Artificial Sweeteners: A Bitter Aftertaste?

Edwin Cox, M.D.OLLI

Basic concepts of NASNAS = Non-nutritive artificial sweeteners or non-caloric artificial sweeteners• AKA “high-intensity sweeteners”

NAS are substances that stimulate sweet receptors in the tongue, providing the pleasurable sensation of sweetness, but do not enter human metabolism directly

NAS are more potent than sugars, thus provide sweetness at lower amount• Exception: poly-alcohols (sorbitol, glycerol, xylitol) have about same

sweetness as sugar but do not raise blood glucose (not absorbed or not metabolically active)

Basic concepts of NAS (cont’d)NAS generally are not absorbed in GI tract and were thought to pass out unchanged in the stool• Those that are absorbed are metabolically inactive• Spoiler alert: We now know that intestinal bacteria metabolize several NAS

and produce active byproducts

NAS that are approved (i.e., FDA) have been tested and not found to cause untoward effects in lab animals or humans • Several are banned due to adverse effects; others were banned temporarily

but reauthorized (e.g., saccharin)• Spoiler alert: New areas of testing give rise to substantial concerns regarding

safety of several NAS that have not been incorporated into official advice

Artificial sweeteners

Popular NAS

Aspartame (left), sucralose (above), saccharin

“Accepted” uses of NAS“Accepted” is in quotes to indicate that these uses are currently under scrutiny due to evidence to be considered here

Prevention & control of diabetes• As an alternative to sugars, would be expected to avoid raising blood glucose

Prevention & reversal of obesity• As an alternative to sugars, would be expected to avoid adding caloric

content to diet

Prevention of dental caries

Prevention of reactive hypoglycemia

Sweetness at lower product cost

FDA guidance on NAS safetyAre high-intensity sweeteners safe to eat?

“Based on the available scientific evidence, the agency has concluded that the high-intensity sweeteners approved by FDA are safe for the general population under certain conditions of use. For certain highly-purified steviol glycosides and extracts obtained from monk fruit, FDA has not questioned the notifiers’ GRAS determinations under the intended conditions of use described in the GRAS notices submitted to FDA.”

GRAS = Generally recognized as safe

May, 2014https://www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients/ucm397716.htm

Medical guidance on NASAmerican Diabetes Association, American Heart Association, etc, are generally affirming of the uses just mentioned

ADA• “The evidence reviewed suggests that when used judiciously, [NAS] could

facilitate reductions in added sugars intake, thereby resulting in decreased total energy and weight loss/weight control, and promoting beneficial effects on related metabolic parameters.” August 2012

AHA• “Foods and beverages that contain [NAS] can be included in a healthy diet, as

long as the calories they save you are not added back by adding more foods as a reward later in the day, adding back calories that take you over your daily limit.” April 2018

Quick review of glucose digestion

Ingested glucose winds its way to the small intestine, where it is absorbed into the intestinal lining cell by a special transporter molecule, SGLT1, in the lumen-facing cell membrane

Glucose proceeds onward into the blood at the basal cell membrane by transporter GLUT2

Blood glucose rises as glucose is absorbed

Pancreas: crucial digestive organNestled in the duodenum (first part of small intestine)

Secretes digestive enzymes amylase, lipase and protease into the duodenum (exocrine gland)

Secretes insulin and glucagon into the blood from islands of tissue studded within pancreas (endocrine gland)

Rising Glucose Insulin release→

Blood passes through pancreas

Islets within the pancreas contain specialized cells for regulating glucose

Rising glucose level stimulates insulin secretion from pancreatic islet beta cells into the blood

Glucose and insulinInsulin is the master control molecule to regulate blood glucose level

Polypeptide (i.e., protein) of 51 amino acids in its monomer active form

Diagram shows storage hexamer (six units) form; greater stability

Monomer secreted by pancreas islet cells in response to rising glucose

Signals liver, muscles and fat cells to remove glucose from blood

Insulin effect on fat and muscleInsulin binds to insulin receptor on liver, fat and muscle cells

Activates glucose transporter to promote glucose uptake

Removing glucose from blood lowers glucose level

Glucose is converted into glycogen for storage in liver

Glucose is converted into fatty acid for storage in fat cells

Glucose is used as the energy supply in muscle and brain

glucosetransporter-4 insulin

receptor

6glycogen 4

3

pyruvate

fatty acids

glucose

Blood glucose following a mealNormal individual has a modest increase in blood glucose, peaking about one hour and returning to normal in two to three hours

Insulin secretion closely matches glucose absorption, driving glucose into fat and muscle cells, thereby keeping glucose level nearly constant

HyperglycemiaRefers to blood glucose levels that rise substantially above those in healthy individuals after a meal, or remain elevated after digestion is complete

Hyperglycemia is the defining characteristic of diabetes mellitus and prediabetes

Hyperglycemia

Hyperglycemia may occur because the pancreas is not secreting enough insulin relative to the glucose level (type 1 diabetes mellitus, advanced T2DM)

Alternatively hyperglycemia may occur because the cells that remove glucose from the blood are not responding to the insulin signal “insulin →resistance” (metabolic syndrome, early T2DM)

Glucose metabolism testingGlucose metabolism is tested by the GTT (glucose tolerance test)

Glucose intolerance is when, after consuming glucose, blood glucose rises too high or/and is elevated for too long

Glucose intolerance indicates either:• Insufficient insulin secretion by pancreas relative to amount of

glucose consumed• Insulin resistance, that is, fat and muscle do not respond to

insulin

Glucose tolerance testOral dose of glucose consumed (50 g)

Blood glucose sampled at intervals

Normal: Slight [1 MIN] to moderate [1 MAX] rise in blood glucose peaking at 60-80 min, falling back to baseline

Prediabetes [2]: Rises higher, falls back more slowly

Diabetes with hypoglycemia [4]: Rises higher, falls below normal later

Poorly controlled diabetes [3]: Elevated baseline glucose, rises even higher with glucose ingestion

So, what’s the problem with NAS?

Nature 2014

Mice given NAS develop glucose intolerance

Mice fed saccharin (Sweet’N Low), sucralose (Splenda) or aspartame (Equal)

NAS added to glucose-containing drinking water

NAS accompanied regular chow

Glucose tolerance curves at 11 weeks of consuming any of the three NAS showed marked glucose intolerance compared to glucose-only controls

Glucose intolerance of NAS in mice depends on gut microbes

Mouse microbiome is markedly altered

Balance in abundance of various species is changed

Production of short chain fatty acids by bacteria is changed• More acetate, propionate, less butyrate

Metabolic signaling and energy harvest is changed, upsetting glucose metabolism and energy balance

These changes can be prevented by antibiotic suppression of bacterial growth

Glucose intolerance transmissible to germ-free mice

Stool from mice rendered glucose intolerant by NAS were transferred to germ-free mice

Recipient mice became glucose intolerant

Glucose intolerance in recipient mice was prevented by giving antibiotics

Therefore glucose intolerance was transmitted with the bacterial transfer

Human high-NAS consumersNon-diabetic subjects of a clinical nutrition study

NAS intake determined from food-frequency questionaire• 40 high-NAS consumers• 236 non-consumers

Blood work taken from subjects included HbA1c, a measure of average blood glucose over preceding 3 months

High-NAS consumers had higher HbA1c (p<0.002)

Was high HbA1c the result of high-NAS consumtion, or the other way around, or neither?

Human subjects given NAS

7 healthy volunteers• Age 28-37, 5 M & 2 F, NAS non-consumers

All given saccharin 120 mg 3 times a day• FDA Acceptable Daily Intake• Daily for seven days

Glucose tolerance test administered daily

Non-responders to NAS

Three subjects had GTT after 5-7 days of saccharin not different from GTT in days 1-4

NAS responders

Four subjects had markedly altered GTT after 5-7 days of saccharin intake

NAS responders vs non-responders

Glucose response area-under-curve (AUC) more than doubled in four responders (R1, R2, R3, R4) after 5-7 days of saccharin

Gut microbiome vs NAS responseNAS responders had distinct bacterial species distribution compared to non-responders

That is, specific species are responsible for the transition to glucose intolerance

Glucose intolerance transmissible from human to mice

Stool transplanted from a human NAS responder to germ-free mice caused those mice to be glucose intolerant

What does it all mean?

NAS are not just metabolically inert compounds that taste sweet and pass on through with no consequences

NAS can suppress desirable bacteria, promote growth of less desirable ones

The promoted bacteria have effects on our metabolism, such as glucose intolerance and weight gain

The authors conclusion

“Our findings suggest that NAS may have directly contributed to enhancing the exact epidemic that they themselves were intended to fight.”

It is entirely possible that NAS used habitually may cause the very complications – diabetes, weight gain – that they are intended to prevent!

My conclusions about NASThese findings regarding effects of NAS in mice and humans should be considered preliminary until confirmed in other labs and other subjects

Nevertheless, sweeteners provide no nutritional value and possibly encourage consumption of other undesirable foods due to their “taste appeal”

It’s conceivable – thought unproven – that it’s as safe to consume modest amounts of sugar to satisfy our sweet tooth rather than use NAS

RecommendationsMinimize your consumption of all sweeteners – sugar (in its many forms) and NAS• Wean off the addiction to sweet foods and beverages

That includes steering clear of manufactured foods containing NAS• “Sugar-free” does not mean healthy

If you are having success in achieving specific goals by using NAS, don’t abandon them – yet• Weight maintenance, diabetic control, for example

Stay informed of further developments