Nuttall FQ, Gannon MC. Metabolic response of people with type 2 diabetes to a high protein diet. Nutr Metab (London) 1, 6

Abstract

Background
One of the major interests in our laboratory has been to develop a scientific framework for dietary advice for patients with diabetes. Knowledge regarding the metabolic consequences and potential effects on health of protein in people with type 2 diabetes has been a particular interest.

Results
We recently have completed a study in which dietary protein was increased from 15% to 30% of total food energy. The carbohydrate content was decreased from 55% to 40%, i.e. dietary protein replaced part of the carbohydrate. This resulted in a significant decrease in total glycohemoglobin, a decrease in postprandial glucose concentrations and a modest increase in insulin concentration. Renal function was unchanged.
Currently we also are determining the metabolic response to a diet in which the carbohydrate content is further decreased to 20% of total food energy. The %tGHb decrease was even more dramatic than with the 40% carbohydrate diet.

Conclusion
From these data we conclude that increasing the protein content of the diet at the expense of carbohydrate can reduce the 24-hour integrated plasma glucose concentration, at least over a 5-week period of time. The reduction was similar to that of oral agents. Renal function was not affected significantly. Thus, increasing the protein content of the diet with a corresponding decrease in the carbohydrate content potentially is a patient empowering way of reducing the hyperglycemia present with type 2 diabetes mellitus, independent of the use of pharmaceutical agents.

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Nutrition & Metabolism
Open Access
Review
Metabolic response of people with type 2 diabetes to a high protein
diet
Frank Q Nuttall*
†1,2
and Mary C Gannon
†1,2,3
Address:
1
Metabolic Research Laboratory, Endocrine, Metabolism & Nutrition Section, Minneapolis VA Medical Center, Minneapolis, USA,
2
Department of Medicine, University of Minnesota, USA and
3
Department of Food Science and Nutrition, University of Minnesota, USA
Email: Frank Q Nuttall* - nutta001@umn.edu; Mary C Gannon - ganno004@umn.edu
* Corresponding author †Equal contributors
Abstract
Background: One of the major interests in our laboratory has been to develop a scientific
framework for dietary advice for patients with diabetes. Knowledge regarding the metabolic
consequences and potential effects on health of protein in people with type 2 diabetes has been a
particular interest.
Results: We recently have completed a study in which dietary protein was increased from 15% to
30% of total food energy. The carbohydrate content was decreased from 55% to 40%, i.e. dietary
protein replaced part of the carbohydrate. This resulted in a significant decrease in total
glycohemoglobin, a decrease in postprandial glucose concentrations and a modest increase in
insulin concentration. Renal function was unchanged.
Currently we also are determining the metabolic response to a diet in which the carbohydrate
content is further decreased to 20% of total food energy. The %tGHb decrease was even more
dramatic than with the 40% carbohydrate diet.
Conclusion: From these data we conclude that increasing the protein content of the diet at the
expense of carbohydrate can reduce the 24-hour integrated plasma glucose concentration, at least
over a 5-week period of time. The reduction was similar to that of oral agents. Renal function was
not affected significantly. Thus, increasing the protein content of the diet with a corresponding
decrease in the carbohydrate content potentially is a patient empowering way of reducing the
hyperglycemia present with type 2 diabetes mellitus, independent of the use of pharmaceutical
agents.
Background
Our research group has been and continues to be inter-
ested in the metabolic response of people with type 2 dia-
betes to macronutrients in the diet in general. More
recently, we have been particularly focused on the meta-
bolic response to a high protein diet. The reason for this is
three fold: First, for several years, one of our major goals
has been to develop a scientific framework for dietary
advice based on sound metabolic principles. Second, we
have data that suggest that an increase in dietary protein
may be salutary for people with diabetes. And lastly,
knowledge regarding the metabolic consequences and
potential effects on health of dietary protein has lagged far
behind that of dietary fats and carbohydrates.
Published: 13 September 2004
Nutrition & Metabolism 2004, 1:6 doi:10.1186/1743-7075-1-6
Received: 03 August 2004
Accepted: 13 September 2004
This article is available from: http://www.nutritionandmetabolism.com/content/1/1/6
© 2004 Nuttall and Gannon; licensee BioMed Central Ltd.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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In this paper we will focus on the concept that an increase
in dietary protein may be salutary for people with diabe-
tes, and particularly for the control of blood glucose.
Results
The concept that an increase in dietary protein may be
useful in controlling the blood glucose would appear to
be counterintuitive, since amino acids derived from
ingested or endogenous proteins are major net gluconeo-
genic substrates.
The first step in the metabolism of amino acids is the
removal of the amino group. This is condensed with CO
2
to form urea. The remaining deaminated product is
largely converted into glucose through gluconeogenesis,
although a small amount is converted into other prod-
ucts. (Figure 1).
Indeed, in 1915, Dr. Janney [1] reported that 3.5 g glucose
can be obtained from 6.25 g of ingested meat or beef pro-
tein. Thus, theoretically for every 100 g of protein
ingested, 56 g of glucose can be produced. For other pro-
teins this varies between 50 and 84 grams. Thus when
developing a dietary regimen for diabetic patients, dieti-
tians were taught to count not only carbohydrate, but also
to count 56% of the protein as carbohydrate. The ration-
ale behind this recommendation was that carbohydrates
raised blood glucose, proteins are converted to glucose,
therefore, dietary proteins will raise blood glucose.
However, in 1924, Dr. MacLean [2] reported that when a
man with diabetes, and a fasting blood glucose of 280
mg/dl, ingested 250 g of meat, which is the equivalent of
50 grams of protein, and which should result in the
production of ~25 g of glucose, there was no change in
blood glucose over the 5 hours of the study. When the
same subject ingested 25 g of glucose, there was a very
large increase in blood glucose; indeed, it increased up to
600 mg/dl.
This lack of increase in blood glucose concentration fol-
lowing the ingestion of protein was confirmed by Conn
and Newburgh in 1936 [3]. These investigators fed a rela-
tively enormous amount of beef, i.e. 1.3 pounds of beef,
which is the equivalent of ~136 g of protein and which
should yield 68 g of glucose, to a normal subject with a
fasting blood glucose of 65 mg/dl and to a subject with
diabetes whose fasting blood glucose concentration was
150 mg/dl. In neither case was there an increase in blood
glucose concentration over the 8 hours of this study. How-
ever, when the same subjects were given 68 g of glucose,
there clearly was an increase in glucose concentration in
both cases.
That ingested protein did not raise the blood glucose was
largely ignored, in spite of this evidence in the scientific
literature. Indeed, in his textbook in 1945 [4], Dr. Joslin,
one of the most influential diabetologists at that time, was
still counseling dietitians and patients to consider 56% of
dietary protein as if it were carbohydrate.
Single meal studies done in our laboratory
With this background information, we decided to do a
study expanding on these early observations. Seven sub-
jects with type 2 diabetes [5], and 8 subjects without dia-
betes [6] ingested 50 g of protein in the form of very lean
beef. In the non-diabetic subjects, there was no change in
blood glucose concentration over the 4 hours of the study,
as had been noted previously. However, in the subjects
with type 2 diabetes, the glucose concentration actually
decreased over the 5 hours of that study (Figure 2).
We also determined the serum insulin response to the
ingested protein and in confirmation of the studies of
Berger [7], Fajans [8] and others, we observed a modest
increase in the insulin concentration in the non-diabetic
subjects [6]. However, there was a relatively large increase
in insulin concentration in the subjects with type 2 diabe-
tes [5]. Indeed, it was about four-fold greater than in the
non-diabetic subjects (Figure 2). We also determined that
the rise in insulin following the ingestion of 50 g of beef
protein was just as potent in raising the insulin concentra-
tion as was the ingestion of 50 g of glucose [5]. That is,
meat protein and glucose were equipotent in stimulating
insulin secretion. In addition, we also demonstrated a
The α amino group from an amino acid is condensed with CO
2
to form ureaFigure 1
The α amino group from an amino acid is condensed
with CO
2
to form urea. The remaining carbon skeleton
can be used to synthesize glucose.

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linear dose-response relationship between the amount of
beef ingested and the insulin response [5].
Since beef protein strongly stimulated insulin secretion,
we next determined whether the simultaneous ingestion
of protein with glucose would stimulate even more insu-
lin and thus reduce the rise in glucose expected when glu-
cose alone is ingested. We also were interested in
determining if all common protein sources were equal in
this regard. Therefore, we designed a study in which 9 – 15
males with untreated type 2 diabetes were given 50 g of
glucose with or without 25 g of protein [9]. Seven protein
sources were used: beef, turkey, gelatin, egg white, cottage
cheese, fish and soy. The rationale behind giving 25 g of
protein with 50 g of glucose, was that this ratio more
closely resembles the ratio of protein to carbohydrate typ-
ically found in the diet. The plasma glucose and serum
insulin concentrations were determined over a 5-hour
period and the areas under the curves were calculated.
The glucose area response clearly was decreased when glu-
cose was ingested with 25 g of protein as beef, turkey, gel-
atin, cottage cheese, fish and soy. Only egg white did not
result in a significant decrease in glucose area response
when compared to the response to ingestion of glucose
alone (Figure 3).
When any of the proteins was added to the ingested glu-
cose, the insulin area response was greatly increased (Fig-
ure 4). The smallest response was obtained with egg
white, which was 190% or 1.9 fold over the response to
glucose ingested alone. The greatest increase was with cot-
tage cheese, which was 360% or 3.6 fold.
As indicated previously, beef protein, on a weight basis,
was just as potent as glucose in raising the insulin concen-
tration. Since only 25 g of beef protein was ingested in the
present study, the expected response would be 150% of
that observed with just glucose ingestion [5]. With beef
and every other protein source studied, the insulin
response was greater than the theoretical expected
response (Figure 4), strongly suggesting that there is a syn-
ergistic insulin response when protein is ingested with
glucose [9].
In summary, in single meal studies in people with type 2
diabetes, dietary protein strongly stimulated insulin
secretion and decreased the plasma glucose response to
ingested glucose.
Insulin and Glucose Response to Mixed Meals
Based on the above observations, we decided to deter-
mine whether an increase in dietary protein in association
with a decrease in carbohydrate would decrease the 24
hour integrated plasma glucose concentration, increase
the 24 hour integrated insulin concentration and decrease
the % total glycohemoglobin in people with type 2
diabetes ingesting mixed meals over an extended period
of time.
Glucose (left panel) and insulin (right panel) response to ingestion of 50 g of protein in the form of lean beefFigure 2
Glucose (left panel) and insulin (right panel) response
to ingestion of 50 g of protein in the form of lean
beef. Data from 8 non-diabetic subjects (white lines, bot-
tom) and 7 subjects with type 2 diabetes (yellow lines, top).
(From [5,6])
Five hour integrated glucose area response to ingestion of 50 g glucose alone (pink bar) or 50 g glucose + 25 g protein in the form of beef, turkey, gelatin, egg white, cottage cheese, fish or soy (yellow bars, left to right)Figure 3
Five hour integrated glucose area response to inges-
tion of 50 g glucose alone (pink bar) or 50 g glucose +
25 g protein in the form of beef, turkey, gelatin, egg
white, cottage cheese, fish or soy (yellow bars, left to
right). (From [9])

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We designed a study in which the protein content of the
diet was increased from 15% of total food energy in a
standard diet, to 30% protein in the experimental diet
[10]. The carbohydrate content was decreased from 55%
carbohydrate to 40% carbohydrate. However, it should be
understood that since the additional protein can result in
an increase in glucose production, the actual carbohydrate
available theoretically would be about 48%, or a decrease
in potential carbohydrate of only 7%. The fat content
remained the same in both diets. Monounsaturated, pol-
yunsaturated and saturated fat ratios were 10:10:10,
respectively.
Twelve people with untreated type 2 diabetes were studied
using a randomized, crossover design. The subjects
received each diet for 5 weeks with a washout period in
between. The diets were isocaloric, and all food was pro-
vided. The subjects came to the Special Diagnostic and
Treatment Unit 2–3 times each week to pick up the food,
to be weighed, and to provide a urine specimen for creat-
inine and urea nitrogen determination.
The major end-point of the study was to determine if there
was a significant decrease in % total glycohemoglobin
(%tGHb).
The reason that 5 weeks was chosen for the study is
because this is the time required for the % total glycohe-
moglobin to decrease 50% of its ultimate value after a
rapid stable decrease in blood glucose concentration (Fig-
ure 5), [11], i.e. the results obtained should represent 50%
of the ultimate % total glycohemoglobin response.
The subjects were weight stable on both diets. We consid-
ered this to be a very important aspect of the study
because we wanted to attribute any metabolic changes to
the diet per se, and not to be confounded by weight loss
(or gain) [10].
Urine urea, normalized to the urine creatinine, was meas-
ured as an index of compliance. Since the protein content
of the diet was doubled, one would expect that the urine
urea:creatinine ratio also would approximately double if
the subjects were compliant. The ratio on the standard
diet was ~7 and was stable throughout the 5 weeks. When
the same subjects were given the 30% protein diet, the
urine urea:creatinine ratio was ~13–14, i.e. a value that
one would expect with good compliance with the diet.
The fasting glucose concentration did not change when
the subjects received the 30% protein diet. However, the
postprandial glucose concentrations were lower through-
out the day [10].
Although the differences in postprandial glucose values
were not very large, when integrated over the 24-hour
period, there was a 38% decrease in postprandial glucose
area response. If the 24-hour integrated area is considered
to be 100% when the subjects ingested the 15% protein
diet, when they ingested the 30% protein diet it was 62%
(Figure 6).
Five hour integrated insulin area response to ingestion of 50 g glucose alone (pink bar) or 50 g glucose + 25 g protein in the form of beef, turkey, gelatin, egg white, cottage cheese, fish or soy (yellow bars, left to right)Figure 4
Five hour integrated insulin area response to inges-
tion of 50 g glucose alone (pink bar) or 50 g glucose +
25 g protein in the form of beef, turkey, gelatin, egg
white, cottage cheese, fish or soy (yellow bars, left to
right). The horizontal line indicates the expected insulin
area response. (From [9])
Rate of change in % tGHbFigure 5
Rate of change in % tGHb

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Even though the postprandial glucose concentration was
decreased on the 30% protein diet, the insulin area
response was modestly increased (Figure 7).
The % total glycohemoglobin decreased slightly from 8%
to 7.7% during the 5 weeks of the study when the subjects
were ingesting the 15% protein diet. When the subjects
ingested the 30% protein diet, it decreased from 8.1 to
7.3%, i.e. the decrease was 0.8 (Figure 8).
To put this decrease in % glycohemoglobin into perspec-
tive, the Physicians Desk Reference for 2003 [12] was
consulted in regard to the decrease in %HbA1c or
%glycohemoglobin when subjects with type 2 diabetes
were given rosiglitazone or metformin, drugs commonly
used to treat people with type 2 diabetes. In subjects
receiving 4 mg rosiglitazone twice a day, which is a
maximal dose, the mean decrease in HbA1c was 0.7%
over a 16-week period of time (Table 1). For metformin,
at a maximum dose of 2500 mg daily, the decrease was
1.4% over a 29-week period.
With the 30% protein diet, the decrease was 0.8% over the
5 weeks of our study. The ultimate decrease could be
1.6%, since at 5 weeks (35 days) the %tGHb would have
decreased by only 50% of the expected final decrease (see
Figure 5). Thus, the decrease would be similar to that
obtained using either of the above two medications.
Since there has been concern that a high protein diet may
impair renal function, the creatinine clearance was deter-
mined at the end of the period of time the subjects
ingested the 15% protein diet and at the end of the period
of time that the subjects ingested the 30% protein diet.
There was essentially no difference. The microalbumin
excretion also did not change (Table 2).
Also the differences in total cholesterol, HDL-cholesterol,
LDL-cholesterol were not significant. The fasting
triacylglycerol concentration decreased significantly when
the subjects were on the 30% protein diet (Table 3).
24-hr integrated plasma glucose area response in 12 subjects with type 2 diabetes after ingesting the 15% protein or the 30% protein diet for 5 weeksFigure 6
24-hr integrated plasma glucose area response in 12
subjects with type 2 diabetes after ingesting the 15%
protein or the 30% protein diet for 5 weeks. (From
[10])
24-hr integrated serum insulin area response in 12 subjects with type 2 diabetes after ingesting the 15% or the 30% pro-tein diet for 5 weeksFigure 7
24-hr integrated serum insulin area response in 12
subjects with type 2 diabetes after ingesting the 15%
or the 30% protein diet for 5 weeks. (From [10])

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Discussion
In summary, the integrated postprandial glucose area
response was 38% less following ingestion of the 30%
compared to the 15% protein diet. Total glycohemo-
globin decreased significantly from 8.1 to 7.3% and
potentially could result in a decrease to 6.5%. The
integrated insulin concentration increased modestly.
Renal function, LDL, HDL, and total cholesterol were
unchanged. The triacylglycerol concentration decreased.
Conclusions
From these data we conclude that increasing the protein
content of the diet at the expense of carbohydrate can
reduce the 24-hour integrated plasma glucose concentra-
tion, at least over a 5-week period of time. The reduction
was similar to that of oral agents and renal function was
not affected significantly. Thus, increasing the protein
content of the diet with a corresponding decrease in the
carbohydrate content potentially is a patient empowering
way of reducing the hyperglycemia present in people with
type 2 diabetes mellitus, independent of the use of phar-
maceutical agents.
Results of a further modification in macronutrient content
More recently we have completed study comparing an
experimental diet to the standard diet, over a 5-week
period of time. In the experimental diet, the protein was
increased from 15% to 30% as in the above study. How-
ever, in this study the carbohydrate content was decreased
from 55% to 20% of total food energy and the fat content
was increased from 30% to 50%. The subjects studied
were people with untreated type 2 diabetes. It was a
weight maintenance diet, with a randomized crossover
design. The %tGHb decrease was even more dramatic (9.8
to 7.6%) [13].
Table 1: Comparison of treatment
Agent Dose Duration of Treatment Decrease in %tGHb or %HbA1c
Rosiglitizone 4 mg bid 16 weeks 0.7%
Metformin 2500 mg 29 weeks 1.4%
30% Protein Diet 5 weeks 0.8% (1.6%)
PDR 2003 [12]
Table 2: Renal data
15% Protein Diet 30% Protein Diet
Creatinine Clearance
(ml/min)
122 ± 11 113 ± 27
Microalbumin (mg) 7.8 ± 1.7 7.0 ± 0.8
Table 3: Lipid data
15% Protein
Diet
30% Protein
Diet
Total Cholesterol (mg/dl) 181 ± 15 171 ± 12
HDL-Cholesterol (mg/dl) 38 ± 3 39 ± 3
LDL-Cholesterol (mg/dl) 100 ± 12 101 ± 12
Triacylglycerol (mg/dl) 199 ± 20 161 ± 21*
* P < 0.05
%tGHb response in 12 subjects with type 2 diabetes at weekly intervals while ingesting a 15% or a 30% protein dietFigure 8
%tGHb response in 12 subjects with type 2 diabetes
at weekly intervals while ingesting a 15% or a 30%
protein diet. (From [10])

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Competing interests
None declared.
Authors' contributions
Both authors were equally responsible for designing the
experiments, evaluating the statistics, interpreting the
data, writing the manuscript, and organizing the figures
and tables.
Acknowledgements
We would like to acknowledge the American Diabetes Association, the
Minnesota Beef Council, the Nebraska and Colorado Beef Councils for
financial support for these studies. Most importantly, we would like to
thank the volunteers who made the studies possible. We also would like to
thank Jennifer Nuttall Martenson, Kelly Jordan Schweim, Heidi Hoover,
Mary Adams, and the SDTU staff for their vital technical assistance in these
studies.
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