Insulin resistance: if what you are doing isn’t working…maybe its time for another perspective

Beth Anne Piper, MDSt Joseph’s Physicians Endocrine

INSULIN RESISITANCE

NAFLDDyslipidemiaHyperinsulinemiaHypertriglyceridemiaLow HDLIncreased small

dense LDL

HTNObesity Dementia Arterial DiseaseT2DM:

neuropathy

retinopathynephropathy

CardiovascularCerebrovascular

Genetic predisposition,High carb/high processed

food diet,Physical inactivity,

Carbohydrate intolerance leading to hyper-insulinemia,

Overstuffed dysfunctional fat cells

Hepatic insulin resistance with increased glucose

productionIncreased fat storage in liver

and other visceral organsDecreased HDL with

increased small dense LDLChronic Inflammation

CARBOHYDRATE INTOLERANCE

CVM indications and Lifestyle

INVOKANA is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM

CONTRAVE is a combination of naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant, indicated as an adjunct to a (reduced-calorie) diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:

30 kg/m2 or greater (obese) or

27 kg/m2 or greater (overweight) with at least one weight-related comorbidity

LIPITOR is an inhibitor of HMG-CoA reductase (statin) indicated as an adjunct therapy to diet to:

Reduce the risk of …. in patients without CHD, but with multiple risk factors .

Reduce the risk of … in patients with type 2 diabetes without CHD, but with multiple risk factors …

Reduce… in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy .

Otenabant Waterfall: weight loss responsethe range goes from exceptional weight loss to weight gain…

Population:

BMI 30 kg/m2 without co-morbidities

BMI 27 kg/m2 with co-morbidities

Why does a responder respond

and why does a non-responder

not respond.

Clinical trial weight gain:

will any weight loss solution

work for these subjects?

+15

+10

+5

0

-5

-10

-15

-20

-25

-30

-35

-40

-45

% B

od

y w

eig

ht

ch

an

ge w

ith

CB

1R

an

tag

on

ist

1 year data,

Otenabant 10/20 mg,

1200 subjects recruited

>=15%

~10%

>=10%

~20%

>=5

~44%

B. Corkey, Diabetes Care, 2012 Dec; 35(12)2432

Diabetes and Insulin Resistance: Have we got it all wrong?

What if we treat the cause,…rather than the effects?...

Diagnosis

Insulin Sensitivity Reduced 13 Years Before T2DM Diagnosis

British WhiteHall Study

Patients with Prediabetes: Intervening early to achieve

normoglycemia results in positive long-term clinical benefit

Diabetes cumulative incidence rates in those who attained normal glucose

regulation at least once vs. with those who consistently had prediabetes

56% lower RR

Of developing

diabetes

27 US Centers, 2761 participants Perreault et al. Lancet. 2012;379(9833):2243-51

Conclusion:

• Prediabetes is a high

risk state for diabetes,

especially in patients

who remain with

prediabetes despite

intensive lifestyle

intervention.

• Reversion to normal

glucose regulation

(NGR), even if transient,

is associated with a

significantly reduced risk

of future diabetes

independent of prior

treatment group.

DPP=Diabetes Prevention Program.

DPPOS=Diabetes Prevention Program Outcomes Study.

NGR=normal glucose regulation.

HungerOvereating

Increased Energy intake

Decreased energy

expenditure

Increased circulating

metabolic fuels(glucose,lipds)

Increased Fat storage(anabolic adiposetissue)

FatiguePhysical inactivity

Conventional View of Obesity and Insulin Resistance

HungerOvereating

Increased Energy intake

Decreased energy

expenditure

Decreased circulating

metabolic fuels(glucose,lipids)

Increased Fat storage(anabolic adiposetissue)

FatiguePhysical inactivity

Alternative View of Obesity and Insulin Resistance

Increased dietary Carb Increased insulin

Wang et al, 2011 Jun;22(6):197-203

The ‘soggy bathroom carpet’ model of insulin resistance

Stephen O’Rahilly, Banting Lecture, American Diabetes Assoication 2019

The ‘fridge freezer’ model of insulin resistance

INSULININSULIN

Excess fuel…Increasing

BMI, IR &

Insulin…

Insulin…is not a glucose lowering hormone…it is THE fat storing hormone

INSULIN

More Carbs

More Insulin

Physiologic adipocentric metabolism evolves to a

glucoentric fat storing metabolism+ =

Modified from Jason Fung MD, various sources

CarbohydrateVegan

Mediterranean

LC – Medit.

PaleoAtkins

SAD

CarnivoreLCHF/Keto

Protein (%) 10% 20% 30% 40%Protein (g/kg) ~0.8 ~1.6 ~2.4 ~3.2

DM50%

40%

30%

20%

10%

CHO(1800 cal)

225 gms

180 gms

135 gms

270 gms

< 50 gms

20-30 gms

60%

90 gms

SADStandardAmerican

Diet

Modified from J.Volek PhD; %nutrient is relative to DEE

LCHFLow carb

HealthyFat

Fat Fuel

Sugar Fuel

Metabolic Flexibility

`INSULIN

Fat Adaptation

ADA Eating Pattern Consensus Recommendations

• A variety of eating patterns are acceptable for the management of diabetes

• Key factors common among all patterns• Emphasize no starchy vegetables• Minimize added sugars and refined grains• Choose whole foods over highly processed foods

• Reducing overall carbohydrate intake has demonstrated the most evidence for improving glycemia and may be applied in a variety of eating patterns that meet individual needs and preference

• Low and very low carbohydrate eating plans are viable approaches for adults with T2DM who • Are not meeting glycemic targets• Wish to reduce antihyperglycemic medications

• Additional benefits of low carb include increased HDL cholesterol, reduced triglycerides and reduced diabetes medications

• Dietary goal often 20-50 gm nonfiber carbohydrate daily

Evert et al, Diabetes Care, 2019

>120Excess

<120High

< 90

< 60

< 30“Keto”

Navigating lower carbohydrates (gm/day)

• Essential macronutrients:• Fat• protein

• Daily carb need = zero

GOAL: Adipocentric fuel metabolism

rather than aGlucocentric fuel metabolism

Time restricted eating (TRE) and intermittent fasting (IF)

16/8

18/6

20/4

> 24 hrs

> 72 hrs

TRE -Time restricted eatingAll food eaten in a limited

time window

IF – Intermit. fastingie. 5:2 diet - 5 days regular meals or TRE with 2 days

fasting for 24hours

EF - Extended fasting for incremental health benefits, ie autophagy

24 hour clock: • Fasting window• Eating window

>120Excess

<120High

< 90

< 60

< 30“Keto”

16/8

18/6

20/4

> 24 hrs

> 72 hrs

Its all about flexibility and what works personally…

< 90

5:2

LCHF with or without

IF/TRE

>120Excess

<120High

< 90

< 60

< 30“Keto”

16/8

18/6

20/4

> 24 hrs

> 72 hrs

Its all about flexibility and what works personally…

18/6

< 30“Keto”

GOAL: Adipocentric fuel metabolism

rather than aGlucocentric fuel metabolism

` `

Feed6 hr

Feed8 hr

Fast Fast

1. Control carbohydrates: 0-30 gms/meal

2. Prioritize protein: 1-2 gms/kg daily

3. Fill with healthy unprocessed fat: depends on goals4. IF/TRE: find what works

LCHF with IF/TRE Practically

Modified: Unicity and others

CVM indications and Lifestyle

INVOKANA is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM

CONTRAVE is a combination of naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant, indicated as an adjunct to a (reduced-calorie) diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:

30 kg/m2 or greater (obese) or

27 kg/m2 or greater (overweight) with at least one weight-related comorbidity

LIPITOR is an inhibitor of HMG-CoA reductase (statin) indicated as an adjunct therapy to diet to:

Reduce the risk of …. in patients without CHD, but with multiple risk factors .

Reduce the risk of … in patients with type 2 diabetes without CHD, but with multiple risk factors …

Reduce… in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy .

CARBOHYDRATE INTOLERANCE:

How Should We Define Optimal Glucose Control?

Mean glucose

concentration in 32

noninsulin-using T2DM

patients with HbA1c

levels 7.0% − 7.9%

Monnier et al.

Diabetes Care.

2007;30(2):263–9.

CHO

Load

CHO

LoadCHO

Load

Blood sugar goal: maximize time within range

Insulin and Body WeightInsulin = dominant anabolic hormone

Regulates availability of all metabolic fuels- stimulates fat synthesis & deposition- inhibits fat release and oxidation

Increased action causes weight gainExcess insulin in all types of diabetes

Insulin secreting tumors

Decreased action causes weight lossUndertreatment of type 1 diabetes

Severe insulin receptor defectsOctreotide treatment of hyperinsulinemia

Insulin=

fat cellfertilizer

Metformin

Pioglitazone

Oral GLP1 agonist

SGLT2

DPPIV

SUs

GLP1 AgonistGLP1 AgonistGLP1 Agonist

Weight based basal insulin and/orbolus insulin

Excess basal and/or

bolus insulin

LCHF with/without IF/TRE

Ora

l med

icat

ion

s Injectab

le med

ication

s

Thank You