On lizard spit and pesto
Jacob Schor, ND
October 9, 2006
As we await the season's first killing frost, I hurry to yank basil from our garden and grind it down to pesto. While doing so I cannot help but think about lizards, Gila Monsters to be exact. Gila Monsters and pesto are both part of the same story.
This story goes back all the way to the beginning of endocrinology, a hundred years or so. Ernest Starling and his brother in law, William Bayless, helped invented the science of endocrinology at the turn of the century. Starling is famous for presenting a paper in 1905 to the Royal College of Physicians in London in which he nominate the word ‘hormone' to describe exocrine messenger secretions within…. Well to describe hormones. [i]
Back in 1902, Bayliss and Starling proposed that intestinal mucosa make a hormone which stimulated the exocrine secretion of the pancreas. Of course, no one was calling them hormones yet. This was also before the word insulin showed up. Skip the terminology for the moment; they knew there was a chemical made in the intestines that stimulated the pancreas to lower blood sugar. They experimented with the obvious; they tried using intestinal mucosa extracts to treat diabetes but, unfortunately, without luck.
In 1932, La Barre gave a name to this intestinal mucosal hormone and called it incretin. LaBarre also knew incretin caused hypoglycemia and again, like Starling and Bayless, proposed it as a therapy for diabetes. [ii] He could not get incretin to work for treating diabetes either and incretin research went nowhere for the next 50 years. Incretin existed, but no one could figure out how to use it. Incretin had a clearly visible effect. Researchers knew that oral glucose stimulates more insulin production than IV glucose [iii] [iv]  , and incretin was the best explanation available. This incretin effect was substantial. Oral glucose produces about 50% to 70% more insulin response. [v]
When the incretin hormones were finally isolated about twenty years ago, it was suddenly clear why early attempts at using them to treat diabetes failed. The active form of the incretin, Glucagon-Like-Protein -1 (GLP-1), the hormone responsible for insulin secretion, has a short half-life; it breaks down to an inactive form in about 90 seconds. Hopeful scientists were stuck just as Bayless and Starling had been 80 years earlier.
The potential for GLP-1 was certainly obvious. People with diabetes either manufacture too little insulin or need extra insulin to get by. GLP-1 appeared safe since it's a natural compound circulating in everyone's body. As exciting as this was, it was still going nowhere fast. With such a short half-life, GLP-1 couldn't be used as a drug. The solution, when it finally arrived, came from an unexpected place, an ugly lizard in the Bronx .
Working in a Bronx Veteran's Administration hospital, John Eng isolated a molecule from the saliva of the Gila Monster, a venomous lizard, native to Mexico . The molecule acted like GLP-1. It bound to GLP-1 receptors and stimulated insulin release. The big difference between Eng's lizard spit chemical and the real GLP-1 was that its effect was long lasting.
Eng named his chemical exendin-4, ‘ex' because the lizard spit it out, in other words excreted it, and ‘end' because it had an endocrine action. He figured out how to make a synthetic version, and patented it for use against diabetes.
Here at last was a long lasting chemical that acted like GLP-1.
What does incretin do? It has multiple effects and for diabetics appears to do exactly what we want:
What started as lizard spit, was quickly turned into a drug and was released on the US market in November 2005. Developed by a partnership between Lilly and Amylin, the drug known as Exenatide is sold under the brand name Byetta . Byetta isn't the actual incretin molecule, GLP-1. Instead, it is a molecule that acts like GLP-1; it mimics it. This is what is meant by the term, incretin mimetic. [not, as the good Dr. Mona Morestein has suggested, a mime pretending to be a very stupid]
There is more to GLP-1 than treating diabetes. A series of recent papers suggests that GLP-1 may provide protection from and treatment for Alzheimer's disease. [vi]
GLP-1 decreases amyloid-beta levels and protects against brain cell death. [vii] So much so that these incretins and incretin mimetics are being considered a new strategy for Alzheimer intervention. [viii] This drug, which everyone is so excited about for diabetes, may find a role in treating an entirely different disease in the near future. [ix]
What about Pesto? We're getting there
Food stimulates the production of incretin hormones. It seems some foods have more effect than other foods. Large meals may stimulate more secretion than small meals. [x] Fatty meals seem to increase GLP-1 production and insulin secretion. This may explain why fats slow digestion because one effect of GLP-1 is that it delays gastric emptying.
Fat effect varies with the type of fat. Olive oil works particularly well and stimulates GLP-1 production. A March 2005 study showed feeding olive oil to healthy rats increased GLP-1 release. [xi] A June 2006 study reports that when human diabetics eat a couple of spoons of olive oil before eating mashed potatoes, it causes a marked improvement in blood sugar levels, slowing gastric emptying, delaying blood sugar rises and increasing GLP-1 production. [xii] Olive oil does this better than butter, increasing GLP-1 and also increasing HDL cholesterol. [xiii] Coconut oil does not help. While olive oil may increase GLP-1 production by as much as 55%, coconut oil does not trigger incretin secretion. [xiv] Remember that GLP-1 delays gastric emptying; we come to understand why some meals sit in the stomach producing hours of satiety while other meals leave one feeling empty and hungry a short time later. Alcohol, sorry to say, decreases GLP-1 production. [xv]
Pine nuts also increase GLP-1 production. In July 2006, Alexandra Einerhand reported that eating wafers made from Korean pine nuts increased GLP-1 production by 25% over the control group. In this study, the control group was given olive oil. Therefore, the pine nuts increased incretin secretion even more than olive oil, which we already know is a decent stimulator. [xvi]
There is a good reason to eat pesto, especially on pasta. Pesto turns on insulin production so when all that starch breaks down to sugar, your body is ready and waiting for it.
This brings us full circle to talking about pesto again. For what is pesto but olive oil and pine nuts with some basil, garlic and parmesan cheese added for flavor These flavor ingredients may also help the cause.
Although nothing suggests that garlic changes incretin or GLP-1 production, garlic does have a beneficial effect in diabetes. An August 2006 study showed that long term feeding of garlic oil to diabetic rats improved glucose tolerance and reduced kidney damage. [xvii]
And basil, well not our Italian basil but Holy Basil ( Ocimum sanctum ), which we know as Thai Basil, lowers blood sugar. A 1996 study reported that eating Holy Basil leaves lowered blood sugar levels in diabetics significantly. [xviii] Perhaps I should not mention this. First, we forgot to plant Thai basil this year and second, even if we had, I'm not sure what ‘Thai Pesto' will taste like.
Before I let this train of thought drop, the incretin mimetics and lizard spit train of thought, not the Thai Pesto one, there is an interesting point to add. Adherence to a Mediterranean-like diet lowers risk of Alzheimer 's disease. Remember that study from June 2006? [xix] In the study, researchers questioned a couple of thousand people in New York City on their diet and ranked them by how closely their diets resembled a Mediterranean diet. The researchers also monitored who got Alzheimer's. The people whose diets were more Mediterranean-like, had the lowest chance of developing the disease. What makes a diet look Mediterranean ? Well, olive oil, of course.
This story took a long time unfolding. It is a full hundred years since Starling and Bayless proposed the concept of an incretin hormone. Although lizard spit has finally made it possible to use this knowledge for our benefit, the story is far from over. Expect to hear more about incretin and GLP-1 in years to come.
quart fresh basil leaves, packed
Making pesto is simple. You throw everything is a food processor and grind it to mush. Actually, grind the basil and oil first, add the garlic and then the nuts and finally, the cheese last. Pack the finished mush into ice cube trays or muffin tins to freeze and, once solid, transfer it to Ziploc freezer bags. This provides meal sized portions to last all winter. A blender will work instead of a food processor, sort of. You may have to increase the oil to get the blender to chop all the basil and you might have to mix the cheese in by hand. Not to worry though, any combination of these ingredients will taste fine.
Jacob Schor, happy pesto maker. October 2006
[i] Henderson , J. Ernest Starling and ‘Hormones': an historical commentary. Journal of Endocrinology (2005) 184, 5-10
[ii] Zunz E and La Barre J. Contributions a l'etude des variations physiologiques de la secretion interne du pancreas. Relations entre les secretions externe et interne du pancreas. Arch Int Physiol Biochim. 1929;31:20-44.
[iii] Elrick H, et al. Plasma insulin responses to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076-1082.
[iv] McIntyre N, Holdsworth CD, Turner DS. Intestinal factors in the control of insulin secretion. J Clin Endocrinol Metab. 1965;25:1317-1324.
[v] Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986 Aug;63(2):492-8.
[vi] Perry T, and Greig NH . Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer's disease. Curr Alzheimer Res. 2005 Jul;2(3):377-85
[vii] Perry T, et al. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron.. J Neurosci Res. 2003 Jun 1;72(5):603-12
[viii] Perry TA and Greig NH. A new Alzheimer's disease interventive strategy: GLP-1. Curr Drug Targets. 2004 Aug;5(6):565-71
[ix] Perry T, et al. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002 Sep;302(3):881-8.
[x] Vilsboll T, et al. Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J Clin Endocrinol Metab. 2003 Jun;88(6):2706-13.
[xi] Prieto PG, et al. Effects of an olive oil-enriched diet on plasma GLP-1 concentration and intestinal content, plasma insulin concentration, and glucose tolerance in normal rats. Endocrine. 2005 Mar;26(2):107-15.
[xii] Gentilcore D, et al. Effects of fat on gastric emptying of and the glycemic, insulin, and incretin responses to a carbohydrate meal in type 2 diabetes. J Clin Endocrinol Metab. 2006 Jun;91(6):2062-7.
[xiii] Thomsen C, et al. Differential effects of saturated and monounsaturated fats on postprandial lipemia and glucagon-like peptide 1 responses in patients with type 2 diabetes. Am J Clin Nutr. 2003 Mar;77(3):605-11.
[xiv] Rocca AS , et al. Monounsaturated fatty acid diets improve glycemic tolerance through increased secretion of glucagon-like peptide-1. Endocrinology. 2001 Mar;142(3):1148-55
[xv] Dalgaard M, et al. Ethanol with a mixed meal decreases the incretin levels early postprandially and increases postprandial lipemia in type 2 diabetic patients. Metabolism. 2004 Jan;53(1):77-83.
[xvi] Korean Pine Nut Oil Boosts Appetite Suppressors Up To 60% For 4 Hours (press release). NewsTarget.com
Originally published July 17 2006
[xviii] Agrawal P, et al. Randomized placebo-controlled, single blind trial of holy basil leaves in patients with noninsulin-dependent diabetes mellitus. . Int J Clin Pharmacol Ther. 1996 Sep;34(9):406-9.
[xix] Scarmeas N, et al. Mediterranean diet and risk for Alzheimer's disease.Ann Neurol. 2006 Jun;59(6):912-21