Type 2 Diabetes – Etiology and Reversibility
The twin cycle hypothesis of type 2 diabetes
Taylor R Dia Care 2013;36:1047-1055
Copyright © 2011 American Diabetes Association, Inc.
Two Phases of Diabetes
Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an
analysis from the Whitehall II study. Lancet 2009; 373: 2215–2221.
Margaret
140
Insulin Dosage (IU)
120
100
80
60
40
20
0
0
1
Number of Weeks on IDM
3
Insulin Dosage
•On 120 units Insulin/ day and 2 g metformin
•Diabetes for 27 years
•HbA1c went from 7.0% to 6.6%
•Lost 64 pounds and 7 inches
The Big Myths
1. Diabetes is a chronic progressive disease
2. Lowering blood sugars is the primary goal of
therapy
The Truth
1. Diabetes is a curable dietary disease
2. Diabetes is a disease of high insulin resistance
Treatment is directed to lowering resistance
Bariatric Surgery
• Long standing diabetic
– morbidly obese
– 500 units insulin/day
– Bariatric surgery
• Diabetes cured
Surgery cures diabetes
Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes
N Engl J Med 2012;366:1567-76 Schauer PR
Gastric Banding cures Diabetes
A: Fasting plasma glucose and weight change 2 years after randomization either to gastric
banding or to intensive medical therapy for weight loss and glucose control.
Adjustable gastric banding and conventional therapy for
type 2 diabetes JAMA 2008;299:316-232
Taylor R Dia Care 2013;36:1047-1055
Fasting
• Diabetes for 10 years
– Loses 50 pounds on diet
including fasting
– Diabetes cured
Treatment of Diabetes
Mellitus 1916
”That temporary periods of under-nutrition are
helpful in the treatment of diabetes will probably be
acknowledged by all after these two years of
experience with fasting” p676
”the practice, observed by many clinicians of the old
school, who advantageously fasted their diabetics
one day a week have given the cue to intermittent
fasting” p679
Can Med Assoc J. Aug 1916; 6(8): 673–684.
Elliot P Joslin
Food Rationing decreases
Diabetes
Fasting vs. Bariatric Surgery
8
7.3
1500
1478
1450
6
5
4
3
2
Diet
4
Diet +
Surgery
Daily Glycemia
Pre vs Post
Weight Loss (kg)
7
1400
1350
1300
1293
1250
1
0
1200
Rapid Improvement of Diabetes After Gastric Bypass Surgery: Is It the Diet or Surgery?
Diabetes Care. 2013 Mar 25, Lingvay I
http://www.ncbi.nlm.nih.gov/pubmed/23530013
Low Carb Diets
• 27 year old graduate student in physiology
– Recent diagnosis of diabetes HgBA1C 10.4%
– Started on 3 medications
– Very low carb diet (ketogenic)
– Weight loss 20 pounds
• HgBA1c 5.5% off all meds
• Diabetes cured
Cases you don’t hear
• Diabetes
– Started on high doses of insulin
– Now completely better and off all medications
• Diabetes
– Started on sulphonyurea
– Now much better and off all medications
• Diabetes NOT CURED
No Cure
Cure
Insulin
Drugs
Bariatric Surgery
Type 2
Diabetes
Low Fat
Diets
Fasting
Very Low Carb
Diets
Current Treatment Protocol
Current Research
Current Goal – normalized blood sugars
Learned Helplessness
• Fact: For most people, type 2 diabetes is a
progressive disease. Actually – this is a lie
• eventually oral medications may not be enough to
keep blood glucose levels normal. Using insulin
to get blood glucose levels to a healthy level is a
good thing, not a bad one. WTF?
http://www.diabetes.org/diabetes-basics/myths
Learned Helplessness
Over time most people with type 2 diabetes will
also need tablets and many will also need
insulin. It is important to note that this is just the
natural progression of the disease
http://www.diabetesaustralia.com.au/UnderstandingDiabetes/What-is-Diabetes/Type-2-Diabetes/
Big Lie #2
Lowering blood sugars is the goal of
treatment
Complications of Diabetes
Type 1 and 2 Diabetes
High Blood Sugars
(Oxidative Stress)
(Advance Glycation
End Products)
Complications of Diabetes
ACCORD
Hazard Ratio 1.22
The Action to Control Cardiovascular Risk in Diabetes Study
Group. N Engl J Med 2008;358:2545-2559
ADVANCE
Cumulative Incidences of Events,
According to Glucose-Control Strategy
The ADVANCE Collaborative Group. N Engl J Med
2008;358:2560-2572
Low A1C is NOT good for you
Oral Combination
Insulin
Adjusted Hazard Ratios by A1c
27,965 patients intensified from oral monotherapy
to combination therapy
Survival as a function of HbA1c in people with type 2 diabetes: a retrospective
cohort study
Lancet 2010; 375:481-89, Currie CJ
Type 2 Diabetes
Disease
Cause
Treatment
Symptom
Symptomatic
Treatment
Diabetes
Insulin Resistance
????
?????
High Blood
Sugars
Insulin
OHA
Infection
Bacteria
Antibiotic
Fever
Acetominophen
Does not alter
disease process
Diabetes is getting worse!
Metformin
Metformin
Glyburide
Insulin
Time
Disease – Insulin Resistance
Current target – Blood Sugar
More
Insulin
More
Insulin
Towards a Cure for Diabetes
???????
Insulin Resistance
Type 2 Diabetes
High Blood
Sugars
What causes type 2 Diabetes?
Start by studying the cure that we know
No Cure
Cure
Insulin
Drugs
Bariatric Surgery
Type 2
Diabetes
Low Fat
Diets
Fasting
Very Low Carb
Diets
Current Treatment Protocol
Current Research
Current Educational Goals
No Cure
Cure
Current treatment
Insulin
Drugs
Bariatric Surgery
Type 2
Diabetes
Fasting
How does Bariatrics work?
1. GI effects
2. Loss of Subcutaneous Fat Mass
3.Acute profound caloric reduction
COUNTERPOINT Study
• Hypothesis: Twin defects of beta cell failure
and insulin resistance can be reversed by
acute negative energy balance alone
• Early change in hepatic insulin sensitivity and
slower change in beta cell function
Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased
pancreas and liver triacylglycerol
Diabetologia 2011;54:2506-14
Counterpoint Study
BG 9.6 mmol/L to 5.9 in 7 days!
Taylor R Dia Care 2013;36:1047-1055
Decreased Liver Fat
Mean 30% decrease in liver fat
Mean weight loss 15kg
Taylor R Dia Care 2013;36:1047-1055
Copyright © 2011 American Diabetes Association, Inc.
Decrease in Pancreatic Fat
Taylor R Dia Care 2013;36:1047-1055
Copyright © 2011 American Diabetes Association, Inc.
Restoration of Beta Cell Function
Taylor R Dia Care 2013;36:1047-1055
Copyright © 2011 American Diabetes Association, Inc.
Steatosis
Insulin Resistance
Does Fatty Liver cause Insulin
Resistance?
Steatohepatitis precedes Diabetes
Diabetes
No Diabetes
18 months prior to diagnosis of DM
Long silent scream from the liver
Serial metabolic measurements and conversion to type 2 diabetes in the west of Scotland coronary prevention study: specific
elevations in alanine aminotransferase and triglycerides suggest hepatic fat accumulation as a potential contributing factor.
Diabetes 2007; 56: 984–991.
Hepatic Fat
Mean loss of liver volume 28.7%
80% by first 2 weeks
Preoperative weight loss with a very-low-energy diet Am J Cli Nutr 2006;84:304-311
Hepatic Fat
Preoperative weight loss with a very-low-energy diet
Am J Cli Nutr 2006;84:304-311
Improved Hepatic Insulin Sensitivity
Reversal of Nonalcoholic Hepatic Steatosis, Hepatic Insulin Resistance, and
Hyperglycemia by Moderate Weight Reduction in Patients With Type 2 Diabetes
Fatty Liver
How do you get fatty liver?
1. High Insulin Levels
2. Carbohydrate Excess
Eat Food
Store Sugar in Liver
Produce Fat in Liver
Increase Insulin
Burn Stored Sugar in Liver
Burn Fat in Liver
Decrease Insulin
Normal Insulin Action
1.
2.
3.
Inhibits Glycogenolysis
Inhibits Gluconeogenesis
Stimulates De Novo Lipogenesis
No Food
“Fasting”
What happens to excess carbs?
Oxidized for Energy
De Novo Lipogenesis
Exported as VLDL
Stored in Liver
How to get Fatty Liver
2% increase weight
27% increase liver fat
27% increase DNL
Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in
overweight humans
Am J Clin Nutr 2012;96:727– 34
How to Get Fatty Liver
1. High Insulin Levels
2. Excess carbohydrates
Correlation of Hepatic Fat and Insulin Dose
Hepatic Fat Content and Insulin Action on Free Fatty Acids and Glucose Metabolism Rather Than Insulin
Absorption Are Associated With Insulin Requirements During Insulin Therapy in Type 2 Diabetic Patients
Diabetes 49:749–758, 2000
Type 1 Diabetes
DM1
Control
Reduced intrahepatic fat content is associated with increased wholebody lipid oxidation in patients with type 1 diabetes
Diabetologia (2005) 48: 2615–2621
Liver Cells
Stored Sugar
Glycogen
High Insulin
Stored Fat
De Novo Lipogenesis Low Insulin
Insulin Resistance!
Stored Sugar
High Insulin
Low Insulin
Stored Fat
Twin Cycles – starting to
connect the dots
Fatty Liver
Excess
Carbs
Insulin
Hepatic
Insulin
Resistance
Twin Cycles
High
Sugars
Beta Cell
Dysfunction
Fatty Pancreas
Insulin
Hepatic
Steatosis
Hepatic
Insulin
Resistance
Insulin causes
type 2 Diabetes
Towards a Cure for Diabetes
Inciting factors
High insulin levels
Excess carbohydrates
Cure for diabetes
Decrease insulin
Decrease carbohydrates
–
–
–
–
Preferential release of fat from liver
Decrease insulin resistance
Removal of fat from pancreas
Reversal of beta cell dysfunction
Worsening
Diabetes
Cure
Insulin
Drugs
Low Fat
Diets
Increase insulin!
Stupid
Bariatric Surgery
Type 2
Diabetes
Fasting
Very Low Carb
Diets
Decrease Insulin!
Smart
Type 2 Diabetes is a disease of too much insulin
Can We Cure Type 2 Diabetes?
No Diabetes – no diabetic
nephropathy, no diabetic foot
ulcers, diabetic retinopathy,
reduced stroke, MI, cancers
No Drugs, No Surgery, No
Cost
It only requires knowledge
and the courage to challenge
conventional thought
The Cure for Diabetic Nephropathy
ACEI
Diabetes
Diabetic
Nephropathy
ARB
DRI
Time to get started…
Diabetes (type 2) is CURABLE in 90% of cases
www.intensivedietarymanagement.com
Richard
60
Insulin Dosage (IU)
50
40
30
20
10
0
0
1
2
3
Number of Weeks on IDM
Eating Day Insulin
•DM for 11 years prior to IDM
•Taking 56 IU of insulin
•Lost 67 pounds and 16 inches
4
6
Beverley
250
Insulin Dosage (IU)
200
150
100
50
0
0
1
2
Number of Weeks on IDM
Fasting Day Insulin
•DM for 7 years
•210 IU of insulin
•HbA1c went from 7.2% to 6.7%
•Lost 30 pounds and 4 inches
3
Michael
Number of OAH Meications Taken
3.5
3
2.5
2
1.5
1
0.5
0
0
1
4
7
Number of Weeks on IDM
10
Eating Day OAH
•DM for 13 years
•Was taking Diamicron, Onglyza, and Metformin
•HbA1c went from 8.6% to 5.7%
•Lost 4 pounds and 5 inches
16
Ranjit
80
70
Insulin Dosage (IU)
60
50
40
30
20
10
0
0
1
10
15
18
22
29
Number of Weeks on IDM
Eating Day Insulin
•DM for 43 years
•Was taking 75 IU of insulin
•HbA1c went from 7.0% to 6.1%
•Lost 37 pounds and 9 inches
31
33
45
Walter
80
70
Insulin Dosage (IU)
60
50
40
30
20
10
0
0
5
8
13
Number of Weeks on IDM
Eating Day Insulin
•DM for 30 years
•Was taking 70 IU of insulin
•HbA1c went from 6.1% to 5.5%
•Lost 7 pounds and 5 inches
18
19
•DM for 18 years
•Reduced from 4 medications to 1
•HgbA1c 7.0% to 6.6%
•53 kg weight loss 117 pounds
B
SAXA+DAPA
+MET
Adjusted Mean (95% CI) Change
From Baseline in Insulin
AUC,  U/mL
Baseline, U/mL
n
SAXA+MET
7278
147
7184
156
DAPA+MET
7634
145
1500
1000
500
0
_
500
_
1000
_
1500
_
2000
1782 U/mL
( 2520, _1044)
_
_
102 U/mL
(_841, 638)
_
C
Rosenstock J, Hansen L, Zee P, Li Y, Cook W, Hirshberg B, Iqbal N. Dual Add-On Therapy in Poorly Controlled Type 2 Diabetes on Metformin: Randomized
Double-Blind Trial of Saxagliptin+Dapagliflozin vs Saxagliptin and Dapagliflozin Alone. 127-LB, American Diabetes Association, 2014.
SAXA+DAPA
SAXA+MET
DAPA+MET
61