Jane Shearer, PhD

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Coffee, Caffeine and Insulin Resistance
Jane Shearer, PhD Faculty of Medicine and
Kinesiology, Department of Biochemistry and
Molecular Biology. University of Calgary, AB.
CANADA jshearer_at_ucalgary.ca
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(No Transcript)
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Dietary Caffeine

• Most widely consumed drug in the world.
• 87 of individuals consume caffeine.
• Average intake 193mg/day for adults or 340ml of
  brewed coffee/day.
• Children Soft drink consumption has increased by
  48 from 1977 to 1998.

Frary CD. J. Am Diet Assoc. 2005
Jan105(1)110-3.
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Caffeine
5mg/kg

• Half life 3-5hr, metabolized by P450.
• At concentrations found in the diet, antagonism
  of adenosine receptors.

?
Fredholm. Pharmacol Toxicol 7693, 1998
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Physiology of Caffeine
THERMOGENESIS
? DIURESIS

• FOOD INTAKE

? GLUCOSE

• GLYCOGEN SYNTHESIS

MOOD
GUT MOTILITY
? CATECHOLAMINES
? HEART RATE
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Acute Caffeine Ingestion
Whole Body Insulin Response to Caffeine
1000
Lean - Placebo
Lean - Caffeine
800
Obese - Placebo
Obese - Caffeine
Insulin (pmol/L)
600
400
Insulin Insensitivity
200
0
0
15
30
60
90
120
150
180
-60
Time (min)
T. Graham, University of Guelph
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Acute Caffeine Ingestion
Whole Body Insulin Response to Caffeine
1000
800
600
Insulin (pmol/L)
400
Insulin Insensitivity
200
0
0
15
30
60
90
120
150
180
-60
Time (min)
T. Graham, University of Guelph
T. Graham, University of Guelph
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Acute Caffeine Ingestion
Whole Body Glucose Response to Caffeine
? Insulin ? Glucose ? Glucose Disposal ? Insulin
Sensitivity
800
600
Insulin (pmol/L)
400
Insulin Insensitivity
200
0
0
15
30
60
90
120
150
180
-60
Time (min)
T. Graham, University of Guelph
T. Graham, University of Guelph
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Insulin Sensitivity Index
8
6
CAFFEINE
4
2
0
0
2
4
6
8
10
12
PLACEBO
Index calculation reference Matsuda De
Fronzo. Diabetes Care 221462, 1999.
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Weight Loss Thermogenesis

• Does caffeine/coffee ingestion alter body
  composition?
• 100kcal/day 10lbs/year?
• Prospective Study 58,157 12yr follow-up.
  Caffeine intake (2-4 y), weight, food frequency.
• Caffeine Weight- Men
• -0.43 kg, Women -0.41 kg

Lopez-Garcia. Am. J. Clin. Nutr. 2006, 83674-80.
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Dietary Supplements

• 15.2 dietary weight loss supplement (21 ?,
  10?)
• 74 caffeine or other stimulant, Average intake
  600mg diet. Expenditure 100kcal/d

• DEPENDENCY headaches, irritability, fatigue
• DIET CAFFEINE?

Blanck HM. J. Am. Diet. Assoc. 107(3), 2007
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Caffeine Weight Loss

• Is there an additive effect?
• 90 obese subjects (76 female/14male), BMI 35,
  Age 36yr.
• 1000kcal/day diet for 24wk with i) placebo ii)
  caffeine (600mg/d).
• No difference in weight loss over 24wk.

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Placebo
Caffeine
20
15
Weight Loss (kg)
10
5
0
12
24
Duration of Treatment (wk)
Astrup, A. Int J. Obesity. 1992, 16269-277
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Habituation/Tolerance
Acquired change in responsiveness to a drug
following repeated exposure
Near complete tolerance of humoral and
hemodynamic variables within 1-4d of
consumption!
Response
Caffeine Dose
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Caffeine Habituation
250mg/meal
300mg caffeine2 per day http//www.muscletech.com
Robertson, D. J. Clin. Invest. 671111-1117, 1981
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Habituation Glucose Intolerance?

350
50000

45000
300
40000
250
35000
30000
200
AUC Glucose (mM/ml/2hr)
AUC Insulin (uIU/ml/2hr)
25000
150
20000
15000
100
10000
50
5000
0
0
PLA
Day1
Day7
Day14
CAFFEINE
Dekker, M.J. British J Clin Nutr. In Press, 2007
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Form of Caffeine

Caffeine
Coffee
Coffee contains hundreds of other biologically
active compounds
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Coffee

• Coffee represents the major source of caffeine in
  the diet
• 54 of adults drink coffee daily
• 25 of adults drink coffee occasionally
• Among regular coffee drinkers, average intake is
  3.1 cups/day
• Overall population4.4 kg/year, 1.9cups/day men,
  1.4 cups per day women

National Coffee Association, 1999
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Coffee Nutrients
Adult Male
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Controversy
Acute Caffeine Insulin insensitivity, worse in
obese type 2 diabetes
Chronic Coffee Beneficial for type 2 diabetes,
liver function, cancer
To Refill or Not to Refill?
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Coffee Consumption and Diabetes Risk
Risk Reduction for Type 2 Diabetes
JAMA. 2004 Mar 10291(10)1213-9 Ann Intern Med.
2004 Jan 6140(1)1-8 J Intern Med. 2004
Jan255(1)89-95 Diabetologia. 2004
Dec47(12)2145-51
Cups of Coffee Consumed per Day
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Acute Coffee Ingestion

• Administered 4.45mg/kg of caffeine in either
  alkaloid or coffee form followed by an OGTT.

a
40000
350
35000
300
b,c
b
30000
250
AUC Glucose (mmol?2h)
25000
200
20000
AUC Insulin (pmol?2h)
c
150
15000
100
10000
50
5000
0
0
Placebo
Caffeine
Coffee
Decaff
Battram, D.S J.Nutr.136 1276-1280, 2006.
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Constituents of Decaffeinated Coffee
Many unique compounds produced in the roasting
process.
( of dry weight) Chlorogenic
acid 5-CQA 0.757 4-caffeoylquinic
acid 4-CQA 0.528 3-caffeoylquinic
acid 3-CQA 0.456 3-caffeoyl-1,5-quin
ide 3-CQL 0.144 5-feruloyl-1,5-quini
c acid 5-FQA 0.137 4-feruloylquinic
acid 4-FQA 0.091 4-caffeoyl-1,5-quin
ide 4-CQL 0.086 3-feruloylquinic
acid 3-FQA 0.085 3-feruloyl-1,5-quin
ide 3-FQL 0.041 3,4-dicaffeoylquinic
acid 3,4-diCQA 0.029 4-feruloyl-1,5-qu
inide 4-FQL 0.018 4,5-dicaffeoylquin
ic acid 4,5-diCQA 0.016 3,5-dicaffeoylq
uinic acid 3,5-diCQA
0.013 4-coumaroyl-1,5-quinide 4-CoQL
0.004 3,4-dicaffeoyl-1,5-quinide 3,4-diCQL
0.003 3-coumaroyl-1,5-quinide 3-CoQL
0.001
Farah, A. J Agric Food Chem. 2006 Jan
2554(2)374-81
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Roasted Coffee ENHANCES Insulin Action
- Liver infusion of a concentrated coffee extract
(DIFEQ) - No caffeine present - DIFEQ increased
the amount of glucose utilized by the body.
Shearer J, J Nutr. Nov133(11) 3529-32, 2003.
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Whole Body Glucose Disposal
NO CHANGE
Shearer J, J Nutr. Nov133(11) 3529-32, 2003.
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Coffee Insulin Sensitivity

• Male, Sprague-Dawley Rats, Fed Water,
  Caffeinated
• Coffee or Decaffeinated Coffee for 4 wk.
• Weight, insulin sensitivity, whole body and
  tissue
• specific glucose disposal.

360
330
300
Weight Gain (g)
270


Decaf
240


CaffC
210

Water


180
0
5
10
15
20
25
30
Days
Shearer, J. CJPP862 In Press, 2007.
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Coffee Insulin Sensitivity
Glucose Infusion Rate (mg/kg/min)
Skeletal Muscle Glucose Metabolic Index (µmol100
g-1min-1)


2.0
10
9
8
1.5
7
6

1.0
5
4
3
0.5
2
1
0
0.0
Caff Coffee
Decaf Coffee
Water
Water
Caff Coffee
Decaf Coffee
Shearer, J. CJPP862 In Press, 2007.
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Antioxidants
Antioxidants

• Due to rates of consumption
• Oxidative stress is a common pathogenic factor
  leading to insulin resistance
• Consequence of hyperglycemia.
• Cause of microvascular and macrovasular
  complications in T2D

Svilaas, A. J. Nutr 134 562-567, 2004
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Antioxidants
Gut Flora

• Mineral absorption, ?inflammation,
• prevent growth of harmful bacteria.
• Coffee contains natural
• antimicrobial agents against
• enterobacteria.
• Caffeine found in coffee
• antimicrobial against Salmonella
• enterica.
• Major causative agent of dental
• caries in humans is inhibited by
• coffee?

J Agric Food Chem. 2006 Nov 1554(23)8738-43
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Glucose Absorption

• Chlorogenic acids inhibit Na
• dependent D-glucose uptake in
• isolated intestinal brush border
• membranes.

• Inhibition is dose dependent, up to 80 decline
  in uptake.
• Lower glucose uptake, lower glucose absorption,
  lower insulin response with coffee?

Welsch CA. J. Nutr. 1191698-1704, 1989.
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Gut Peptides

• Gut expresses peptide hormones in endocrine
  cells.
• Released after meal ingestion and stimulate
  insulin secretion.
• Glucose-dependent insulinotropic polypeptide
  (GIP) and glucagon-like peptide-1 (GLP-1)

Johnston, KL. Am. J. Clin. Nutr. 78(4) 728-33,
2003.
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Coffee Consumption and Liver Function
Ruhl et al. Gastroenterology, 12824-32. 2005.
(X) represent amount of caffeine consumed per
day. NHANES, n5944

Marker of Liver Dysfunction or Injury

- Liver dysfunction, cirrhosis and cancer are
reduced with coffee consumption. - Liver
cancer 547.2/100,000 no coffee vs. 214.6/100 000
in those who consume coffee (Shimazu, T. Int J
Cancer, 2005).
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Hepatic Glucose Management
COFEEE Chlorogenic acid inhibits
glucose-6-phosphatase (G-6-P) activity?
CAFFEINE Increases net hepatic glucose uptake.
Pencek RR , J. Nutr. 2004 Nov 134(11)3042-6.
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Net Hepatic Glucose Fractional Extraction
Caffeine Alters Liver Glucose Dynamics
0.12

0.08
0.04
0.00
Saline
Caffeine
Net Hepatic Lactate Output

• Caffeine infusion increased hepatic glucose
  uptake but not glycogen synthesis
• Additional glucose taken up by the liver is
  partially converted to lactate

1.6
1.2
mgkg-1min-1
0.8
0.4
0.0
Saline
Caffeine
Pencek RR , J. Nutr. 2004 Nov 134(11)3042-6.
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Summary

• Acute caffeine ingestion Insulin insensitivity
  for 3-5h, worse in obese.
• Chronic caffeine is ineffective for weight loss
  due to rapid habituation.
• Coffee and not caffeine mediates its beneficial
  effects on the development of type 2 diabetes.
• Chronic coffee consumption interacts with the
  body to reduce disease incidence. Antioxidant
  properties?
• Answer DECAFF!

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Acknowledgements

• Dr. Terry Graham, University of Guelph
• Dr. David Wasserman, Vanderbilt University
• Dr. Adriana Farah, University of Rio de Janeiro
• Elizabeth Sellars, University of Arkansas
• Shearer Laboratory, University of Calgary
• National Coffee Association