Reversibility of Type 2 Diabetes with Plant Diet Nutrition

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Reversibility of Type 2 Diabeteswith Plant Diet Nutrition

John Kelly, MD, MPH, LM Specialist

Lead Faculty, ACLM ‘Reversing Type 2 Diabetes and Insulin

Resistance with Lifestyle Medicine’ Course

Co-author, Type 2 Diabetes Remission and Lifestyle Medicine: A

Position Statement From the American College of Lifestyle

Medicine

Adjunct Faculty, Preventive Medicine, Loma Linda University

Founding President, American College of Lifestyle Medicine

Disclosures

•No Conflicts of Interest or commercial interests

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Learning Objectives1. Discuss the definition and criteria for type 2 diabetes remission as

published in the ADA Diabetes Care Journal

2. Examine the evidence-based research that establishes that type 2 diabetes and insulin resistance are reversible

3. Summarize the ACLM Position Statement on Type 2 Diabetes Remission and Lifestyle Medicine

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Just imagine…

•A diet that could induce b-cell neogenesis

•A way of eating that could restore b-cell function in the pancreas without stem cells and the risks they pose…

•Well, you do not have to imagine it!

• It has been done twice in a mouse model of diabetes!

•Using an Intermittent Fasting-Mimicking Diet…

Wei, S., Han, R., Zhao, J. et al. Intermittent administration of a fasting-mimicking diet intervenes in diabetes progression, restores β cells and reconstructs gut microbiota in mice. Nutr Metab(Lond) 15, 80 (2018).

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Just imagine…

• In mice a 4-day fasting-mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing b-cells resembling that observed during pancreatic development

•FMD cycles restore insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models

Cheng et al. Fasting-Mimicking Diet Promotes Ngn3-Driven b-Cell Regeneration to Reverse

Diabetes. Cell. 2017;168:775-788.

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Just imagine…

• In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production.

•The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition.


Diabetes. Cell. 2017;168:775-788.

Authors conclusion…

“These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models.”


Diabetes. Cell. 2017;168:775-788.

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Discuss the definition and criteria for type 2 diabetes remission as published in the ADA Diabetes Care Journal

Progressive History of Diabetes Remission• For decades the official ADA position stated

that diabetes was an “incurable, progressive” condition, based upon UKPDS findings [1]

• With time multiple lines of evidence indicated that lifestyle change, with subsequent weight loss, could reverse the disease [2]

• A 2009 Consensus group proposed a definition with criteria for remission/reversal [3]

1. UK Prospective Diabetes Study Group. UKPDS 38. BMJ 1998 Sep 12;317(7160):703-13.

2. Trapp KB, Barnard ND. Curr Diab Rep. 2010;10:152-58. Lim EL, et al. Reversal of type 2 diabetes: normalization of beta cell function in

association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011 Oct;54(10):2506-14. Lean MEJ, et al. Primary care-led

weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 2018 Feb;391:541-551.

3. Buse JB, et al. How do we define cure of diabetes? Diabetes Care 2009 Nov;32(11):2133-35.

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Criteria for DM Remission/Reversal• 2009 consensus statement definition and

clinical criteria for reversal/remission

Buse JB, et al. How do we define cure of diabetes? Diabetes Care 2009 Nov;32(11):2133-35.

Level of Remission .

Measure Partial Complete Prolonged

HbA1c <6.5 <5.7 <5.7

mmol/mol <39 <48 <48

Time ≥ 1 year ≥ 1 year ≥ 5 years

Therapy No active pharmacology or procedures

Criteria for DM Remission/Reversal• 2009 consensus statement definition and

clinical criteria for reversal/remission

Buse JB, et al. How do we define cure of diabetes? Diabetes Care 2009 Nov;32(11):2133-35.

Level of Remission .

Measure Partial Complete Prolonged

HbA1c % <6.5 <5.7 <5.7

mmol/mol <48 <39 <39

Time ≥ 1 year ≥ 1 year ≥ 5 years

Therapy No active pharmacology or procedures

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Criteria for DM Remission/Reversal• Association of British Clinical

Diabetologists and the Primary Care Diabetes Society published a different definition and criteria1. Glycemia below the threshold currently for

T2D diagnosis (HbA1c <48 mmol/mol, or fasting glucose <7.0 mmol/L, <126 mg/dL),

2. For ≥ 6 months,

3. With no glucose-lowering therapies.

Nagi D, Hambling C, Taylor R. Remission of type 2 diabetes: a position statement from the Association of

British Clinical Diabetologists (ABCD) and the Primary Care Diabetes Society (PCDS). Br J Diabetes.

2019;19:73-76.

Examine the evidence-based research that establishes that type 2 diabetes and insulin resistance are reversible

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Evidence of Remission: More Dramatic Changes Required •UKPDS actually proved T2DM is progressive and irreversible with no lifestyle changes

•Gastric bypass has ~60-85% remission rate by ‘forcing’ reduction of caloric intake (starvation also puts T2DM in remission)

•Counterpoint very-low calorie diet (VLCD) reversed liver and pancreas triacylglycerol in 4-8 weeks

Mazur A. Why were "starvation diets" promoted for diabetes in the pre-insulin period? Nutr J. 2011;10;23.

Khorgami Z, Shoar S, Saber AA, et al. Outcomes of Bariatric Surgery Versus Medical Management for Type 2 Diabetes

Mellitus: a Meta-Analysis of Randomized Controlled Trials. Obes Surg. 2018 Nov 6.

Lim EL, et al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and

liver triacylglycerol. Diabetologia 2011 June 9.

Dramatic Changes Required: Counterpoint Study



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Dramatic Changes Required: Counterpoint Study



LookAHEAD Diabetes Trial•Remission rate of type 2 diabetes with lifestyle change unclear.

•Measured association of long-term intensive weight-loss intervention with remission of type 2 diabetes to prediabetes or normoglycemia.

•Observational analysis of 4-year randomized controlled trial (Aug 2001 - April 2008) comparing an intensive lifestyle intervention (ILI) with diabetes support & education controls (DSE) in 4,503 US adults with BMI (body mass index) 25 or higher and type 2 diabetes.

Gregg EW, et al. Association of Intensive Lifestyle Intervention with Remission of Type 2 Diabetes. JAMA

2012;308(23):2489-96.

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LookAHEAD Diabetes Trial

•Randomly assigned to ILI, which included weekly group and individual counseling in the first 6 months, followed by 3 sessions per month for the second 6 months, and twice-monthly contact and regular refresher group series and campaigns in years 2 to 4 (n=2,241), OR to

•DSE, which was an offer of 3 group sessions per year on diet, physical activity, and social support (n=2,262).


2012;308(23):2489-96.

LookAHEAD Diabetes Trial

•MEASURES: Partial or complete remission defined as transition from meeting diabetes criteria to prediabetes or nondiabetic glycemia (fasting glucose <126 mg/dL (<7 mmol/L) and hemoglobin A1c <6.5% (<48 mmol/mol) with no anti-hyperglycemic medication)

•RESULTS: ILI participants lost more weight than DSE participants at years 1 & 4, and had greater fitness increases at years 1 & 4 (P < .001)


2012;308(23):2489-96.

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LookAHEAD Diabetes Trial•RESULTS: •The ILI group was significantly more likely to experience any remission (partial or complete), with prevalence of 11.5% during year 1 and 7.3% at year 4, compared with 2.0% for the DSE group at both time points (P < .001)

•More ILI participants had continuous, sustained remission for at least 2, 3, and 4 years compared with DSE participants

•CONCLUSIONS: Intensive lifestyle intervention was associated with greater likelihood of partial remission of type 2 diabetes compared with diabetes support & education


2012;308(23):2489-96.

DiRECT Diabetes Trial• GOALS: Assess whether intensive weight management within routine

primary care would achieve remission of type 2 diabetes

• METHODS: • Open-label, cluster-randomized trial at 49 primary care practices in

Scotland and the Tyneside region of England. • Practices were randomly assigned (1:1) to provide either a weight

management program (intervention) or best-practice care by guidelines (control)

• Stratification for study site (Tyneside or Scotland) and practice size (>5,700 or ≤5,700)

• Inclusion criteria: 20-65 years who had been diagnosed with type 2 diabetes within the past 6 years, had a body-mass index of 27-45 kg/m2, not receiving insulin.

Lean MEJ, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-

label, cluster-randomised trial. Lancet 2018 Feb;391:541-51.

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DiRECT Diabetes Trial• INTERVENTION: Withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825-853 kcal/day formula diet for 3-5 months), stepped food reintroduction (2-8 weeks), and structured support for long-term weight loss maintenance

•OUTCOMES: Co-primary weight loss of 15 kg or more, and remission of diabetes (defined as glycated hemoglobin (HbA1c) < 6·5% (<48 mmol/mol) after at least 2 months off all antidiabetic medications, from baseline to 12 months. These outcomes were analyzed hierarchically.



DiRECT Diabetes Trial•FINDINGS:

•A 1-year weight loss of 15 kg or more in 36 (24%) intervention group vs none in control group (p<0·0001). Diabetes remission achieved in 68 (46%) intervention group vs six (4%) controls (odds ratio 19·7, p<0·0001).

•Remission correlated to weight loss: no remission in 76 participants who gained weight, six (7%) of 89 participants with 0-5 kg weight loss, 19 (34%) of 56 participants with 5-10 kg loss, 16 (57%) of 28 participants with 10-15 kg loss, and 31 (86%) of 36 participants who lost 15 kg or more.



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DiRECT Diabetes Trial•Weight loss 10 kg intervention and 1 kg controls (diff -8·8 kg, p<0·0001).

•Quality of life, measured by the EuroQol 5 Dimensions visual analogue scale, improved by 7.2 points in intervention and decreased by 2.9 in controls (diff 6.4 points, p=0·0012).

• INTERPRETATION: Findings show that, at 12 months, almost half of participants had remission to non-diabetic state off antidiabetic drugs. “Remission of type 2 diabetes is a practical target for primary care.”



Dramatic Changes Required: The DiRECT Study



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Evidence of Remission: More Dramatic Changes Required (Higher Dosing)• DiRECT VLCD & weight-maintenance diet reversed 46% T2DM

• With ≥15 kg loss → reversed 86% (similar to gastric bypass, but without adverse side-effects)

• LookAHEAD study: DSE ~2% remission (partial or complete), intensive lifestyle intervention (ILI) ~12% year-1 and <6% year-4 (ILI ~300-400% better than DSE)

• Conclusion? ILI doesn’t work → need gastric bypass

• Actually demonstrates ILI treatment not dramatic enough (too mild)Lean MEJ, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-


Gregg EW, et al. Association of an Intensive Lifestyle Intervention With Remission of Type 2 Diabetes. JAMA

2012 Dec 19;308(23):2489-96.

Prevalence of Any Remission (%)

0%

10%

20%

30%

40%

50%

Year 1 Year 2 Year 3 Year 4

2.0% 2.3% 2.2% 2.0%

11.5% 10.4% 8.7% 7.3%

ADA Diab Support&EducLookAHEAD Intensive LifestyleDiRECT Very-Low Cal Diet


2012;308(23):2489-96.

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Prevalence of Any Remission (%)

0%

10%

20%

30%

40%

50%

Year 1 Year 2 Year 3 Year 4

2.0% 2.3% 2.2% 2.0%

11.5% 10.4% 8.7% 7.3%

46%ADA Diab Support&EducLookAHEAD Intensive LifestyleDiRECT Very-Low Cal Diet


2012;308(23):2489-96.

Evidence of Remission: Dramatic Changes Required (Higher Dosing)

Lean MEJ, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial.

Lancet 2018 Feb 10;391(10120):541-551.

Gregg EW, et al. Association of an Intensive Lifestyle Intervention With Remission of Type 2 Diabetes. JAMA 2012 Dec 19;308(23):2489-96.

Group Year 1 Year 4

LookAHEAD (DSE) 2.0% 1.5%

LookAHEAD (ILI ~17 lbs) 11.5% 7.3%

DiRECT (All ~22 lbs) 46% - %

DiRECT (≥33 lbs, 15kg) 86% - %

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Clinical Remission/ Reversal: Actual Patient Outcomes

•Years of LM specialty practice outcomes show consistent drop in insulin resistance (InsR) measured with HOMA-IR

•Medication reductions with glucose improvement can indicate InsR remission – not as certain or quantifiable as when measured with HOMA-IR

•Dramatic dietary and lifestyle changes essential for remission/reversal

Beginning Ending Difference

Item Count Mean Min Max Count Mean Min Max Count Mean % p-val

Weight, lbs 55 189 86.5 392 55 183 87.5 373 0 -5.6 -2.9 <0.000

BMI 55 31.2 16.1 62.0 55 30.3 16.3 59.0 0 -0.9 -2.9 <0.000

Waist, inch 55 40.2 22.5 60 52 39.4 23 57.5 -3 -0.8 -1.9 <0.000

SBP 55 126 84 170 54 112 68 150 -1 -14 -11 <0.000

≥140 12 152 142 " 1 126 82 142 -11 -27 -18 <0.000

DBP 55 83 50 138 54 73 54 100 -1 -9.4 -11 <0.000

≥90 18 106 90 " 2 78 54 " -16 -28 -27 <0.000

Glucose† 55 106 62 365 55 96 67 162 0 -10 -10 0.015

≥126 10 173 131 " 3 121 86 " -7 -52 -30 0.014

Insulin 22 15.2 3.7 39 21 11.4 2.4 30.1 -1 -3.8 -25 0.010

HOMA-IR 22 4.51 1.05 14.8 21 3.0 0.5 11.0 -1 -1.5 -33 0.004

TChol† 55 195.8 109 296 55 170 93 253 0 -26 -13 <0.000

>220 17 245 221 " 3 198 166 " -14 -46 -19 <0.000

LDL† 54 109 51 221 54 93 36 182 0 -16 -15 <0.000

>120 18 148 121 " 5 116 89 " -13 -31 -21 <0.000

HDL*† 55 58 26 120 55 52 22 104 0 -5.6 -9.7 <0.000

TGL† 55 144 40 532 55 124 38 405 0 -20 -14 0.007

>150 20 235 152 " 12 163 67 " -8 -72 -31 0.002

hsCRP 55 2.02 0.04 95.0 54 1.41 0.01 91.2 -1 -0.6 -30 0.048

>3 12 4.71 3.05 8.81 11 2.65 0.53 6.12 -1 -2.1 -44 0.003

Beck 55 15 0 48 30 8 0 31 -25 -7.4 -49 <0.000

>19 20 29 20 " 2 9 0 " -18 -20 -69 <0.000

SF36* 43 58 13 90 43 72 29 95 0 15 25 <0.000

<75 32 38 " 75 21 68 29 95 -11 29 76 <0.000

Notes: * higher values are lower risk; † mg/dL

LM Clinic convenience

sample of 55 patients

in an 18-day ITLC

Immersion program

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Weight, lbs 55 189 86.5 392 55 183 87.5 373 0 -5.6 -2.9 <0.000

BMI 55 31.2 16.1 62.0 55 30.3 16.3 59.0 0 -0.9 -2.9 <0.000

Waist, inch 55 40.2 22.5 60 52 39.4 23 57.5 -3 -0.8 -1.9 <0.000

SBP 55 126 84 170 54 112 68 150 -1 -14 -11 <0.000

≥140 12 152 142 " 1 126 82 142 -11 -27 -18 <0.000

DBP 55 83 50 138 54 73 54 100 -1 -9.4 -11 <0.000

≥90 18 106 90 " 2 78 54 " -16 -28 -27 <0.000

Glucose† 55 106 62 365 55 96 67 162 0 -10 -10 0.015

≥126 10 173 131 " 3 121 86 " -7 -52 -30 0.014

Insulin 22 15.2 3.7 39 21 11.4 2.4 30.1 -1 -3.8 -25 0.010

HOMA-IR 22 4.51 1.05 14.8 21 3.0 0.5 11.0 -1 -1.5 -33 0.004

TChol† 55 195.8 109 296 55 170 93 253 0 -26 -13 <0.000

>220 17 245 221 " 3 198 166 " -14 -46 -19 <0.000

LDL† 54 109 51 221 54 93 36 182 0 -16 -15 <0.000

>120 18 148 121 " 5 116 89 " -13 -31 -21 <0.000

HDL*† 55 58 26 120 55 52 22 104 0 -5.6 -9.7 <0.000

TGL† 55 144 40 532 55 124 38 405 0 -20 -14 0.007

>150 20 235 152 " 12 163 67 " -8 -72 -31 0.002

hsCRP 55 2.02 0.04 95.0 54 1.41 0.01 91.2 -1 -0.6 -30 0.048

>3 12 4.71 3.05 8.81 11 2.65 0.53 6.12 -1 -2.1 -44 0.003

Beck 55 15 0 48 30 8 0 31 -25 -7.4 -49 <0.000

>19 20 29 20 " 2 9 0 " -18 -20 -69 <0.000

SF36* 43 58 13 90 43 72 29 95 0 15 25 <0.000

<75 32 38 " 75 21 68 29 95 -11 29 76 <0.000




in an 18-day ITLC

Immersion program



Weight, lbs 55 189 86.5 392 55 183 87.5 373 0 -5.6 -2.9 <0.000

BMI 55 31.2 16.1 62.0 55 30.3 16.3 59.0 0 -0.9 -2.9 <0.000

Waist, inch 55 40.2 22.5 60 52 39.4 23 57.5 -3 -0.8 -1.9 <0.000

SBP 55 126 84 170 54 112 68 150 -1 -14 -11 <0.000

≥140 12 152 142 " 1 126 82 142 -11 -27 -18 <0.000

DBP 55 83 50 138 54 73 54 100 -1 -9.4 -11 <0.000

≥90 18 106 90 " 2 78 54 " -16 -28 -27 <0.000

Glucose† 55 106 62 365 55 96 67 162 0 -10 -10 0.015

≥126 10 173 131 " 3 121 86 " -7 -52 -30 0.014

Insulin 22 15.2 3.7 39 21 11.4 2.4 30.1 -1 -3.8 -25 0.010

HOMA-IR 22 4.51 1.05 14.8 21 3.0 0.5 11.0 -1 -1.5 -33 0.004

TChol† 55 195.8 109 296 55 170 93 253 0 -26 -13 <0.000

>220 17 245 221 " 3 198 166 " -14 -46 -19 <0.000

LDL† 54 109 51 221 54 93 36 182 0 -16 -15 <0.000

>120 18 148 121 " 5 116 89 " -13 -31 -21 <0.000

HDL*† 55 58 26 120 55 52 22 104 0 -5.6 -9.7 <0.000

TGL† 55 144 40 532 55 124 38 405 0 -20 -14 0.007

>150 20 235 152 " 12 163 67 " -8 -72 -31 0.002

hsCRP 55 2.02 0.04 95.0 54 1.41 0.01 91.2 -1 -0.6 -30 0.048

>3 12 4.71 3.05 8.81 11 2.65 0.53 6.12 -1 -2.1 -44 0.003

Beck 55 15 0 48 30 8 0 31 -25 -7.4 -49 <0.000

>19 20 29 20 " 2 9 0 " -18 -20 -69 <0.000

SF36* 43 58 13 90 43 72 29 95 0 15 25 <0.000

<75 32 38 " 75 21 68 29 95 -11 29 76 <0.000




in an 18-day ITLC

Immersion program

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Weight, lbs 55 189 86.5 392 55 183 87.5 373 0 -5.6 -2.9 <0.000

BMI 55 31.2 16.1 62.0 55 30.3 16.3 59.0 0 -0.9 -2.9 <0.000

Waist, inch 55 40.2 22.5 60 52 39.4 23 57.5 -3 -0.8 -1.9 <0.000

SBP 55 126 84 170 54 112 68 150 -1 -14 -11 <0.000

≥140 12 152 142 " 1 126 82 142 -11 -27 -18 <0.000

DBP 55 83 50 138 54 73 54 100 -1 -9.4 -11 <0.000

≥90 18 106 90 " 2 78 54 " -16 -28 -27 <0.000

Glucose† 55 106 62 365 55 96 67 162 0 -10 -10 0.015

≥126 10 173 131 " 3 121 86 " -7 -52 -30 0.014

Insulin 22 15.2 3.7 39 21 11.4 2.4 30.1 -1 -3.8 -25 0.010

HOMA-IR 22 4.51 1.05 14.8 21 3.0 0.5 11.0 -1 -1.5 -33 0.004

TChol† 55 195.8 109 296 55 170 93 253 0 -26 -13 <0.000

>220 17 245 221 " 3 198 166 " -14 -46 -19 <0.000

LDL† 54 109 51 221 54 93 36 182 0 -16 -15 <0.000

>120 18 148 121 " 5 116 89 " -13 -31 -21 <0.000

HDL*† 55 58 26 120 55 52 22 104 0 -5.6 -9.7 <0.000

TGL† 55 144 40 532 55 124 38 405 0 -20 -14 0.007

>150 20 235 152 " 12 163 67 " -8 -72 -31 0.002

hsCRP 55 2.02 0.04 95.0 54 1.41 0.01 91.2 -1 -0.6 -30 0.048

>3 12 4.71 3.05 8.81 11 2.65 0.53 6.12 -1 -2.1 -44 0.003

Beck 55 15 0 48 30 8 0 31 -25 -7.4 -49 <0.000

>19 20 29 20 " 2 9 0 " -18 -20 -69 <0.000

SF36* 43 58 13 90 43 72 29 95 0 15 25 <0.000

<75 32 38 " 75 21 68 29 95 -11 29 76 <0.000




in an 18-day ITLC

Immersion program



Weight, lbs 55 189 86.5 392 55 183 87.5 373 0 -5.6 -2.9 <0.000

BMI 55 31.2 16.1 62.0 55 30.3 16.3 59.0 0 -0.9 -2.9 <0.000

Waist, inch 55 40.2 22.5 60 52 39.4 23 57.5 -3 -0.8 -1.9 <0.000

SBP 55 126 84 170 54 112 68 150 -1 -14 -11 <0.000

≥140 12 152 142 " 1 126 82 142 -11 -27 -18 <0.000

DBP 55 83 50 138 54 73 54 100 -1 -9.4 -11 <0.000

≥90 18 106 90 " 2 78 54 " -16 -28 -27 <0.000

Glucose† 55 106 62 365 55 96 67 162 0 -10 -10 0.015

≥126 10 173 131 " 3 121 86 " -7 -52 -30 0.014

Insulin 22 15.2 3.7 39 21 11.4 2.4 30.1 -1 -3.8 -25 0.010

HOMA-IR 22 4.51 1.05 14.8 21 3.0 0.5 11.0 -1 -1.5 -33 0.004

TChol† 55 195.8 109 296 55 170 93 253 0 -26 -13 <0.000

>220 17 245 221 " 3 198 166 " -14 -46 -19 <0.000

LDL† 54 109 51 221 54 93 36 182 0 -16 -15 <0.000

>120 18 148 121 " 5 116 89 " -13 -31 -21 <0.000

HDL*† 55 58 26 120 55 52 22 104 0 -5.6 -9.7 <0.000

TGL† 55 144 40 532 55 124 38 405 0 -20 -14 0.007

>150 20 235 152 " 12 163 67 " -8 -72 -31 0.002

hsCRP 55 2.02 0.04 95.0 54 1.41 0.01 91.2 -1 -0.6 -30 0.048

>3 12 4.71 3.05 8.81 11 2.65 0.53 6.12 -1 -2.1 -44 0.003

Beck 55 15 0 48 30 8 0 31 -25 -7.4 -49 <0.000

>19 20 29 20 " 2 9 0 " -18 -20 -69 <0.000

SF36* 43 58 13 90 43 72 29 95 0 15 25 <0.000

<75 32 38 " 75 21 68 29 95 -11 29 76 <0.000




in an 18-day ITLC

Immersion program

5/12/2021

20



Weight, lbs 55 189 86.5 392 55 183 87.5 373 0 -5.6 -2.9 <0.000

BMI 55 31.2 16.1 62.0 55 30.3 16.3 59.0 0 -0.9 -2.9 <0.000

Waist, inch 55 40.2 22.5 60 52 39.4 23 57.5 -3 -0.8 -1.9 <0.000

SBP 55 126 84 170 54 112 68 150 -1 -14 -11 <0.000

≥140 12 152 142 " 1 126 82 142 -11 -27 -18 <0.000

DBP 55 83 50 138 54 73 54 100 -1 -9.4 -11 <0.000

≥90 18 106 90 " 2 78 54 " -16 -28 -27 <0.000

Glucose† 55 106 62 365 55 96 67 162 0 -10 -10 0.015

≥126 10 173 131 " 3 121 86 " -7 -52 -30 0.014

Insulin 22 15.2 3.7 39 21 11.4 2.4 30.1 -1 -3.8 -25 0.010

HOMA-IR 22 4.51 1.05 14.8 21 3.0 0.5 11.0 -1 -1.5 -33 0.004

TChol† 55 195.8 109 296 55 170 93 253 0 -26 -13 <0.000

>220 17 245 221 " 3 198 166 " -14 -46 -19 <0.000

LDL† 54 109 51 221 54 93 36 182 0 -16 -15 <0.000

>120 18 148 121 " 5 116 89 " -13 -31 -21 <0.000

HDL*† 55 58 26 120 55 52 22 104 0 -5.6 -9.7 <0.000

TGL† 55 144 40 532 55 124 38 405 0 -20 -14 0.007

>150 20 235 152 " 12 163 67 " -8 -72 -31 0.002

hsCRP 55 2.02 0.04 95.0 54 1.41 0.01 91.2 -1 -0.6 -30 0.048

>3 12 4.71 3.05 8.81 11 2.65 0.53 6.12 -1 -2.1 -44 0.003

Beck 55 15 0 48 30 8 0 31 -25 -7.4 -49 <0.000

>19 20 29 20 " 2 9 0 " -18 -20 -69 <0.000

SF36* 43 58 13 90 43 72 29 95 0 15 25 <0.000

<75 32 38 " 75 21 68 29 95 -11 29 76 <0.000




in an 18-day ITLC

Immersion program



Servings /week

Chol foods 41 18 0 84 5 3.6 0 10 -36 -14 -80 <0.000

High fat 42 17 0 67 20 4.7 0 10 -22 -12 -71 <0.000

Sweets 41 13 0 84 19 4.2 0 12 -22 -8.9 -68 <0.000

Sodas 19 2.8 0 10 2 2.0 0 3 -17 -0.8 -89 <0.000

Water*, cup /d 46 6.1 1 24 46 8.7 5 20 0 2.5 41 <0.000

Big suppers 19 0 -19 -100

No breakfast 15 2 -13 -87

Sleep <6hr 18 17 -1 -6

Exercise*, min 45 73 /wk 46 85 /d 1 440 605

Ex <30m /wk 19 15 1 15 /d -19 -100

Ex 30-90m /wk 10 60 30 60 /d -10 -100

Ex 1.5-3h /wk 7 135 14 135 /d -7 -100

Ex >3h /wk 6 240 1 240 /d -6 -100

Ex ≥30m /d 10 30 /d 45 87 /d 35 57 190

MetS 48 1.9 40 1.6 -8 -0.3 -15 0.031

≥3 16 9 -7 -44

≥4 7 3 -4 -57

5 0 0 0


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Servings /week

Chol foods 41 18 0 84 5 3.6 0 10 -36 -14 -80 <0.000

High fat 42 17 0 67 20 4.7 0 10 -22 -12 -71 <0.000

Sweets 41 13 0 84 19 4.2 0 12 -22 -8.9 -68 <0.000

Sodas 19 2.8 0 10 2 2.0 0 3 -17 -0.8 -89 <0.000

Water*, cup /d 46 6.1 1 24 46 8.7 5 20 0 2.5 41 <0.000



Sleep <6hr 18 17 -1 -6

Exercise*, min 45 73 /wk 46 85 /d 1 440 605

Ex <30m /wk 19 15 1 15 /d -19 -100

Ex 30-90m /wk 10 60 30 60 /d -10 -100

Ex 1.5-3h /wk 7 135 14 135 /d -7 -100

Ex >3h /wk 6 240 1 240 /d -6 -100

Ex ≥30m /d 10 30 /d 45 87 /d 35 57 190

MetS 48 1.9 40 1.6 -8 -0.3 -15 0.031

≥3 16 9 -7 -44

≥4 7 3 -4 -57

5 0 0 0




Servings /week

Chol foods 41 18 0 84 5 3.6 0 10 -36 -14 -80 <0.000

High fat 42 17 0 67 20 4.7 0 10 -22 -12 -71 <0.000

Sweets 41 13 0 84 19 4.2 0 12 -22 -8.9 -68 <0.000

Sodas 19 2.8 0 10 2 2.0 0 3 -17 -0.8 -89 <0.000

Water*, cup /d 46 6.1 1 24 46 8.7 5 20 0 2.5 41 <0.000



Sleep <6hr 18 17 -1 -6

Exercise*, min 45 73 /wk 46 85 /d 1 440 605

Ex <30m /wk 19 15 1 15 /d -19 -100

Ex 30-90m /wk 10 60 30 60 /d -10 -100

Ex 1.5-3h /wk 7 135 14 135 /d -7 -100

Ex >3h /wk 6 240 1 240 /d -6 -100

Ex ≥30m /d 10 30 /d 45 87 /d 35 57 190

MetS 48 1.9 40 1.6 -8 -0.3 -15 0.031

≥3 16 9 -7 -44

≥4 7 3 -4 -57

5 0 0 0


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Diabetes and MetSMeasures

Measure Begin End Mean %Δ p-val

Weight, lbs 189 183 -5.6 -2.9% <0.000

BMI 31.2 30.3 -0.9 -2.9% <0.000

Waist, inch 40.2 39.4 -0.8 -1.9% <0.000

Glucose† 106 96.2 -10.3 -9.7% 0.015

≥126 173 121 -52.3 -30% 0.014

Insulin 15.2 11.4 -3.8 -25% 0.010

HOMA-IR 4.5 3.0 -1.5 -33% 0.004


Change


Waist, inch 40.2 39.4 -0.8 -1.9% <0.000

SBP 126 112 -14.3 -11% <0.000

≥140 152 126 -26.7 -18% <0.000

DBP 83 73 -9.4 -11% <0.000

≥90 106 78 -28.2 -27% <0.000

Glucose† 106 96.2 -10.3 -9.7% 0.015

≥110 156 116 -39.7 -25% 0.011

Insulin 15.2 11.4 -3.8 -25% 0.010

HDL*† 58 52 -5.6 -10% <0.000

TGL† 144 124 -19.9 -14% 0.007

>150 235 163 -72.3 -31% 0.002

MetS, number 1.9 1.6 -0.3 -15% 0.031

≥3 16 9 -7 -44% 0.000

≥4 7 3 -4 -57% 0.000

5 0 0 0


Change

Diabetes and MetSMeasures


Weight, lbs 189 183 -5.6 -2.9% <0.000

BMI 31.2 30.3 -0.9 -2.9% <0.000

Waist, inch 40.2 39.4 -0.8 -1.9% <0.000

Glucose† 106 96.2 -10.3 -9.7% 0.015

≥126 173 121 -52.3 -30% 0.014

Insulin 15.2 11.4 -3.8 -25% 0.010

HOMA-IR 4.5 3.0 -1.5 -33% 0.004


Change


Waist, inch 40.2 39.4 -0.8 -1.9% <0.000

SBP 126 112 -14.3 -11% <0.000

≥140 152 126 -26.7 -18% <0.000

DBP 83 73 -9.4 -11% <0.000

≥90 106 78 -28.2 -27% <0.000

Glucose† 106 96.2 -10.3 -9.7% 0.015

≥110 156 116 -39.7 -25% 0.011

Insulin 15.2 11.4 -3.8 -25% 0.010

HDL*† 58 52 -5.6 -10% <0.000

TGL† 144 124 -19.9 -14% 0.007

>150 235 163 -72.3 -31% 0.002

MetS, number 1.9 1.6 -0.3 -15% 0.031

≥3 16 9 -7 -44% 0.000

≥4 7 3 -4 -57% 0.000

5 0 0 0


Change

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Depression and Standard Function (QoL)

0

10

20

30

40

50

60

70

80

SF36 SF-36 <75 Beck Beck >19

Begin EndMeasure Begin End Mean %Δ p-val

Beck 15 8 -7 -49% <0.000

>19 29 9 -20 -69% <0.000

SF36* 58 72 15 25% <0.000

<75 38 68 29 76% <0.000


Change

Clinical Remission/ Reversal• So… how can we best reduce calories, without losing nutrients?

• Reduce caloric density without dropping essential nutrients (health = nutrients / calories)

• Simplest way: greatly increase whole, unprocessed plant foods of color

• Plants high in nutrients, fiber and water, low in fats and calories

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Clinical Remission/ Reversal• Fills up stomach but with fewer calories (low calorie density)

• Michael Pollan’s 3 rules:

1. eat food - not ‘food-like’ substances (manufactured),

2. not too much,

3. mostly plants.

• Fasting-mimicking diet cycles (FMD)

• Intermittent fasting (routinely put body briefly in fasting state)

Summarize the ACLM Position Statement on Type 2 Diabetes Remission and Lifestyle Medicine

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Kelly J, Karlsen M, Steinke G. Type 2 Diabetes Remission and Lifestyle Medicine: A Position Statement From the American College of

Lifestyle Medicine. American Journal of Lifestyle Medicine. 2020;14(4):406-419. doi:10.1177/1559827620930962

CONCLUSION: As incidence of T2D continues

to rise, the current best evidence from multiple

intervention studies supports remission with

intensive lifestyle modifications as the prefer-

red treatment and standard of care. To

achieve remission, appropriate, therapeutic

dosing of lifestyle modifications is necessary,

including a hypocaloric diet.

Future research should focus on high-quality

intervention trials to further quantify the

potential of different lifestyle modifications,

including consumption of a whole-food plant

diet, to achieve remission of T2D in

comparison to standard pharmacologic

treatment and surgical interventions.

ACLM’s Position1. Sufficiently intensive lifestyle modifications are capable of producing

clinical improvements and/or remission in T2D patients.

2. The optimal treatment to bring about remission includes a whole food, plant-based (WFPB) dietary pattern, coupled with regular moderate exercise.

Therefore:

3. Remission should always be the preferred clinical goal, and lifestyle medicine interventions shown to produce remission should therefore become the standard of care.

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Appropriate Therapeutic Dosing

• Intensity of lifestyle interventions must be matched to the severity and acuteness of the condition being treated (just as with medication and surgery)

•Reversal of advanced hyperglycemia requires intensive lifestyle interventions that produce significant weight loss

•Counterpoint, Counterweight and DiRECT trials demonstrate that liquid meal substitutes can achieve this

Clinical Experience with Plant Diet

•ACLM members and others have shown that WFPB diets can also achieve remission, esp. combined with fasting

•The position paper reviewed multiple intervention studies and found that dosing intensity largely determines success or failure to achieve remission

•Research needed to compare meal substitutes with WFPB diet, and other diets and interventions

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Clinical Goal of T2D Remission

•Weight of evidence shows that properly-dosed lifestyle interventions can produce remission in a major portion of T2D patients

•Medication-based treatment alone is insufficient to achieve remission

•Surgical interventions can achieve remission, but with significant risk and undesired side-effects

Questions?

•[email protected]

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Fasting-mimicking Diet•The FMD is a plant-based diet designed to attain fasting-like effects on the serum levels of IGF-1, IGFBP-1, glucose, and ketone bodies while providing both macro-and micronutrients to minimize the burden of fasting and adverse effects.

•Day 1 of the FMD supplies ~4600 kJ (11% protein, 46% fat, and 43% carbohydrate), whereas days 2 to 5 provide ~3000 kJ (9% protein, 44% fat, and 47% carbohydrate) per day.

Wei M, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and

cardiovascular disease. Sci Transl Med 2017 Feb 15;9:eaai8700.

Fasting-mimicking Diet•The FMD comprises proprietary formulations belonging to USC and L-Nutra (www.prolonfmd.com) of vegetable-based soups, energy bars, energy drinks, chip snacks, tea, and a supplement providing high levels of minerals, vitamins, and essential fatty acids (fig. S4).

•All items to be consumed per day were individually boxed to allow the subjects to choose when to eat while avoiding accidentally consuming components of the following day.



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Fasting-mimicking Diet Content• The human version of the FMD is a propriety (L-Nutra) plant-based diet designed to

attain fasting-like effects on the serum levels of IGF-I, IGFBP1, glucose and ketone bodies while providing both macro and micronutrients to minimize the burden of fasting and adverse effects (Brandhorst et al., 2015).

• Day 1 of the FMD supplies ~4600 kJ (1060 kcal; 11% protein, 46% fat, 43% carbohydrate), whereas days 2-5 provide ~3000 kJ (690 kcal; 9% protein, 44% fat, 47% carbohydrate) per day.

• The FMD comprises proprietary formulations of vegetable-based soups, energy bars, energy drinks, chip snacks, tea, and a supplement providing high levels of minerals, vitamins and essential fatty acids (Figure S3). All items to be consumed per day were individually boxed to allow the subjects to choose when to eat while avoiding accidentally consuming components of the following day. For the human subjects, a suggested FMD meal plan was provided that distributes the study foods to be consumed as breakfast, lunch, snacks, and dinner. See lists below for ingredients and supplements.



Fasting-mimicking Diet Ingredients• Mushroom Soup: Rice flour, Carrot powder, Dried onion, Champignon

mushroom powder, Inulin (chicory fiber), Dried champignon mushroom, Salt, Yeast extract, Potato starch, Olive oil, Dried parsley, Natural flavor.

• Vegetable Soup: Rice flour, Dried onion, Inulin(chicory fiber), Dried tomato, Dried carrot, Salt, Dried red pepper, Dried leek, Potato starch, Olive oil, Freeze-dried basil, Spinach powder, Dried parsley, Natural flavor.

• Tomato Soup: Rice flour, Dried tomato powder, Dried onion, dried tomato pieces, dried carrot, chicory fiber, potato starch, olive oil, Salt, Yeast extract, Dried basil, Dried parsley, Natural flavor.

• Pumpkin Soup: Pumpkin powder, rice flour, inulin (chicory fiber), dried carrot, salt, yeast extract, potato starch, olive oil, dried onion, dried parsley, natural flavor.



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Fasting-mimicking Diet Ingredients• Energy Bar: Almond meal, Macadamia nut butter, Honey, Pecan,

Coconut, Flaxseed meal, Coconut oil, Vanilla extract, Sea salt.

• Kale Crackers: kale, golden flax seeds, sunflower seeds, cashews, Sesame seeds, nutritional yeast, apple cider vinegar, hemp seeds, pumpkin seeds, sea salt, onion powder, dill week, black pepper.

• Algal Oil Capsule: Algal oil, Gelatin, Glycerin, Purified water, Turmeric, Annatto extract.

• Teas: chamomile, spearmint, or Lemon.

• Energy drink: Purified water, natural vegetable glycerin, polylysine.



Fasting-mimicking Diet Supplements• Vitamin A (as Beta Carotene), Vitamin C (Ascorbic Acid), Vitamin D

(as Cholecalciferol), Vitamin E (as DL-Alpha Tocopherol Acetate), Vitamin K (as Phytonadione), Thiamine (as Thiamine Mononitrate), Riboflavin, Niacin (as Niacinamide), Vitamin B6 (as Pyridoxine HCI), Folic Acid, Vitamin B12 (as Cyanocobalamin), Biotin, Pantothenic Acid (as Calcium-D-Pantothenate), Calcium (as Calcium Carbonate and Tribasic Calcium Phosphate), Iron (as Ferrous Fumarate), Phosphorous (as Tribasic Calcium Phosphate), Iodine (as Potassium Iodine), Magnesium (as Magnesium Oxide), Zinc (Zinc Oxide), Selenium (as Sodium Selenate), Copper (as Cupric Sulfate), Manganese (as Manganese Sulfate), Chromium (as Chromium Picolinate), Molybdenum (as Sodium Molybdate).



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Fasting mimicking Diet Supplements

•Proprietary Blend: Beet Root Powder, Spinach Leaf Powder, Tomato Fruit Powder, Carrot Root Powder, Collards Greens Powder, Collards (Kale) Leaf Powder. Other Ingredients: Stearic Acid, Microcrystalline Cellulose, Dicalcium Phosphate, Croscarmellose Sodium, Magnesium Stearate, Silicon Dioxide, Pharmaceutical Glaze.



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Reversibility of Type 2 Diabetes with Plant Diet Nutrition

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