William T. Cefalu, M.D. Executive Director Professor of Diabetes Pennington Biomedical Research Center Louisiana State University How Your Gut Works For You
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Slide 1Professor of Diabetes Pennington Biomedical Research
Center
Louisiana State University
How Your Gut Works For You
Slack T et al. The geographic concentration of U.S adult obesity prevalence and associated social, economic, and environmental factors. Obesity 2013
Not Significant Low Obesity Region High Obesity Region
U.S. regional concentrations of county-level obesity prevalence
Epidemic is the result of a normal physiology ( genetic variability) in a pathoenvironment)
Gelfand EV et al, 2006; Vasudevan AR et al, 2005 * working definition
Obesity: “Epicenter” of Global CardioMetabolic Risk
• Diabetes prevalence is ≥11% • Includes 644 counties in 15 mostly southern states
Barker, LE, et al. Am J Prev Med. 2011;40(4):434-439.
DIABETES BELT
Pre-diabetes
Onset Diagnosis
Insulin secretion
Insulin “inefficiency
Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 Nathan DM. N Engl J Med. 2002;347:1342-1349
Post-Meal glucose
Fasting glucose
Pancreas function
Natural History of Type 2 Diabetes
PLASMA GLUCOSE Normal: 99 mg/dl or less Pre-Diabetes: 100-125 mg/dl) Diabetes > 126 mg/dl fasting); > 200 mg/dl )(PostPrandial)
Brain Cerebrovascular disease
• Transient ischemic attack
failure
Eye Retinopathy Cataracts Glaucoma
Where Diabetes Drugs Work !
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281– 303; Inzucchi SE. JAMA 2002;287:360–372; Porte D et al. Clin Invest Med. 1995;18:247–254.
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Glucose absorption
Not enough insulin secreted
Pancreas
Liver
gastric emptying
ileum effluent to colon
Successive dynamic conditions in the GI Tract
Me al
Data from Muller WA, et al. N Engl J Med 1970; 283:109-115
Insulin Deficiency and Glucagon Hypersecretion in Type 2 Diabetes
120
60
0
100
120
140
360
300
Nondiabetic Subjects (n=14) Type 2 Diabetes (n=12)
Defects in diabetes Insulin secretion delayed and reduced after a meal
Glucagon not suppressed after a meal
Hyperglycemia: fasting and postprandial
What are Incretin Hormones?
• Glucagon-like peptide-1 (GLP-1 is a major
incretins in humans • Both are peptide hormones (30 and 42 amino acids)
• Secreted from cells small intestinal mucosa • Released in response to meal ingestion • Responsible for the incretin effect
GLP-1 positive endocrine L-cells in human small intestine
Proteins from the gut that increase insulin secretion
Mean (SE); *P≤0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498
Plasma Glucose (mg/dL)
0 60 120 180 Time (min)
The Incretin Effect Insulin release enhanced when you eat a meal
Insulin Secretion
200
100
*
*
*
*
* *
*
Incretin Effect
Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876-913 Deacon CF et al. Diabetes. 1995;44:1126-1131
INCRETIN (GLP-1) Secretion and Metabolism
Mixed meal
INCRETIN actions
Stomach emptying
Food intake
1. Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190; 2. Nielsen LL, et al. Regul Pept. 2004;117:77-88
Continuously Infused Incretins Improves the Defects of Type 2 Diabetes
14
Exendin-4
Gly His
Val Ala
Ser Gly Pro Ala Pro Ser Pro H2N-
His Ala
Ala Ala
Glu
C-16 fatty acid (palmitoyl)
• Based on human GLP-1 (7-37) • 97% homologous with GLP-1 • Resistant to DPP-4 • Full agonist at the GLP-1 receptor
• Non-covalent binding to albumin, self- association, slow release from injection site gives prolonged survival time
– t½ 12 hr after sc injection
• From saliva of the Gila Monster • 53% homologous with GLP-1 • Insensitive to DPP-4 • Full agonist at the GLP-1 receptor • Metabolically stable – t½ 4-5 hr after sc injection
Liraglutide
Conserved Substituted Additional (relative to human GLP-1 7-37)
15
N = 217; Mean (- SE); P<0.0001 from baseline to 30 weeks and baseline to 3 years.
Incretins improve glucose in Type 2 diabetes
0 26 52 78 104 130 156 4
5
6
7
8
9
10
-1.0 ± 0.1%
46% 54%
Buse JB et al. Presented at ADA Annual Meeting 2007; Chicago IL. Abstract #0283-OR.
16
No diet and exercise regimen was provided. N = 217; Mean (- SE); P<0.0001 from baseline to 3 years and between 30 weeks and 3 years.
Incretin Drugs reduce weight in Type 2 diabetes
0 26 52 78 104 130 156 -7
-6
-5
-4
-3
-2
-1
0
1
-5.3 ± 0.4 kg
Buse JB et al. Presented at ADA Annual Meeting 2007; Chicago IL. Abstract #0283-OR.
Where Diabetes Drugs Work !
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281– 303; Inzucchi SE. JAMA 2002;287:360–372; Porte D et al. Clin Invest Med. 1995;18:247–254.
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Glucose absorption
Not enough insulin secreted
Pancreas
Liver
Gut
Incretins
The Microbiome represents over 9 million different genes compared to our paltry 20,000
The Human Microbiome Population of more than 100 trillion microorganisms that live in our gut, mouth,
skin and elsewhere in our bodies
Thousands of different species
on the skin alone
There are millions of microbes per square inch on your body
It is estimated that there are more microbes in your intestine than there are human cells in your body!
Gut Microbiome
Gut Microbiome Effects noted throughout the Body
Gut Bacteria Detoxify Mercury*
• Gut bacteria demethylate organic mercury forming insoluble free mercury which is excreted
• Mice fed methyl- mercury (toxic)
• Antibiotics added in test group
*Figure 5 in IR Rowland, Toxicol Pathol 1988 16:147-153.
(less toxic)
produced short chain fatty acids (SCFA) differed
significantly between stool of
cancer. Weir TL, Manter DK, Sheflin AM, Barnett BA, et al. (2013) Stool Microbiome and Metabolome Differences between Colorectal Cancer Patients and Healthy Adults. PLoS ONE 8(8): e70803. doi:10.1371/journal.pone.0070803 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070803
Our microbiome organisms secrete compounds that may determine our future health
Source: Krajmalnik-Brown R et al. Nutr Clin Pract 2012;27:201-214
Disruptions to the gut microbiome • Diet: eg High fat diet is associated with altering
bacteria number and type • Disease states: Mainly association studies (causal
direction unclear) for diabetes, some cancers, obesity, “irritable bowel”, others
• Antibiotics: Effects are immediate and potentially long lasting, especially important for children
• Bariatric Surgery: Rapid changes in food intake, metabolism (including reversal of T2diabetes), fat mass, inflammation, microbiome composition.
Gut Microbiome differs in individuals with and wtihout diabetes
The gut micro-biome
l Our gut hosts billions of microorganisms which contain more than 150 times the genetic diversity of the human genome
l The micro-biome performs digestive and metabolic functions, and “evolves” over our life course
l The micro-biome “talks” to the liver, the brain, organs controlling metabolism, inflammation and the immune system
l The micro-biome is affected by what we put into our mouths
…and finally,
Michael Pollan, “What to eat”
“Eat and Drink the Rainbow”
Slide Number 1
Slide Number 2
Slide Number 3
Slide Number 4
Slide Number 5
Complications of Diabetes
What are Incretin Hormones?
The Incretin Effect Insulin release enhanced when you eat a meal
Slide Number 12
Slide Number 13
Incretin Drugs reduce weight in Type 2 diabetes
Where Diabetes Drugs Work !
Slide Number 31
Slide Number 32
The gut micro-biome
Louisiana State University
How Your Gut Works For You
Slack T et al. The geographic concentration of U.S adult obesity prevalence and associated social, economic, and environmental factors. Obesity 2013
Not Significant Low Obesity Region High Obesity Region
U.S. regional concentrations of county-level obesity prevalence
Epidemic is the result of a normal physiology ( genetic variability) in a pathoenvironment)
Gelfand EV et al, 2006; Vasudevan AR et al, 2005 * working definition
Obesity: “Epicenter” of Global CardioMetabolic Risk
• Diabetes prevalence is ≥11% • Includes 644 counties in 15 mostly southern states
Barker, LE, et al. Am J Prev Med. 2011;40(4):434-439.
DIABETES BELT
Pre-diabetes
Onset Diagnosis
Insulin secretion
Insulin “inefficiency
Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 Nathan DM. N Engl J Med. 2002;347:1342-1349
Post-Meal glucose
Fasting glucose
Pancreas function
Natural History of Type 2 Diabetes
PLASMA GLUCOSE Normal: 99 mg/dl or less Pre-Diabetes: 100-125 mg/dl) Diabetes > 126 mg/dl fasting); > 200 mg/dl )(PostPrandial)
Brain Cerebrovascular disease
• Transient ischemic attack
failure
Eye Retinopathy Cataracts Glaucoma
Where Diabetes Drugs Work !
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281– 303; Inzucchi SE. JAMA 2002;287:360–372; Porte D et al. Clin Invest Med. 1995;18:247–254.
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Glucose absorption
Not enough insulin secreted
Pancreas
Liver
gastric emptying
ileum effluent to colon
Successive dynamic conditions in the GI Tract
Me al
Data from Muller WA, et al. N Engl J Med 1970; 283:109-115
Insulin Deficiency and Glucagon Hypersecretion in Type 2 Diabetes
120
60
0
100
120
140
360
300
Nondiabetic Subjects (n=14) Type 2 Diabetes (n=12)
Defects in diabetes Insulin secretion delayed and reduced after a meal
Glucagon not suppressed after a meal
Hyperglycemia: fasting and postprandial
What are Incretin Hormones?
• Glucagon-like peptide-1 (GLP-1 is a major
incretins in humans • Both are peptide hormones (30 and 42 amino acids)
• Secreted from cells small intestinal mucosa • Released in response to meal ingestion • Responsible for the incretin effect
GLP-1 positive endocrine L-cells in human small intestine
Proteins from the gut that increase insulin secretion
Mean (SE); *P≤0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498
Plasma Glucose (mg/dL)
0 60 120 180 Time (min)
The Incretin Effect Insulin release enhanced when you eat a meal
Insulin Secretion
200
100
*
*
*
*
* *
*
Incretin Effect
Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876-913 Deacon CF et al. Diabetes. 1995;44:1126-1131
INCRETIN (GLP-1) Secretion and Metabolism
Mixed meal
INCRETIN actions
Stomach emptying
Food intake
1. Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190; 2. Nielsen LL, et al. Regul Pept. 2004;117:77-88
Continuously Infused Incretins Improves the Defects of Type 2 Diabetes
14
Exendin-4
Gly His
Val Ala
Ser Gly Pro Ala Pro Ser Pro H2N-
His Ala
Ala Ala
Glu
C-16 fatty acid (palmitoyl)
• Based on human GLP-1 (7-37) • 97% homologous with GLP-1 • Resistant to DPP-4 • Full agonist at the GLP-1 receptor
• Non-covalent binding to albumin, self- association, slow release from injection site gives prolonged survival time
– t½ 12 hr after sc injection
• From saliva of the Gila Monster • 53% homologous with GLP-1 • Insensitive to DPP-4 • Full agonist at the GLP-1 receptor • Metabolically stable – t½ 4-5 hr after sc injection
Liraglutide
Conserved Substituted Additional (relative to human GLP-1 7-37)
15
N = 217; Mean (- SE); P<0.0001 from baseline to 30 weeks and baseline to 3 years.
Incretins improve glucose in Type 2 diabetes
0 26 52 78 104 130 156 4
5
6
7
8
9
10
-1.0 ± 0.1%
46% 54%
Buse JB et al. Presented at ADA Annual Meeting 2007; Chicago IL. Abstract #0283-OR.
16
No diet and exercise regimen was provided. N = 217; Mean (- SE); P<0.0001 from baseline to 3 years and between 30 weeks and 3 years.
Incretin Drugs reduce weight in Type 2 diabetes
0 26 52 78 104 130 156 -7
-6
-5
-4
-3
-2
-1
0
1
-5.3 ± 0.4 kg
Buse JB et al. Presented at ADA Annual Meeting 2007; Chicago IL. Abstract #0283-OR.
Where Diabetes Drugs Work !
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281– 303; Inzucchi SE. JAMA 2002;287:360–372; Porte D et al. Clin Invest Med. 1995;18:247–254.
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Glucose absorption
Not enough insulin secreted
Pancreas
Liver
Gut
Incretins
The Microbiome represents over 9 million different genes compared to our paltry 20,000
The Human Microbiome Population of more than 100 trillion microorganisms that live in our gut, mouth,
skin and elsewhere in our bodies
Thousands of different species
on the skin alone
There are millions of microbes per square inch on your body
It is estimated that there are more microbes in your intestine than there are human cells in your body!
Gut Microbiome
Gut Microbiome Effects noted throughout the Body
Gut Bacteria Detoxify Mercury*
• Gut bacteria demethylate organic mercury forming insoluble free mercury which is excreted
• Mice fed methyl- mercury (toxic)
• Antibiotics added in test group
*Figure 5 in IR Rowland, Toxicol Pathol 1988 16:147-153.
(less toxic)
produced short chain fatty acids (SCFA) differed
significantly between stool of
cancer. Weir TL, Manter DK, Sheflin AM, Barnett BA, et al. (2013) Stool Microbiome and Metabolome Differences between Colorectal Cancer Patients and Healthy Adults. PLoS ONE 8(8): e70803. doi:10.1371/journal.pone.0070803 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070803
Our microbiome organisms secrete compounds that may determine our future health
Source: Krajmalnik-Brown R et al. Nutr Clin Pract 2012;27:201-214
Disruptions to the gut microbiome • Diet: eg High fat diet is associated with altering
bacteria number and type • Disease states: Mainly association studies (causal
direction unclear) for diabetes, some cancers, obesity, “irritable bowel”, others
• Antibiotics: Effects are immediate and potentially long lasting, especially important for children
• Bariatric Surgery: Rapid changes in food intake, metabolism (including reversal of T2diabetes), fat mass, inflammation, microbiome composition.
Gut Microbiome differs in individuals with and wtihout diabetes
The gut micro-biome
l Our gut hosts billions of microorganisms which contain more than 150 times the genetic diversity of the human genome
l The micro-biome performs digestive and metabolic functions, and “evolves” over our life course
l The micro-biome “talks” to the liver, the brain, organs controlling metabolism, inflammation and the immune system
l The micro-biome is affected by what we put into our mouths
…and finally,
Michael Pollan, “What to eat”
“Eat and Drink the Rainbow”
Slide Number 1
Slide Number 2
Slide Number 3
Slide Number 4
Slide Number 5
Complications of Diabetes
What are Incretin Hormones?
The Incretin Effect Insulin release enhanced when you eat a meal
Slide Number 12
Slide Number 13
Incretin Drugs reduce weight in Type 2 diabetes
Where Diabetes Drugs Work !
Slide Number 31
Slide Number 32
The gut micro-biome
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