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

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.

•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

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Margaret

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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 disease2. 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

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;299:316-232Taylor R Dia Care 2013;36:1047-1055

Gastric Banding cures Diabetes

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” p679Can Med Assoc J. Aug 1916; 6(8): 673–684.

Elliot P Joslin

Food Rationing decreases Diabetes

Fasting vs. Bariatric Surgery

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

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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

Type 2Diabetes

CureNo Cure

Bariatric SurgeryInsulin

Drugs

Low Fat Diets

Fasting

Very Low CarbDiets

Current Treatment ProtocolCurrent ResearchCurrent Goal – normalized blood sugars

Learned Helplessness

• Fact: For most people, type 2 diabetes is a progressive disease.

• 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.

http://www.diabetes.org/diabetes-basics/myths

Actually – this is a lie

WTF?

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/Understanding-Diabetes/What-is-Diabetes/Type-2-Diabetes/

Big Lie #2

Lowering blood sugars is the goal of treatment

Complications of DiabetesType 1 and 2 Diabetes

High Blood Sugars (Oxidative Stress) (Advance Glycation End Products)

Complications of Diabetes

The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

ACCORD

Hazard Ratio 1.22

Cumulative Incidences of Events, According to Glucose-Control Strategy

The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

ADVANCE

Low A1C is NOT good for you

27,965 patients intensified from oral monotherapy to combination therapySurvival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study

Lancet 2010; 375:481-89, Currie CJ

Oral CombinationInsulin

Adjusted Hazard Ratios by A1c

Type 2 Diabetes

Disease Cause Treatment Symptom Symptomatic Treatment

DiabetesInsulin Resistance

???? ????? High Blood Sugars

InsulinOHA

Infection Bacteria Antibiotic Fever Acetominophen

Does not alter disease process

Diabetes is getting worse!

Disease – Insulin ResistanceCurrent target – Blood Sugar

Metformin MetforminGlyburide Insulin More

InsulinMoreInsulin

Time

Towards a Cure for Diabetes

??????? Insulin ResistanceType 2 Diabetes

High BloodSugars

What causes type 2 Diabetes?Start by studying the cure that we know

Type 2Diabetes

CureNo Cure


Drugs

Low Fat Diets

Fasting

Very Low CarbDiets

Current Treatment ProtocolCurrent ResearchCurrent Educational Goals

Type 2Diabetes

CureNo Cure


Drugs

How does Bariatrics work?1. GI effects2. Loss of Subcutaneous Fat Mass3.Acute profound caloric reduction

Current treatment

Fasting

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 triacylglycerolDiabetologia 2011;54:2506-14


Counterpoint Study

BG 9.6 mmol/L to 5.9 in 7 days!



Decreased Liver Fat

Mean 30% decrease in liver fatMean weight loss 15kg



Decrease in Pancreatic Fat



Restoration of Beta Cell Function

Steatosis Insulin Resistance

Does Fatty Liver cause Insulin Resistance?

Steatohepatitis precedes Diabetes

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.

18 months prior to diagnosis of DMLong silent scream from the liver

Diabetes

No Diabetes

Hepatic Fat

Preoperative weight loss with a very-low-energy diet Am J Cli Nutr 2006;84:304-311

Mean loss of liver volume 28.7%80% by first 2 weeks

Hepatic Fat

Preoperative weight loss with a very-low-energy dietAm 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 Levels2. Carbohydrate Excess

Eat FoodStore Sugar in LiverProduce Fat in Liver

Increase Insulin

No Food“Fasting”

Burn Stored Sugar in LiverBurn Fat in Liver Decrease Insulin

Normal Insulin Action1. Inhibits Glycogenolysis2. Inhibits Gluconeogenesis3. Stimulates De Novo Lipogenesis

De Novo Lipogenesis

Oxidized for Energy

Exported as VLDL

Stored in Liver

What happens to excess carbs?

How to get Fatty Liver

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

2% increase weight27% increase liver fat27% increase DNL

How to Get Fatty Liver

1. High Insulin Levels2. 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

Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes Diabetologia (2005) 48: 2615–2621

DM1 Control

Liver Cells

Stored SugarGlycogen

Stored FatDe Novo Lipogenesis

High Insulin

Low Insulin

Food/Energy

Insulin Resistance!

Stored Sugar

Stored Fat

High Insulin

Low Insulin

Food/Energy

Twin Cycles – starting to connect the dots

Insulin

Fatty Liver

HepaticInsulinResistance

ExcessCarbs

Twin Cycles

Insulin HepaticSteatosis

HepaticInsulinResistance

Fatty Pancreas

Beta CellDysfunction

High Sugars

Insulin causes type 2 Diabetes

Towards a Cure for Diabetes

Inciting factors High insulin levelsExcess carbohydrates

Cure for diabetes Decrease insulinDecrease carbohydrates– Preferential release of fat from liver– Decrease insulin resistance– Removal of fat from pancreas– Reversal of beta cell dysfunction

Reversing the Twin Cycles!

Type 2Diabetes

CureWorsening Diabetes


Drugs

Low Fat Diets

Fasting

Very Low CarbDiets

Increase insulin! Decrease Insulin!

Type 2 Diabetes is a disease of too much insulin

Stupid Smart

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

DiabetesDiabeticNephropathy

ACEI

ARB

DRI

Time to get started…

Diabetes (type 2) is CURABLE in 90% of caseswww.intensivedietarymanagement.com

•DM for 11 years prior to IDM•Taking 56 IU of insulin•Lost 67 pounds and 16 inches

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•DM for 7 years•210 IU of insulin•HbA1c went from 7.2% to 6.7%•Lost 30 pounds and 4 inches

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•DM for 13 years•Was taking Diamicron, Onglyza, and Metformin•HbA1c went from 8.6% to 5.7%•Lost 4 pounds and 5 inches

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•DM for 43 years•Was taking 75 IU of insulin•HbA1c went from 7.0% to 6.1%•Lost 37 pounds and 9 inches

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•DM for 30 years•Was taking 70 IU of insulin•HbA1c went from 6.1% to 5.5%•Lost 7 pounds and 5 inches

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•DM for 18 years•Reduced from 4 medications to 1•HgbA1c 7.0% to 6.6%•53 kg weight loss 117 pounds

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SAXA+MET DAPA+MET

Baseline, mg/dL 41033 43248 41666 n 156 150 145

_6631 mg/dL(_8285, _4977)

_1693 mg/dL (_3355, _30)

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SAXA+MET DAPA+MET

Baseline, U/mL 7184 7278 7634 n 156 147 145

_1782 U/mL(_2520, _1044)

_102 U/mL

(_841, 638)

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Baseline, pg/mL 21339 21910 22346 n 155 144 146

127 pg/mL(_1176, 1429)

_2635 pg/mL

(_3931, _1339)

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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.

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Documents

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