Ryan Kirdahy

Adopt a HormoneSomatostatin

April 27, 2017

1.) List the class topics that addressed your adopted hormone in terms of its normal

function and pathophysiology, citing specific topics by number and name.

Summarize the context in which the hormone was used

Topic 8: Organization of the Hypothalamus-Pituitary Axes

Growth hormone-releasing hormone from the periventricular nucleus will stimulate

somatotropes from the adenohypophysis in order to release growth hormone when somatostatin

is not present. Insulin-like growth factors are released by target cells due to the stimulation of the

growth hormone released.

Topic 10: Regulation of Tropic Hormone Secretion

Leptin and NE stimulate TRH release from the hypothalamus. Somatostatin as well as

dopamine and negative feedback control inhibit TRH release. Somatostatin, also known as

Growth Hormone-inhibiting hormone, inhibits Growth hormone release from the

adenohypophysis. Growth hormone release relies on the presence of growth hormone-releasing

hormone and the lack of somatostatin. Somatostatin plays other roles in the body like the

gastrointestinal tract and the pancreas.

Topic 20: Feeding Digestion, and Metabolism

GI hormones like somatostatin (pancreas) are able to also be released by the

hypothalamus due to the endocrine cells called amine precursor uptake and decarboxylase

(APUD). Somatostatin also has a role on the regulation of pepsin. The inactive precursor

pepsinogen is activated from the parietal cells by HCl. This release is regulated by
parasympathetic control along with secondary gastrointestinal autoregulation. Motilin may

contribute to the increase in pepsinogen release whereas somatostatin would inhibit the release of

pepsinogen.

Topic 21: The Mammalian Pancreas

Pancreatic somatostatin leads to the paracrine inhibition of pancreatic polypeptide, glucagon,

and insulin. In addition to the paracrine inhibition, there is hormonal inhibition of the release of

gastrin in the stomach and secretin in the small intestine.

2.) Historical perspective- provide a historical narrative about the discovery of your

hormone, citing references as appropriate

Somatostatin was discovered over 40 years ago. Scientists revealed the 14 amino-acid-long

peptide (SST-14) that was responsible for inhibiting growth hormone release from the

hypothalamus. Additionally, somatostatin was found in a 28 amino-acid-long peptide (SST-28)

(Belen, 2012). The scientists originally named it somatotropin release inhibiting factor (SIRF).

Another name that it was called was somatostatin which can be abbreviated in several different

ways. Most commonly it is abbreviated as SST, SS, or SOM. It did not take long before

scientists discovered that somatostatin could be found in places other than the hypothalamus.

Somatostatin can be found in regions of the peripheral and central nervous system as well as the

thyroid, endocrine pancreas, and gastrointestinal tract. Eventually, it was found that somatostatin

is synthesized in even more places such as cells of the immune system, the kidney, the placenta,

and the retina (Liguz-Lecznar, 2016).

 3. Summarize the roles that the hormone plays in vertebrate physiology, citing

references as appropriate

Typically, somatostatins physiological effects are inhibitory. Neurotransmission in the brain

can also be inhibited by somatostatin, however, it depends on the neural pathways that are

affected. In the central nervous system somatostatin could stimulate endocrine secretion. An

example of this would be that in the brain there is an increase of plasma ghrelin levels when

somatostatin receptors are activated. On the other hand, the release of ghrelin from cells of the

gastric mucosa would be inhibited in the presence of somatostatin. The function of somatostatin,

in peripheral organs, is to lower the exocrine and endocrine secretion and blood flow, reduces

gallbladder contraction and gastrointestinal motility, and inhibit gastrointestinal hormone

secretion (Liddle, 2015).

In the gastrointestinal tract, somatostatin inhibits the release of gastrin. The secretion of

gastric acid can be inhibited by both the circulating peptide (hormonal) and paracrine effects of

somatostatin. Somatostatin cells are unharmed by the axonal blocked tetrodotoxin which is a

potent neurotoxin. This allows somatostatin secretion to be caused by acid on a somatostatin cell.

In the regards to gastric acid secretion, if there were to be a lack in the inhibitory function of

somatostatin, then it could lead to peptic ulcer disease (Krejs, 1986)

4. Read and summarize for research papers, as described below, and provide the
following information for each paper.
Author, Title, Link
Hypothesis
Experimental design
Results
Conclusions
Two (2) papers on the effects or mechanisms of action or regulation of the hormone, one
each using a non-human vertebrate model and humans
Non-human Model:

Authors: Mitra Khumbatta, Bahrom Firozgary, David John Tweardy, Joel Weinstock, Gohar

Firozgary, Zal Bhatena, Tushar Bulsara, Ricoardo Siller, and Prema Robinson

Title: Somatostatin Negatively Regulates Parasite Burden and Granulomatous Reponses in

Cysticercosis

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121154/

Hypothesis: That SOM down modulates granulomatous inflammation in cysticercosis, thereby

promoting parasite growth

Experimental design:

Ten cysts of the PRF strain of T. crassiceps were used to infect WT mice and

somatostatin knockout (SOM-/-) mice through the peritoneal. After three months the infected

mice were sacrificed. The peritoneal cavity of the mice was opened in order to obtain the

granulomas and cysts by using HBSS to wash the peritoneal cavity. The washed contents were

put into a petri dish to be counted. Liquid nitrogen was used to flash freeze the granulomas. The

granulomas were then weighed as well as homogenized in aprotinin (500KIU/mL, Sigma) that

was ice-cold. Next, a centrifuge was used at 16,000 g at 4 degrees Celsius. The Bradford method

was used to calculate all of the protein in the supernatant. Sandwich ELISA assay are used to

determine The levels of the following proteins: IL-2, IFN-, IL-4, IL-10, IL-1, IL-6, and TNF-

Results:

In the peritoneum, the number of cysts was reduced by 83% in the SOM/ mice (714

79) in comparison to (4,222 173; P < 0.05) in the WT mice. The number of granulomas stayed

the same, however, there was an increase in weight by 95% in the SOM/ mice (17.9 0.6mg)
relative to the WT mice (9.2 0.2mg; P < 0.05) IFN- levels in the granuloma of the

SOM/ mice were increased 1.5 times (219 32pg/mg total protein) compared to WT mice

(142 21pg/mg; P < 0.05). IL-2 levels in granulomas of SOM/ mice (548 91pg/mg total

protein) were the same as the levels of the granulomas level in WT mice (714 255pg/mg; P >

0.05). IL-4 levels increased in SOM/ mice granulomas (1,084 130pg/mg total protein)

relative to the WT mice granulomas (568 97pg/mg; P < 0.05). This was the same result for an

increase in IL-10 levels in SOM/ mice granulomas (157 29pg/mg total protein) in

comparison to the granuloma levels in WT mice (66 15pg/mg; P < 0.05). IL-1 levels in the

granulomas in the SOM/ mice decreased (12 3pg/mg total protein) relative to the granuloma

levels in the WT mice (305 135pg/mg; P < 0.05). IL-6 levels (82 22pg/mg total protein) and

TNF- levels (365 48pg/mg total protein) had no differences in granulomas from

SOM/ mice relative to WT mice (189 76pg/mg and 502 117, resp.; P > 0.05 for both)

Conclusion:

The mice without somatostatin had less cysts by 83% when examined compared to the mice

who did have somatostatin. The weight of the granulomas increased by 95% in the mice where

somatostatin was not present when compared to the mice who did have somatostatin. IFN-

contributes to an increase in granuloma size not IL-2 in SOM/ mice. This means that increased

granulomatous response from SOM/ mice is not related to reduced levels of IL-4, IL-10, and

TH2 cytokines. The increase in pro-inflammatory cytokines is unlikely from the increase in the

size of the granuloma observed in SOM/ mice.

Human Model

Authors: Catalina Norman, Nanette L. Rollene, Dana Erickson, John M. Miles, Cyril Y.

Bowers, Johannes D. Veldhuis

Title: Estradiol Regulates GH Releasing Peptides Interactions with GH-Releasing Hormone and

Somatostatin in Postmenopausal Women

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892701/

Hypothesis: Estradiol (E2) drives GH secretion by amplifying interactions among GH-releasing

hormone (GHRH), somatostatin (SS) and GH-releasing peptide (GHRP)

Experimental Design:

A double blind design that randomized the administration of the placebo vs. transdermal

E2 to women who are healthy and postmenopausal (N=24). This was followed with pulsatile

somatostatin or growth hormone-releasing hormone infusions overnight, for a 13-hour time

period, or without continuous GHRP-2 stimulation. Transdermal E2 patches were used for E2

supplementation. The starting dose was 0.05mg/day and increased to 0.10 mg/day after four

days, and increased again after 4 days to 0.15 mg/day and stayed at this dose for the next 20

days. After E2 supplementation, Medroxyprogesterone acetate (5 mg) was taken orally for 12

days. The volunteers were controlled to a meal consisting of 30% fat, 20% protein, and 50%

carbohydrates. After this meal they fasted, did not drink caffeine or alcohol until the next say at

noon. Sleeping during the day and exercise were prohibited. The participants had to partake in 6

double-blind overnight consecutive 13-hour and 3-hour infusion sessions. These were random

and happened at least 48 hours apart. Approximate entropy (1, 20%) was the scale as well as the

model-independent statistic used in order to quantify the irregularity and regularity.

Results:

Somatostatin did not have much of an impact on the endpoint of growth hormone

responses during the first 3 hours saline or peptide infusions. The following ten hours showed

that somatostatin was inhibitory when E2/GHRP-2 and p1/GHRP-2 were present. The

approximate entropy of growth hormone secretion across the continuous ten hour time period of

peptide or saline infusions exposed the main effects of E2 (P=0.028), continued growth hormone

releasing peptides-2 (P<0.0001), pulsed growth hormone-releasing hormone (P<0.0001), and

pulsed somatostatin (P=0.013) in order to increase approximate entropy. Under

Saline/Somatostatin (P<0.001), E2 vs. P1 increased growth hormone approximate entropy. This

intensely suggests a decreased feedback.

Conclusion:

Supplementation of E2 in postmenopausal women increases the quantity as well as change

the pattern of growth hormone secretion. This occurs through the interactions between growth

hormone-releasing hormone, somatostatin, growth hormone releasing peptides, and BMI. The

results present a more intricate model of E2 supplementation in organizing growth hormone

secretion in individuals.

Two (2) papers on the pathophysiology of the hormone or effects of endocrine disruptors

on the hormone, one each using a non-human vertebrate model and humans.

Non-human Model:

Authors: Magdy El-Salhy, Jan Gunnar Hatlebakk, Odd Helge Gilja

Title: Abnormalities in endocrine and immune cells are correlated in dextran-sulfate-sodium-

induced colitis in rats

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355736/

Hypothesis: Inflammation induces the proliferation of serotonin cells and inhibits that of

somatostatin cells, in response to which there is a secondary change in the densities of CgA,

PYY, oxyntomodulin and PP cells.

Experimental design:

The animals used in this experiment were twenty-four male Wistar rats with an average

body weight of 280 grams. These rats were fed a standard diet of soy proteins (6%), cereal

products (88.5%), soy oil (0.5%), animal protein (2.5%), as well as vitamin, mineral, and amino

acid supplements (2.5%). The rats were kept under a light dark cycle of 12/12-h, humidity of

555%, and a temperature of 121 degree Celsius. They were given seven days in the animal

house to acclimate before the experiment. The rats were split into two groups of twelve. These

two groups consisted of the Control group and the DDS-induced colitis group. The DDS- colitis

group was given distilled water that contained 5% DSS while the control group was given

normal drinking water for seven days. The rats were weighed once a day and monitored twice a

day. The rats were sacrificed by CO2 inhalation after 7 days. Postmortem laparotomy was used to

dissect the colon. In order to perform additional immunohistochemical examinations, samples of

tissue were collected from the lower part of the colon. The tissue samples were fixed in a 4%

buffered paraformaldehyde solution overnight, embedded in paraffin, and cut at a 5mm

thickness. They were stained by using hematoxylin-eosin, or they were immonostained with the

ultraView Universal DAB Detection kit. The sections were incubated for 32 minutes at 37

degrees Celsius with a primary antibody. Counted the number of endocrine and immune cells by
counting the amount of each cell present in 10 microscope fields that were chosen at random. A

computer linked to the microscope performed the measurements. The Mann-Whitney

nonparametric test was used to test the differences between the DSS group and control group.

The relationship among abnormalities/alterations in the densities of immune cells and endocrine

cells were evaluated using the nonparametric Spearmans correlation test.

Results:

The histopathological examinations revealed the colonic tissues produced expected

results for the control group, but the DSS group experienced severe-to-moderate inflammation as

well as crypt abscesses, disturbed mucosal architecture, edema, infiltration of immune cells into

the submucosa mucosa and bleeding. In endocrine cells the CgA densities of serotonin,

enteroglucagon, and PYY were all greater in the DDS group compared to in the control group.

Densities of somatostatin cells and PP were significantly greater in the control group compared

to the DDS group. All types of immune cells had a much greater density in the DDS group

compared to the control group. The Spearman correlation coefficients and P-values among

immune cells and endocrine cells were recorded. Somatostatin cells and PP had a negative

correlation with immune cell alterations.

Conclusion:

The decrease in somatostatin cell density disagrees with previous studies where the density

has stayed the same. The alterations in the somatostatin cells and PP densities lead to the

involvement they have in the inflammatory activity. There is a possibility that an increase in

serotonin paired with the decrease in somatostatin cell densities is caused by inflammation. Also,

the alterations in PYY, CgA, PP cells, and oxyntomodulin are secondary responses to the change

in somatostatin and serotonin. The inflammation along with an increase in cytokine creation
decreases the somatostatin and increases serotonin cell densities. This occurs due to the impact

of cytokine on somatostatins and serotonins early progenitors. These changes cause an increase

in GI secretion and motility as well as visceral hypersensitivity. All of the colonic endocrine cells

of rats were impacted by introduction of colitis by DSS.

Human Model:

Authors: Modarai SR, Opdenaker LM, Viswanathan V, Fields JZ, Boman BM.

Title: Somatostatin signaling via SSTR1 contribute to the quiescence of colon cancer stem cells

Link: https://www.ncbi.nlm.nih.gov/pubmed/27927191

Hypothesis: SSTR1 cells maintain SCs in a quiescent state, and aberrant SST signaling

contributes to SC overpopulation in colorectal cancer (CRC).

Experimental design

The relationship of stem cells to neuroendocrine cells was counted using flow cytometry.

This was done within colorectal cancer cell lines as well as primary normal/tumor tissues

established on SSTR1 and ALDH levels. Stemness and cell proliferation were evaluated by

doubling time and the use of sphere-formation. Exogenous somatostatin and somatostatin

inhibitor cyclosomatostatin was used to treat colorectal cancer cell lines. The colorectal cancer

cell lines were then observed for changes in growth rate as well as stem cells. Paracrine signaling

among stem cells and neuroendocrine cells was discovered through the use of transwell cultures

of somatostatin receptor type 1+ and ALDH+.

Results:

ALDH+ cells negatively correlate with the rate of sphere formation and proliferation as

well as somatostatin receptor type 1+ cells. Colorectal cancer cells only show somatostatin
receptor type 1 while the normal tissues typically tend to show the somatostatin receptor type 1

and somatostatin. In addition, somatostatin receptor type 1 and somatostatin were not shown by

the ALDH+ cells. Exogenous somatostatin was able to subdue the proliferation but could not

suppress the population size of ALDH+ and could not suppress the viability. Cell proliferation as

well as sphere formation and population size of ALDH+ was decreased by the inhibition of

somatostatin receptor type 1 signaling. ALDH+ cell proliferation and sphere formation was

inhibited if co-cultured with somatostatin receptor type 1+ cells.

Conclusions:

There is a unique ALDH+/ somatostatin receptor type 1+ ratio for each colorectal cancer

cell line. This correlates to its specific growth dynamics. In addition, this implies feedback

mechanisms are present among stem cells and neuroendocrine cells. Somatostatin signaling

regulates the feedback mechanism of growth suppression. The results that somatostatin receptor

type 1+ lower proliferation of ALDH+ and lower sphere formation decrease due to somatostatin

receptor type 1+ shows that the subpopulation of ALDH is controlled by somatostatin receptor

type 1+ through paracrine mechanisms. ALDH+ lacks somatostatin and somatostatin receptor

type 1+ expression so that means that somatostatin signaling regulates the neuroendocrine cell

maturation rate as the stem cells for neuroendocrine cells mature. This adds to the quiescence of

stem cells as well as the inhibition of proliferation.

 Works Cited

Belen, C., Martnez-Fuentes, A. J., & Gracia-Navarro, F. (2012). Role of SST, CORT and

ghrelin and its receptors at the endocrine pancreas. Frontiers in Endocrinology, 3, 114.

http://doi.org/10.3389/fendo.2012.00114

El-Salhy, M., Hatlebakk, J. G., & Gilja, O. H. (2016). Abnormalities in endocrine and immune

cells are correlated in dextran-sulfate-sodium-induced colitis in rats. Molecular Medicine

Reports, 15(1), 1220. http://doi.org/10.3892/mmr.2016.6023

Khumbatta, M., Firozgary, B., Tweardy, D. J., Weinstock, J., Firozgary, G., Bhatena, Z.,

Robinson, P. (2014). Somatostatin Negatively Regulates Parasite Burden and

Granulomatous Responses in Cysticercosis. BioMed Research International, 2014,

247182. http://doi.org/10.1155/2014/247182

Krejs, G. (1986). Physiological role of somatostatin in the digestive tract: gastric acid secretion,

intestinal absorption, and motility. Scand J Gastroenterol Suppl.,119, 47-53. Retrieved

April 23, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/2876506.

Liddle, R. (2015, March 11). Physiology of somatostatin and its analogues. Retrieved April 26,

2017, from https://www.uptodate.com/contents/physiology-of-somatostatin-and-its

analogues#H6)

Liguz-Lecznar, M., Urban-Ciecko, J., & Kossut, M. (2016). Somatostatin and Somatostatin

Containing Neurons in Shaping Neuronal Activity and Plasticity. Frontiers in Neural

Circuits, 10, 48. http://doi.org/10.3389/fncir.2016.00048

Modarai, S. R., Opdenaker, L. M., Viswanathan, V., Fields, J. Z., & Boman, B. M. (2016).

Somatostatin signaling via SSTR1 contributes to the quiescence of colon cancer stem

cells. BMC Cancer, 16, 941. http://doi.org/10.1186/s12885-016-2969-7

Norman, C., Rollene, N. L., Erickson, D., Miles, J. M., Bowers, C. Y., & Veldhuis, J. D. (2014).

Estradiol Regulates GH Releasing-Peptides Interactions with GH-Releasing Hormone

and Somatostatin in Postmenopausal Women. European Journal of Endocrinology /

European Federation of Endocrine Societies, 170(1), 121129.

http://doi.org/10.1530/EJE-13-0733