Entry Level Clinical Nutrition

Part XIX

Carbohydrate-protein
Carbohydrate-
imbalances and the impact of
fructose
Jeffrey Moss, DDS, CNS, DACBN
[email protected]
413--530
413 530--0858 (cell)
1

Agrawal R & Gomez-Pinilla F. ‘Metabolic syndrome’ in the brain:

deficiency in omega-3
omega 3 fatty acid exacerbates dysfunctions in insulin
receptor signalling and cognition, J Physiology, Vol. 590, No. 10, pp.
2485-2499, 2012.

“All parameters of metabolic dysfunction related to fructose treatment were

ameliorated by the presence of dietary n-3 fatty acid. Results showed that
dietary n-3 fatty acid deficiency elevates the vulnerability to metabolic
dysfunction and impaired cognitive functions by modulating insulin receptor
signalling and synaptic plasticity.”

60 Minutes – Sunday, April 1, 2012

Is sugar toxic?

1
 Daily Hampshire
Gazette, May 29,
2012

USA Today, Friday, June 1, 2012 6

2
 7

USA Today, June 4, 2012

Daily Hampshire Gazette, June 4, 2012

3
The New York Times, June 5, 2012

10

11

12

4
13

14

15

5
 Quality of life issues are the
major concerns more than
ever now.

16

Summer of work exposes medical students to system’s ills, The New

York Times, September 9, 2009

“…a tidal wave of chronic illness…”

17

Baracos VE. Overview on

metabolic adaptation to
stress, pp. 1-13.

“An understanding of the

nature of stress is
fundamental to the rational
design of nutrient mixtures to
feed patients whose
homeostasis has been altered
by one or more stressors.”

“All stresses may be

presumed to be associated
with characteristic
modifications in the
metabolism of lipids,
carbohydrates, amino acids,
and micronutrients.”

18

6
 Bengmark S. Acute and “chronic” phase
reaction – a mother of disease, Clin Nutr,
Vol. 23, pp. 1256-66, 2004

19

Su KP. Biological mechanism of antidepressant effect of omega-3

fatty acids: How does fish oil act as a ‘mind-body interface’?
Neurosignals,
g , Vol. 17,, pp.
pp 144-152,, 2009

20

21

7
 Key metabolic imbalances seen
with the acute phase response
• Metabolic acidosis
• Loss of lean body mass (sarcopenia)
• Insulin resistance
• I fl
Inflamm-aging
i (I(Increased
d iinnate
t iimmunity
it
and decreased adaptive immunity)
• Suboptimal caloric intake and
carbohydrate:protein ratio (Refeeding
syndrome)
• Gastrointestinal dysfunction/gut atrophy
• Deficiencies of key micronutrients such as
zinc, selenium, and vitamin D
22

Underlying hypotheses of
Entry Level Clinical Nutrition:

• Chief complaints in chronically ill

patients are not diseases but responses
that have gone on too long (Allostatic
load).
• The metabolic imbalances that combine
to form this response have been well
defined by critical care nutritionists.

23

Entry Level Clinical Nutrition:

A new model of functional

medicine that incorporates
allostatic load and the “chronic”
acute phase response

24

8
 Chronic inflammation,
inflammaging, metainflamm.
Key deficiencies or Low calorie intake
excesses, i.e., and excessive
Calories, carbohydrate/protein
macronutrients, B ratio – Refeeding
vitamins, zinc, syndrome
selenium, iodine,
sleep, psychological
and chemical stress,
movement against Hyperinsulinemia/Insulin
gravity, weight resistance

Sarcopenia/Loss of lean
Gut body mass
dysfunction/atrophy Low grade chronic
metabolic acidosis/fluid
electrolyte imbalance

THE CREATION OF THE EXCESSIVE CATABOLIC

PHYSIOLOGY “RESPONSE” 25

Refeeding syndrome

26

Stanga Z et al. Nutrition in clinical practice – the refeeding syndrome:

illustrative cases and guidelines for prevention and treatment, Eur J Clin
Nutr, Vol. 62, pp. 687-694, 2008.

27

9
• “The refeeding syndrome was first reported
among those released from concentration
camps following the Second World War.”
• “Oral feeding of these grossly malnourished
individuals often resulted in fatal diarrhea,
heart failure and neurological complications,
including coma and convulsions
convulsions.”
• “Milder symptoms were later reported by
Keys et al. during the refeeding of healthy
volunteers with a mean weight loss of 23%
after starvation.”

28

29

30

10
 Skipping meals and then
binging on fructose-
fructose-laden
refined foods:
Is it more fuel on the fire?

31

Tappy L et al. Fructose and metabolic diseases: New findings,

new questions, Nutrition, Vol. 26,
26 pp. 10
1044-1049,
10 9 2010
2010.

32

Basic information on fructose

• “Sugar, a natural sweetener obtained

from either sugar cane or beets, is a
disaccharide composed of one glucose
molecule linked through an α1-4
glycoside bond to a fructose molecule.”
• “Fructose besides contributing to half
the total content of sugar, can also be
found as a hexose in fruits and honey.”

33

11
• “More recently, sweeteners started to
be produced from corn through starch
isolation and hydrolysis to glucose,
followed by enzymatic isomerization of
part of the glucose into fructose.”
• “The resulting mixture, known as high-
fructose corn syrup (HFCS)
(HFCS), has several
industrial advantages over sugar, the
most important being its low price, and
has progressively replaced sugar
consumption in North America over the
past 30 years.”

34

Intestinal metabolism of fructose

• “In the gut, fructose is transported by specific

transporters , GLUT5.”
• “In some subjects, fructose absorption is
quantitatively
tit ti l limited,
li it d andd some
malabsorption occurs when large amounts of
fructose are ingested.”
• “This can cause abdominal discomfort and
diarrhea, and production of volatile fatty acids
from colonic fructose fermentation.”

35

• “Fructose absorbed from the gut into the

portal vein is nearly completely
metabolized in the liver through
metabolic pathways distinct from those
of glucose; furthermore, the initial steps
of its metabolism are insulin-
independent, and hence, fructose is
largely metabolized without requiring
insulin secretion and without increasing
plasma glucose.”

36

12
• “This is due to the fact that 1) part of the
fructose appears to be directly
metabolized in enterocytes, where it is
converted into lactate and glucose, and
2)the bulk of absorbed fructose is taken
up by liver cells, where it is rapidly
converted into fructose 1-phosphate
and triose-phosphates through the
sequential actions of fructokinase and
aldolase B and triokinase.”

37

• “Fructokinase and aldolase B are not

inhibited by ADP and citrate and hence
are not regulated by the cellular energy
status.”
• “In fact, fructose differs from glucose,
because the ADP and citrate
concentrations exert a negative
feedback control of the initial steps of
glycolysis.”

38

• “Because fructose metabolism is not

dependent on insulin secretion, at least
in its initial steps, and because fructose
ingestion causes only a limited rise in
glycemia, fructose was initially proposed
as a natural substitute of sucrose for
di b ti patients.”
diabetic ti t ”
• “It however became rapidly apparent
that an increased dietary intake of
fructose had serious adverse metabolic
effects in both rodents and humans.”

39

13
 “Thus it was recognized that a high-
fructose intake is associated with
increased plasma triglyceride
concentrations, hepatic steatosis,
impaired glucose tolerance and
insulin resistance, and even high
blood pressure.”

40

Dietary fructose vs. HFCS

• “In our everyday diet, naturally occurring, free

fructose (essentially with fruits and honey) is
a modest component of energy intake.”
• “Furthermore, there is some evidence that
consumption of fructose with fruits or honey
does not produce the same adverse
metabolic effects as added fructose.”

41

• “This may be due to the presence of natural

antioxidants and/or dietary fibers with fruits
and honey.”
• “The vast majority of fructose in our diet
corresponds to added sugars, the two main
sources being sucrose (containing 50%
fructose) and HCFS (containing 42%-55%
42% 55%
fructose).”
• “As a consequence, the intakes of fructose
and glucose always vary simultaneously, and
therefore, high-fructose consumers are also
high-glucose consumers.”

42

14
 Overall conclusions

• “There is compelling evidence that a hypercaloric,

high fructose diet can induce, not only in animal
models, but also in humans, a whole range of
metabolic alterations, the most prominent being a
disturbance of hepatic lipid metabolism and of
plasma lipid profile.”
• “It appears therefore sound at this stage to advise
limiting consumption of sugar calories to less than
140 kcal/d for men and 100 kcal/d for women
(corresponding to about one can of sweetened
beverage/d), as recently proposed by the American
Heart Association.”

43

Fructose and systemic health:

The work of Robert Lustig
Lustig, MD

44

The case against Robert

Lustig

45

15
 Byerley LO & Lee WNP. Are ethanol and fructose similar? J Am Dietetic
Assoc, Vol. 110, No. 9, pp. 1300-1301, September 2010.

“The major premise of the review is that neither ethanol nor fructose provokes
a satiety signal (insulin or leptin), so feedback on the consumption of these
nutrients is lacking, leading to hedonic and societal consequences.”

46

Arguments against Lustig

• “Most of the data Lustig presents are

from rodent studies.”
• “The
The development of obesity is
caused by an energy imbalance such
that energy intake exceeds energy
expenditure from the body.”

47

“The conventional wisdom these days-promoted by government,

obesity researchers, physicians, and probably your personal trainer as
well-is that we get fat because we have too much too eat and not
enough reasons to be physically active.”

“There is an alternative theory, one that has been also around for
decades but that the establishment has largely ignored. This theory
implicates specific foods-refined sugars and grains-because of their
48
effect on the hormone insulin, which regulates fat accumulation.”

16
 • “The authority figures in obesity and
nutrition are so fixed on the simplistic
calorie-balance idea that they’re willing
to ignore virtually any science to hold on
to it.”
• “The
The first and most obvious mistake
they make is embracing the notion that
the only way foods can influence how
fat we get is through the amount of
energy-calories they contain.”

49

Bremer AA et al. Toward a unifying hypothesis of metabolic syndrome,

Pediatrics, Vol. 129, No. 3, pp. 557-570, March 2012

50

• “Whereas the majority of studies document a

relationship of visceral fat to insulin
resistance, ectopic liver fat correlates better
with dysfunctional insulin dynamics from
which the rest of metabolic syndrome
derives.”
• “In contrast to the systemic metabolism of
glucose, the liver is the primary metabolic
clearinghouse for 4 specific foodstuffs that
have been associated with the development
of metabolic syndrome: trans-fats, branched-
chain amino acids, ethanol, and fructose.”

51

17
“These 4 substrates (1) are not insulin
regulated and (2) deliver metabolic
intermediates to hepatic
mitochondria with an appropriate
pp p
‘pop-off’ mechanism for excess
substrate, enhancing lipogenesis
and ectopic adipose storage.”

52

Lustig RH. Fructose: Metabolic, hedonic, and societal parallels

with ethanol, J Amer Dietetic Assoc, Vol. 110, No. 9, pp. 1307-
1321, September 2010.

See Sugar: The Bitter Truth by Robert Lustig on You Tube

53

• “Elucidation of fructose metabolism in liver

and fructose action in brain demonstrate
three parallelisms with ethanol.”
• “First, hepatic fructose metabolism is similar
to ethanol, as they both serve as substrates
for de novo lipogenesis, and in the process
both promote hepatic insulin resistance,
dyslipidemia, and hepatic steatosis.”
• “Second, fructosylation of proteins with
resultant superoxide formation can result in
hepatic inflammation similar to acetaldehyde,
and intermediary metabolite of ethanol.”

54

18
• “Lastly, by stimulating the ‘hedonic
pathway’ of the brain both directly and
indirectly, fructose creates habituation,
and possibly dependence; also
paralleling ethanol.”
• “Thus, fructose induces alterations in
both hepatic metabolism and central
nervous system energy signaling,
leading to a ‘vicious cycle’ of excessive
consumption and disease consistent
with metabolic syndrome.”

55

Epidemiologic data

• “…our absolute consumption of dietary fat

has not changed in these last 30 years, and
high-fat, low-carbohydrate diets appear to be
protective against the metabolic syndrome.”
• “Before 1900, Americans consumed
approximately 15g/day fructose (4% of total
calories, mainly through fruits and
vegetables.”

56

• “Before World War II, fructose intake had

increased to 24 g/day; by 1977, 37 g/day (7%
of total calories); by 1994, 55 g/day (10% of
total calories); and current estimates put
fructose consumption by adolescents at 73
g/day (12% of total calories).”
• “Although high-fructose corn syrup in soda
has received most of the attention, high fruit
juice intake (sucrose) is also associated with
childhood obesity, although it is not captured
in the Economic Research Service.”

57

19
• “Thus, after adjustment for juice intake,
per capita consumption of fructose or
fructose-containing disaccharides is at
approximately 156 lb/year or 0.4 lb/day
for the average American.”

58

“To explain the dichotomy of

selective insulin resistance in the
pathogenesis of metabolic
syndrome, it is essential to
delineate the hepatic metabolism
of three energy substrates:
glucose, ethanol, and fructose.”

59

Hepatic glucose metabolism

60

20
• “Upon ingestion of 120 kcal of glucose
(eg, two slices of white bread), plasma
glucose levels rise and insulin is
released by the pancreas through
glucose stimulation of β-cell
depolarization via the Glut2 transporter.”
Ninety six kilocalories (80%) of the
• “Ninety-six
glucose bolus are utilized by other
organs immediately.”
• “Only 24 kcal (20%) enter the liver
through the Glut2 transporter.”

61

• “The liver can store large amounts of

glycogen without experiencing dysfunction or
damage, as demonstrated by the continued
normal hepatic function into adulthood of
patients with glycogen storage diseases.”
• “Only a small amount of glucose-6-phosphate
(the exact amount is dependent on quantity of
other substrates, and magnitude of insulin
action) is broken down by the Embden-
Meyerhoff glycolytic pathway to pyruvate.”

62

• “Pyruvate enters the mitochondria,

where it is converted to acetyl-CoA,
which then participates in the Krebs
tricarboxylic acid (TCA) cycle to
generate adenosine triphosphate, the
chemical storage form of energy,
carbon dioxide
dioxide, and water
water.”
• “The hepatic TCA cycle has a relatively
fixed maximum velocity, modulated only
by thyroid status, cold exposure,
altitude, and exercise.”

63

21
• “Thus, whatever tiny fraction of pyruvate
is not metabolized by the mitochondria
exits back into the cytoplasm as citrate
through the ‘citrate shuttle’.
• “This small amount of cytoplasmic
citrate can serve as substrate for the
process of de novo lipogenesis (DNL).
(DNL).”
• “…only a tiny fraction of glucose can be
hepatically metabolized to VLDL, which
could contribute slowly to
cardiovascular disease during a
lifetime.”

64

65

Hepatic ethanol metabolism

66

22
• “Upon oral ingestion of 120 kcal of
ethanol (eg, 1.5 oz hard spirits at 80
proof, or 40%), approximately 10% is
metabolized by the stomach and
stomach and intestine in a ‘first-pass’
effect before entry into the portal
circulation.”
• “Another 10% are metabolized by
muscle and kidney.”
• “So approximately 96 calories reach the
liver accounting for four times the
substrate as for glucose.”

67

• “Ethanol enters the hepatocyte through

osmosis and does not stimulate insulin
secretion.”
• “Once inside the liver, ethanol bypasses
glycolysis and is converted by alcohol
dehydrogenase 1B to form
acetaldehyde, which, because of its free
aldehyde, can generate reactive oxygen
species (ROS) formation and toxic
damage if not quenched by hepatic
antioxidants such as glutathione or
ascorbic acid.”

68

• “Acetaldehyde is then quickly

metabolized by the enzyme aldehyde
dehydrogenase 2 to the intermediary
acetic acid.”
• “From there, acetic acid is metabolized
by the enzyme acyl-CoA synthetase
short chain family member 2 to form
short-chain
acetyl-CoA, which can then enter the
mitochondrial TCA cycle; or, in the
presence of other caloric substrate, it is
more likely to participate in synthesis of
fatty acids through DNL.”

69

23
• “In the process of DNL, the intermediary
malonyl-CoA is formed in excess.”
• “However, malonyl-CoA is a steric inhibitor of
the mitochondrial enzyme carnitine palmitoyl
transferase-1.”
• “Carnitine palmitoyl transferase-1 is the key
rate-limiting
rate limiting and regulatory step in
mitochondrial β-oxidation; the fatty acid
transporter carnitine must be regenerated for
transesterification and import of fatty acids
into the mitochondrial matrix to generate two-
carbon fragments for ketone formation.”

70

• “Thus, increased DNL inhibits

intrahepatic lipid β-oxidation,
resulting in further intrahepatic lipid
buildup.”

• “Lastly
Lastly, ethanol is a known
contributor to hepatic insulin
resistance.”

71

72

24
 Hepatic fructose metabolism

73

• “Upon ingestion of 120 kcal of sucrose

(eg, 8 oz of orange juice; composed of
60 kcal fructose and 60 kcal glucose),
the overwhelming majority of the 60-
kcal fructose bolus reaches the liver,
along with 20% of the glucose bolus (12
kcal), for a total of 72 kcal; thus, the
liver must handle triple the substrate as
it did for glucose alone.”
• “In the liver, fructose is converted to
fructose 1-phosphate by the enzyme
fructokinase.”

74

• “This is an adenosine triphosphate-

requiring reaction, depleting available
intracellular phosphate.”
• “Phosphorylation of this large substrate
load leads to activation of the scavenger
enzyme adenosine monophosphate
deaminiase-1
deaminiase 1, which
which…[leads]
[leads] to the
cellular waste product uric acid.”
• “Buildup of urate in the circulation
inhibits endothelial nitric oxide synthase,
resulting in decreased nitric oxide in the
vasculature.”

75

25
• “In contrast to glucose’s conversion to
glycogen, the fructose-1-phosphate load
enters the Embden-Meyerhoff glycolytic
cascade.”
• “The majority of fructose-1-phosphate is
metabolized directly to pyruvate, with the
resultant large volume of acetyl-CoA entering
the mitochondrial TCA cycle.”
cycle.
• “The liver mitochondria cannot metabolize the
entire fructose-derived pyruvate/acetyl-CoA
substrate excess; any extra will exit the
mitochondria into the cytoplasm as citrate via
the ‘citrate shuttle.”

76

Fructose and de novo

lipogenesis (DNL)

• “DNL is markedly increased by excess dietary

CHO, rather than excess dietary fat.”
• “For example, if total CHO energy intake
exceedsd ttotal
t l energy expenditure,
dit h
hepatic
ti
DNL is incremented 10-fold.”
• “Similarly, on a high-CHO diet, DNL synthesis
is 27 times increased in the fasting state as
compared with a low-CHO diet, and 4 times
increased in the fed state.”

77

• “Fructose is a primary driver of DNL.”

• “Human studies demonstrate a rate of
fractional DNL of 2% with glucose and 10%
after 6 days of high-fructose feeding.”
• “A recent human study demonstrated that
fructose feeding increased fractional DNL to
17% ”
17%.
• “Elevated circulating VLDL in animal models
of high-fructose feeding may be a result of
overproduction driven by insulin resistance;
increased triglyceride flux and hepatic
inflammation; and decreased clearance.”

78

26
• “Animal studies demonstrate increased
hepatic lipid deposition in response to high-
fructose feeding.”
• “In human studies, eucaloric replacement of
glucose with fructose increased intrahepatic
lipid levels by 38% within 8 days, as
measured by magnetic resonance
spectroscopy.”
• “Our group also has found a correlation
between soft drink consumption and alanine
aminotransferase levels in obese children.”

79

Fructose and insulin resistance

• “Numerous human studies demonstrate the

induction of hepatic insulin resistance in
response to increased fructose feeding and,
in p
particular,, peripheral
p p markers of
inflammation.”
• “Excessive FFA exported from the liver leads
to increased uptake into skeletal muscle.”
• There, diacylglycerides reassembled from
FFA, reduces glucose transport, resulting in
skeletal muscle resistance.”

80

Fructose and hyperinsulinemia

• “Hepatic and skeletal muscle insulin

resistance, through increases FFA levels,
promotes reciprocal hyperinsulinemia.”
• “Thus,
“Th fructose’s
f t ’ action
ti on the
th liver
li iis unique
i
among carbohydrates and appears
independent of insulin.”
• “Fructose metabolism gives rise to the
phenotype of ‘selective hepatic insulin
resistance’ typical of metabolic syndrome…”

81

27
 Fructose vs. ethanol

• “Thus, hepatic metabolism of either fructose

or ethanol results in energy substrate
conversion to acetyl-CoA, with any insulin
regulation and with limited diversion to
nontoxic intermediaries such as glycogen.”
• “The overwhelming majority of the acetyl-CoA
produced will find its way into DNL,
generating intrahepatic lipid, inflammation,
and insulin resistance.”

82

Some final thoughts from Lustig

• “Ethanol is manufactured by
fermentation of fructose; the only
difference is that for fructose
fructose, humans
perform the glycolysis, while for ethanol,
yeast have already performed the
glycolysis.”

83

• “Aside from restriction of intake there are two

‘antidotes’ to the hepatic effects of fructose.”
• Exercise – “By increasing hepatic TCA cycle
maximal velocity, less acetyl-CoA will be
converted to citrate, providing less substrate
for DNL and reducing fructose’s downstream
effects.”
• “Fiber…enjoys two benefits. By reducing
glycemic load and rate of carbohydrate
absorption, fiber reduces the bolus of energy
substrate the liver has to metabolize acutely,
thereby reducing the rate of DNL and
improving insulin sensitivity. Fiber also
increases satiety, reducing further
consumption.”

84

28
“Health care providers must recognize
the differences between glucose and
fructose and that despite fructose’s
fructose s
classification as a carbohydrate, it is
metabolized more like a fat.”

85

86

Fructose and leaky gut

87

29
Lim JS et al. The role of fructose in the pathogenesis of NAFLD and the
metabolic syndrome. Nat Rev Gastroenterol Hepatol, Vol. 7, pp. 251-264,
May 2010.

88

• “Fructose consumption may also contribute to

bacterial overgrowth and increased intestinal
permeability.”
• “Animal and human studies suggest that non-
alcoholic fatty liver disease (NAFLD) is
associated with small intestinal bacterial
overgrowth, which is linked to circulating
endotoxemia and inflammatory cytokines.”
• “The
“Th presence off th these ffactors
t iin th
the bl
blood
d
has also been reported in patients with
alcoholic fatty liver disease.”
• “Translocation of bacterial endotoxins through
a leaky gut lumen to the portal blood
increases the exposure of the liver to
inflammation and injury.”

89

• “The gut microflora, therefore, may be a

key link between fructose feeding,
plasma endotoxin levels, and systemic
and hepatic inflammation associated
with the metabolic syndrome.”

90

30
Parting word

HORMESIS

91

Thank you!!

92

31