Prediabetes: Pathophysiology,

Complications and Management

Sam Dagogo-Jack, MD, DM, FACP, FACE

A. C. Mullins Endowed Chair in Translational Research

Professor of Medicine & Director

Division of Endocrinology, Diabetes, and Metabolism

Director, General Clinical Research Center

University of Tennessee Health Science Center

Memphis, Tennessee

Disclosures

I have no conflicts of interest regarding this lecture.

Learning Objectives

1. Understand the prevalence and key contributors to the

pathophysiology of prediabetes

2. Appreciate the continuum of microvascular and

Macrovascular complications associated with prediabetes

3. Review lifestyle and multimodality interventions for

diabetes prevention and reversal of dysglycemia

Global Burden of Diabetes

IDF Diabetes Atlas. 7th edition 2015.

IDF. Global burden. IDF Diabetes Atlas. 6th ed. 2013.

Global Burden of Prediabetes (IGT)

Top 10 countries for prevalence of IGT, 2013

The Continuum of Dysglycemia

HbA1c-based diagnosis of diabetes mellitus

Ethnic conundrum

October 2010

• Age

• RBC turnover

• Pregnancy

• Vitamins

• EtOH, Liver dz

• Iron deficiency

• Pregnancy

• CKD, Uremia

• Transplants

• Race/Ethnicity

A1c should be considered as an additional

criterion, not the primary criterion.

Pathophysiology of Diabetes Mellitus

Type 1

Diabetes Mellitus

Genes Environment

b-Cell Destruction

Insulin

Resistance

Type 2

Diabetes Mellitus

b-Cell

Dysfunction +

Dagogo-Jack S. Diabetes Care. 2012;35:193-195.

Dagogo-Jack S, Askari H, Tykodi G. JCEM. 2009;94:2031-2036.

<90 90-99 100-125 100-125 FPG

2-H PG <140 <140 <140 >140

0

.02

.04

.06

.08

.10

.12

.14

.16 IS

I-c

lam

p(m

mo

l/k

g.m

in-1

/p

M)

**

0

2

4

6

8

10

12

HO

MA

-IR

*

**

***

*

IFG IFG-IGT

Insulin Sensitivity

Insulin Resistance

Glucoregulation in Normal vs Prediabetic Subjects by Glucose Criteria

IFG IFG-IGT

2-H PG

FPG <90 90-99 100-125 100-125

<140 <140 <140 >140

Dis

po

sit

ion

In

de

x

0

.02

.04

.06

.08

.1

.12

.14

.16

# #

Disposition Index

*P = 0.04. **0.002, ***P < 0.0001, #P = 0.02

Ins

uli

n S

ec

reti

on

(p

M)

Cavaghan et al. J Clin Invest 1997;100:530-37

0

10

20

30

40

50

60

70

80

90

NE

FA S

up

pre

ssio

n (

%)

*

<90

IFG IFG-IGT

90-99 100-125 100-125

2-hrPG <140 <140 <140 >140

FPG

* P=0.001

Increased Lipolysis

Basal State

Dagogo-Jack S, Askari H, Tykodi G. JCEM 2009;94:2031

Cycling x 20 min

@ 60 rpm

Cycling x 20 min

@ 60 rpm

DM Patients

Cerasi E, Luft R. Diabetes 1972; 21 (Suppl 2 ):685-694

Prediabetes

Insulin resistance

Increased hepatic glucose production

Hyperglycemia

Incr

ease

d g

luco

se

reab

sorp

tio

n

Incr

ease

d

lipo

lysi

s

Pathophysiological Defects in T2DM and Prediabetes

✓ ✓

✓

✓

✓

✓ Present in

prediabetes

From Dagogo-Jack S. Diabetes Risks from Prescription and Nonprescription Drugs. ADA Press, Alexandria, VA, 2016

?

U. S. DPP

Da Qing

FDPS

IDPP

Understanding the Continuum of Dysglycemia

Pathobiology of Prediabetes in A Bi-racial Cohort (POP-ABC)

Dagogo-Jack S, et al. Ethn Dis 21:33–39, 2011; Dagogo-Jack S, et al. J Clin Endocrinol Metab 98:120-128, 2013.

Baseline/ repeated

assessments every

3 months x 5 years

OGTT in

African-

Americans

Caucasians

with parental

T2DM

Age: 18-65 yr

NFG

NGT

Pro

gre

sso

rs

IGT

NFG

NGT

T2DM

IFG/

IGT

IFG

Baseline

NFG, Normal fasting glucose; NGT, Normal glucose tolerance

IFG, Impaired fasting glucose; IGT, Impaired glucose tolerance

, Lipid profile

Demographic, Parental, and Enrollment Characteristics

Dagogo-Jack S, et al. J Clin Endocrinol Metab 98: 120–128, 2013 a P =0.005

Dagogo-Jack S, et al. J Clin Endocrinol Metab 99(6):E1078-87, 2014

Progression from Normoglycemia to Prediabetes

Mean Follow-up 2.62 yr

Prediabetes:

• 101 (29.5%)

• ~11%/yr*

T2DM: 10 (2.9%)

Maintained NGR:

• 232 (67.6%)

Pima Indians

NGTIGT : ~8%/yr

Weyer C, et al. Diabetes Care 2000;24:89–94.

(P=0.7855)

White

Black

Prediabetes Survival Probability

Predictors of Incident Prediabetes

Dagogo-Jack S, et al. JCEM 99:1078-87, 2014; Boucher A, et al. Metabolism 64:1060-1067, 2015;

Jiang Y, Owei I, Wan J, Ebenibo S, Dagogo-Jack S. BMJ Open Diabetes Research and Care 2016;4:e000194

• Age

• Adiposity

• FPG

• 2-hrPG

• Behavioral

• Lipid profile

• Si-clamp

• B-cell fx

• Cytokines

* P = 0.003-<0.0001

16 18 20 22 24 26 28 30 32 34

BM

I (k

g/m

2)

NP P

**

60

70

80

90

100

110

Wais

t C

ircu

m.

(cm

) NP P NP P

60

70

80

90

100

110

120

130

140

2-h

r P

lasm

a G

luco

se (

mg

/dl)

*

Predictors of Incident Prediabetes

Dagogo-Jack S, et al. JCEM 2014;99:1078; Boucher A, et al. Metabolism 2015;64:1060;

Jiang Y, Owei I, Wan J, Ebenibo S, Dagogo-Jack S. BMJ Open Diabetes Research and Care 2016;4:e000194

• Age

• Adiposity

• FPG

• 2-hrPG

• Behavioral

• Lipid profile

• Si-clamp

• B-cell function

• Cytokines

Progressors Nonprogressors

NP P 10

11

12

13

14

15

16

17

18

Tru

nk

Fa

t M

as

s (

kg

)

20

22

24

26

28

30

32

34

To

tal F

at

Ma

ss

(k

g)

NP P

*

*

Pro

gre

ss

ion

(%

) 100

10

20

30

40

50

0

MAQ/FHQ Quartiles 1 2 3 4

38.6% 38.1%

31.0% 28.4%

Physical Activity

Predictors of Incident Prediabetes

Dagogo-Jack S, et al. JCEM 99:1078-87, 2014; Boucher A, et al. Metabolism 64:1060-1067, 2015; Jiang Y, Owei I, Wan J, Ebenibo S, Dagogo-Jack S.

BMJ Open Diabetes Research and Care 2016;4:e000194; Owei I, Umekwe N, Wan J, Dagogo-Jack S, Exp Biol Med 2016

• Age

• Adiposity

• FPG

• 2-hrPG

• Behavioral

• Lipid profile

• Si-clamp

• B-cell fx

• Cytokines

*

NP P 0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Si-

clam

p x

10

(u

mo

l/kg

FF

M-m

in/p

M)

0

200

400

600

800

1000

1200

Dis

po

siti

on

In

dex

NP P

*

Progressors Nonprogressors

Predictors of Incident Prediabetes

• Age

• Adiposity

• FPG

• 2-hrPG

• Behavioral

• Lipid profile

• Insulin sensitivity

• B-cell function

• Adipocytokines

NP P 60

70

80

90

100

110

120

130

140

2-h

r P

lasm

a G

luco

se (

mg

/dl)

* *

NP P 10

11

12

13

14

15

16

17

18

Tru

nk

Fa

t M

as

s (

kg

) Progressors Nonprogressors

Dagogo-Jack S, et al. JCEM 99:1078-87, 2014; Boucher A, et al. Metabolism 64:1060-1067, 2015; Jiang Y, Owei I, Wan J, Ebenibo S, Dagogo-Jack S.

BMJ Open Diabetes Research and Care 2016;4:e000194; 149. Owei I, Umekwe N, Wan J, Dagogo-Jack S, Exp Biol Med 2016

Interim Conclusions

• The pathophysiological defects and complications associated

with T2DM are evident in persons with prediabetes.

• AA and EA offspring of T2DM parents develop prediabetes at a

rate of ~10% per year. Robust insulin secretion in AA serves as a

mechanism for maintaining normoglycemia.

• Progression from NGR to prediabetes is predictable, using

numerous clinical and biochemical indicators.

• The combination of increased trunk fat and 2-hr PG >90th pctile

confers high risk for prediabetes.

23

Pathobiology of Prediabetes in A Bi-racial Cohort (POP-ABC)

Plasma Insulin (uU/ml)

Plasma Glucose (mg/dl)

0

0.1

0.2

0.3

0.4

Si-clamp

(umol/kgFFM.min/pM)

0 25 50 75 100

Percentile

-1

0

2

4

6

8

HOMA-IR

0 25 50 75 100

Percentile

March 17, 2016

The Continuum of Dysglycemia and Complications

DPP Research Group. Diabet Med 24:137-144, 2007; Haffner SM, et al. Diabetologia 36:1002-1006, 1993; Papanas N, et al.Nat Rev Endocrinol 7:682-690, 2011

Microvascular Complications of Prediabetes

• Retinopathy in 7.9% of IGT subjects

and 12.6% of new T2DM in DPP

• Documented increased risks of

microalbuminuria and neuropathy

• 11%-25% of prediabetic subjects show

evidence of peripheral neuropathy

• 13%-21% present with neuropathic pain

• 25%- 62% of idiopathic peripheral

neuropathy patients have prediabetes

DPP Research Group. Diabet Med. 2007;24:137-144. Haffner SM, et al. Diabetologia. 1993;36:1002-1006.

Papanas N, Vinik AI, Ziegler D. Nat Rev Endocrinol. 2011;7:682-690.

Population Prevalence (%) of CKD Stages 1–4 by Diabetes

Mellitus and Prediabetes Status, NHANES 1999-2006

Plantinga L, et al. Clin J Am Soc Nephrol. 2010;5:673-682.

CKD diagnosed with eGFR by MDRD equation

28

Risk of CVD Is Elevated Prior to Diagnosis of T2DM

CVD=cardiovascular disease.

Hu F, et al. Diabetes Care. 2002;25:1129-1134.

Nondiabetic Throughout

Study

Rela

tive R

isk o

f

MI

or

Str

oke

1.00

15 y or More Before Diagnosis

2.40

10-14.9 y Before

Diagnosis

3.19

<10 y Before

Diagnosis

3.64

0.00

1.00

2.00

3.00

4.00 NHS: 117,629 female nurses aged 30-55 years who were free of diagnosed

CVD at baseline were recruited in 1976 and followed for 20 years.

Caucasian

55%

African

American

20%

Hispanic

American

16%

Asian

4% American

Indian

5%

Diabetes Prevention Program Study Population

Caucasian 1768

African-American 645

Hispanic-American 508

Asian-American & 142

Pacific Islander

American Indian 171

DPP Research Group. NEJM 346:393-403, 2002

DPP Study

Diabetes Prevention Program Research Group. N Engl J Med. 2002;346(6):393-403.

• 3234 individuals at risk for T2DM

• Randomized to:

a) Placebo,

b) Metformin, or

c) Lifestyle – Increased activity – Improved eating

habits

• Mean follow-up of 2.8 years

Weig

ht

Ch

an

ge (

kg

)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 -8

-6

-4

-2 0

2

4

Placebo

Metformin Lifestyle

Ac

tiv

ity C

ha

ng

e

(ME

T-h

r/w

k)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

0

2

4

6

8

Lifestyle

Metformin

Placebo

Year

% M

ed

icati

on

Ad

here

nce

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 60

65

70

75

80

85

Metformin

Placebo

-80

-60

-40

-20

0

Caucasian

(n=1768)

African-

American

(n=645)

Hispanic

(n=508)

American

Indian

(n=171)

Asian

(n=142)

%

Lifestyle Metformin

Diabetes Mellitus Risk Reduction by Ethnicity

DPP Research Group. N Engl J Med. 2002;346:393-403.

DPP: Regression from

Prediabetes to Normal

Glucose Regulation

Fre

qu

ency

(%

)

Lifestyle Metformin Placebo

Normal Diabetes

NEJM 346:393-403, 2002

Eriksson KF, Lindgärde F. Diabetologia 1991;34: 891– 898;Perreault L, et al and DPP Research Group. Diabetes Care 32:1583-1588, 2009.

• Malmö study: ~50% of IGT subjects reverted to NGT with lifestyle

modification after a mean follow-up of 6 years.

• DPP study: ~40% of IGT subjects in ILI arm (vs. ~20% in placebo)

reverted to NGT during ~3 years of follow-up.

• Predictors of prediabetes reversal in DPP

• ILI intervention (P < 0.01)

• Lower baseline fasting glucose (< 0.01)

• Weight loss (P < 0.01)

• Lower 2-hrPG (P < 0.01)

• Younger age (P < 0.01)

• Greater insulin secretion (P = 0.04)

Reversibility of Prediabetes

Smith AG, Hamwi J, Russell J, et al. Diabetes Care 29:1294-1299, 2006

• 32 subjects with symptomatic IGT neuropathy received

individualized diet and exercise counseling

• Assessments at Baseline and after 1 year:

• Michigan Diabetic Neuropathy score

• Visual analog pain scale

• 75-g OGTT, Lipid profile

• 3-mm skin biopsies with measurement of IENFD

• Nerve conduction studies, quantitative sensory testing,

• Quantitative sudomotor axon reflex testing

Baseline

8.2 fibers/mm After 1 Year

15.1 fibers/mm

Primary T2DM Prevention Trials

Year Study Follow-up Intervention Outcome

1982 Bedford 10 yr Diet + SU Decrease

1991 Malmo 10 yr Diet + exercise Decrease

1997 Da Quing 6 yr Diet + exercise Decrease, 51%

2001 DPS, Finland 3 yr Diet + exercise Decrease, 58%

2002 DPP 2.8 yr Diet+Ex vs. Met Decrease, 58%

2002 TRIPOD 2.6 yr Troglitazone Decrease, 59%

2002 STOP-NIDDM 3.3 yr Acarbose + Diet Decrease, 25%

2004 XENdos 4 yr Orlistat + Diet Decrease, 37%

2006 DREAM 3 yr Rosiglitazone Decrease, 60%

2008 ACT NOW 2-4 yr Pioglitazone Decrease, 72%

2006 IDPP-1 3 yr L/S + Met Decrease, 26-28%

2009 IDPP-2 3 yr L/S + Pio Pio not additive to L/S

2010 Navigator 5 yr Nateglinide No effect

Valsartan Decrease, 14%

2010 CANOE 4 yr Rosi+Met Decrease 69%

Echouffo-Tcheugui JB, Dagogo-Jack S. Nat Rev Endocrinol 8:557-562, 2012

Legacy Effect: Lifestyle vs. Drugs

• FDPS: sustained benefit of lifestyle (10 yr)

• DPP: sustained benefit of lifestyle (10 yr)

• Da Qing: sustained benefit L/S (20 yr)

• Metformin wash-out study: Failed in 3 mo

• Rosiglitazone washout: faileded in 3 mo

• Pioglitazone washout: failed in 3 mo

FDPS. Lancet 2006;368:1673-1679; Da Qing. Lancet 371, 1783-1789, 2008. DPP Lancet 2009;374:1677-1686;

ACTNOW. J CEM 2016 Mar 16:jc20154202

DPP Research Group. Lancet 374:1677-1686, 2009.

DPPOS: 10-yr Follow-up of Diabetes Incidence and Weight Loss

Ch

an

ge in

weig

ht

(kg

)

DPPOS

Cu

mu

lati

ve

inci

den

ce (

%)

DPPOS

Non-glycemic Benefits

• BP

• Lipids

• Met. Syndrome

• Adipocytokines

• Other

Da Qing Study: Cumulative Incidence of Diabetes and Mortality in

Lifestyle Intervention and Control Groups during 23 Years of follow-up

Li G, et al.

Lancet Diabetes Endocrinol

2014; 2: 474–80.

Control group

Intervention group

All-cause mortality

HR 0.71, 95% CI(0.51-0.99)

CVD mortality

Diabetes incidence

HR 0.55, 95% CI(0.40-0.76)

Prevention of T2DM: Current Recommendations

• Screen asymptomatic people

• Diagnose prediabetes

• Refer for ILI (-7% wt):

– -500 kcal + 150min/wk

• Selective use of metformin

• Education and support

• Assess/control CVD risks

GOAL:

• Prevention of T2DM

• Reversal to NGR?

American Diabetes Association . Diabetes Care 2017; 40(Suppl. 1):S44-S48; DPP Research Group. NEJM 2002;346:393

• Analyzed data from the 2012 National Ambulatory Medical Care Survey

• Identified adults >45 yr without diagnosed DM who had an HbA1c test

within 90 days of the visit (1,167,004 weighted visits)

• HbA1c results:

Normal 54.6%

Prediabetes 33.6%

Diabetes 11.9%

• Of prediabetic HbA1c values, the number of patients diagnosed with

prediabetes was too low (<1%) for a reliable population estimate.

• Indication of treatment in the record (LS counseling and/or metformin)

was present in 23% of those with diagnosed or undiagnosed prediabetes.

(J Am Board Fam Med 2016;29:283–285)

Alerts/Reminders

• Lab reports

• EMR flags

• HMOs

• ACOs

Conclusions

• Prediabetes is a toxic environment that predisposes to

T2DM and multiple complications.

•Lifestyle modification is the best documented, least toxic,

and most appealing option for diabetes prevention.

• Prediabetes is predictable using simple heuristics

(waist, FPG, 2hPG) and reversible with lifestyle

intervention.

• Standards of Care/Best Practices: Screening of

asymptomatic individuals, active diagnosis, and prompt

intervention in persons with prediabetes.