Intermittent fasting vs daily calorie restriction

for type 2 diabetes prevention: a review of

human findings

ADRIENNE R. BARNOSKY, KRISTIN K. HODDY, TERRY G. UNTERMAN, and KRISTA A. VARADY

CHICAGO, ILL

Intermittent fasting (IF) regimens have gained considerable popularity in recent

years, as some people find these diets easier to follow than traditional calorie restric-
tion (CR) approaches. IF involves restricting energy intake on 1–3 d/wk, and eating
freely on the nonrestriction days. Alternate day fasting (ADF) is a subclass of IF, which
consists of a ‘‘fast day’’ (75% energy restriction) alternating with a ‘‘feed day’’ (ad
libitum food consumption). Recent findings suggest that IF and ADF are equally as
effective as CR for weight loss and cardioprotection. What remains unclear, however,
is whether IF/ADF elicits comparable improvements in diabetes risk indicators, when
compared with CR. Accordingly, the goal of this review was to compare the effects of
IF and ADF with daily CR on body weight, fasting glucose, fasting insulin, and insulin
sensitivity in overweight and obese adults. Results reveal superior decreases in body
weight by CR vs IF/ADF regimens, yet comparable reductions in visceral fat mass,
fasting insulin, and insulin resistance. None of the interventions produced clinically
meaningful reductions in glucose concentrations. Taken together, these preliminary
findings show promise for the use of IF and ADF as alternatives to CR for weight loss
and type 2 diabetes risk reduction in overweight and obese populations, but more
research is required before solid conclusions can be reached. (Translational
Research 2014;164:302–311)

Abbreviations: ADF ¼ Alternate day fasting; BMI ¼ Body mass index; CR ¼ Calorie restriction;
HOMA-IR ¼ Homeostatic model assessment-insulin resistance; IF ¼ Intermittent fasting

INTRODUCTION betes within 5 years.1 A key strategy to prevent the

A
t present, 35% of adults older than 20 years in
the United States have prediabetes.1 If no life-
style changes are made to improve health,
15%–30% of these individuals will develop type 2 dia-
From the Division of Endocrinology, Department of Medicine,
University of Illinois at Chicago, Chicago, Ill; Department of
Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, Ill.
Submitted for publication January 15, 2014; revision submitted May
5, 2014; accepted for publication May 8, 2014.
Reprint requests: Krista A. Varady, Department of Kinesiology and
Nutrition, University of Illinois at Chicago, 1919 West Taylor Street,
Room 506F, Chicago, IL 60612; e-mail: varady@uic.edu.
1931-5244/$ - see front matter
Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.trsl.2014.05.013
progression of prediabetes to type 2 diabetes is weight
loss.2 Accumulating evidence suggests that even modest
weight loss (5%–7% of initial weight) helps to improve
several diabetes risk parameters, including fasting
glucose, insulin, and insulin sensitivity.3,4
Daily calorie restriction (CR) regimens are still the
most common diet strategies implemented for weight
loss.5 CR regimens involve reducing energy intake
every day by 20%–50% of needs.5 Although CR is
effective for weight loss in some individuals, many peo-
ple find this type of dieting difficult, as it requires vigi-
lant calorie counting on a daily basis.6 People also grow
frustrated with this diet, as they are never able to eat
freely throughout the day. In light of these issues with
CR, another approach termed intermittent fasting (IF)
has shown promise in achieving weight loss goals.7 IF
differs from CR, in that it only requires an individual
to restrict energy 1–3 d/wk, and allows for ad libitum

302
Translational Research
Volume 164, Number 4
food consumption on the nonrestriction days.7 Alternate
day fasting (ADF) is a subclass of IF, which consists of a
‘‘fast day’’ (75% energy restriction) alternating with
a ‘‘feed day’’ (ad libitum food consumption). Recent
reviews suggest that IF and ADF are equally as effective
as CR for weight loss cardioprotection.7,8 What has yet
to be elucidated, however, is whether IF and ADF elicit
comparable improvements in diabetes risk indicators,
when compared with CR. Accordingly, the goal of this
review was to compare the effects of IF and ADF with
daily CR on body weight, fasting glucose, fasting
insulin, and insulin sensitivity in overweight and
obese adults.
METHODS
We performed a systematic search in MEDLINE
PubMed using the following search strings: (1) ‘‘inter-
mittent fasting and weight loss,’’ (2) ‘‘alternate day fast-
ing and weight’’ or ‘‘alternate day calorie restriction,’’
(3) ‘‘calorie restriction and weight loss and insulin,’’
(4) ‘‘caloric restriction and weight loss and obesity,’’
and (5) ‘‘calorie restriction and metabolic syndrome.’’
Two reviewers (A.B. and K.H.) separately screened
the abstracts for inclusion and exclusion. Full text arti-
cles were retrieved from all abstracts that were poten-
tially relevant and were reviewed independently by
the 2 researchers. The comprehensive literature search
revealed 108 articles under the umbrella category of
IF and 4945 articles in the category of CR. Articles
that were excluded if they did not meet the inclusion
criteria, were review articles, editorials, letters, com-
ments, or conferences proceedings. References of the
retrieved articles were also screened for additional
studies. Inclusion criteria were as follows: (1) random-
ized control trials and nonrandomized trials, (2) total
sample size $8 subjects, (3) primary endpoints of
body weight and one or more relevant diabetes risk
parameter, (4) average daily energy restriction ,50%
(to exclude very low calorie diets that result in muscle
wasting9), (5) trial duration between 3 and 24 weeks,
(6) male and female subjects, (7) age between 25 and
75 years, (8) body mass index (BMI) between 25 and
40 kg/m2, (9) nonsmokers (because of the effects of
smoking on lipid metabolism),10 (10) sedentary or
moderately active individuals, and (11) articles pub-
lished after 2003. We chose 2003 as a cutoff date
because all the IF studies found were published within
this time frame, and we wanted to use the same time
frame for CR studies. Exclusion criteria were as fol-
lows: (1) cohort and observational studies; (2) trials
that combined CR/IF with supplements, pharmacologic
substances, or exercise; (3) diabetic; and (4) very active
individuals or athletes. Ten CR trials and 9 IF trials were
Barnosky et al 303
found that matched these criteria. None of the papers
retrieved implemented intention to treat analyses.
BODY WEIGHT AND VISCERAL FAT MASS
Obesity is a well-established risk factor for the devel-
opment of type 2 diabetes. Findings from the Nurses’
Health Study demonstrate a 100-fold increase in diabetes
risk over 14 years in those with a BMI .35 kg/m2
compared with normal weight individuals.11 At least
one contributing factor to insulin resistance that occurs
in obesity is the decrease in insulin-mediated peripheral
glucose uptake.12 Weight loss results in substantial
reductions in insulin resistance, with every 1 kg lost asso-
ciated with a 16% reduction in estimated risk of devel-
oping diabetes.2
The distribution of excess fat mass also contributes
to the risk for metabolic derangements.13 In 1947, the
concept of regional fat distribution having different
physiological and metabolic effects was first introduced
by Vague.14 Over the subsequent decades, it has been
shown that visceral obesity has a stronger correlation
with a risk for the development of diabetes, hyperten-
sion, hyperlipidemia, hepatic steatosis, and coronary
artery disease compared with that of a gluteoemoral
fat distribution.13 The presence of visceral obesity has
also been shown to have a strong inverse relationship
with insulin sensitivity.13 Evaluation of glucose disposal
rates by euglycemic insulin clamps and visceral adipose
tissue by the computed tomography technique, illus-
trated an inverse association.15 Thus a higher visceral
fat content is correlated with lower insulin sensitivity.15
Weight loss has been shown to decrease both visceral fat
and improve markers of insulin sensitivity.16
IF: effects on body weight and visceral fat mass. Body
weight changes were assessed in 2 IF studies17,18 and 7
ADF studies19-25 (Table I). Findings from these trials
demonstrate 3%–8% reductions in body weight after
3–24 weeks of treatment. Providing food to subjects on
the fast day appears to be a key factor in determining
greatest weight loss. For instance, the most pronounced
weight loss was seen in a study performed by Johnson
et al,21 where ADF subjects were provided with a
320–380 kcal meal replacement shake on each fast day.
After 8 weeks of treatment, subjects lost 8% of
body weight.21 Comparable decreases in body weight
(6%–7%) were also noted in the other 8-week ADF
studies that provided food on the fast day.22,23,25
An exception to this rule is the ADF study by Bhutani
et al.24 In this 12-week trial, fast day food was
provided, but only a 4% weight loss was observed.24
This limited weight loss may be explained by the fact
that food was only provided for the first 4 weeks of the
study,24 and not for the entire duration of trial. Another
Table I. Intermittent fasting: effect on body weight and type 2 diabetes risk parameters

304
Insulin
Average Fasting Fasting resistance/

Barnosky et al
Trial prescribed Body weight Body Visceral fat Lean mass Lean glucose insulin sensitivity
Reference Subjects length Intervention restriction/d (% change) weight (kg) (% change) (% change) mass (kg) (% change) (% change) (% change)

Intermittent fasting studies

Klempel et al17 n 5 54, F 8 wk 1.1 d/wk 100% CR, 1.40% 1.Y4%* 1.Y4* WC — DXA 1.Y3%* 1.Y21%* HOMA-IR
48 6 2 y 6 d/wk 30% 2.40% 2.Y3%* 2.Y3* 1.Y7%* 1.Y1 2.Y2% 2.Y13% 1.Y23%*
Obese CR-liquid diet 2.Y5%* 2.0 2.Y12%
Prediabetic 2.1 d/wk 100% CR,
6 d/wk 30%
CR-food diet
Food provided
Harvie et al18 n 5 53, F 24 wk 1.2 d/wk 75% CR, 1.20% 1.Y7%* 1.Y6* WC BIA BIA 1.Y2% 1.Y29%* HOMA-IR
30–45 y 5 d/wk ad libitum 1.Y6%* 1.Y3%* 1.Y1* 1.Y27%*
Overweight Food not provided
Obese
Alternate day fasting studies
Heilbronn et al19 n 5 16, MF 3 wk 1. Fast day: 100% 1.50% 1.Y3%* — — DXA DXA 1.Y1% 1.Y57%* —
23–53 y CR, feed day: 1.Y1%* 1.Y1*
Overweight ad libitum
Food not provided
Eshghinia and n 5 15, F 6 wk 1. Fast day: 70% CR, 1.35% 1.Y7%* 1.Y3 WC DXA DXA 1.Y6% — —
Mohammadzadeh20 34 6 6 y feed day: ad libitum 1.Y6%* 1.Y1% 1.Y2
Obese Food not provided
Johnson et al21 n 5 10, MF 8 wk 1. Fast day: 80% CR, 1.40% 1.Y8%* 1.Y9* — — — 1.[6% 1.Y37%* HOMA-IR
Age NR feed day: ad libitum 1.Y33%*
Obese Food provided on the
fast day
Varady et al22 n 5 16, MF 8 wk 1. Fast day: 75% CR, 1.35% 1.Y6%* 1.Y6* WC BIA BIA 1.Y4%* 1.Y20%* HOMA-IR
46 6 2 y feed day: ad libitum 1.Y4%* 1.0% 1.0 1.Y19%*
Obese Food provided on the
Prediabetic fast day
Klempel et al23 n 5 32, F 8 wk 1. Fast day: 75% CR, 1.35% 1.Y5%* 1.Y4* WC DXA DXA 1.Y2% — —
42 6 2 y feed day: ad 2.35% 2.Y4%* 2.Y4* 1.Y7%* 1.[1% 1.[1
Obese libitum-HF 2.[1% 2.[1
2. Fast day: 75% CR,
feed day: ad
libitum-LF

Translational Research
Food provided on the
fast day
Bhutani et al24 n 5 32, MF 12 wk 1. Fast day: 75% CR, 1.35% 1.Y4%† 1.Y3† WC BIA BIA 1.Y3% 1.Y11%† HOMA-IR

October 2014
43 6 3 y feed day: ad libitum 2.0% 2.0% 2.0 1.Y4%† 1.Y1 1.Y2% 2.[3% 2.[1% 1.Y9%†
Obese 2. Control: ad libitum 2.Y1% 2.0% 2.0% 2.[2%
fed every day
Food provided on the
fast day (week
1–4 only)
Translational Research
Volume 164, Number 4 Barnosky et al 305

factor that appears to impact degree of weight loss is the

Abbreviations: BIA, bioelectrical impedance analysis; CR, calorie restriction; DXA, dual-energy X-ray absorptiometry; F, female; HF, high-fat diet; HOMA-IR, homeostatic model of assessment for
HOMA-IR
1.Y28%†
2.[2%
number of fast days per week. Not surprisingly, a faster
rate of weight loss was observed in the ADF studies,19-
25
which required subjects to fast 3–4 d/wk, compared
with the IF studies,17,18 which required subjects to only
1.Y31%†
2.[2%

fast 1–2 d/wk. On average, ADF appears to produce a

0.75 kg weekly reduction in body weight, whereas IF
produces a 0.25 kg weekly weight loss. As such,
Significantly different from the control group (P , 0.05). Prescribed daily restriction estimated assuming 0% restriction (ie, 100% intake) on the ad libitum feed days.
1.Y6%†

clinicians may want to recommend ADF to their

2.[1%

patients who are eager to lose weight more rapidly, and

IF to patients who would prefer to lose weight at a
slower pace.
2.0%
1.Y2

Visceral fat changes were assessed in 2 IF studies17,18

DXA

and 5 ADF studies.20,22-25 Results reveal 4%–7% re-

ductions in visceral fat after 6–24 weeks of treatment.
1.Y3%
2.Y1%

In most studies, the percentage of visceral fat loss

DXA

closely paralleled the percentage of weight loss. For

example, in the ADF study by Varady et al,22 a 6%
decrease in visceral fat was observed corresponding to
1.Y6%†
2.Y1%

7% weight loss. Bhutani et al24 had a similar study

WC

design, however, only a 4% decrease in visceral fat was

observed corresponding to a 4% weight loss. Similar
reductions in visceral fat were also demonstrated in
1. Y5†
2.Y1

IF studies (3%–7%),17,18 suggesting that IF and ADF

produce comparable decreases in this body composition
parameter. It should be noted, however, that visceral fat
1.Y7%†
2.Y1%

was assessed indirectly in each of these trials by

measuring waist circumference. Thus, these studies are
limited, in that actual kilogram decreases in visceral fat
were not determined. Future studies of IF and ADF
insulin resistance; LF, low-fat diet; M, male; NR, not reported; WC, waist circumference.
1.35%

should therefore strive to use more robust techniques,

2.0%

such as magnetic resonance imaging, to measure actual

kilogram changes in visceral fat mass.
feed day: ad libitum

CR: effects on body weight and visceral fat mass. Body

n 5 32, MF 12 wk 1. Fast day: 75% CR,

Food provided on the

2. Control: ad libitum

weight changes were assessed in 10 CR trials16,18,26-33

*Post-treatment value significantly different from baseline (P , 0.05).
fed every day

(Table II). Findings from these studies demonstrate

All data reported are for subjects who completed the entire trial.

a 4%–14% reduction in weight after 6–24 weeks of

fast day

treatment. The greatest weight loss was observed in

the trials with the largest average weekly caloric
restriction.16,27,33 In a study by Larsen-Meyer et al,33
overweight participants were randomized into 1 of 3
groups: (1) 50% CR every day, (2) 25% CR every day,
Overweight
Prediabetic

or (3) a control group with ad libitum feeding every

Normal wt
47 6 4 y

day. After 24 weeks of treatment, participants in the

50% CR group had greater weight loss (14%), when
compared with the 25% CR group (10% weight
loss).33 A faster rate of weight loss was also noted in
the other studies which implemented 50% CR16,27
when compared with the 25% CR trials.18,26,28-32 The
Varady et al25

background macronutrient composition of the CR

diets, however, did not seem to have any impact on
rate of weight loss. This is evidenced in the trial by
Melanson et al,32 which compared the effects of a 30%
CR-low energy density diet with that of a 30% CR-
†
Table II. Daily CR: effect on body weight and type 2 diabetes risk parameters

306
Insulin

Barnosky et al
Average Fasting Fasting resistance/
Trial prescribed Body weight Body Visceral fat Lean mass Lean glucose insulin sensitivity
Reference Subjects length Intervention restriction/d (% change) weight (kg) (% change) (% change) mass (kg) (% change) (% change) (% change)

Xydakis et al16 n 5 80, MF 6 wk 1.50% CR-high- 1.50% 1.Y7%* 1.Y18* WC — — 1.Y15%* 1.Y65%* HOMA-IR
47 6 1 y protein diet 1.Y8%* 1.Y70%*
Obese Food provided
Trussardi Fayh n 5 35, MF 6 wk 1.25% CR 1.25% 1.Y5%* 1.Y4* WC — — 1.Y3% 1.Y11%* HOMA-IR
et al26 30 6 6 y Food not provided 1.Y4%* 1.Y20%*
Obese
Prediabetic
Svendsen et al27 n 5 17, F 8 wk 1.50% CR-high- 1.50% 1.Y11%* WC 1.Y8%* 1.Y35%* HOMA-IR
25 6 3 y protein diet 1.Y22%* 1.Y32%*
Overweight Food not provided
Mollard et al28 n 5 40, MF 8 wk 1.25% CR-high- 1.25% 1.Y1% 1.Y1 WC — — 1.0% 1.[2% HOMA-IR
46 6 1 y fiber diet 1.Y2%* 1.[1%
Obese Food provided
Clifton et al29 n 5 62, F 12 wk 1.25% CR-LF diet 1.25% 1.Y11%* 1.Y10* — — — 1.Y1%* 1.Y26%* —
47 6 10 y 2.25% CR-high 2.25% 2.Y8%* 2.Y9* 2.Y2%* 2.Y41%*
Obese MUFA low-
Prediabetic protein diet
Food provided
De Luis et al30 n 5 40, MF 12 wk 1.25% CR-liquid diet 1.25% 1.Y8%* 1.Y8* WC BIA BIA 1.0% 1.Y24%* HOMA-IR
65 6 8 y 2.25% CR-food diet 2.25% 2.Y5%* 2.Y5* 1.Y5%* 1.Y1%* 1.Y1* 2.[1% 2.Y25% 1.Y25%*
Obese Food provided in the 2.Y4%* 2.Y3%* 2.Y1* 2.Y12%
liquid diet group
Agueda et al31 n 5 78, F 12 wk 1.25% CR every day 1.25% 1.Y9%* Y 8* WC DXA DXA 1.Y2%* 1.Y27%* HOMA-IR
37 6 7 y Food not provided 1.Y7%* 1.Y5%* 1.Y3* 1.Y30%*
Obese
Melanson et al32 n 5 157, MF 12 wk 1.30% CR-low 1.30% 1.Y5%* 1.Y4* — — 1.[1 1.[1% 1.Y16%* HOMA-IR
38 6 7 y energy density diet 2.30% 2.Y4%* 2.Y3* — 2.Y1 2.[1% 2.Y8%* 1.Y17%*
Obese 2.30% CR-low 3.30% 3.Y4%* 3.Y4* — 3.0 3.Y1% 3.Y12%* 2.Y7%*
Prediabetic glycemic index 3.Y17%*
diet
3.30% CR-portion
control diet
Food not provided

Translational Research
Larson-Meyer n 5 48, MF 24 wk 1.25% CR every day 1.25% 1.Y10%† 1.Y8† CT DXA DXA 1.Y1% 1.Y29%† OGTT-IS
et al33 25–50 y 2.50% CR every day 2.50% 2.Y14%† 2.Y11† 1.Y28%† 1.Y5%† 1.Y3† 2.[1% 2.Y15%† 1.[27%*
Overweight until 15% body 3. No CR 3.0% 3.0 2.Y38%† 2.6%† 2.Y3† 3.[2% 3.[2% 2.[52%*

October 2014
weight lost 3.Y3% 3.0% 3.0 3.[11%
3. Control: ad libitum
fed every day
All food provided for
weeks 1–12 and
22–24
Translational Research
Volume 164, Number 4 Barnosky et al 307

low glycemic index diet. After 12 weeks of treatment,

Abbreviations: BIA, bioelectrical impedance analysis; CR, calorie restriction; DXA, dual-energy x-ray absorptiometry; F, female; HOMA-IR, homeostasis model of assessment for insulin resistance; LF,
HOMA-IR
1.Y19%*
both groups lost similar amounts of weight (4%–5%)
despite differences in the background macronutrient
profiles.32 It was also noted that the rate of weight loss
by CR is similar in overweight and obese individuals,
1.Y15%*

and males and females, when the same degree of CR

is applied. Similar amounts of weight loss were also
noted in older30 vs younger adult subjects.29 For
instance in the study by De Luis et al,30 elderly men
1.Y2%

and women experienced comparable weight loss after

12 weeks of 25% CR, when compared with middle-
aged adults undergoing a similar intervention.29 Thus,
CR appears to be effective for weight loss independent
1.Y1*

of BMI class, sex, and age.

low-fat diet; M, male; MUFA, monounsaturated fatty acid; OGTT-IS, oral glucose tolerance test for insulin sensitivity; WC, waist circumference.

Visceral fat changes were assessed in 8 CR

studies.16,18,26-31,33 After 6–24 weeks of diet, 2%–38%
1.Y2%*

reductions in visceral fat mass were observed. Similar

to what was seen in IF studies, percentage of visceral
fat loss generally paralleled the percentage of weight
circumference

loss. For example, the greatest decrease in visceral fat

1.Y4%*

(38%) was observed in the study by Larson-Meyer

Waist

et al,33 which implemented a 50% CR protocol for

24 weeks. This degree of visceral fat loss corresponded
to a 14% weight loss.33 Within the same study, a 28%
reduction in visceral fat was seen in the 25% CR group
1.Y6*

with a 10% weight loss.33 Moreover, Svendsen et al27

showed a 22% decrease in visceral fat, corresponding
to an 11% reduction in body weight. Taken together, it
would appear as although greater degrees of energy
1.Y5%*

restriction produce the most optimal changes in body

weight and visceral fat mass.
1.25%

GLUCOSE AND INSULIN

Individuals are categorized as having ‘‘prediabetes’’
*Post-treatment value significantly different from baseline (P , 0.05).

when (1) fasting glucose falls between 100 and

All data reported are for subjects who completed the entire trial.
24 wk 1.25% CR every day

125 mg/dL, (2) plasma glucose falls between 140 and

No food provided

199 mg/dL 2 after an oral glucose tolerance test, or

(3) hemoglobin A1c falls between 5.7% and 6.4%.34
Significantly different from control group (P , 0.05).

Lifestyle modification, namely dietary changes and

exercise with the goal of weight loss, are commonly
used as the first line therapy. Randomized, controlled
trials have shown that with intensive dietary counseling
and increased physical activity, type 2 diabetes can be
prevented in high-risk individuals with prediabetes.35,36
As expected, these studies have shown decreases in
Overweight
n 5 54, F
30–45 y

fasting glucose levels and improvements in glucose

Obese

tolerance. The Finnish Diabetes Prevention Study

found a 58% reduction in the overall incidence of
diabetes in the intensive lifestyle group compared with
Harvie et al18

that of controls with similar benefit seen in other

studies.35-37
IF: effects on fasting glucose and insulin levels. Changes
in fasting glucose were assessed in 2 IF studies17,18 and
†

308 Barnosky et al
7 ADF studies19-25 (Table I). However, the present
discussion will be limited to studies that recruited
prediabetic individuals,17,22,25 as it may not be scien-
tifically valid to assess the effect of these diets on
glucose and insulin levels of normoglycemic subjects.
Results from these trials demonstrate consistent yet
minor decreases (3%–6%) in fasting glucose after
8–12 weeks of treatment. The greatest decrease in
glucose was observed in the study by Varady et al.25 In
this trial,25 participants were randomized to an ADF
group (35% average daily CR) vs a control group (no
restriction). After 12 weeks of diet, a 6% reduction
in glucose concentrations was observed in the ADF
group relative to controls.25 Reductions in glucose
concentrations (3%–4%) were also observed in the
8-week ADF study by Varady et al22 and the 8-week
IF study by Klempel et al.17 These less pronounced
decreases in glucose are most likely because of the
shorter intervention period imposed by these 2 studies,
that is 8 weeks17,22 vs the 12-week intervention imple-
mented by Varady et al.25
Fasting insulin levels were assessed in 2 IF studies17,18
and 5 ADF studies.19,21,22,24,25 However, as mentioned
previously, only studies that recruited prediabetic in-
dividuals will be discussed here.17,22,25 In these trials,
decreases in fasting insulin ranged from 20% to 31%
after 8–12 weeks of treatment.17,22,25 Similar reduc-
tions in fasting insulin were seen with ADF (20%)22
and IF (21%)17 after 8 weeks of diet. Remarkably, these
comparable decreases occurred despite the greater num-
ber of fasting days implemented by the ADF study (3–4
fast days)22 vs the IF study (1 fast day).17 However, it
should be noted that, overall, both interventions prescri-
bed the same level of energy restriction (35%–40%).17,22
Thus, degree of restriction may be a stronger pre-
dictor of insulin lowering when compared with the
number of fasting days. The greatest decreases in
insulin concentrations (31%) were noted in the study
by Varady et al.25 These superior reductions are most
likely the result of the longer intervention period
(12 weeks) used by this trial.25
CR: effects on fasting glucose and insulin levels. Fasting
glucose levels were assessed in all the CR studies
reviewed here16,18,26-33 (Table II). Similar to IF and
ADF, we will limit our discussion for glucose to
those trials that recruited prediabetic subjects.26,29,32
Results from these studies indicate that 6–12 weeks
of 25%–30% CR has virtually no effect on fasting
glucose concentrations.26,29,32 Moreover, modulating
the background nutrient composition of the diet (via a
high monounsaturated fat, low fat, or glycemic index
diet) also does not appear to impact fasting glucose
levels.29,32 It will be of interest in future trials to
examine whether improvements in glucose can be seen
Translational Research
October 2014
with greater energy restriction or longer treatment
durations in this population group.
Fasting insulin levels were assessed in 10 CR
studies.16,18,26-33 However, our discussion will be
limited to those trials that recruited prediabetic subjects
only.26,29,32 Findings from these trials demonstrate
fairly consistent reductions in insulin levels, ranging
from 11% to 41% after 6–12 weeks of treatment.26,29,32
The most pronounced reductions in insulin (41%) were
noted in the study by Clifton et al,29 which implemented
a 25% CR-high monounsaturated fat-low-protein diet
intervention for 12 weeks. In a separate arm of this
study,29 less pronounced reductions in insulin (26%)
were observed in response to a 25% CR-low-fat diet.
Thus, a background diet that is high monounsaturated
fat may produce more optimal changes in insulin
compared with a diet that is low in fat. The degree to
which insulin is lowered may also be related to amount
of weight loss. For instance, the study by Clifton et al29
observed the greatest degree of weight loss (8%–11%)
when compared with the studies by Trussardi Fayh
et al26 (5%) and Melanson et al32 (4%–5%). Thus, there
may be a dose-response relationship between weight loss
and insulin lowering by CR in prediabetic individuals.
INSULIN SENSITIVITY
Insulin resistance is seen in virtually all patients
with type 2 diabetes and occurs early in the disease,
before overt diabetes is diagnosed. Both a decrease in
insulin sensitivity and insulin deficiency are thought to
contribute to type 2 diabetes. Interventions directed
at reducing body weight have shown promise for
improving insulin sensitivity, and have also been shown
to delay or prevent onset of type 2 diabetes.38
IF: effects on insulin sensitivity. Changes in insulin
sensitivity were assessed in 2 IF studies17,18 and 4
ADF studies21,22,24,25 (Table I). Results from these
trials demonstrate consistent improvements in insulin
sensitivity after 3–24 weeks of treatment in normo-
glycemic and prediabetic subjects. The primary
method of measuring insulin sensitivity was homeo-
static model assessment (HOMA-IR). In reviewing
these results, it would appear as although the greatest
improvements in insulin sensitivity occurred with
the highest amount of weight loss. For instance, in the
ADF study by Johnson et al,21 subjects experienced
the greatest degree of weight loss (8%), which cor-
responded to the largest decline in HOMA-IR (33%).
In the ADF trial by Bhutani et al,24 body weight
decreased by 4% from baseline, which produced
moderate reductions in HOMA-IR (9%). Impressive
reductions in insulin resistance were also noted by IF.
For instance, 23% decreases in HOMA-IR were noted
Translational Research
Volume 164, Number 4
after 8 weeks of fasting 1 d/wk with a liquid diet.17
Moreover, 27% decreases in HOMA-IR were obser-
ved after 24 weeks of fasting 2 d/wk.18 Weight loss in
these 2 IF trials was 4%17 and 7%,18 respectively.
Although reductions in body weight appear to be
an important factor in determining improvements in
insulin sensitivity, no relationship between visceral fat
mass and insulin sensitivity could be established from
the studies reviewed here. This is most likely because
of the small number of studies, and because visceral
fat mass was only measured indirectly via waist cir-
cumference. Implementing techniques that can quan-
tify actual kilogram decreases in visceral fat mass
(ie, magnetic resonance imaging), may help clarify the
relationship between abdominal fat reductions and
improvements in insulin sensitivity in future IF and
ADF trials.
CR: effects on insulin sensitivity. Modulations in insulin
sensitivity by CR were assessed in 9 studies16,18,26-28,30-33
(Table II). Substantial improvements in insulin sensitivity
after 6–24 weeks were noted in all but one CR study.28
The primary method for measuring insulin sensitivity
was HOMA-IR, with the exception of the study by
Larson-Meyer et al,33 which implemented an oral
glucose tolerance test. The most important factor in
determining improvement in insulin sensitivity appears
to be the degree of energy restriction imposed. For
instance, in the study by Xydakis et al,16 a 6-week 50%
CR-high-protein diet resulted in a 70% decrease in
HOMA-IR. Similarly, Svendsen et al27 demonstrated
a 32% decrease in insulin resistance after 8 weeks of a
high restriction regimen (50% CR combined with a
high-protein background diet). Findings from 25% CR
studies also demonstrated reductions in insulin resis-
tance,18,26,30,31 although these effects were less pro-
nounced than the 50% CR studies. For example, Harvie
et al18 implemented a 25% CR protocol in overweight
and obese subjects for 24 weeks, and a 15% decrease in
HOMA-IR was observed. Likewise, Trussardi Fayh
et al26 prescribed a 25% CR diet, and HOMA-IR
decreased by 20% from baseline. Although the higher
energy restriction diets (50% CR) seem to show a
greater decrease in HOMA-IR, sustainability of this
type of diet is likely to be challenging. This should be
considered when prescribing CR protocols to patients in
a clinical setting. Unfortunately, none of these studies
included a follow-up period to investigate what happens
when the individual ceases the diet altogether. Whether
insulin resistance rebounds more quickly after stopping
a 50% CR protocol, vs a 25% protocol, warrants further
investigation, as this may help in determining which
level of energy restriction should be prescribed for
longer-term success.
Barnosky et al 309
SUMMARY OF FINDINGS: EFFECTIVENESS OF IF VS CR
FOR TYPE 2 DIABETES PREVENTION
Body weight and visceral fat mass. Findings from the
present review indicate that CR produces slightly supe-
rior weight loss when compared with IF/ADF after
similar durations of treatment. For instance, after
3–24 weeks of IF or ADF, 3%–8% reductions in body
weight were observed. As for CR, 6–24 weeks of diet
produced reductions ranging from 4% to14%. Not sur-
prisingly, greater degrees of energy restriction and
longer treatment durations produced larger reductions
in body weight. IF, ADF, and CR appear to be effective
for reducing body weight in men and women, older and
younger adults, and prediabetic individuals. Similar
decreases in visceral fat mass were also noted by all 3
interventions, and the degree to which visceral fat
mass was reduced paralleled the degree of weight loss.
Glucose and insulin. The impact of IF, ADF, and
CR on fasting glucose concentrations in prediabetic
subjects was variable. Although IF and ADF studies
demonstrated minor decreases in glucose (3%–6%
from baseline), CR studies general report no effect after
6–12 weeks of diet. Fasting insulin, on the other hand,
was highly responsive to all 3 interventions. In general,
insulin concentrations were reduced by 20%–31% after
8–12 weeks of IF and ADF, and by 11%–41% after
6–12 weeks of CR. Reductions in insulin concentrations
by IF, ADF, and CR appeared to be most strongly related
to the degree the of imposed restriction and amount of
weight loss.
Insulin sensitivity. Consistent improvements in insulin
sensitivity were noted by all 3 interventions after
3–24 weeks of treatment. These improvements occurred
in prediabetic subjects and subjects with normal fasting
glucose values. The degree to which insulin sensitivity
was improved appeared to be most strongly related
to the degree of energy restriction and amount of total
weight loss. This observation is supported by other
studies in this field.39,40 For instance, in a study by
Wing et al,39 subjects were randomized to either a
400 kcal/d group or a 1000 kcal/d group, with the goal
of losing 11% of baseline body weight in both groups.
Results reveal that those individuals in the 400 kcal/d
group had lower fasting glucose and increased insulin
sensitivity when compared with the 1000 kcal/d group,
despite the same weight loss.39 Moreover, in an early
study by Henry et al,40 improvements in glycemic
control were noted within 3 days of starting a hypo-
caloric diet, suggesting that dietary restriction can
affect glycemia even before actual weight loss occurs.
Limitations. This review has a number of limitations.
Firstly, the protocols, interventions, and populations
between studies are quite heterogeneous. This

310 Barnosky et al
heterogeneity makes it difficult to draw clear conclu-
sions from the data as a whole, and needs to be taken
into consideration when interpreting the present find-
ings. Secondly, the number of studies that have been
conducted in the IF and ADF field are very limited.
Thus, it is not possible to make clinical recommenda-
tions as to the efficacy of these dietary restriction proto-
cols for use by the general public. Thirdly, we were not
able to report weight loss as change in mass per week,
because most of these studies only reported baseline
and post-treatment body weight values. Including
these data would have offered an indication of trends
in weight loss, that is whether weight loss was linear
or greater at the beginning of the trial, which would
have been of value.
CONCLUSIONS
In sum, IF, ADF, and CR regimens appear to be effec-
tive for reducing body weight, although CR may result
in slightly greater weight loss. As for visceral fat mass,
and fasting insulin and insulin sensitivity, the effect of
IF, ADF, and CR on these diabetic risk parameters
appears comparable. Whether these regimens are effec-
tive for glucose lowering remains uncertain, and war-
rants further investigation. Although these preliminary
findings show promise for the use of IF and ADF as
alternatives to CR for weight loss and type 2 diabetes
risk reduction, clear conclusions cannot be drawn
because of the limited number of studies published in
this field. Much work remains to be done to understand
these diet strategies fully.
ACKNOWLEDGMENTS
This work was funded by grants from the National
Institutes of Health (NIDDK T32DK080674, NHLBI
1R01HL106228-01).
Conflict of interests: None.
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