Disclaimer

This seminar is given with the understanding that the lecturer is

not rendering medical advice of any kind. The information in
these notes and lectures is not intended to replace medical
advice, have not been evaluated by the Food and Drug
Administration and are not intended to diagnose, treat, cure or
prevent any disease. Full medical clearance from a licensed
physician should be obtained before beginning any diet.
The information and opinions expressed in this lecture and these
slides/notes are intended for educational purposes only. The
lecturer, claims no responsibility to any person or entity for any
liability, loss, or damage caused or alleged to be caused directly
or indirectly as a result of the use, application or interpretation
of the material herein
 Brain detects sweet taste,
which triggers the cephalic
Carbohydrate phase of digestion.

This begs the question, what

happens when we consume
products that taste sweet but
have no caloric content (i.e.
artificial sweeteners)?
 Brain detects sweet taste, which
triggers the cephalic phase of
Carbohydrate digestion.

The carbohydrate is mixed with

saliva to form a bolus.
Breakdown of carbohydrates
begins here with the enzyme
salivary amylase.

The bolus is sent to the stomach,

which triggers the gastric phase
of digestion.

The free glucose present will

suppress the hunger hormone
ghrelin. Fructose, on the other
hand, does not suppress ghrelin.
 Cells lining the wall of the
stomach secrete leptin in
Carbohydrate response to the meal.

Leptin crosses the blood-brain

barrier, enters the central
nervous system, and acts on
receptors that control energy
intake and expenditure. In this
case leptin signals that food has
been consumed.

Digestion of carbohydrates
does not occur to a significant
extent in the stomach because
salivary amylase is deactivated
by the digestive acids.
 The chyme is released into the
duodenum, which triggers the
Glucose secretion of cholecystokinin (CCK)
from enteroendocrine cells.

CCK suppresses hunger and

stimulates pancreatic amylase
secretion from the acinar cells of the
pancreas. The amylase breaks down
carbohydrates to oligo- and
disaccharides.

-dextrinase in combination with the

brush border enzymes lactase,
maltase, and sucrase (found in the
mucosa of the small intestine)
complete the breakdown of oligo-
and disaccharides to
monosaccharides.
The monosaccharides are absorbed
by the blood vessels in the villi, which
triggers the release of PYY. The gut
hormone PYY reduces hunger and
improves CNS leptin sensitivity. The
quantity released depends on the
nature and quantity of the
macronutrient. Protein releases more
than fat, which releases more than
carbohydrate.

The monosaccharides enter the

bloodstream where glucose
stimulates secretion of insulin
by the pancreas. There is no
insulin secretion in response to
fructose because it can only be
metabolized by the liver.
 Insulin will bind to its receptor
on the surface of muscle and
fat cells as well as the cells of
tissues and organs.

The binding of insulin to its

receptor stimulates glucose
uptake into cells through the
glucose transporter protein
called GLUT4.

Glucose metabolism by
adipocytes stimulates the
secretion of leptin. This does
not occur with fructose.

Muoio, D. M.; Newgard, C. B. Metabolism: A is for adipokine Nature 2005, 436, 337-338
 An enzyme called hexokinase
Glucose attaches a phosphate group to free
ATP glucose molecules inside the cell.

Hexokinase
ADP The phosphate group serves as a
leash and prevents the glucose
from being transported outside of
Glucose-6-Phosphate the cell by GLUT4.

Glucose phosphorylation is only reversible in liver and kidney cells because

only they possess the glucose-6-phosphatase enzyme. As such, the liver
and kidney can both absorb and release glucose whereas other tissues and
organs can only absorb glucose.

Regulation of the activity (whether the enzyme is turned on or off) of

phosphorylating enzymes determines glucose uptake by various tissues
and organs.
 Glucose
In fat cells, the phosphorylated
ATP glucose is metabolized for energy
via the Krebs cycle. Metabolism of
Hexokinase glucose by fat cells triggers the
ADP release of leptin.

Glucose-6-Phosphate In muscle cells, glucose can be

metabolized for energy via the
Krebs cycle or stored in the form
of glycogen.

Glucose-1- The glucose that was not utilized

Phosphate Pyruvate
by organs and tissues, and all of
ATP the ingested fructose, make their
+ way to the liver.
CO2 Krebs
Cycle
O2
Glycogen
Glycogen
 Insulin Receptor Carbohydrate Metabolism in
the Liver:
IRS-1 Insulin, which was released in
response to glucose, binds to its
Insulin Receptor receptor on the liver cell membrane
and triggers the phosphorylation of a
tyrosine residue of Insulin Receptor
Substrate-1 (IRS-1).
Glucokinase pTyr-IRS-1

Pl3K The resulting pTyr-IRS-1 activates

Activation
the signaling protein AKT, which
SREBP-1 AKT activates Sterol Regulatory Element
Binding Protein-1 (SREBP-1).
Activation

SREBP-1 activates glucokinase as

De Novo Lipogenesis Enzymes:
well as a triad of enzymes involved
ATP Citrate Lyase
in de novo lipogenesis.
Acetyl-CoA Carboxylase
Fatty Acid Synthase
Carbohydrate Metabolism in
the liver Glucose enters the liver via GLUT2
and is phosphorylated by
glucokinase whereas fructose
enters via GLUT5 and is
phosphorylated by fructokinase.

The liver has a huge capacity for

the uptake and phosphorylation of
fructose. The livers
phosphorylation capacity for
fructose is about twice that for
glucose.

As was discussed above,

glucokinase is turned on by the
insulin response to rising blood
glucose. Glucokinase is also turned
on by fructose itself.
Carbohydrate Metabolism in the liver
We now have all the information we need to look at the effects of various
meals while in various metabolic states.

An individuals liver glycogen stores are rarely full under the following
conditions:

Adequate caloric intake or calorically restricted

Physically active (especially HIIT)
Low carbohydrate or ketogenic Diet

Lets see what happens when liver glycogen stores are not full (i.e. under
the above conditions) and we ingest 1 serving of a food that is mostly
glucose with a little bit of fructose.

The carbohydrate breakdown of a sweet potato, for example, is 12

grams of available fructose and 22 grams of glucose per 100 gram serving.
Carbohydrate Metabolism in the liver

When liver glycogen stores are not full and we ingest 1 serving of a food
that is mostly glucose with a little bit of fructose (i.e. sweet potato) the liver
glycogen stores are replenished and carbohydrate is burned for energy in
the Krebs cycle.

The small amount of fructose improves the livers ability to phosphorylate

glucose, which enhances liver glycogen replenishment.

Fructose increases liver concentration of dihydroxyacetone phosphate

and glyceraldehyde-3-phosphate, which promotes the gluconeogenic
pathway (i.e. glucose-6-phosphate to glucose-1-phosphate to liver
glycogen)

A small amount of fructose with a bolus of glucose enhances liver

glycogen replenishment, which takes precedence over triglyceride
formation.
Carbohydrate Metabolism in the liver: The
Fasted State
Now lets look at what happens in the fasted state
Carbohydrate Metabolism in the liver: The
Fasted State
In the fasted state, glucagon stimulates the liver to release glucose and
also stimulates fat cells to release triglycerides.

Any fructose in the bloodstream will enter the liver and will be converted
to glucose-6-phosphate.

Low levels of insulin and the absence of fructose deactivates glucokinase

and allows the liver to release glucose from glycogen stores by making the
system work in reverse.

Glucose transport via GLUT2 depends on the concentration of glucose

inside and outside the cell (i.e. concentration gradient). Glucose is
released into the bloodstream when the concentration of glucose inside
the cell is higher than that outside the cell.
Carbohydrate Metabolism in the liver: Acute,
Short-Term Exposure to A High Dose of
Carbohydrate

Now lets look at what happens when we ingest a large, calorically-

dense, carbohydrate-rich meal that contains a sufficient amount of
carbohydrate to completely fill liver glycogen and a sufficient amount of
calories to create a hypercaloric state (i.e. a cheat meal or a bender).
Carbohydrate Metabolism in the liver: Acute,
Short-Term Exposure to A High Dose of
Carbohydrate

Liver glycogen is quickly replenished.

Excess carbohydrate overwhelms the Krebs cycle, which causes

citrate to leave the cycle and enter the de novo lipogenesis pathway.

The citrate is turned into palmitoyl-CoA (one molecule of palmitic acid

and one molecule of CoA bound together), which is transformed into
triglyceride and packaged into VLDL to be exported into the
bloodstream.

The VLDL will transport the triglyceride to the fat cells where it will be
stored given the high levels of insulin in the bloodstream that result
from the meal.
Carbohydrate Metabolism in the Liver: Chronic,
Long-Term Exposure To High Carbohydrate
Doses

Now lets look at what happens when large amounts of carbohydrates,

especially fructose, are consumed on a daily basis, for a prolonged period
of time, in a sedentary, hypercaloric state. (i.e. the average north
American).

Remember that fructose quickly replenishes liver glycogen, does not

suppress ghrelin, and does not stimulate insulin or leptin secretion.
The majority of the palmitic acid in the north American diet originates from
de novo lipogenesis in the liver as a result of excess carbohydrates
consumption NOT fat consumption.
Carbohydrate Metabolism in the Liver: Chronic,
Long-Term Exposure To High Carbohydrate Doses

Excess carbohydrate is specifically converted to a saturated fatty acid

called palmitic acid.

The fatty acid is then synthesized into a triglyceride (1 molecule of

glycerol + 3 molecules of palmitic acid), packaged into VLDL and sent into
the bloodstream.

The triglycerides will be hydrolyzed to glycerol and palmitic acid in the

bloodstream. The free palmitic acid will be transported in the bloodstream
by a protein called albumin. The palmitic acid will make its way to the
central nervous system where it will impait hypothalamic insulin and leptin
signaling.

Leptin regulates appetite and metabolism. Leptin resistance prevents the

brain from detecting signals of satiety and energy reserves (fat mass). This
results in hyperphagia (overeating) and changes the bodys fat mass set-
point, which leads to weight gain.
Carbohydrate Metabolism in the Liver: Chronic,
Long-Term Exposure To High Carbohydrate Doses

Insulin resistance of the brain causes Alzheimers disease

The following is an excerpt from Alzheimers Scary Link to Diabetes by

Sophie L. Rovner, Chemical and Engineering News, May 18th 2009,
87(20), 42-46.

[So what's the bottom line on the link between Alzheimer's

and diabetes? De la Monte takes the most radical stance on
that question. "Alzheimer's disease and type 2 diabetes
affect different parts of the body, but they are manifestations
of the same disease," she contends. Indeed, she refers to
Alzheimer's as type 3 diabetes.]
 Insulin Receptor c-jun N-terminal kinase-1
(JNK1) causes inflammation
IRS-1
JNK1
Insulin Receptor
pSer-IRS-1

Glucokinase pTyr-IRS-1 In addition, JNK1 also promotes

the phosphorylation of IRS-1 at a
Pl3K serine residue, which leads to the
Activation
inactive pSer-IRS-1. This results in
SREBP-1 AKT liver insulin resistance.

Activation pSer-IRS-1 does not activate

De Novo Lipogenesis Enzymes:
ATP Citrate Lyase
Acetyl-CoA Carboxylase
Fatty Acid Synthase
glucokinase, which hinders the
livers ability to absorb glucose.
This leads to higher blood glucose
and insulin levels.
 In normal individuals,
binding of insulin to its
receptor on the liver cell
membrane inhibits
glucose production in
the liver (the liver imports
glucose as opposed to
exporting glucose). This
process maintains
normal glucose levels in
the blood.

In adipose tissue,
glucose provides fuel for
the synthesis of fat
stores, which serve as
the body's main energy
reservoir.

Muoio, D. M.; Newgard, C. B. Metabolism: A is for adipokine Nature 2005, 436, 337-338
 Once liver insulin
resistance sets in, the
liver goes into a constant
state of gluconeogenesis
and releases glucose
into the bloodstream
regardless of blood
glucose levels.

The resulting high levels

of blood glucose, insulin
and triglycerides (from de
novo lipogenesis) will
stimulate adipocytes to
store fat and muscle cells
to store glucose as
glycogen.

Muoio, D. M.; Newgard, C. B. Metabolism: A is for adipokine Nature 2005, 436, 337-338
 As fat and muscle cells
become saturated with
glucose, expression of GLUT4
is decreased in order to
prevent further storage to
occur. This causes insulin
resistance in muscle and fat
cells.

In addition, expression and

secretion of the fat-derived
factor RBP4 is increased. This
factor, possibly working in
concert with retinol (vitamin A),
impairs insulin signaling in
muscle, inhibiting glucose
uptake, and interferes with
insulin-mediated suppression
of glucose production in the
liver, causing blood glucose
Muoio, D. M.; Newgard, C. B. Metabolism: A is for adipokine levels to rise.
Nature 2005, 436, 337-338
 Advanced Glycation End Products (AGEs)
Glucose and fructose become toxic to cells in high concentrations (this is
one of the reasons why the body tightly regulates blood glucose levels).
Glucose and fructose can bind and crosslink proteins as well as other
biomolecules to form advanced glycation end products (AGEs). Fructose
is 7 times more likely than glucose to form AGEs.
The body attaches specific saccharides to various sites on proteins as
part of normal metabolism. These saccharides send important signals
and confer unique properties to the proteins. AGEs interfere with this
process and cause a variety of undesirable outcomes, such as improper
protein folding, that lead to inflammation.
Hemoglobin is often glycated by blood sugars. As such, glycated
hemoglobin (HbA1c, hemoglobin A1c, A1C, or Hb1c, HbA1c) is an
excellent predictor of health.
 Glucose Toxicity and Type-2 Diabetes
A phenomenon called glucose toxicity underlies the development of
diabetes and pre-diabetes.
Glucose toxicity refers to the irreversible damage that high blood sugars
inflict on the delicate beta cells of the pancreas (the cells that produce
insulin).
Beta cells eventually burn out when incessantly stimulated to produce
insulin by high blood glucose levels.
Glucose toxicity that occurs over many years eventually leaves an
individual with impaired insulin production.
Diabetes develops when insulin production is inadequate for a given level
of insulin resistance.
Patients at High Risk of Type 2 Diabetes Have
Inadequate -Cell Compensation for Degree of
Insulin Resistance

700
AIR Glucose, pmol/L

600 IGT 75th

500 n=21
Relatives
400 of Type 2 50th
Type 2 Diabetes
300
Diabetes Older n=14
25th
200 n=10 subjects
n=13 5th
100
0
0 1 2 3 4 5 6 7
Insulin Sensitivity Index, Si x 105 min1/pmol/L
Percentile lines based on data from 93 healthy subjects.
AIR glucose=first-phase insulin response.
Adapted from Vidal J, Kahn SE. In: Genetics of Diabetes Mellitus. Kluwer Academic Publishers;
2001;109131. Figure 3. With kind permission from Springer Science and
Business Media.
The high levels of glucose will
result in high insulin and
triglyceride (from de novo
lipogenesis) levels in the
bloodstream. This will trigger
fat storage in fat cells
(remember that lipoprotein
lipase in adipocytes is
stimulated by insulin whereas
that in muscle cells is not).

Fat accumulation around the

waste (visceral fat) leads to
the production of adipokines
(cell-to-cell signaling proteins
produced by adipose tissue).
These adipokines wreak
further hovok on the system.
Targets of PAI-1, adipokines, Endothelial
Visceral FFA, adiponectin dysfunction

Adipose Monocyte inflammatory

Adipokines
gene expression

Adipokines, Nonalcoholic
FFA steatohepatitis in liver

Adipokines, Skeletal muscle

FFA insulin resistance

Adipokines, Cardiac insulin resistance,

interstitial fibrosis, LVH,
FFA diastolic dysfunction

Adipokines, -cell apoptosis

FFA, glucose

Adipokines Alzheimers
disease

FFA = free fatty acids; LVH = left ventricular hypertrophy;

PAI-1 = plasminogen activator inhibitor 1; PPARs = peroxisome
proliferators-activated receptors; RXR = retinoid x receptor
 IRS-1 pSer-IRS-1
JNK1

Glucokinase

Activation
pTyr-IRS-1

Pl3K

ChREBP SREBP-1 AKT

Chronic fructose over-
consumption increases the
Activation Activation
activity of ChREBP
(carbohydrate response
De Novo Lipogenesis Enzymes: element binding protein).
ATP Citrate Lyase
Acetyl-CoA Carboxylase
Fatty Acid Synthase
ChREBP activates the enzymes ACL, ACC,
and FAS, which further increases de novo
lipogenesis.
The Role of Cholesteryl Ester Transfer Protein and
the Dyslipidemia Found with the Metabolic
Syndrome
Adiposopathy Renal clearance
TG

Small
FFA TG dense HDL
CETP
Cholesterol

TG
Lipases

Cholesterol
CETP Small
TG dense LDL
Fatty liver
Lipases
TG

Reproduced from Bays H. Expert Rev Cardiovasc Ther 2004;2:89-105, with permission from
Future Drugs Ltd.
The Role of Cholesteryl Ester Transfer Protein
(CETP) and the Dyslipidemia Found with the
Metabolic Syndrome

CETP facilitates the exchange of triglyceride (for cholesterol) from VLDL

particles to HDL particles, which are more readily cleared by the kidneys
resulting in lower HDL-C levels.
CETP may also facilitate the exchange of triglyceride (for cholesterol) from
VLDL particles to LDL particles. The more triglyceride-rich LDL particles
undergo metabolism by various lipases resulting in small, dense LDL
particles.
In the presence of excess VLDL, the normal action of CETP contributes to
the common lipid profile, or dyslipidemia, that is a characteristic of the
metabolic syndrome.

(1) Bays HE. Extended-release niacin/lovastatin: the first combination product for dyslipidemia. Expert Rev Cardiovasc Ther
2004;2:485-501.(2) Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes
Res 2004;12:1197-1211. (3) Bays H, Abate N, Chandalia M. Adiposopathy: sick fat causes high blood sugar, high blood
pressure and dyslipidemia. Future Cardiology (2005) 1(1), 39-59.
Small-Dense LDL

Small-dense LDL persists longer in the bloodstream compared to

Large-buoyant LDL
Small-dense LDL adheres to components of atherosclerotic plaque and
is more likely to gain entry to plaque
Small-dense LDL is more likely to be taken up by inflammatory white
blood cells, which in turn become the mast cells that fill coronary
plaque
Small-dense LDL is more likely to be oxidized

Small-dense LDL is 8 times more susceptible to glycation than large-

buoyant LDL
Excess triglyceride synthesis by the liver leads to the formation of lipid
droplets within the liver. This process leads to non-alcoholic fatty liver
disease.
 Purine Metabolism: Degradation
Fructose Glucose
ATP
Fructokinase Glucokinase

Fructose-6- ADP + Pi Glucose-6-

phosphate phosphate

Activate
AMP

Ammonia AMP-Deaminase-1

IMP or Inosinic Acid

ATP = Adenosine Monophosphate
ADP = Adenosine Diphosphate Nucleotidase
AMP = Adenosine Monophosphate
IMP = Inosine Monophosphate
Pi = Inorganic Phosphate
or Hydrogen Phosphate
Inosine
Purine Metabolism: Degradation
Inosine

Purine Nucleoside
Phosphorylase

Hypoxanthine

Xanthine
Oxidoreductase

Xanthine

Xanthine
Oxidoreductase
Nitric Oxide
Uric Acid Inhibits
Synthase
 Hypertension: Uric Acid & Aldosterone
Acute loading of the liver with fructose causes sequestration of inorganic
phosphate in frustose-1-phosphate and diminishes ATP synthesis. Under
normal conditions, ATP inhibits enzymes involved in adenine nucleotide
degradation. When this inhibition is removed, uric acid synthesis is
accelerated and hyperuriciemia results.
Uric acid inhibits nitric oxide synthase, which decreases the synthesis of
nitric oxide (NO), an important signaling molecule that happens to be a
vasodilator (dilates blood vessels). Lower concentrations of nitric oxide
lead to hypertension.
Excess uric acid can also precipitate out of the bloodstream in crystal
form, which leads to the painful condition known as gout.
The high blood levels of insulin, resulting from previously described
processes, increases the concentration of the hormone aldosterone,
which triggers sodium and water retention and further increases blood
pressure.
Reactive Oxygen Species
Carbohydrate metabolism in the mitochondria requires cofactors and
antioxidants (a.k.a. vitamins) in order to quench reactive oxygen species
that are generated by the process.
Reactive oxygen species (a.k.a. free radicals) that are not quenched by
antioxidants may escape into the cytosol of the cell and cause oxidative
damage, which is associated with aging.
There is a reason why fruit contains vitamins. The cofactors allow your
body to process the carbohydrate while the antioxidants are there to
prevent damage control. Unfortunately, we have been selecting for
increasingly sweeter fruits to the point where the concentration of
carbohydrate outweighs the vitamin content.
What does this say about refined carbohydrates that are devoid of
vitamins, minerals, and nutrients?
Reactive Oxygen Species
Almost all of the reducing equivalents
produced by glucose metabolism in the
Krebs cycle are in the form of NADH with the
exception of the succinate dehydrogenase
step, which takes place in mitochondrial
complex II and makes FADH2.

Metabolism of one molecule of glucose produces an NADH:FADH2 ratio

of 5:1 whereas fatty acid metabolism in the Krebs cycle will produce a
ratio of 3:1 depending on the length of the fatty acid.
NADH is oxidized only in mitochondrial complex I whereas FADH2 is
oxidized only in complex II. Complex I produces more reactive oxygen
species than complex II.
Production of a specific number of ATP molecules from glucose will
generate more reactive oxygen species compared to the generation of
the same number of ATP molecules from fatty acids.
 Peroxisome Proliferator-Activated
Receptor and Adiponectine
Peroxisome proliferator-activated receptors (PPARs) are a group of
nuclear receptor proteins that function as transcription factors regulating the
expression of genes. PPARs play essential roles in the regulation of cellular
differentiation, development, metabolism (carbohydrate, lipid, or protein), and
tumorigenesis of higher organisms.

Adiponectin is a protein hormone that is secreted by adipose tissue and

has the following effects: decreases gluconeogenesis, increases glucose
uptake, protects from endothelial dysfunction, increases -oxidation,
decreases triglycerides (by increasing their clearance), and improves insulin
sensitivity. Although released by adipose tissue, levels of adiponectin in the
bloodstreams of adults are inversely correlated with percentage of body fat
(i.e. more body = less adiponectin).

Chronic fructose consumption reduces adiponectin secretion from

Peroxisome proliferator-activated receptor-gamma (PPAR-).
Chronic, Long-Term, Consumption of Excess
Carbohydrate, Especially Fructose, Induces Many
Aspects of the Metabolic Syndrome
Leptin resistance

Insulin resistance

Inflammation

High fasting blood glucose levels

High fasting insulin

Increased adiposity

Non-alcoholic Fatty liver disease

Dyslipidemia
1) Elliot et al, Am. J. Clin. Nutr. 2002, 76, 911922. 2) Bray et
Hypertension al, Am. J. Clin. Nutr., 2004, 79, 537543. 3) Johnson et al,
Am. J. Clin. Nutr., 2007, 86, 899906. 4) Teff et al, J. Clin.
Endocrinol. Metab. 2004, 89, 29632972. 5) Gaby, Alt. Med.
Advanced glycation end products Rev. 2005, 10, 294306. 6) L and Tappy, Curr. Opin. Clin.
Nutr. Metab. Care 2006, 9, 469475. 7) Wei et al, J. Nutr.
Biochem. 2007, 18, 19. 8) Rutledge and Adeli, Nutr. Rev.
Type 2 diabetes 2007, 65, S13S23
Acute Ethanol Exposure Acute Fructose Exposure
CNS depression

Vasodilation (decreased blood

pressure)

Hypothermia

Tachycardia

Myocardial Depression

Variable pupillary responses

Respiratory depression

Diuresis

Hypoglycemia

Loss of fine motor control

Chronic Ethanol Exposure
Hematologic Disorders
Electrolyte Abnormalities
Hypertension
Cardiac Dilatation
Cardiomyopathy
Dyslipidemia
Pancreatitis
Malnutrition
Obesity
Hepatic Dysfunction
(Alcoholic Steatohepatitis)
Fetal Alcohol Syndrome
Addiction
Chronic Fructose Exposure
Hypertension
Myocardial Infarction
Dyslipidemia
Pancreatitis
Obesity
Hepatic Dysfunction
(non-Alcoholic Steatohepatitis)
Fetal insulin resistance
Habituation (if not addiction)
 Fructose: How Much is Too Much?
The ratio of glucose:fructose that can be tolerated without causing adverse health
effects will depend on the total caloric content of the diet, the percentage of total
calories from carbohydrate. The volume and intensity of physical activity, etc
A value of <1520 grams per day, which comes from the moderate consumption
of fruits an vegetables, is recommended for sedentary individuals.
Athletes can tolerate higher amounts of fructose but should probably not exceed
50 grams per day.
A diet that is moderate to high in carbohydrate (40-60%) should be low in
fructose (i.e. sweet potatoes and starchy vegetables are permissible but fruit
should be limited or avoided).
A low-carbohydrate or ketogenic diet allows for a greater fructose:glucose ratio.
In a hypercaloric, high-carbohydrate diet, more fructose = more problems.
Fructose Consumption: Historical Perspective

World Sugar Consumption in Millions of Tons

Year Sucrose Fructose
1800 0.25 0.125
1850 1.5 0.75
1880 3.8 1.9
1890 5.2 2.6
1900 11.0 5.5
1950 35.0 17.5
1970 70.0 35.0
1990 110.0 55.0
2000 128.0 64.0

George A Bray Fructose - How Worried Should We Be? Medscape Journal of Medicine 2008, 10(7), 159898.
Fructose Consumption: Historical Perspective

Natural consumption of fruits and vegetables: 15g/day

Prior to World War II (Estimated): 16-24 g/day

1977-1978 (USDA Nationwide Food Consumption Survey): 37

g/day (8% of total caloric intake)
1994 (NHANES III): 54.7 g/day (10.2% of total caloric intake)

Adolescents in 2008: 72.8 g/day (12.1% of total caloric intake,

25% of adolescents consumed at least 15% of total calories from
fructose)

(1) George A Bray How Bad is Fructose American Journal of Clinical Nutrition 2007, 86(4), 895898. (2) Miriam B. Vos et al.
Dietary Fructose Consumption Among US Children and Adults: The Third National Health and Nutrition Examination Survey
Medscape Journal of Medicine 2008, 10(7), 160.
Is There a Difference Between High Fructose
Corn Syrup (HFCS) and Table Sugar (Sucrose)

Pharmacology, Biochemistry and behavior Published ahead of print 2010 doi:10.1016/j.pbb.2010.02.012

Low- Versus High-Carb Diets: The
Metabolic Advantage

When comparing slightly hypocaloric (typical intake500 calories)

and isocaloric (same amount of calories in each) diets, the low-carb
diet will tend to lead to more weight loss.

This is thought to be due to a metabolic advantage.

During a low-carb or ketogenic diet, the body must synthesize

needed glucose from glucogenic amino acids and glycerol. This
process requires energy and increases the bodys basal metabolic rate
(i.e. energy expenditure increases and is greater when compared to
the high-carb diet)
Common Misconceptions: Ketogenic
Diets and Kidney Stones

Ketogenic diets per se do not cause kidney stones.

The kidney stones occur when excess dairy is consumed as part of a

ketogenic diet.

Kidney stones arise due to excess calcium, not in response to a

ketogenic state.
 Ketogenic Diets and Insulin Sensitivity
Ketogenic diets involve a level of carbohydrate restriction that forces the
body to rely on ketone bodies for fuel. All of the organs and peripheral
tissues of the body can use ketones as fuel.
The brain cannot operate on ketones alone. The maximum
ketones:glucose ratio that can be used by the brain is 75:25.
Ketone bodies increase the insulin resistance of peripheral tissues and
organs, thus forcing them to run on ketones while the brain gets the lions
share of the available blood glucose.
Note that this insulin resistant state is reversible via the ingestion of
carbohydrate and is not pathological because it is not accompanied by
high blood sugars or hyperinsulinemia.
A diet that is ketogenic may be high in palmitic acid from animal sources.
The palmitic acid will increase insulin resistance but, again, this is a
reversible and non-pathological state.
Insulin resistance can be employed as a glucose sparing mechanism and
is not always pathological.