose level. We showed that an increase in blood glucose content produced an increase in the activity of the pancreatic branch of the vagus nerve, whereas it induced a decrease in the activity of the adrenal nerve. It was also shown that a decrease in blood glucose activated the sympatho-adrenal system and suppressed the vago-pancreatic system. It seems rational that these responses are involved in the maintenance of blood glucose level. Studies on the innervation of the liver led us to a conclusion that sympathetic innervation of the liver might play a role in eliciting a prompt hyperglycemic response through liberation of norepinephrine from the nerve terminals, and that the vagalinnervationsynergically worked with the humoral factor (insulin) for glycogen synthesis in the hyperglycemic condition. The glucose-sensitive afferents from the liver seem to initiate a reflex control of blood glucose level. The gustatory information on EIR response, reported by STEFFENS, is supported by the electrophysiological observations. MEI's reports also indicated the importance of information from the intestinal glucoreceptors in the reflex control of insulin secretion. The role of integrative functions of the hypothalamus and brainstem through neuronal networks on neural control of blood glucose levels is also evident. A schematic diagram of the nervous networks involved in the regulation of the blood glucose levels is shown in Fig. 3. Neural control of blood glucose level.
Cell Metab. 2007 Feb;5(2):91-102. An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-induced insulin resistance and hypertension. Bernal-Mizrachi C, Xiaozhong L, Yin L, Knutsen RH, Howard MJ, Arends JJ, Desantis P, Coleman T, Semenkovich CF. Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Glucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of PPARalpha (Ppara) is required for glucocorticoid-induced insulin resistance. Here we demonstrate that afferent fibers of the vagus nerve interface with hepatic Ppara expression to disrupt blood pressure and glucose homeostasis in response to glucocorticoids. Selective hepatic vagotomy decreased hyperglycemia, hyperinsulinemia, hepatic insulin resistance, Ppara expression, and phosphoenolpyruvatecarboxykinase (PEPCK) enzyme activity in dexamethasone-treated Ppara(+/+) mice. Selective vagotomy also decreased blood pressure, adrenergic tone, renin activity, and urinary sodium retention in these mice. Hepatic reconstitution of Ppara in nondiabetic, normotensive dexamethasone-treated PPARalpha null mice increased glucose, insulin, hepatic PEPCK enzyme activity, blood pressure, and renin activity in sham-operated animals but not hepatic-vagotomized animals. Disruption of vagal afferent fibers by chemical or surgical means prevented glucocorticoid-induced metabolic derangements. We conclude that a dynamic interaction between hepatic Ppara expression and a vagal afferent pathway is essential for glucocorticoid induction of diabetes and hypertension. An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-induced insulin resistance and hypertension.
Endocrinology. 1985 Jul;117(1):307-14. The hepatic vagus nerve and the neural regulation of insulin secretion. Lee KC, Miller RE. Despite considerable evidence that vagal neural efferent pathways between brainstem and pancreatic islets may alter the secretion of insulin, afferent pathways which might affect this system have received little attention. In the present work we have examined the effects on plasma insulin concentration of several treatments designed to alter the neural activity of the hepatic vagus nerve, a major afferent pathway between the liver and the medulla. The hepatic vagus nerve was acutely sectioned or stimulated electrically in separate experiments in rats. In a third experiment, glucose or 3-O-methylglucose was given ip to stimulate or inhibit, respectively, the hypothetical hepatic glucoreceptors. The effects of these treatments were assessed by measuring arterial or portal plasma insulin concentrations. Anesthesia and its possible secondary inhibitory effects on insulin secretion were avoided by a spinal sectioning of the rats in the cervical region, before experimentation. Acute section of the hepatic vagus nerve between the liver and the main anterior vagal trunk caused an increase in both arterial and portal plasma insulin concentrations. Stimulation of the central end of the nerve suppressed the concentration of the hormone in both the arterial and portal plasma relative to sham-stimulated controls. Section of the celiac vagal branches to the pancreas abolished these changes. Intraperitoneal glucose enhanced arterial insulin more in sham-vagotomized than in hepatic-vagotomized rats. After 3-O-methylglucose was given ip, the response was the opposite: insulin rose more in the arterial plasma of the hepatic-vagotomized animals than in those sham vagotomized. These results suggest that the hepatic vagus nerve plays a role in the regulation of insulin secretion. They are consistent with the hypothesis that afferent fibers in this nerve exert a tonic inhibition on the brainstem centers of an efferent vagal pancreatic neuroendocrine system. The hepatic vagus nerve and the neural regulation of insulin secretion.
J Endocrinol Invest. 2005 Nov;28(10):899-904. Peroxisomeproliferator-activated receptor (PPAR)gamma is highly expressed in normal human pituitary gland. Bogazzi F, Russo D, Locci MT, Chifenti B, Ultimieri F, Raggi F, Viacava P, Cecchetti D, Cosci C, Sardella C, Acerbi G, Gasperi M, Martino E. Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy. firstname.lastname@example.org OBJECTIVE: Expression of peroxisomeproliferator-activated receptor (PPAR)gamma in normal pituitary seems to be restricted to ACTH-secreting cells. The aim of the study was to evaluate the expression of PPARgamma in normal human pituitary tissue and to study its localization in the pituitary secreting cells. MATERIALS AND METHODS: Normal pituitary tissue samples were obtained form 11 patients with non-secreting adenoma who underwent surgical excision of the tumor. Expression of PPARgamma was evaluated by immunostaining and western blotting; localization of PPARgamma in each pituitary secreting cell lineage was evaluated by double immunofluorescence using confocal microscopy. Pituitary non-functioning adenomas served as Controls. RESULTS: PPARgamma was highly expressed in all pituitary samples with a (mean +/- SD) 81 +/- 6.5% of stained cells; expression of PPARgamma was confirmed by western blotting. Non-functioning pituitary adenomas had 74 +/- 11% PPARgamma positive cells. Expression of PPARy was either in cytoplasm or nuclei. In addition, treatment of GH3 cells, with a PPARgammaligand was associated with traslocation of the receptor from cytoplasm into the nucleus. Double immunostaining revealed that every pituitary secreting cell (GH, TSH, LH, FSH, PRL and ACTH) had PPARgamma expressed. DISCUSSION: The present study demonstrated that PPARgamma is highly expressed in every normal pituitary secreting cell lineage. It can translocate into the nucleus by ligand binding; however, its role in pituitary hormone regulation remains to be elucidated. (PPAR)gamma is highly expressed in normal human pituitary gland.
Exp Neurol. 2007 Jun;205(2):396-406. Epub 2007 Feb 27. The PPAR gamma agonist Pioglitazone improves anatomical and locomotor recovery after rodent spinal cord injury. McTigue DM, Tripathi R, Wei P, Lash AT. Department of Neuroscience, Center for Brain and Spinal Cord Repair and the Neuroscience Graduate Studies Program, Ohio State University, Columbus, OH 43210, USA. email@example.com Traumatic spinal cord injury (SCI) is accompanied by a dramatic inflammatory response, which escalates over the first week post-injury and is thought to contribute to secondary pathology after SCI. Peroxisomeproliferator-activated receptors (PPAR) are widely expressed nuclear receptors whose activation has led to diminished pro-inflammatory cascades in several CNS disorders. Therefore, we examined the efficacy of the PPARgamma agonist Pioglitazone in a rodent SCI model. Rats received a moderate mid-thoracic contusion and were randomly placed into groups receiving vehicle, low dose or high dose Pioglitazone. Drug or vehicle was injected i.p. at 15 min post-injury and then every 12 h for the first 7 days post-injury. Locomotor function was followed for 5 weeks using the BBB scale. BBB scores were greater in treated animals at 7 days post-injury and significant improvements in BBB subscores were noted, including better toe clearance, earlier stepping and more parallel paw position. Stereological measurements throughout the lesion revealed a significant increase in rostral spared white matter in both Pioglitazone treatment groups. Spinal cords from the high dose group also had significantly more gray matter sparing and motor neurons rostral and caudal to epicenter. Thus, our results reveal that clinical treatment with Pioglitazone, an FDA-approved drug used currently for diabetes, may be a feasible and promising strategy for promoting anatomical and functional repair after SCI. Pioglitazone improves anatomical and locomotor recovery after rodent spinal cord injury
J Pharmacol Exp Ther. 2007 Mar;320(3):1002-12. Epub 2006 Dec 13. Thiazolidinedione class of peroxisomeproliferator-activated receptor gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats. Department of Neurological Surgery, University of Wisconsin, Madison, WI 53792, USA. Park SW, Yi JH, Miranpuri G, Satriotomo I, Bowen K, Resnick DK, Vemuganti R. Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisomeproliferator-activated receptor-gamma (PPARgamma). TZDs were shown to induce neuroprotection after cerebral ischemia by blocking inflammation. As spinal cord injury (SCI) induces massive inflammation that precipitates secondary neuronal death, we currently analyzed the therapeutic efficacy of TZDs pioglitazone and rosiglitazone after SCI in adult rats. Both pioglitazone and rosiglitazone(1.5 mg/kg i.p.; four doses at 5 min and 12, 24, and 48 h) significantly decreased the lesion size (by 57 to 68%, p < 0.05), motor neuron loss (by 3- to 10-fold, p < 0.05), myelin loss (by 66 to 75%, p < 0.05), astrogliosis (by 46 to 61%, p < 0.05), and microglial activation (by 59 to 78%, p < 0.05) after SCI. TZDs significantly enhanced the motor function recovery (at 7 days after SCI, the motor scores were 37 to 45% higher in the TZD groups over the vehicle group; p < 0.05), but the treatment was effective only when the first injection was given by 2 h after SCI. At 28 days after SCI, chronic thermal hyperalgesia was decreased significantly (by 31 to 39%; p < 0.05) in the pioglitazone group compared with the vehicle group. At 6 h after SCI, the pioglitazone group showed significantly less induction of inflammatory genes [interleukin (IL)-6 by 83%, IL-1beta by 87%, monocytechemoattractant protein-1 by 75%, intracellular adhesion molecule-1 by 84%, and early growth response-1 by 67%] compared with the vehicle group (p < 0.05 in all cases). Pioglitazone also significantly enhanced the post-SCI induction of neuroprotective heat shock proteins and antioxidant enzymes. Pretreatment with a PPARgamma antagonist, 2-chloro-5-nitro-N-phenyl-benzamide (GW9662), prevented the neuroprotection induced by pioglitazone. TZD’s prevent neuronal damage, motor dysfunction, myelin loss and inflammation
Trends Pharmacol Sci. 2007 May;28(5):244-9. Epub 2007 Apr 9. PPAR-gamma: therapeutic target for ischemic stroke. Culman J, Zhao Y, Gohlke P, Herdegen T. Institute of Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Hospitalstrasse 4, 24105 Kiel, Germany. The peroxisomeproliferator activated receptors (PPARs), which belong to the nuclear receptor superfamily, are key regulators of glucose and fat metabolism. The PPAR-gamma isoform is involved in the regulation of cellular glucose uptake, protection against atherosclerosis and control of immune reactions. In addition, the activation of PPAR-gamma effectively attenuates neurodegenerative and inflammatory processes in the brain. Here, we review a novel aspect of beneficial and clinically relevant PPAR-gamma actions: neuroprotection against ischemic injury mediated by intracerebral PPAR-gamma, which is expressed in neurons and microglia. Together with the recent observation that the PPAR-gamma ligandpioglitazone reduces the incidence of stroke in patients with type 2 diabetes, this review supports the concept that activators of PPAR-gamma are effective drugs against ischemic injury. PPAR-gamma: therapeutic target for ischemic stroke.
Vasc Health Risk Manag. 2007;3(4):355-70. PROactive 07: pioglitazone in the treatment of type 2 diabetes: results of the PROactive study. Erdmann E, Dormandy J, Wilcox R, Massi-Benedetti M, Charbonnel B. Department III of Internal Medicine, University of Cologne, Germany. firstname.lastname@example.org Patients with type 2 diabetes face an increased risk of macrovascular disease compared to those without. Significant reductions in the risk of major cardiovascular events can be achieved with appropriate drug therapy, although patients with type 2 diabetes remain at increased risk compared with non-diabetics. The thiazolidinedione, pioglitazone, is known to offer multiple, potentially antiatherogenic, effects that may have a beneficial impact on macrovascular outcomes, including long-term improvements in insulin resistance (associated with an increased rate of atherosclerosis) and improvement in the atherogenic lipid triad (low HDL-cholesterol, raised triglycerides, and a preponderance of small, dense LDL particles) that is observed in patients with type 2 diabetes. The recent PROspectivepioglitAzone Clinical Trial In macroVascular Events (PROactive) study showed that pioglitazone can reduce the risk of secondary macrovascular events in a high-risk patient population with type 2 diabetes and established macrovascular disease. Here, we summarize the key results from the PROactive study and place them in context with other recent outcome trials in type 2 diabetes. Pioglitazone can reduce the risk of secondary macrovascular events in a high-risk patient population with type 2 diabetes and established macrovascular disease
Biochem Soc Trans. 2006 Dec;34(Pt 6):1341-6. PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Bordet R, Ouk T, Petrault O, Gelé P, Gautier S, Laprais M, Deplanque D, Duriez P, Staels B, Fruchart JC, Bastide M. EA1046 Department of Medical Pharmacology, Faculty of Medicine, Institute of Predictive Medicine and Therapeutic Research, University Lille 2 and Lille University Hospital, 1 place de Verdun, 59045 Lille Cedex, France. email email@example.com PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors belonging to the so-called nuclear receptor family. The three isoforms of PPAR (alpha, beta/delta and gamma) are involved in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARalpha and PPARgamma activation also induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain why PPARalpha or PPARgamma activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates and other non-fibratePPARalpha activators as well as thiazolidinediones and other non-thiazolidinedionePPARgamma agonists have been demonstrated to induce both preventive and acute neuroprotection. This neuroprotective effect involves both cerebral and vascular mechanisms. PPAR activation induces a decrease in neuronal death by prevention of oxidative or inflammatory mechanisms implicated in cerebral injury. PPARalpha activation induces also a vascular protection as demonstrated by prevention of post-ischaemic endothelial dysfunction. These vascular effects result from a decrease in oxidative stress and prevention of adhesion proteins, such as vascular cell adhesion molecule 1 or intercellular cell-adhesion molecule 1. Moreover, PPAR activation might be able to induce neurorepair and endothelium regeneration. Beyond neuroprotection in cerebral ischaemia, PPARs are also pertinent pharmacological targets to induce neuroprotection in chronic neurodegenerative diseases. PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases.
Do Atypical Antipsychotics precipitate diabetes through their effect on the brain? Aripiprazole (marketed as Abilify) Clozapine (marketed as Clozaril) Olanzapine (marketed as Zyprexa) Olanzapine/Fluoxetine (marketed as Symbyax) Risperidone (marketed as Risperdal) Quetiapine (marketed as Seroquel) Ziprasidone (marketed as Geodon)
Int J Neuropsychopharmacol. 2005 Mar;8(1):49-57. Epub 2004 Oct 7. Neuroendocrine effects of quetiapine in healthy volunteers. de BorjaGonçalves Guerra A, Castel S, Benedito-Silva AA, Calil HM. Department of Psychobiology, Federal University of São Paulo, São Paulo School of Medicine, São Paulo, Brazil. The present study measured prolactin, cortisol, ACTH and growth hormone in healthy male volunteers following an acute oral administration of quetiapine, an atypical antipsychotic with high affinity for H1 and moderate affinity for sigma, alpha1, 5-HT2, alpha2 and D2 receptors. Fifteen male volunteers entered this randomized double-blind, cross-over, placebo-controlled study. Blood samples were drawn every 30 min from 09:00 hours to 13:00 hours. The first samples were drawn immediately before the administration of 150 mg quetiapine or placebo. Mean results for each hormone and ANOVA for repeated measures were performed. The area under the curve (AUC) hormonal values were calculated and compared by paired t test. The ANOVA showed an increase of prolactin after quetiapine administration from time 60 min up to the end of the observation period. Cortisol decreased after quetiapine administration from time 150 min to time 240 min. ACTH secretion showed no difference compared to placebo. There was a late increase in growth hormone secretion, significant in comparison with placebo only at time 210 min. The AUC values were statistically different for prolactin and cortisol compared to placebo. A single dose of quetiapine (150 mg) increased prolactin secretion probably due to a transiently high D2 receptor occupancy at the anterior pituitary. Cortisol secretion decreased as was expected from quetiapine'spharmacodynamic profile. The lack of response of ACTH might be, at least in part, explained by the low hormonal assay sensitivity. The late growth hormone increase might have been due to quetiapine's antagonism of H1 receptors. Neuroendocrine effects of quetiapine in healthy volunteers
J Clin Psychiatry. 2004 Jun;65(6):857-63. A survey of reports of quetiapine-associated hyperglycemia and diabetes mellitus. Koller EA, Weber J, Doraiswamy PM, Schneider BS. Division of Metabolic and Endocrine Drug Products, Center for Drug Evaluation and Review, US Food and Drug Administration, Rockville, MD, USA. OBJECTIVE: To explore the clinical characteristics of hyperglycemia in patients treated with quetiapine. METHOD: A pharmacovigilance survey of spontaneously reported adverse events in quetiapine-treated patients was conducted using reports from the U.S. Food and Drug Administration MedWatch program (January 1, 1997, through July 31, 2002) and published cases using the search terms hyperglycemia, diabetes, acidosis, ketosis, and ketoacidosis. RESULTS: We identified 46 reports of quetiapine-associated hyperglycemia or diabetes and 9 additional reports of acidosis that occurred in the absence of hyperglycemia and were excluded from the immediate analyses. Of the reports of quetiapine-associated hyperglycemia, 34 patients had newly diagnosed hyperglycemia, 8 had exacerbation of preexisting diabetes mellitus, and 4 could not be classified. The mean +/- SD age was 35.3 +/- 16.2 years (range, 5-76 years). New-onset patients (aged 31.2 +/- 14.8 years) tended to be younger than those with preexisting diabetes (43.5 +/- 16.4 years, p = .08). The overall male:female ratio was 1.9. Most cases appeared within 6 months of quetiapine initiation. The severity of cases ranged from mild glucose intolerance to diabetic ketoacidosis or hyperosmolar coma. There were 21 cases of ketoacidosis or ketosis. There were 11 deaths. CONCLUSION: Atypical antipsychotic use may unmask or precipitate hyperglycemia. UPDATE: An additional 23 cases were identified since August 1, 2002, the end of the first survey, by extending the search through November 30, 2003, bringing the total to 69. Quetiapine-associated hyperglycemia and diabetes mellitus.
J Clin Psychiatry. 2006 May;67(5):789-97. Glucose metabolism in patients with schizophrenia treated with olanzapine or quetiapine: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Henderson DC, Copeland PM, Borba CP, Daley TB, Nguyen DD, Cagliero E, Evins AE, Zhang H, Hayden DL, Freudenreich O, Cather C, Schoenfeld DA, Goff DC. Schizophrenia Program, Massachusetts General Hospital, Boston, USA. firstname.lastname@example.org OBJECTIVE: Clozapine and olanzapine treatment has been associated with insulin resistance in non-obese schizophrenia patients. Much less is known regarding other agents such as quetiapine. The objective of this study was to compare matched olanzapine- and quetiapine-treated schizophrenia patients and normal controls on measures of glucose metabolism. METHOD: A cross-sectional comparison of quetiapine-treated and olanzapine-treated non-obese (body mass index < 30.0 kg/m2) schizophrenia subjects (DSM-IV) with matched normal controls using a frequently sampled intravenous glucose tolerance test and nutritional assessment was conducted from April 2002 to October 2004. Data from 24 subjects were included in the analysis (7 quetiapine, 8 olanzapine, 9 normal controls). RESULTS: There was a significant difference among groups for fasting baseline plasma glucose concentrations (p = .02), with olanzapine greater than normal controls (p = .01). The insulin sensitivity index (SI) differed significantly among groups (p = .039); olanzapine subjects exhibited significant insulin resistance compared to normal controls (p = .01), but there was no significant difference for quetiapine versus olanzapine (p = .1) or quetiapine versus normal controls (p = .40). SI inversely correlated with quetiapine dose (p = .0001) and waist circumference (p = .03) in quetiapine-treated subjects. Insulin resistance calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) also differed significantly among groups (p = .03). The olanzapine group had a higher HOMA-IR level than normal controls (p = .01). There was a significant difference in glucose effectiveness (SG) among the groups (p = .049). SG was lower in the olanzapine group than in the quetiapine group (p = .03) and in the olanzapine group compared to normal controls (p = .049). CONCLUSIONS: Our findings are consistent with our previous report that nonobeseolanzapine-treated subjects showed insulin resistance, measured by both HOMA-IR and SI, and reduction in SG. Studies that include larger samples, unmedicated patients, and varying durations of antipsychotic exposure are necessary to confirm these results. “Insulin resistance” in olanzapine (Zyprexa) treated patients
J Clin Psychiatry. 2003 Dec;64(12):1436-9. Olanzapine induces insulin resistance: results from a prospective study. Ebenbichler CF, Laimer M, Eder U, Mangweth B, Weiss E, Hofer A, Hummer M, Kemmler G, Lechleitner M, Patsch JR, Fleischhacker WW. Department of Medicine, University of Innsbruck, Innsbruck, Austria. Christoph.Edenbichler@uibk.ac.at BACKGROUND: The aim of this study was to compare glucose metabolism in patients with schizophrenia receiving olanzapine with that in control subjects. METHOD: We conducted a prospective, controlled, open study comparing body weight, fat mass, and indices of insulin resistance/ sensitivity in 10 olanzapine-treated patients with ICD-10 schizophrenia (olanzapine dose range, 7.5-20 mg/day) with those of a group of 10 mentally and physically healthy volunteers. Weight, fat mass, and indices of insulin resistance/sensitivity were assessed over individual 8-week observation periods from November 1997 to October 1999. RESULTS: Fasting serum glucose and fasting serum insulin increased significantly in the olanzapine-treated patients (p =.008 for glucose and p =.006 for insulin). The homeostasis model assessment (HOMA) index for beta cell function did not change significantly in the olanzapine-treated patients, whereas the HOMA index for insulin resistance did increase (p =.006). In the control group, these parameters were stable. A significant increase in body weight (p =.001) and body fat (p =.004) was seen in patients treated with olanzapine, while the control group showed no significant changes. CONCLUSION: This study indicates that the disturbances in glucose homeostasis during antipsychotic treatment with olanzapine are mainly due to insulin resistance. However, beta cell function remains unaltered in olanzapine-treated patients. We conclude that treatment with some second-generation antipsychotic drugs may lead to insulin resistance. Olanzapine induces insulin resistance
J Clin Psychiatry. 2000 Oct;61(10):742-9. Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. Melkersson KI, Hulting AL, Brismar KE. Department of Psychiatry, St Görans Hospital, Stockholm, Sweden. BACKGROUND: The aim of this study was to investigate the influence of the antipsychotic agent olanzapine on glucose-insulin homeostasis to explain possible mechanisms behind olanzapine-associated weight gain. METHOD: Fourteen patients on treatment with olanzapine (all meeting DSM-IV criteria for schizophrenia or related psychoses) were studied. Fasting blood samples for glucose, insulin, the growth hormone (GH)-dependent insulin-like growth factor I, and the insulin-dependent insulin-like growth factor binding protein-1 (IGFBP-1) were analyzed, as well as GH, leptin, and blood lipid levels and the serum concentrations of olanzapine and its metabolite N-desmethylolanzapine. In addition, body mass index (BMI) was calculated. Moreover, weight change during olanzapine treatment was determined. RESULTS: Twelve of the 14 patients reported weight gain between 1 and 10 kg during a median olanzapine treatment time of 5 months, whereas data were not available for the other 2 patients. Eight patients (57%) had BMI above the normal limit. Eleven patients were normoglycemic, and 3 showed increased blood glucose values. Most patients (10/14; 71%) had elevated insulin levels (i.e., above the normal limit). Accordingly, the median value of IGFBP-1 was significantly lower for the patients in comparison with healthy subjects. Moreover, 8 (57%) of 14 patients had hyperleptinemia, 62% (8/13) had hypertriglyceridemia, and 85% (11/13) hypercholesterolemia. Weight change correlated positively to blood glucose levels and inversely to the serum concentration level of N-desmethylolanzapine. Additionally, the levels of blood glucose, triglycerides, and cholesterol correlated inversely to the serum concentration of N-desmethylolanzapine. CONCLUSION: Olanzapine treatment was associated with weight gain and elevated levels of insulin, leptin, and blood lipids as well as insulin resistance, with 3 patients diagnosed to have diabetes mellitus. Both increased insulin secretion and hyprleptinemia may be mechanisms behind olanzapine-induced weight gain. Moreover, it is suggested that the metabolite N-desmethylolanzapine, but not olanzapine, has a normalizing effect on the metabolic abnormalities. Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients
Limitation of the validity of the homeostasis model assessment as an index of insulin resistance HOMA-IR
Metabolism. 2005 Feb;54(2):206-11. Limitation of the validity of the homeostasis model assessment as an index of insulin resistance in Korea. Kang ES, Yun YS, Park SW, Kim HJ, Ahn CW, Song YD, Cha BS, Lim SK, Kim KR, Lee HC. Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 120-752, Korea. Homeostasis model assessment of insulin resistance (HOMA-IR) is a less invasive, inexpensive, and less labor-intensive method to measure insulin resistance (IR) as compared with the glucose clamp test. The aim of this study was to evaluate the validity of HOMA-IR by comparing it with the euglycemic clamp test in determining IR. We assessed the validity of HOMA-IR by comparing it with the total glucose disposal rate measured by the 3-hour euglycemic-hyperinsulinemic clamp in subjects with type 2 diabetes (n = 47), impaired glucose tolerance (n = 21), and normal glucose tolerance (n = 22). There was a strong inverse correlation (r = -0.558; P < .001) between the log-transformed HOMA-IR and the total glucose disposal rate. There was moderate agreement between the 2 methods in the categorization according to the IR (weighted kappa = 0.294). The magnitude of the correlation coefficients was smaller in the subjects with a lower body mass index (BMI <25.0 kg/m2 , r = -0.441 vs BMI > or =25.0 kg/m2 , r = -0.615; P = .032), a lower HOMA-beta cell function (HOMA- beta <60.0, r = -0.527 vs HOMA- beta > or =60.0, r = -0.686; P = .016), and higher fasting glucose levels (fasting glucose < or =5.66 mmol/L, r = -0.556 vs fasting glucose >5.66 mmol/L, r = -0.520; P = .039). The limitation of the validity of the HOMA-IR should be carefully considered in subjects with a lower BMI, a lower beta cell function, and high fasting glucose levels such as lean type 2 diabetes mellitus with insulin secretory defects. Limitation of the validity of the homeostasis model assessment as an index of insulin resistance
Medical Research Society 1976 meeting Turner R.C., Holman R.R., Hockaday T.D.R. Beta Cell Deficiency in maturity onset diabetes Diabetics have normal basal plasma insulin levels, and a raised basal plasma glucose which is characteristic for each person. It has been suggested that only stimulated and not basal insulin secretion is deficient in diabetes. We show that both are impaired and postulate that in diabetes insulin control of hepatic glucose efflux acts as insulin ‘sensor’. This causes the basal plasma glucose to rise until the reduced number of beta cells are sufficiently stimulated to secrete normal basal insulin levels. Thus glucose regulation is of secondary importance to maintenance of basal insulin secretion. The increased plasma glucose load further stresses the remaining beta cells which then have to operate nearer their maximal capacity. The degree of basal hyperglycaemia provides a bioassay of the decrease in insulin secretion capacity, enabling one to estimate the number of functioning beta cells. The observed insulin secretion in diabetes is similar to that predicted from this estimate. The height of the basal plasma insulin gives a measure of the degree of insulin resistance associated with obesity, and from the estimated beta cell defect one can indicate the extent to which dieting alone would reduce the fasting plasma glucose ORIGINAL THEORY BEHIND HOMA CALCULATION (1976) DOES NOT TAKE INTO ACCOUNT CNS CONTROL OF GLUCOSE or DISEASE OF THE ALPHA CELLS IN ALL DIABETICS WHICH INFLUENCES HEPATIC OUTPUT OF GLUCOSE. IT ONLY CONSIDERS THE BETA CELLS AND THE LIVER AS KEY PLAYERS.
Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and livercells. Circular argument Definition: any discussion in which one argues the conclusion as a premise; a discussion that makes a conclusion based on material that has already been assumed in the argument “Insulin resistance” is a circular argument
HOMA Calculator v2.2.2 released 12 December 2007. The Homeostasis Model Assessment (HOMA) estimates steady state beta cell function (%B) and insulin sensitivity (%S), as percentages of a normal reference population. These measures correspond well, but are not necessarily equivalent, to non-steady state estimates of beta cell function and insulin sensitivity derived from stimulatory models such as the hyperinsulinaemic clamp, the hyperglycaemic clamp, the intravenous glucose tolerance test (acute insulin response, minimal model), and the oral glucose tolerance test (0-30 delta I/G). In 1976, Robert Turner and Rury Holman developed the concept that fasting plasma insulin and glucose levels were determined, in part, by a hepatic-beta cell feedback loop [Abstract]. They postulated that elevated fasting glucose levels reflected a compensatory mechanism that maintained fasting insulin levels when there was a reduced insulin secretory capacity, and that fasting insulin levels were elevated in direct proportion to diminished insulin sensitivity. A mathematical feedback model based on these hypotheses was constructed to estimate the degrees of beta cell function and insulin sensitivity that would equate to the steady state plasma glucose and insulin levels observed in an individual [Metabolism 1979; 28:1086-96]. In 1985, David Matthews et al published an expanded and more comprehensive structural model known as the Homeostasis Assessment Model (HOMA). This model, written in Fortran, took greater account of peripheral glucose uptake and could use fasting levels of specific insulin or C-peptide in addition to RIA insulin [Diabetologia 1985; 28(7): 412-9]. As an alternative to running the Fortran computer model, a set of linear equations were also made available. These gave approximate values of %B and, instead of %S, HOMA IR (insulin resistance) which is the reciprocal of %S (100/%S). The equations have been used widely, particularly for estimates of beta cell function and insulin resistance in large-scale studies, but are not appropriate for use with currently available insulin assays. In 1998, Jonathan Levy et al published an updated HOMA model (HOMA2) which took account of variations in hepatic and peripheral glucose resistance, increases in the insulin secretion curve for plasma glucose concentrations above 10 mmol/L (180 mg/dL) and the contribution of circulating proinsulin [Diabetes Care 1998; 21: 2191-92]. The model was recalibrated also to give %B and %S values of 100% in normal young adults when using currently available assays for insulin, specific insulin or C-peptide. In 2004, the HOMA Calculator was released. This provides quick and easy access to the HOMA2 model for researchers who wish to use model-derived estimates of %B and %S, rather than linear approximations. It runs on a variety of computer platforms and can be downloaded from this site. HOMA
Epidemiology of Severe Hypoglycemia in the Diabetes Control and Complications TrialThe DCCT Research Group (The American Journal of MedicineVol 90, pg 450, April 1991) Part III “20% of all episodes resulted in emergency room treatment or hospitalization.” “Automobile accidents associated with property damage occurred in 1.5% of all severe hypoglycemia events.” A disproportionate number of severe hypoglycemic events occurred during the night: 43% between midnight and 8 AM and 26% between 4 AM and 8 AM. 55 % of events began during sleep. Of 36 % of severe events beginning during waking hours “subjects could not recall having noted warning symptoms.”
Epidemiology of Severe Hypoglycemia in the Diabetes Control and Complications TrialThe DCCT Research Group (The American Journal of MedicineVol 90, pg 450, April 1991) Part IVPredictors of Severe Hypoglycemia Younger age and younger age of onset of diabetes Adolescence (Personal note: High risk of noncompliance and hypoglycemia in this population) Lower stimulated C-peptide values (disease more severe and possible worsening injury to beta cells from hypoglycemia?) “Greater insulin dose per kg.”
Central Control of the ANS Control by the brain stem and spinal cord Reticular formation exerts most direct influence Medulla oblongata Periaqueductal gray matter Control by the hypothalamus and amygdala Hypothalamus – the main integration center of the ANS Amygdala – main limbic region for emotions Control by the cerebral cortex
The Nervous System Central Nervous System (CNS) Peripheral Nervous System (PNS) Brain Sensory Neurons Motor Neurons Spinal Cord Somatic Nervous System Autonomic Nervous System Sympathetic Parasympathetic
Brain 100 billion neurons. 10x more glial cells! Weighs about 1.5 kg, uses 20% of blood flow.
CNS CNS = Brain plus spinal cord - Gray matter consists of neuron cell bodies and dendrites. - White matter (myelin) consists of axon tracts. - Ventricles - CSF secreted by meninges, cushions brain - Skull protects - No pain sensors! - Blood-brain barrier.
Preganglionic fibers run via: Oculomotor nerve (III) Facial nerve (VII) Glossopharyngeal nerve (IX) Vagus nerve (X) Cell bodies located in cranial nerve nuclei in the brain stem Cranial Outflow
Fibers innervate visceral organs of the thorax and most of the abdomen Stimulates - digestion, reduction in heart rate and blood pressure Preganglionic cell bodies Located in dorsal motor nucleus in the medulla Ganglionic neurons Confined within the walls of organs being innervated Outflow via the Vagus Nerve (X)
Sympathetic Trunk Ganglia Located on both sides of the vertebral column Linked by short nerves into sympathetic trunks Joined to ventral rami by white and gray rami communicantes Fusion of ganglia fewer ganglia than spinal nerves
The Role of the Adrenal Medulla in the Sympathetic Division Major organ of the sympathetic nervous system Secretes great quantities epinephrine (a little norepinephrine) Stimulated to secrete by preganglionic sympathetic fibers
GHIH GHRH cAMP cAMP Feedback inhibition Feedback activation GH bound to GHBP Feedback inhibition IGF-1 bone & muscle HYPOTHALAMUS Periventricular area above optic chiasm Arcuate nucleus Somatotrophs secrete GH JAK Liver Overview of release and feedback control of GH by somatotrophs in the anterior pituitary.
INSULIN-LIKE GROWTH FACTOR I Synthesized mainly by liver in response to GH - somatomedin Mediates effects of GH on bone and cartilage 85% homology with proinsulin Continuous peptide chain unlike insulin Starvation or illness blocks IGF-I formation in response to GH –growth ceases during severe illness Does it make sense that starvation activates GHRH release? YES – in starvation GH exerts glucagon-like effects but its ability to promote IGF-I synthesis and secretion is blocked
Relative GH receptor mRNA levels l i v e r adipose pancreas brain kidney intest ine l ung muscle test is spleen bone cart i lage Figure 7. Tissue distribution of GH receptor mRNA. *Tissues with high levels of IGF-I receptor. Muscle contains GH and IGF-1; bone and cartilage only IGF-1
Summary of GH and IGF-I effects Direct effects of GH include Muscle amino acid uptake resulting in protein synthesis Glucose use peripherally (anti-insulin) Glucose output from liver (anti-insulin) Fat Mobilization (anti-insulin) Ketogenesis in liver (anti-insulin) IGF-I release from liver Direct effects of IGF-I include Cartilage/bone growth Muscle growth/proliferation
Hypophysiotopic hormones (A hormone secreted by the hypothalamus that stimulates or inhibits the adenohypophysis portion of the pituitary gland) CRH - corticotropic releasing hormone - released from the hypothalamus. It interacts with the pituitary to produce adrenocorticotropin hormone. Involved in the stress response. GHRH - growth hormone releasing hormone - The hormone released from the hypothalamus that causes the release of growth hormone from the pituitary gland GHIH - growth hormone inhibitory hormone - (somatostatin) - inhibits the release of GH and TSH, suppresses the release of gastrointestinal and pancreatic hormones and also suppressed the exocrine secretory function of the pancrease PRH - prolactin releasing hormone - A polypeptidehormone that originates in the hypothalamus and stimulates the secretion of prolactin in the pituitary gland. GnRH- gonadotropin releasing hormone - A hormone made by the hypothalamus (part of the brain). GnRH causes the pituitary gland to make luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones are involved in reproduction TRH - thyrotopin-releasing hormone - hormone released by the hypothalamus that controls the release of thyroid-stimulating hormone from the anterior pituitary
Pituitary hormones ACTH - adrenocorticotropin hormone - Hormone produced by the pituitary gland, which stimulates the adrenal glands to produce cortisone LH - lutenizing hormone - A pituitary hormone that stimulates the gonads. In the man LH is necessary for spermatogenesis (Sertoli cell function) and for the production of testosterone (Leydig cell function). In the woman LH is necessary for the production of estrogen. When oestrogen reaches a critical peak, the pituitary releases a surge of LH (the LH spike), which releases the egg from the follicle. [Gonadotropin] FSH - follicle stimulating hormone - hormone secreted by the pituitary gland in the brain that stimulates the growth and maturation of eggs in females and sperm in males, and sex hormone production in both males and females. [Gonadotropin] Vasopressin: hormone secreted by the posterior pituitary gland and also by nerve endings in the hypothalamus; affects blood pressure by stimulating capillary muscles and reduces urine flow by affecting reabsorption of water by kidney tubules Oxytocin: involved in reproductive behaviour in both men and women, and apparently triggers "caring" behavior. It is also the hormone which allows contractions of the womb during pregnancy and labour
Pituitary hormones (con’t) PL - prolactin - hormone produced by the pituitary gland that stimulates breast development and milk production. TSH - thyroid stimulating hormone - Ahormone secreted by the anterior pituitary gland, that controls the production and release of the thyroid hormones (T4 and T3) GH - growth hormone - A peptide hormone, made in the anterior pituitary, that stimulates tissue and skeletal growth MSH - melanocyte stimulating hormone - stimulates the production and release of melanin (melanogenesis) by melanocytes in skin and hair. MSH is also produced by a subpopulation of neurons in the arcuate nucleus of the hypothalamus. MSH released into the brain by these neurons has effects on appetite and sexual arousal.
Adrenal hormones (glucocortocoids) Cortisol - One of the primary catabolic hormones in the body. It is typically secreted in response to physical trauma or prolonged stress. Its functions include controlling inflammation, increasing muscular catabolism and glycolysis, suppressing immune response, and maintaining normal vascular circulation and renal function, among others. Epinephrine (Adrenaline) - A hormone produced by the adrenal glands that also acts as a neurotransmitter for nerve cells. As part of the fight-or-flight response, epinephrine signals the heart to pump harder, increases blood pressure and has other effects on the cardiovascular system. It helps the liver release glucose (sugar) and limits the release of insulin. Norepinephrine (Noradrenaline) - A neurotransmitter and a hormone. It is released by the sympathetic nervous system onto the heart, blood vessels, and other organs, and by the adrenal gland into the bloodstream as part of the fight-or-flight response. Norepinephrine in the brain is used as a neurotransmitter in normal brain processes. DHEA - (dehydroepiandrosterone) steroid precursor produced by the adrenal gland and converted to testosterone or the estrogens by the body's tissues. Adequate DHEA levels give the body the building blocks necessary to produce these hormones.
Thyroid: Thyroxine: The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are tyrosine-based hormones produced by the thyroid gland. They act on the body to increase the basal metabolic rate, affect protein synthesis and increase the body's sensitivity to catecholamines (such as adrenaline). An important component in the synthesis is iodine. Sex hormones: Testosterone - the male sex hormone, secreted by the testes but also synthesised in small quantities in the adrenal glands. Testosterone is necessary in the foetus for the development of male genitalia, and increased levels of testosterone at puberty result in the further growth of genitalia and the development of male secondary sex characteristics such as facial hair. DHT - Dihydrotestosterone - The enzyme 5 alpha reductase converts testosterone into its more potent form DHT. considered to be an aging-bio-marker. Among its affects are the appearance of body-hair, the loss of scalp hair and the onset of prostate gland problems. Estrogen - The female sex hormone produced by the ovary. Estrogens are responsible for the development of secondary sexual characteristics and cyclic changes in the viginal epithelium and endothelium of the uterus.
Sex hormones (con’t) Progesterone: A female hormone secreted by the corpus luteum after ovulation during the second half of the menstrual cycle (luteal phase). It prepares the lining of the uterus (endometrium) for implantation of a fertilized egg and allows for complete shedding of the endometrium at the time of menstruation. In the event of pregnancy, the progesterone level remains stable beginning a week or so after conception. Inhibin: Peptide that is an inhibitor of FSH synthesis and secretion and participates in the regulation of the menstrual cycle.
People with a mutated gene for the receptors melanocortin overeat and become obese. Melanocortin is a neuropeptide responsible for hunger. Prader-Willis syndrome is a genetic condition marked by mental retardation, short stature, and obesity. Blood levels of the peptide ghrelin is five times higher than normal. Hunger
Hunger Glucagon is also a hormone released by the pancreas when glucose levels fall. Glucagon stimulates the liver to convert some of its stored glycogen to glucose to replenish low supplies in the blood. As insulin levels drop, glucose enters the cell more slowly and hunger increases.
If insulin levels constantly stay high, the body continues rapidly moving blood glucose into the cells long after a meal. Blood glucose drops and hunger increases in spite of the high insulin levels. Food is rapidly deposited as fat and glycogen. The organism gains weight. Hunger
Hunger In people with diabetes, insulin levels remain constantly low, but blood glucose levels are high. People eat more food than normal, but excrete the glucose unused and lose weight.
Long-term hunger regulation is accomplished via the monitoring of fat supplies by the body. The body’s fat cells produce the peptide leptin, which signals the brain to increase or decrease eating. Low levels of leptin increase hunger. Hunger
Hunger High levels of leptin do not necessarily decrease hunger. Most people are obese because they are less sensitive to leptin. Some people are obese because of a genetic inability to produce leptin.
Hunger Information from all parts of the body regarding hunger impinge into two kinds of cells in the arcuate nucleus. The arcuate nucleus is a part of the hypothalamus containing two sets of neurons: neurons sensitive to hunger signals. neurons sensitive to satiety signals.
Hunger Neurons of the arcuate nucleus specifically sensitive to hunger signals receive input from: The taste pathways. Axons releasing the neurotransmitter ghrelin. Ghrelin is released as a neurotransmitter in the brain and also in the stomach to trigger stomach contractions.
Input to the satiety-sensitive cells of the arcuate nucleus include signals of both long-term and short-term satiety: Distention of the intestine triggers neurons to release the neurotransmitter CCK. Blood glucose and body fat increase blood levels of the hormone insulin. Some neurons release a smaller peptide related to insulin as a transmitter. Leptin provides additional input. Hunger
Output from the arcuate nucleus goes to the paraventricular nucleus of the hypothalamus. The paraventricular nucleus is a part of the hypothalamus that inhibits the lateral hypothalamus which is important for feelings of hunger and satiety. Axons from the satiety-sensitive cells of the arcuate nucleus deliver an excitatory message to the paraventricular nucleus which triggers satiety. Hunger
Input from the hunger-sensitive neurons of the arcuate nucleus is inhibitory to both the paraventricular nucleus and the satiety-sensitive cells of the arcuate nucleus itself. inhibitory transmitters include GABA, neuropeptide Y (NPY), and agouti-related peptide (AgRP). Neuropeptide Y (NPY) and agouti-related peptide (AgRP) are inhibitory transmitters that block the satiety action of the paraventricular nucleus and provoke overeating. Hunger
Output from the paraventricular nucleus acts on the lateral hypothalamus. The lateral hypothalamus controls insulin secretion and alters taste responsiveness. Animals with damage to this area refuse food and water and may starve to death unless force fed. Hunger
The lateral hypothalamus contributes to feeding by: Detecting hunger and sending messages to make food taste better. Arousing the cerebral cortex to facilitate ingestion, swallowing, and to increase responsiveness to taste, smell and sights of food. Increasing the pituitary gland’s secretion of hormones that increase insulin secretion. Increasing digestive secretions. Hunger
Damage to the ventromedial hypothalamus that extends to areas outside can lead to overeating and weight gain. Those with damage to this area eat normal sized but unusually frequent meals. Increased stomach secretions and motility causes the stomach to empty faster than usual. Damage increases insulin production and much of the meal is stored as fat. Hunger
Obesity can also be a function of genes interacting with changes in the environment. Example: Diet changes of Native American Pimas of Arizona and Mexico. Obesity has become common in the United States and has increased sharply since the 1970’s. Attributed to life-style changes, increased fast-food restaurants, increased portion sizes, and high use of fructose in foods. Hunger
Bulimia nervosa is an eating disorder in which people alternate between extreme dieting and binges of overeating. Some force vomiting after eating. Associated with decreased release of CCK, increased release of ghrelin, and alterations of several other hormones and transmitters. May be the result and not the cause of the disorder. Reinforcement areas of the brain also implicated. Hunger
Bias Toward Weight Gain Arc destruction causes weight gain. Response to weight loss bidirectional; weight gain unidirectional. DMc4r=> weight gain whereas Dnpy=>no weight loss. AgRP/Npy neurons are more sensitive to adiposity signals than Pomc/Cart neurons. HOWEVER: Anabolic pathways are required for intact responses to negative energy balance (IDDM causes negative energy balance in Npy-/- mice). Anabolic pathways are required for response to decreased leptin (Npy-/- over ob/ob mice show reduced hyperphagia).
Neurotransmitters of Autonomic Nervous System Neurotransmitter released by preganglionic axons Acetylcholine for both branches (cholinergic) Neurotransmitter released by postganglionic axons Sympathetic – most release norepinephrine (adrenergic) Parasympathetic – release acetylcholine