The nervous system maintains glucose homestasis.
The nervous system is involved in:
1. The secretion of insulin from beta cells.
2. The secretion of glucagon from alpha cells.
3. The release of glucagon from alpha cells in response to
hypoglycemia (sympathetic fibers)
4. 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
5. 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
in the pituitary and may exist in the hypothalmus.
Hypothalamic lesions in rats with long-term streptozotocin-induced
Journal Acta Neuropathologica 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, degranulated ergastoplasm, loss of organelles, increased number of
microtubuli, myelin figures, irregulatities in the form of nuclei, and appearance of chr
omatin . 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 Schweizer Nationalfonds
grant No. 3. 198-0.77
Reinnervation of transplanted pancreatic islets
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
Pancreatic beta cells secrete nerve growth factor
Proc Natl Acad Sci 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
Department of Biophysics, Instituto de Fisiología Celular, Universidad
Nacional Autónoma 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 dibutyryl
cAMP. Moreover, steady-state levels of NGF mRNA are down-regulated by
dibutyryl cAMP, 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 dibutyryl cAMP. 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.
The Source of “Insulin Resistance” must emanate, at least, in part, from a
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
glucagon response to insulin-induced hypoglycaemia.
Diabetes Nutr Metab. 2002 Oct;15(5):318-22
Autonomic mechanism and defects in the glucagon response to
Taborsky GJ Jr, Ahren B, Mundinger TO, Mei Q, Havel PJ.
Division of Metabolism, Endocrinology and Nutrition, University of
Washington, Seattle, WA, USA. firstname.lastname@example.org
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
These data raise the novel possibility that an autonomic defect
contributes to the loss of the glucagon response to IIH in T1DM.
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
Pancreatic beta cells resemble neurons
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
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 2
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
glucagon-like peptide-1 activates hypothalamic neuroendocrine
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-fos immunocytochemistry as an index of stimulated
neuronal activity. The distribution and quantity of GLP-1-induced c-fos immunoreactivity 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 parvicellular subregion 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 parvicellular subregion
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 vasopressinergic
magnocellular neurons of the PVN/SON contained c-fos- positive nuclei, whereas approximately 38% of the
magnocellular oxytocinergic 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 I receptors in the subfornical organ and the area
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
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
Mechanism of Action of Exenatide to Reduce Postprandial Hyperglycemia In Type 2 Diabetes
Am J Physiol Endocrinol Metab. 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
Remission of early onset childhood diabetes mellitus induced with TZD and DPP-IV inhibitor
The CNS and The Etiology of Diabetes Mellitus
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
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
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.
Glucagon response to hypoglycemia is predominantly the result of autonomic neural activation
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.
A brain-liver circuit regulates glucose homeostasis
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
This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient
production and its disruption may lead to hyperglycemia
Hypothalamic K(ATP) channels control hepatic glucose production.
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,
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.
Neural control of blood glucose level.
Jpn J Physiol. 1986;36(5):827-41.
Neural control of blood glucose level.
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 vagal innervation synergically
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.
An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-
induced insulin resistance and hypertension.
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,
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
phosphoenolpyruvate carboxykinase (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
The hepatic vagus nerve and the neural regulation of insulin secretion.
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.
(PPAR)gamma is highly expressed in normal human pituitary gland.
J Endocrinol Invest. 2005 Nov;28(10):899-904.
Peroxisome proliferator-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.
OBJECTIVE: Expression of peroxisome proliferator-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 PPARgamma
ligand 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.
Pioglitazone improves anatomical and locomotor recovery after rodent spinal cord injury
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. Peroxisome proliferator-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.
TZD’s prevent neuronal damage, motor dysfunction, myelin loss and inflammation
J Pharmacol Exp Ther. 2007 Mar;320(3):1002-12. Epub 2006 Dec 13.
Thiazolidinedione class of peroxisome proliferator-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 peroxisome proliferator-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%, monocyte chemoattractant 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.
PPAR-gamma: therapeutic target for ischemic stroke.
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 peroxisome proliferator 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 ligand
pioglitazone 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.
Pioglitazone can reduce the risk of secondary macrovascular events in a high-
risk patient population with type 2 diabetes and established macrovascular
Vasc Health Risk Manag. 2007;3(4):355-70.
PROactive 07: pioglitazone in the treatment of type 2 diabetes: results of the
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 PROspective pioglitAzone 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
PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative
Biochem Soc Trans. 2006 Dec;34(Pt 6):1341-6.
PPAR: a new pharmacological target for neuroprotection in stroke and
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-fibrate PPARalpha activators as well as thiazolidinediones and other
non-thiazolidinedione PPARgamma 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
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)
Do Atypical Antipsychotics
precipitate diabetes through their
effect on the brain?
Neuroendocrine effects of quetiapine in healthy volunteers
Int J Neuropsychopharmacol. 2005 Mar;8(1):49-57. Epub 2004 Oct 7.
Neuroendocrine effects of quetiapine in healthy volunteers.
de Borja Gonçalves 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's
pharmacodynamic 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.
Quetiapine-associated hyperglycemia and diabetes mellitus.
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.
“Insulin resistance” in olanzapine (Zyprexa) treated patients
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
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.
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 nonobese
olanzapine-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.
Olanzapine induces insulin resistance
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.
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.
Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients
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.
Limitation of the validity of the
homeostasis model assessment as an
index of insulin resistance
Limitation of the validity of the homeostasis model assessment as an index of insulin resistance
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,
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.
ORIGINAL THEORY BEHIND HOMA CALCULATION (1976) DOES NOT
TAKE INTO ACCOUNT
CNS CONTROL OF GLUCOSE
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.
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
“Insulin resistance” is a circular argument
Insulin resistance is the condition in which
normal amounts of insulin are inadequate to
produce a normal insulin response from fat,
muscle and liver cells.
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
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.
“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
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
Epidemiology of Severe Hypoglycemia in the Diabetes Control and
The DCCT Research Group (The American Journal of Medicine Vol 90, pg
450, April 1991) Part III
Epidemiology of Severe Hypoglycemia in the Diabetes Control and
The DCCT Research Group (The American Journal of Medicine Vol 90, pg
450, April 1991) Part IV
Predictors 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
“Greater insulin dose per kg.”
Central Control of the ANS
Control by the brain stem and spinal cord
◦ Reticular formation exerts most direct influence
Periaqueductal gray matter
◦ Control by the hypothalamus and amygdala
Hypothalamus – the main integration center of
Amygdala – main limbic region for emotions
◦ Control by the cerebral cortex
Central Nervous System (CNS)
Brain Spinal Cord
Peripheral Nervous System (PNS)
Sensory NeuronsMotor Neurons
Somatic Nervous System Autonomic Nervous System
The Nervous System
◦100 billion neurons.
◦10x more glial cells!
◦Weighs about 1.5 kg, uses 20% of blood flow.
CNS = Brain plus spinal cord
◦- Gray matter consists of neuron cell bodies
- White matter (myelin) consists of axon tracts.
◦- 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
Outflow via the Vagus Nerve (X)
Fibers innervate visceral organs
of the thorax and most of the
Stimulates - digestion, reduction
in heart rate and blood pressure
Preganglionic cell bodies
◦ Located in dorsal motor
nucleus in the medulla
◦ Confined within the walls of
organs being innervated
Sympathetic Trunk Ganglia
Located on both sides of the vertebral
Linked by short nerves into sympathetic
Joined to ventral rami by white and gray
Fusion of ganglia fewer ganglia than
The Role of the Adrenal Medulla in the
Major organ of the sympathetic nervous
Secretes great quantities epinephrine (a
Stimulated to secrete by preganglionic
IGF-1 bone &
above optic chiasm
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 -
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
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
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
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
(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
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 polypeptide hormone 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
TRH - thyrotopin-releasing hormone - hormone released by the hypothalamus that
controls the release of thyroid-stimulating hormone from the anterior pituitary
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 - A hormone 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
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.
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
◦ Melanocortin is a neuropeptide responsible
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.
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
◦ Blood glucose drops and hunger increases in
spite of the high insulin levels.
◦ Food is rapidly deposited as fat and
◦ The organism gains weight.
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.
High levels of leptin do not necessarily
◦ Most people are obese because they are less
sensitive to leptin.
◦ Some people are obese because of a genetic
inability to produce leptin.
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
1. neurons sensitive to hunger signals.
2. neurons sensitive to satiety signals.
Neurons of the arcuate nucleus specifically
sensitive to hunger signals receive input
◦ 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.
Output from the arcuate nucleus goes to
the paraventricular nucleus of the
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.
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
◦ inhibitory transmitters include GABA,
neuropeptide Y (NPY), and agouti-related
Neuropeptide Y (NPY) and agouti-related
peptide (AgRP) are inhibitory transmitters
that block the satiety action of the
paraventricular nucleus and provoke
Output from the paraventricular nucleus acts on the
◦ 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.
The lateral hypothalamus contributes to
◦ 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
◦ Increasing the pituitary gland’s secretion of
hormones that increase insulin secretion.
◦ Increasing digestive secretions.
Damage to the ventromedial
hypothalamus that extends to areas
outside can lead to overeating and
Those with damage to this area eat
normal sized but unusually frequent
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.
Obesity can also be a function of genes
interacting with changes in the
◦ 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.
Bulimia nervosa is an eating disorder in
which people alternate between
extreme dieting and binges of
◦ Some force vomiting after eating.
Associated with decreased release of
CCK, increased release of ghrelin, and
alterations of several other hormones
◦ May be the result and not the cause of the
◦ Reinforcement areas of the brain also
Bias Toward Weight Gain
1. Arc destruction causes weight gain.
2. Response to weight loss bidirectional; weight gain
3. DMc4r=> weight gain whereas Dnpy=>no weight loss.
4. AgRP/Npy neurons are more sensitive to adiposity
signals than Pomc/Cart neurons.
5. Anabolic pathways are required for intact responses to
negative energy balance (IDDM causes negative energy
balance in Npy-/- mice).
6. Anabolic pathways are required for response to
decreased leptin (Npy-/- over ob/ob mice show
Factor CNS Effect Peripheral Effect
-MSH (melanocortin) satiety increased energy
regulated transcript (CART)
(and other effects)
CCK-PZ satiety gallbladder contraction/
GLP-I satiety stimulates insulin
neuropeptide Y (NP-Y) hunger -------
(for fatty food)
orexins A and B hunger -------
Table I: Neural control of appetite
The Pancreatic Islet. Alpha Cells and Delta Cells surround Beta Cells
The endocrine portion of the pancreas takes
the form of many small clusters of cells
called islets of Langerhans or, more
simply, islets. Humans have roughly one
million islets. In standard histological
sections of the pancreas, islets are seen as
relatively pale-staining groups of cells
embedded in a sea of darker-staining
exocrine tissue. The image to the right
shows three islets in the pancreas of a horse.
Cells of the Pancreatic islet
Pancreatic islets house three major cell types, each of which produces a different
Alpha cells (A cells) secrete the hormone glucagon.
Beta cells (B cells) produce insulin and are the most abundant of the islet cells.
Delta cells (D cells) secrete the hormone somatostatin, which is also produced by
a number of other endocrine cells in the body.
Interestingly, the different cell types within an islet are not randomly distributed - beta
cells occupy the central portion of the islet and are surrounded by a "rind" of alpha and
delta cells. Aside from the insulin, glucagon and somatostatin, a number of other "minor"
hormones have been identified as products of pancreatic islets cells.
Islets are richly vascularized, allowing their secreted hormones ready access to the
circulation. Although islets comprise only 1-2% of the mass of the pancreas, they receive
about 10 to 15% of the pancreatic blood flow. Additionally, they are innervated by
parasympathetic and sympathetic neurons, and nervous signals clearly modulate secretion
of insulin and glucagon.
Neurotransmitters of Autonomic
Neurotransmitter released by
◦ Acetylcholine for both branches (cholinergic)
Neurotransmitter released by
◦ Sympathetic – most release norepinephrine
◦ Parasympathetic – release acetylcholine