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