Insulin

DIET  fads and their fleeting results aside, I sometimes think if we could just pause before tucking our forks into that enormous slice of chocolate cake and envision the physiological effects it is about to have on our bodies, we might, if not put our forks down, at least be more inclined to pace ourselves a bit. 

The hormone insulin is synthesized in the pancreas

within the β-cells of the islets of Langerhans.[1]

(Pancreatic islet on diagram)

By physiological effects, I am referring to the demands our increasingly high sugar diets are placing on the vital ability of pancreatic cells to regulate blood glucose levels through the production and release of insulin.

Although glucose is essential to our survival (which is why it makes our brains so hap-hap-happy!) its over-consumption can have negative consequences when the demands it places on our bodies surpasses the ability to meet those demands. 

I am not a proponent of eliminating certain foods from our diet completely. As with most things in life, moderation is key. My own experience has taught me that the second I tell myself I cannot have something, the value my brain places on that item increases a million fold. 

That said, I have also learned that we can train-trick-reprogram our brains into feeling satisfied by more healthy eating patterns and options; to the point where the time may come when we can look at an item we would have previously devoured and quite easily either pace ourselves, or, even better, turn away and reach instead for a more healthy alternative. 

INSULIN

The strong homology seen in the insulin sequence of diverse species suggests that it has been conserved across much of animal evolutionary history.[1][2][3]

Bovine insulin differs from human insulin in only three amino acids.[1]

Porcine insulin differs from human insulin in only one amino acid.[1]

DIRECT & INDIRECT REGULATORY EFFECTS OF INSULIN ON CELLS [1]

Insulin regulates ...

• The cellular intake of glucose in muscle and adipose tissue.
• The storage of glucose in liver and muscle cells in the form of glycogen. When insulin is low, liver cells convert glycogen to glucose and excrete it into the blood. 
• The formation of triglycerides from fatty acid esters in adipose tissue. 
• The cellular absorption of circulating amino acids and potassium.
• Insulin decreases the production of glucose from non-carbohydrate carbon substrates such as pyruvate, lactate, glycerol, and glucogenic amino acids.[4]
• Insulin increases arterial blood flow.
• Insulin decreases renal sodium excretion.[1][5]
• Insulin influences cognition. Once insulin enters the human brain, it enhances learning and memory, and benefits verbal memory in particular.[1][6][7]
• Insulin has also been shown to be produced inside the neurons of the brain, and reduced insulin levels has been linked to Alzheimer's disease.[1][8][9][10]

EFFECT OF INSULIN ON GLUCOSE UPTAKE & METABOLISM.[1] 

(1) Insulin binds to its receptor.

(2) Which starts many protein activation cascades. These include:

(3) Translocation of Glut-4 transporter to the plasma membrane and influx of glucose.

(4) GLYCOGEN synthesis - stored form of energy.

(5) GLYCOLYSIS -  usable energy. 

(6) Formation of TRIGLYCERIDES - stored form of energy. 

HYPERGLYCEMIA & KETOACIDOSIS[11][21]

• Hyperglycemia, or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma.

• This is generally a glucose level higher than 11.1 mmol/l.

• If untreated, hyperglycemia, can result in ketoacidosis (diabetic coma).

• Ketoacidosis develops in the absence of sufficient levels of insulin. Without insulin's regulatory presence, glucose cannot be converted into usable energy. As a result, the body breaks down fats to use for energy.

• This process generates waste products called ketones.

• When these ketones cannot be efficiently eliminated (in the urine), they build up in the blood; and this, can lead to ketoacidosis.

HYPOGLYCEMIA[1]

• Low blood glucose level is known as hypoglycemia.

• As neurons depend solely upon glucose for energy, low blood glucose can impair the normal functioning of the central nervous system.

• Dizziness, speech problems, and loss of consciousness can result; the latter also referred to as hypoglycemic coma or insulin shock.

• Intentional overdoses have been reported, but most insulin shocks appear to be due to errors in dosage of insulin or other unanticipated factors like inadequate diet coupled with over-exertion.

DIABETES

When control of insulin levels fails, diabetes mellitus can result.

TYPE 1 DIABETES is characterized by the loss of insulin-producing β-cells in the pancreas.[1][12][13]

• This type can be further classified as either immune-mediated or triggered by unknown or environmental factors.

• The majority of cases are of the immune-mediated class, in which a T-cell-mediated autoimmune attack leads to the loss of β-cells and thus insulin.[14]

• It can be accompanied by irregular and unpredictable hyperglycemia and sometimes with serious hypoglycemia.[22]

• It is partly inherited, with multiple genes believed to be of influence.[15][22]

• However, genes alone do not determine disease state. This is exemplified in identical twins; as when one twin has type 1 diabetes, the other gets the disease at most, only half the time.[15]

TYPE 2 DIABETES is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion.[16] 

• About 90% of people with diabetes have type 2 diabetes.[13]

• The predominant abnormality at the onset of the condition is reduced insulin sensitivity. At this stage, hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver.[22]

• A number of lifestyle factors are known to be important to the development of type 2 diabetes, including obesity, lack of physical activity, poor diet, and stress.[17]

• Excess body fat is associated with 30% of cases in those of Chinese and Japanese descent, 60–80% of cases in those of European and African descent, and 100% of Pima Indians and Pacific Islanders.[16] 

• Consumption of sugar-sweetened drinks in excess is associated with an increased risk.[18][19] 

• The type of fats in the diet is also important, with saturated fats and trans fatty acids increasing the risk and polyunsaturated and monounsaturated fat decreasing the risk.[20]

DIABETES RELATED COMPLICATIONS CAN INCLUDE: chronic kidney disease, erectile dysfunction, nerve damage, eye disease that can lead to blindness, heart attack, stroke, and non-traumatic lower limb amputation.[13]

Insulin is usually taken as subcutaneous injections.[1]

Oral administration of insulin is precluded by its digestion in the gastrointestinal tract.[1]

Biosynthetic human insulin for large scale clinical use is produced in either yeast or E. coli using recombinant DNA technology.[1][23][24] 

Researchers have also succeeded in introducing the gene for human insulin into safflower plants as another potential means of its production.[1][25][26]

**Notably absent from this entry on insulin are the accomplishments of, Banting, Best, Sanger, Langerhans, and Paulescu, to name a few. Scientists to whom we owe a debt of gratitude for the countless lives saved as a result of their tireless efforts. Mais, si vous voulez, you may click on this LINK for a timeline of insulin’s discovery and initial medical applications.

***

FIN

RELATED LINKS FROM MY NEWS FEED:

February 6, 2015  New Scientist    Both Cause and Cure for Diabetes Could be Your Gut

Jan 21, 2015   New Scientist    Cunning Fish Drug Snails With Insulin Then Eat Them

January 20, 2015  Popular Science   Stick-on Tattoo Measures Blood Sugar Without Needles

REFERENCES

[1] http://en.wikipedia.org/wiki/Insulin
[2] Le Roith, D.; Shiloach, J.; Heffron, R.; Rubinovitz, C.; Tanenbaum, R.; Roth, J. (1985). "Insulin-related material in microbes: similarities and differences from mammalian insulins".Can. J. Biochem. Cell Biol 63: 839–849. doi:10.1139/o85-106.
[3] Alzira Martins Ferreira de Souza, Jorge A. López (2004). Insulin or insulin-like studies on unicellular organisms: a review. Braz. arch. biol. technol. vol.47 no.6 Curitiba Nov. 2004.
[4] http://en.wikipedia.org/wiki/Gluconeogenesis
[5] Gupta AK, Clark RV, Kirchner KA (1992). "Effects of insulin on renal sodium excretion".Hypertension 19 (1 Suppl): 178–182. doi:10.1161/01.HYP.19.1_Suppl.I78.PMID 1730458.
[6] Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W. (November 2004). "Intranasal insulin improves memory in humans". Psychoneuroendocrinology 29 (10): 1326–34. doi:10.1016/j.psyneuen.2004.04.003. PMID 15288712.
[7] Benedict C, Brede S, Schiöth HB, Lehnert H, Schultes B, Born J, Hallschmid M. (2010)."Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men". Diabetes 60 (1): 114–118. doi:10.2337/db10-0329.PMC 3012162. PMID 20876713 [Epub'd ahead of print]
[8] Gustin N (2005-03-07). "Researchers discover link between insulin and Alzheimer's".EurekAlert!. American Association for the Advancement of Science.
[9] de la Monte SM, Wands JR (February 2005). "Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease". J. Alzheimers Dis. 7 (1): 45–61. PMID 15750214.
[10] Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (February 2005). "Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes?". J. Alzheimers Dis. 7 (1): 63–80. PMID 15750215.
[11] "Hyperglycemia"
[12] Comninos AN, Jayasena CN, Dhillo WS (2014). "The relationship between gut and adipose hormones, and reproduction". Hum. Reprod. Update 20 (2): 153–74.doi:10.1093/humupd/dmt033. PMID 24173881.
[13] http://www.diabetes.ca/about-diabetes/what-is-diabetes
[14] Rother KI (April 2007). "Diabetes treatment—bridging the divide". The New England Journal of Medicine 356 (15): 1499–501. doi:10.1056/NEJMp078030. PMID 17429082.
[15] http://www.diabetes.org/diabetes-basics/genetics-of-diabetes.html
[16] Shoback, edited by David G. Gardner, Dolores (2011). "Chapter 17".Greenspan's basic & clinical endocrinology (9th ed.). New York: McGraw-Hill Medical.ISBN 0-07-162243-8.
[17] Williams textbook of endocrinology (12th ed.). Philadelphia: Elsevier/Saunders. pp. 1371–1435. ISBN 978-1-4377-0324-5.
[18] Malik VS, Popkin BM, Bray GA, Després JP, Hu FB (2010-03-23). "Sugar Sweetened Beverages, Obesity, Type 2 Diabetes and Cardiovascular Disease risk". Circulation 121(11): 1356–64. doi:10.1161/CIRCULATIONAHA.109.876185. PMC 2862465.PMID 20308626
[19] Malik VS, Popkin BM, Bray GA, Després JP, Willett WC, Hu FB (November 2010)."Sugar-Sweetened Beverages and Risk of Metabolic Syndrome and Type 2 Diabetes: A meta-analysis". Diabetes Care 33 (11): 2477–83. doi:10.2337/dc10-1079.PMC 2963518. PMID 20693348.
[20] Risérus U, Willett WC, Hu FB (January 2009). "Dietary fats and prevention of type 2 diabetes". Progress in Lipid Research 48 (1): 44–51.doi:10.1016/j.plipres.2008.10.002. PMC 2654180. PMID 19032965.
[21] http://www.diabetes.org/living-with-diabetes/treatment-and-care/blood-glucose-control/hyperglycemia.html
[22] http://en.wikipedia.org/wiki/Diabetes_mellitus
[23] Drug Information Portal NLM – Insulin human USANhttp://druginfo.nlm.nih.gov/drugportal/
[24] Kjeldsen T (2000). "Yeast secretory expression of insulin precursors". Applied Microbiology and Biotechnology 54 (3): 277–86. doi:10.1007/s002530000402.PMID 11030562.
[25] From SemBiosys, A New Kind Of Insulin INSIDE WALL STREET By Gene G. Marcial(AUGUST 13, 2007)
[26] "GM Safflower with Human Pro-Insulin". I-sis.org.uk

OTHER SOURCES

http://www.medicinenet.com/insulin/article.htm
http://www.doctoroz.com/article/alzheimers-diabetes-brain
http://www.endocrineweb.com/conditions/type-1-diabetes/what-insulin

IMAGE CREDITS

"Blausen 0701 PancreaticTissue" by BruceBlaus. When using this image in external sources it can be cited as:Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762. - Own work. Licensed under CC BY 3.0 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Blausen_0701_PancreaticTissue.png#mediaviewer/File:Blausen_0701_PancreaticTissue.png

"InsulinHexamer" by Original uploader was Takometer at en.wikipedia - Originally from en.wikipedia; description page is/was here.. Licensed under CC BY 2.5 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:InsulinHexamer.jpg#mediaviewer/File:InsulinHexamer.jpg

"Insulin glucose metabolism ZP" by XcepticZP at en.wikipedia - Transferred from en.wikipedia to Commons by User:Shizhao using CommonsHelper.. Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Insulin_glucose_metabolism_ZP.svg#mediaviewer/File:Insulin_glucose_metabolism_ZP.svg

"Inzulín" by Original uploader was Mr Hyde at cs.wikipedia(Original text : moje foto) - Originally from cs.wikipedia; description page is/was here.(Original text : moje foto). Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Inzul%C3%ADn.jpg#mediaviewer/File:Inzul%C3%ADn.jpg

"C. H. Best and F. G. Banting ca. 1924" by Unknown - University of Toronto. Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:C._H._Best_and_F._G._Banting_ca._1924.png#mediaviewer/File:C._H._Best_and_F._G._Banting_ca._1924.png

Aspartame

Artificial Sweeteners, turns out it’s a rather broad subject to tackle all at once. So, today I will narrow my focus down to the one, and arguably the most disreputable of their class: Aspartame - Though, personally I am far more apprehensive about the stealthy and ubiquitous ‘natural sweetener’ corn syrup, but that is a topic for another day.

Artificial sweeteners are indeed in a great many things these days, and it is ultimately up to us—the consumer—to keep our eyes peeled to the list of ingredients that make up what we ingest. And as an extension of that, (and for the sake of this entry) one might ask: Is there really a need for us to be bothered about aspartame? Should we care if it is in what we are consuming? - Or are the concerns we hear about just hype, floated into the ether from sources unknown.

Sweetener	Common/brand name	Forms & uses	Other things you should know
Aspartame	Equal®  NutraSweet®  Private label  brand	Available in  packets, tablets or  granulated form  Added to drinks,    yogurts, cereals,  low-calorie  desserts, chewing  gum and many  other foods  Flavour may  change  when  heated	ADI = 40 mg/kg body weight per day.  For example, a 50 kg (110 lb) person  could safely have 2000 mg of aspartame  per day. One can of diet pop may  contain up to 200 mg of aspartame. *ADI = Acceptable Daily Intake

Source: The Canadian Diabetes Association [1]

The Potential Benefits

Weight control:

Artificial sweeteners have virtually no calories. In contrast, each gram of regular table sugar contains 4 calories. A teaspoon of sugar is about 4 grams. [2]

Since the caloric contribution of aspartame is negligible, it has been used as a means for weight loss through its role as a sugar substitute. On its own, aspartame is not known by medical literature to cause weight gain or weight loss.[3][4] 
Although some researchers have theorized that aspartame contributes to hunger or increases appetite psychologically,[3][5] physiologically, aspartame has not been shown to have an appreciable effect on appetite.[3][6]

Diabetes:

Artificial sweeteners may be a good alternative to sugar if you have diabetes. Unlike sugar, artificial sweeteners generally don't raise blood sugar levels because they are not carbohydrates.[2]

Dental care:

Sugar substitutes are tooth-friendly, as they are not fermented by the micro-flora of the dental plaque, so the bacteria have difficulty thriving, thus helping to prevent plaque formation.[7][8]

Cost:

Alternative sweeteners are often low in cost because of their long shelf-life and high sweetening intensity. This allows alternative sweeteners to be used in products that will not perish after a short period of time.[7][9] 

Aspartame was discovered accidentally by a chemist named James M. Schlatter while assessing an anti-ulcer drug candidate. By accidentally I mean, he discovered its sweet taste when he licked his finger (which had become contaminated with aspartame) to lift up a piece of paper.[3][10][11][12]

Upon ingestion, aspartame breaks down into residual components, including aspartic acid, phenylalanine**, and methanol.[10][13] Further breakdown products include formaldehyde [10][14] and formic acid. 

Methanol, Formaldehyde & Formic acid, yummy... well, if it's any consolation:

At the highest expected human doses of consumption of aspartame, there are no increased blood levels of methanol or formic acid.[3][4][10]

(**We’ll come back to phenylalanine in a wee bit.)

The Claims and the Counter-Claims:

Concern about possible carcinogenic properties of aspartame was originally raised and popularized in the mainstream media by John Olney in the 1970s; and again in 1996 when it was suggested that aspartame may be related to brain tumors. 

Numerous carcinogenicity studies in animals, epidemiological studies in humans, as well as in vitro genotoxicity studies have found no significant evidence that aspartame causes cancer in animals, damages the genome, or causes cancer in humans at doses currently used.[3][4][6][10] These studies support the position held by multiple regulatory agencies like the US Food and Drug Administration (FDA),[10][19] the European Food Safety Authority (EFSA) as well as scientific bodies such as the National Cancer Institute.[10][21]

In 2006, The Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation of Oncology and Environmental Sciences released several studies which claimed that aspartame can increase multiple malignancies in rodents, concluding that aspartame is a potential carcinogen at normal dietary doses.[10][16][17] 

The European Food Safety Authority (EFSA)[10][18][20] and the FDA[10][19] discounted these claims due to lack of transparency and numerous flaws in the studies' results, finding no reason to revise their previously established acceptable daily intake levels for aspartame.

***

Many allegations have been made on the Internet and in consumer magazines purporting that neurotoxic effects of aspartame lead to neurological or psychiatric symptoms such as seizures, headaches, and mood changes.[3][10] 

 A review of the pediatric literature did not show any significant findings for safety concerns with regard to neuropsychiatric conditions such as panic attacks, mood changes, hallucinations or with ADHD or seizures.[10][24] Additionally, comprehensive reviews have not found any evidence for aspartame as a cause for these symptoms.[3][4][6][10][22]

One review that did provide a theoretical biochemical background of neurotoxicity, (enough at least to warrant further testing)[10][23] was discredited by a panel of EFSA experts.

The EFSA experts noted that this review's conclusions were partially based on Internet sources and therefore were not scientifically robust. These experts also concurred with a critique that significant scientific errors were made in the critical review that led to unsubstantiated and misleading interpretations.[6][10] 

Headaches are the most common symptom reported by consumers.[3][10] While one review noted aspartame is likely a dietary trigger of migraines, it was among a list that included "cheese, chocolate, citrus fruits, hot dogs, monosodium glutamate (MSG), aspartame, fatty foods, ice cream, caffeine withdrawal, and alcoholic drinks, especially red wine and beer."[10][25] Other reviews have noted conflicting studies about headaches[3][10][26]and still more reviews lack any evidence and references to support this claim.[4][6][10][24]

So, to recap:

Peer-reviews, as well as independent reviews by governmental regulatory bodies have analyzed the published research on the safety of aspartame and have found aspartame is safe for consumption at current levels.[3][4][6][10][25] Aspartame has been found to be safe for human consumption by more than ninety countries worldwide,[10][27][28] and by over 100 regulatory agencies in their respective countries,[4][10] including the UK Food Standards Agency,[10][29] the EFSA[10][30] and Health Canada.[10][31] 

The question is, does this fact make you feel any safer about consuming products containing aspartame? Or, would you perhaps be better served by seeking out more natural sugar sources; and in the interest of maintaining balanced blood sugar levels - strictly monitoring the amount you consume.

***

The consumer advocacy group the Center for Science in the Public Interest continues to promote the position that aspartame is not safe.[10][15]

***

That all said, there is one undisputed cause for serious concern on the subject of Aspartame, and that is Phenylalanine:

High levels of the essential amino acid phenylalanine are a health hazard to those born with the genetic disorder phenylketonuria (PKU), a rare inherited disease that prevents phenylalanine from being properly metabolized.[10]

The typical human diet (milk, meat, and fruit etc.) will lead to ingestion of significantly higher amounts of phenylalanine than would be expected from aspartame consumption.[4][10] Still, people with PKU are advised to avoid aspartame due to their decreased ability to metabolize phenylalanine.[10]

The US, UK and Canada have legal requirements to clearly label foods containing aspartame as a source of phenylalanine.[4][10][32][33][34]     

Updates

Does Aspartame Cause MS? HowStuffWorks / June 19, 2015

Artificial Sweeteners May Change Our Gut Bacteria In Dangerous Ways  Scientific American / March 17, 2015

References

[1] http://www.diabetes.ca/diabetes-and-you/healthy-living-resources/diet-nutrition/sugar-sweeteners

[2] http://www.mayoclinic.org/healthy-living/nutrition-and-healthy-eating/in-depth/artificial-sweeteners/art-20046936

[3] Magnuson BA, Burdock GA, Doull J et al. (2007). "Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies". Critical Reviews in Toxicology 37 (8): 629–727.doi:10.1080/10408440701516184. PMID 17828671

[4] Butchko, H; Stargel, WW; Comer, CP; Mayhew, DA; Benninger, C; Blackburn, GL; De Sonneville, LM; Geha, RS; Hertelendy, Z (2002). "Aspartame: Review of Safety". Regulatory Toxicology and Pharmacology 35 (2 Pt 2): S1–93.doi:10.1006/rtph.2002.1542. PMID 12180494.

[5] "Gain weight by "going diet?" Artificial sweeteners and the neurobiology of sugar cravings". Yale Journal of Biology and Medicine 83 (2): 101–108.PMC 2892765. PMID 20589192.

[6] EFSA National Experts (May 2010). "Report of the meetings on aspartame with national experts". EFSA. 

[7] http://en.wikipedia.org/wiki/Sugar_substitute

[8] (2010). "Unique Sweetener Supports Oral health". vrp.com.

[9] Coultate, T. (2009). Food: The chemistry of its components. Cambridge, UK: The Royal Society of chemistry

[10] http://en.wikipedia.org/wiki/Aspartame

[11] Lewis, Ricki (2001). Discovery: windows on the life sciences. Oxford: Blackwell Science. p. 4. ISBN 0-632-04452-7.

[12] Mazur, R.H. (1984). Discovery of aspartame. In Aspartame: Physiology and Biochemistry (L. D. Stegink and L. J. Filer Jr., Eds.). Marcel Dekker, New York, pp. 3–9.

[13] "Aspartame disease: a possible cause for concomitant Graves' disease and pulmonary hypertension". Texas Heart Institute Journal 31 (1): 105; author reply 105–6. PMC 387446. PMID 15061638.

[14] Trocho C, Pardo R, Rafecas I et al. (1998). "Formaldehyde derived from dietary aspartame binds to tissue components in vivo". Life Sciences 63 (5): 337–49.doi:10.1016/S0024-3205(98)00282-3. PMID 9714421.

[15] Coke Shouldn't Bother Rehabilitating Aspartame's Image, Says CSPI ~ Newsroom ~ News from CSPI ~ Center for Science in the Public Interest

[16]Soffritti, M.; Belpoggi, F.; Esposti, D.D.; Lambertini, L.; Tibaldi, E.; Rigano, A. (2006)."First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats". Environ Health Perspect 114 (3): 379–385. doi:10.1289/ehp.8711. PMC 1392232.

[17] Soffritti, M.; Belpoggi, F.; Tibaldi, E.; Esposti, D.D.; Lauriola, M. (2007). "Life-span exposure to low doses of aspartame beginning during prenatal life increases cancer effects in rats". Environ Health Perspect 115 (9): 1293–1297. doi:10.1289/ehp.10271.PMID 17805418.

[18] Panel on Food Additives and Nutrient Sources added to Food (2006). "Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to a new long-term carcinogenicity study on aspartame". The EFSA Journal 356: 1–44. doi:10.2903/j.efsa.2006.356.

[19]  "US FDA/CFSAN – FDA Statement on European Aspartame Study". Archivedfrom the original on 23 September 2010. 

[20] "Aspartame in Soda is Safe: European Review". Associated Press. Retrieved16 December 2013.

[21] "Aspartame and Cancer: Questions and Answers". National Cancer Institute. 12 September 2006. Archived from the original on 12 February 2009. 

[22] Lajtha, A (1994). "Aspartame consumption: lack of effects on neural function". The Journal of Nutritional Biochemistry 5: 266–83. doi:10.1016/0955-2863(94)90032-9.

[23] Humphries, P; Pretorius, E; Naudé, H (2007). "Direct and indirect cellular effects of aspartame on the brain". European Journal of Clinical Nutrition 62 (4): 451–62.doi:10.1038/sj.ejcn.1602866. PMID 17684524.

[24] "Inactive" Ingredients in Pharmaceutical Products: Update (Subject Review)".Pediatrics 99 (2): 268–78. 1997. doi:10.1542/peds.99.2.268. PMID 9024461.

[25] Millichap, J; Yee, MM (2003). "The diet factor in pediatric and adolescent migraine".Pediatric Neurology 28 (1): 9–15. doi:10.1016/S0887-8994(02)00466-6.PMID 12657413.

[26] Sun-Edelstein, Christina; Mauskop, Alexander (2009). "Foods and Supplements in the Management of Migraine Headaches". The Clinical Journal of Pain 25 (5): 446–52.doi:10.1097/AJP.0b013e31819a6f65. PMID 19454881.

[27]Health Canada: "Aspartame – Artificial Sweeteners".

[28] Food Standards Australia New Zealand: "Food Standards Australia New Zealand: Aspartame (Updated January 2013)". Retrieved 26 November 2014.

[29] "Aspartame". UK FSA. 17 June 2008. Archived from the original on 7 October 2010. 

[30] "Aspartame". EFSA. 

[31] "Aspartame". Health Canada. Archived from the original on 22 September 2010. 

[32] Code of Federal Regulations Title 21

[33]  Aspartame – Labelling, UK Food Standards Agency, 18 July 2006. Retrieved on 22 July 2007.

[34]  "NGREDIENT S PECIFICATIONS NutraSweet ® Custom Powder". NutraSweet. 

http://www.webmd.com/food-recipes/features/are-artificial-sweeteners-safe

Image Credit

"Aspartame-from-hydrate-xtal-2000-3D-balls" by Ben Mills - Own work. Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Aspartame-from-hydrate-xtal-2000-3D-balls.png#mediaviewer/File:Aspartame-from-hydrate-xtal-2000-3D-balls.png