Transcript Ethnic differences in glucose metabolism

“You can’t run from a bad diet*.”
A dietary approach to prevention
and treatment of cancer
Barbara A. Gower, PhD
UAB Department of Nutrition Sciences
/
*http://fanaticcook.com/2014/05/08/study-inactivity-does-not-lead-to-fatness-its-the-other-way-around
Obesity and Cancer
• “Obesity is a major under-recognized contributor
to the nation’s cancer toll and is quickly
overtaking tobacco as the leading preventable
cause of cancer.”
• “As many as 84,000 cancer diagnoses each year
are attributed to obesity, and overweight and
obesity are implicated in 15% to 20% of total
cancer-related mortality.”
J. Clin. Oncol. 32:3568, 2014. American Society of Clinical
Oncology Position Statement
Why is obesity associated with cancer?
Genes
Obesity
High blood insulin,
High blood sugar, inflammation
Diabetes
CVD
PCOS
Diet
AD
Obesity is a MARKER for a metabolic environment that
predisposes to chronic diseases including cancer
Cancer
Insulin (not obesity!) predicts
breast cancer
• Sub-cohort (n=2830) of WHI with fasting sera
• 497 incident cases of breast cancer over ~8 yr follow-up
Cancer Research 2014 75:270
Insulin is commonly elevated in
obesity; only insulin predicts BC
2.5
*
2
**
1.5
1
0.5
0
NWtLoIns
NWtHiIns
OvWtLoIns
OvWtHiIns
Adjusted for age, ethnicity, age at menarche and menopause, parity, 1st degree relative,
education, alcohol, physical activity, site, arm, study, assignment.
Insulin and cancer
• “Mitogenic”: causes cancer cells to divide
• Promotes glucose (blood sugar) uptake
– Cancer cells burn sugar as a fuel
• Damaged “engines” (mitochondri)a
• “Warburg effect” (aerobic glycolysis)
• ↑oxidative stress/inflammation/mutations
• Prevents burning fat as a fuel
– Normal products of fat burning inhibit cancer cell
metabolism
Insulin is secreted in response to
carbohydrate foods: sugar, starch, grain
A
140
Diet quality
affects blood
sugar and insulin
Glucose concentration (mg/dL)
STD
redCHO
120
*
*
100
80
15
60
90
120
180
240
Minutes after meal
Chandler-Laney and Gower 2014
Appetite, 80:236-41
B
150
*
Insulin concentration (uIU/ml)
High glycemic load (standard)
vs.
Low glycemic load
(reduced carbohydrate) diet
STD
redCHO
100
*
50
0
15
60
90
120
Minutes after meal
180
240
Carbohydrate quality associated
with breast density
• 5-yr longitudinal study; n=1668
• Tested hypothesis that total carbohydrate
(CHO), starches, sugars, or Glycemic Index,
Glycemic load would increase risk for high
mammographic breast density
• Breast density is a risk factor for cancer
Masala G et al. 2013 PLoS1 8:e70943
>Glycemic load = denser breast
Risk of dense breast
3
2.5
2
1.5
Risk of dense
breast
1
0.5
0
1
2
3
4
5
Dietary Glycemic Load
>GL, total CHO, and simple sugar intake = >breast density
Our Model
Insulin
Glucose
“Engines” of the cells;
Burn fuel, produce energy
(ATP)
Mitochondria
Genetic
Changes
Gene expression
↑Fermentation genes
↑Oncogenes
• Myc
CH3
• TOR
• NFKB
• CHOP
• Ras
↓DNA repair genes
Oxidative
Stress
Mutations
Genomic instability
Summary: Obesity-cancer
connection
• Obesity is a “marker” for high blood sugar
and high insulin
• Cancer cells need sugar and insulin
• Reducing sugar and insulin may reduce
cancer risk
• Reducing sugar and insulin could be used to
treat cancer
Treatment of cancer with a
carbohydrate restricted diet
• 10 cancer patients
– Different types of cancer (lung, ovarian, etc.)
– 9/10 with progressive disease
• 28-d diet intervention (26-28 d)
– “Ketogenic” diet
• PET scan for glucose uptake
• Serum insulin and ketones
Fine et al 2012 Nutrition 28:1028-1035
What is a ketogenic diet?
•
•
•
•
•
Carbohydrate <5% total energy
Healthy cells burn mainly fat
Fat burning by the liver produces ketones
Ketones are used as a fuel for the brain
Ketones inhibit cancer cell metabolism X
Higher ketone production = stable
disease and partial remission
Current (ongoing) cancer project
UAB CCC support
• Recurrent ovarian cancer
• 12 weeks of ketogenic diet (KD)
• Outcomes related to cancer, metabolic
health, quality of life
UAB Ketogenic diet prescription
Transition to fat oxidation and ketone production
• <20 g/d CHO
– 2 cup/day salad greens
– 1 cup/day non-starchy vegetables
• <100 g/d protein (poultry, fish, red meat, pork, eggs)
• Unlimited fat
– Olive oil, coconut oil, coconut milk, butter, meat fat
• Limited fat
– Cheese (4 oz/d)
– Olives (6/d); ½ avocado
– Mayonnaise and cream (2 Tb/d)
• This diet will “starve” cancer cells
Sample menu
Breakfast
Coffee
Cream
Three eggs
Bacon
Broccoli, cooked
Lunch
Greek salad
Olive oil
Dinner
Coconut oil
Kale, cooked
Salmon, cooked
Snack
Macadamia nuts
Total
Calories
Fat (g)
Carbohydrates (g)
Protein (g)
2
117
262
54
16
0
10.3
20.3
4.2
0.8
0.1
3.9
1.3
0.1
2.1
0.2
2.7
18.7
3.7
0.7
212
239
14.6
27
6.7
0
14
0
234
138
118
27.2
8.4
3.7
0
14.7
0
0
4.9
19.9
406
1,799
43.1
159.6
7.3
36.2
4.4
69.3
Preliminary data
• 9 patients enrolled
• 1 completed
• Patient 1:
– 22 lb weight loss
– Decrease in CA-125: 380-135 (-245 units/mL)
– Smaller tumor
• 20x17mm to 7x5 mm (one-tenth)
– Decrease in total cholesterol (-30 mg/dL)
– Elected to stay on the diet
Upcoming cancer project
Funded by the AICR
• Recurrent ovarian or endometrial cancer
– 60 patients (30 KD + 30 AICR diet)
• 12 weeks of diet therapy
• Outcomes:
Body composition by DXA
GE-Lunar Prodigy
Body composition by impedance
analysis
Blood work
•
•
•
•
•
Markers of inflammation
Blood sugar (glucose)
Insulin
IGF-1
Cholesterol and triglycerides
Quality of Life
Questionnaires:
• Hunger and satiety
• Fatigue and perceived energy
• Depression
Cancer outcomes
• Tumor size by CT scan
• RECIST criteria
• Blood cancer markers
• CA-125 marker
More information
Treatment
• Ketogenic diet
• 2-bromo-pyruvate
(blocks glucose metabolism)
• Hyperbaric oxygen
3-bromo-pyruvate to treat cancer
•
•
•
•
•
Hexokinase 2 (glucose→ G6P) inhibitor
The pivotal player in the Warburg effect
Complete eradication (19 mice); normal life span
1 case report
No toxicity