Improvements in Glucose Metabolism and Insulin Sensitivity with a
Low-Carbohydrate Diet in Obese Patients with Type 2 Diabetes
Jeremy D Krebs1,2, Damon Bell1, Rosemary Hall1, Amber Parry-Strong1,2, Paul D
Docherty3, Kristen Clarke1, J. Geoffry Chase3.
1. Endocrine, Diabetes and Research Centre, Wellington Hospital, Private Bag 7902 Wellington, New Zealand. 2.
Wellington School of Medicine. University of Otago Wellington, New Zealand. 3. Centre for Bioengineering, University
of Canterbury. Private Bag 4800 Christchurch.
Author Information
Dr Jeremy Krebs MB ChB, MD, FRACP, Head of Endocrine, Diabetes and Research
Centre, Wellington Hospital, Wellington New Zealand, and Senior Clinical Lecturer,
University of Otago Wellington, New Zealand; Dr Damon Bell MB ChB, FRACP,
FRCPA Endocrinologist Endocrine, Diabetes and Research Centre, Wellington Hospital,
Wellington New Zealand, Dr Rosemary Hall MB ChB, FRACP Endocrinologist
Endocrine, Diabetes and Research Centre, Wellington Hospital, Wellington New
Zealand, Amber Parry-Strong, Research Dietitian Endocrine, Diabetes and Research
Centre, Wellington Hospital, Wellington New Zealand, Paul Docherty, Centre for
Bioengineering, University of Canterbury, Christchurch New Zealand, Kristen Clarke,
Research Dietitian, Endocrine, Diabetes and Research Centre, Wellington Hospital,
Wellington New Zealand, and Professor Geoff Chase, Head of Centre for
Bioengineering, University of Canterbury, Christchurch, New Zealand.
Correspondence
Dr Jeremy Krebs, Endocrine Diabetes and Research Centre, Capital and Coast Health
Private Bag 7902, Wellington, New Zealand. Email: Jeremy.krebs@ccdhb.org.nz.
Telephone: 0064 4 3855999, Fax: 0064 4 3855819
Running Title: Low-Carbohydrate Diet in Type 2 Diabetes
Abstract
Objective:
The optimal diet for weight loss in type 2 diabetes remains controversial.
This study examined a low-carbohydrate, high-fat diet with detailed physiological
assessments of insulin sensitivity, glycaemic control, and risk factors for cardiovascular
disease.
Methods: 14 obese patients (BMI 40.6 4.9 kg/m2) with type 2 diabetes were recruited
for an “Atkins” type low-carbohydrate diet. Measurements were made at 0, 12 and 24
weeks of weight, insulin sensitivity, HbA1c, lipids and blood pressure.
Results: 12 completers lost a mean of 9.7  1.8kg over 24 weeks attributable to a major
reduction in carbohydrate and resultant reduction in total energy intake. Glycaemic
control significantly improved (HbA1c -1.10.25%) with reductions in hypoglycaemic
medication. Fasting glucose, HOMA and AUC glucose (IVGTT) were significantly
reduced by week 12 (p<0.05). There were non-significant improvements in insulin
sensitivity (SI) at weeks 12 (p =0.19) and 24 (p=0.31). Systolic blood pressure reduced
(mean -10.0mmHg between week 0 and 24 (p=0.13). Mean HDL, LDL and total
cholesterol all increased. The ratio of total:HDL cholesterol and triglycerides reduced.
Conclusion: A low-carbohydrate diet was well tolerated and achieved weight loss over
24 weeks in subjects with diabetes. Glycaemic control improved with a reduction in
requirements for hypoglycaemic agents.
Keywords: Low-Carbohydrate diet. Type 2 diabetes. Weight loss. Glycaemic control.
Insulin sensitivity.
Introduction: Obesity and type 2 diabetes have reached epidemic proportions worldwide
with major implications for individual health outcomes and health care resources [1].
There is an urgent need to find effective dietary strategies to manage weight, glucose
homeostasis and risk factors for cardiovascular disease. Weight loss in patients with type
2 diabetes improves glycaemic control, largely by improving insulin sensitivity [2].
However, the most appropriate dietary macronutrient composition of a weight reduction
diet remains controversial, particularly in individuals with Type 2 diabetes. Current
recommendations by the American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD), promote reduced energy intake with
reduced fat, and a relatively high intake of carbohydrate (45-60% of total daily energy)
[3-4].
Diets high in fat are associated with development of obesity, primarily due to passive
over-consumption [5], and there is evidence to support a low-fat, high-carbohydrate diet
in promoting weight loss [3]. However, there is some evidence that diets high in
carbohydrate result in an exaggerated insulin response and elevated triglycerides,
potentially increasing risk for cardiovascular disease [6-7]. This concern fuels the notion
that a low-carbohydrate, high-fat diet may be more beneficial in promoting weight loss
with improvements in insulin resistance and health outcomes. Low carbohydrate diets,
particularly the “Atkins diet”[8], have received considerable attention in popular press
and are endorsed by high profile celebrities. However, there is surprisingly little
evidence to support the claims for low carbohydrate diets [9-10].
Studies in people without diabetes have shown greater initial weight loss at 6 and even 12
months, but no difference by 2 years when comparing low carbohydrate diets with low fat
diets or high protein diets [11-17]. Some authors have concluded that the macronutrient
composition is less important than adherence when it comes to achieving weight loss per
se [18]. These studies have prompted the American Diabetes Association to alter their
dietary guidelines to state that for short-term weight loss either a low-fat or lowcarbohydrate calorie-restricted diet may be effective [4, 19]. However, what remains
unclear is whether in people with established diabetes in the setting of weight loss, does
the macronutrient composition of the diet affect the metabolic profile and risk factors for
cardiovascular disease. Concerns exist about the use of a low-carbohydrate high-fat diet
in people with Type 2 diabetes and the potential associations with a worsening of the
lipid profile, cardiovascular risk factors and deterioration in renal function [10, 20].
Additionally recent data suggest that a low-carbohydrate diet including predominantly
animal protein may increase cardiovascular mortality, whereas a protein source may
reduce all cause mortality [21].
Several small and very short studies ranging from seven days to five weeks have variably
demonstrated reduced glucose and insulin concentrations and improved glycaemic
control [22-25]. Gannon et al demonstrated in a weight neutral five week crossover study
of individuals with poorly controlled type 2 diabetes on no medication that substituting
protein for carbohydrate reduced HbA1c by reducing postprandial glucose [22]. In the
longest trial currently reported, Davis et al demonstrated similar modest weight loss but
no significant improvement in glycaemic control in those with type 2 diabetes on a lowfat or low-carbohydrate diet after one year [26].
From the studies conducted to date it is unclear whether changes in glucose metabolism
with low-carbohydrate diets are simply due to reduced absorption of glucose or whether
there are also changes in insulin sensitivity. Therefore this pilot study was conducted to
examine the effects of a low carbohydrate, high fat diet, on body weight and composition,
with detailed physiological assessments of insulin sensitivity, glycaemic control, and risk
factors for cardiovascular disease specifically in patients with type 2 diabetes.
Methods: Fourteen overweight individuals with type 2 diabetes were recruited through
the hospital diabetes clinic and newspaper advertising, and prescribed a low
carbohydrate, high fat/protein diet (LCHF) for six months. Subjects were included if they
had known established type 2 diabetes and were either diet controlled or required oral
hypoglycaemic agents or insulin, were aged between 30 and 65 yrs and had a BMI
between 30 and 50 kg/m2. Exclusion criteria were pregnancy or lactation, severe kidney
or liver disease, malignancy, severe cardiovascular disease (New York Heart Association
classification III and IV), drug or alcohol dependency, current or recent weight loss >3kg
in previous three months, chronic inflammatory disease, steroid or other antiinflammatory medications, lipid lowering therapy. Ethical approval for this investigation
was granted by the New Zealand Ministry of Health central regional ethics committee.
Dietary Intervention
Subjects were prescribed a low-carbohydrate diet based on the Dr Atkin’s Diet
Revolution book with fat intake >40% of total energy intake and reduced carbohydrate
intake [8]. This was divided into three phases; Induction phase (weeks 1-2) – restricting
carbohydrate to <20g/day. Weight loss phase (weeks 3-12) – 5g additional carbohydrate
intake per week until overall composition is 20-25% carbohydrate, 30% protein and 45 –
50% fat. Maintenance phase (weeks 12-24) – continued 5g additional carbohydrate per
week until weight is stable without weight gain. Subjects attended 12 group sessions with
a dietitian over the 24 weeks. Lists of food choices and menu ideas were provided and
subjects were advised to take a general multivitamin supplement. Subjects were freeliving making their own food choices based on these guidelines. All participants were
encouraged to maintain their current levels of physical activity and not to increase this
during the six months of the study.
Compliance
Compliance with the prescribed diet was assessed by three day non-weighed food diaries
including two week days and one weekend day at baseline, 12 and 24 weeks using the
2006 New Zealand Food Composition Database, and urinary ketones.
Outcome Measurements
Subjects attended for investigations between 0800 and 0900 at baseline (week 0) 12 and 24 weeks
and had the following measurements: Weight, waist circumference (smallest circumference
between lower ribs and iliac crest) and body fat measured using bioimpedence techniques
(Internal equation of theTanita-305 body fat analyser Tanita Corp., Tokyo, Japan). Resting seated
blood pressure was measured three times and the average of the second and third measures taken.
HbA1c, lipid profile and serum creatinine were measured using standard commercial
assays (Roche diagnostics) by an accredited laboratory (Diabetes and Lipid Laboratory,
University of Otago, Dunedin). A 24-hour urine sample was collected for assessment of
proteinuria. Requirement for oral hypoglcaemic agents and insulin are described.
Subjects underwent a frequently sampled insulin-modified intravenous glucose tolerance
test (IVGTT) [27]. The protocol used was that modified by Ward et al employing an
insulin infusion, rather than bolus administration, to maximise the ability to determine
insulin sensitivity (SI) in subjects with diabetes [28]. However insulin sensitivity was
poorly defined using the typical minimal model in several subjects. Therefore,
alternative methods of estimating insulin sensitivity were also used. First the homeostasis
model assessment (HOMA) was calculated using the standard formula [29]. Second, the
area under the curve for glucose from the IVGTT was evaluated using the trapezium rule.
Third, insulin sensitivity was evaluated using a modified dynamic insulin sensitivity and
secretion test (DISST) model [30-31]. The model has an added glomerular glucose
filtration term [32] as several subjects had significantly elevated fasting hyperglycaemia.
Model variables, including SI are identified with the iterative integral method [33-34].
For more detail see appendix i.
Statistics and Data Analysis
Based on previous studies by the investigators, weight loss of 10% body weight is
achievable with the conventional dietary prescription over 24 weeks [35-36]. In obese
insulin resistant non-diabetic subjects this was associated with a mean 50% improvement
in insulin sensitivity using an IVGTT [35]. It is unknown whether similar improvements
are likely in those with diabetes on a low carbohydrate, high fat/protein diet. This pilot
study will enable more accurate power calculations to be made to carefully design a
larger prospective randomised dietary intervention study to compare low-fat with lowcarbohydrate dietary prescriptions. Data were analysed comparing baseline with 12 and
24 weeks using the non-parametric Wicoxon Signed Rank Test with a p<0.05 accepted as
significant. The prospective dietary intervention study cohort size was determined using a
bootstrap with replacement approach that incorporated reported coefficients of variation
of SI [37].
Results: 14 obese patients (BMI 40.6  4.9 kg/m2), eight men and six women with type
2 diabetes (duration 5.0  3.7 yrs) were recruited. Of these patients, 3 were using insulin,
7 were using oral hypoglycaemics and 4 had diet controlled diabetes. Twelve of the 14
subjects recruited completed the 24 weeks. One subject withdrew for personal reasons at
week 3 and the other was removed from the study at week 4 due to an exacerbation of a
renal stone. The remaining 12 subjects are included in this analysis and individual
characteristics are shown in Table 1 and group mean data in Table 2. Subjects lost a mean
of 8.5  1.2kg (7.1  0.9%) of body weight over 12 weeks and 9.7  1.8kg (8.2  1.5%)
over 24 weeks. This was achieved by a reduction in total energy intake attributable to a
major reduction in carbohydrate intake and relatively small increases in absolute protein
and fat intake (Figure 1). This is despite the fact that no instruction to limit overall intake
was given.
This weight loss was associated with significant improvements in glycaemic control
(HbA1c) with improvements in insulin sensitivity as measured from the IVGTT (Table
3). Fasting glucose decreased from a mean of 9.7mmol/L to 7.6 at week 12 (p =0.049)
and 8.0 at week 24 (p =0.27). Fasting insulin decreased from a mean of 126.8 pmol/L at
baseline to 81.7 at week 12 (p =0.09) and 102.8 at week 24 (p =0.26). HOMA improved
from a mean of 8.2 at baseline to 5.1 at week 12 (p =0.03) and 4.8 at week 24 (p =0.09).
The AUC glucose was significantly reduced by week 12 (p=0.03). There were nonsignificant improvements in insulin sensitivity (SI) at weeks 12 (p =0.19) and 24
(p=0.31). All of the 3 subjects on insulin had reductions in dose, as did some of those on
oral hypoglycaemics. Systolic blood pressure was reduced by a clinically significant
degree (mean -5.3mmHg between week 0 and 12 (p=0.34) and -10.0mmHg between
week 0 and 24 (p=0.13), although this did not reach statistical significance in this small
sample. Diastolic blood pressure did not change. Some subjects were able to reduce
doses of anti-hypertensive medication. No change was observed in renal function or
urinary protein excretion.
Changes in lipid profile were mixed (Table 2). Mean total cholesterol concentrations
increased, which was a combination of increased HDL cholesterol and LDL cholesterol.
The ratio of total:HDL cholesterol reduced as did triglyceride concentrations, though
neither reached statistical significance using non-parametric tests in this small sample.
Discussion: A low carbohydrate diet was well tolerated and achieved weight loss
associated with a reduction in total energy intake over 24 weeks in subjects with type 2
diabetes. Glycaemic control improved with a reduction in requirements for
hypoglycaemic agents, and there were no clear overall adverse effects on cardiovascular
risk factors or renal function. This provides support for this dietary approach, at least in
the short-term, for promoting weight loss in patients with type 2 diabetes.
Although the “Atkins” dietary prescription does not include specific instruction to reduce
total energy intake, this pilot study has confirmed the findings of previous studies that by
removing carbohydrate from the diet, compensatory increases in fat and protein intake do
not bring total energy intake back up to baseline. This supports the conclusions of Boden
et al that weight loss is not due to the generation of ketosis, but simply due to the
reduction in energy intake [25].
There was a clear improvement in glucose metabolism, with reductions in hypoglycaemic
medications, particularly insulin doses, and clinically and statistically significant
reductions in HbA1c. This confirms the changes observed by Boden et al [25] over just a
7 day intervention and those of Nuttel and Gannon [22-24]. However, the reduction in
HbA1c of 1.3% is particularly impressive in comparison, especially with the nonsignificant change seen by Davis et al [26]. There was a statistically significant
improvement in fasting glucose, HOMA and AUC glucose during the IVGTT and nonsignificant improvements in fasting insulin. These findings are similar to that of Nuttel et
al [24] where a diet with carbohydrate reduced to 30% of energy intake, but specifically
tailored to be weight neutral over 5 weeks, showed reduction in fasting glucose and
integrated glucose over 24 hours with standard meals, but no changes in insulin. The
individuals in that study were poorly controlled with higher baseline fasting glucose and
HbA1c and were not taking glucose lowering medication. The explanation for the
metabolic improvements was concluded to be related to the reduced absorbed
carbohydrate, and possibly to reduced stored glycogen. No specific assessment of insulin
sensitivity was made. It is important to note that whilst the weight loss was maintained at
24 weeks, the metabolic improvements in fasting glucose, AUC glucose and fasting
insulin were more variable, and a larger study over a longer period of weight maintenance
on this diet would be required to determine whether initial benefits can be sustained.
In the present study, not only were there changes in macronutrient composition of the
diet, but subjects also lost weight. Therefore, it is likely that improvements in glucose
metabolism are a composite of the changes proposed by Nuttell et al but also changes in
insulin sensitivity [24]. The lack of statistically significant improvements in fasting
insulin and whole body insulin sensitivity (SI) in this study may be due to several factors.
In this very small sample the group data is skewed by 2 individuals. One (Number 8,
Table 1) was considerably more insulin sensitive than the rest at baseline, had lower
baseline insulin levels, was controlled with diet and was less overweight. This subject’s
diabetes is likely to be driven more by reduced beta cell function than insulin resistance.
Another individual (Number 10, Table 1) was unable to successfully achieve or maintain
a low carbohydrate diet. Consequently, his total energy intake, fat and protein intakes all
increased. This was associated with weight gain and worsening of glycaemic control,
insulin sensitivity and lipid profile. However, based on the changes seen in this small
sample, a sample size of 35-50 subjects would have given 80-90% power to detect a
significant improvement in insulin sensitivity.
The mean group data also hides somewhat greater individual variability in lipid profile
changes. Although total cholesterol and LDL cholesterol increased, so did HDL
cholesterol with no change in the ratio. Whilst there may be important changes in LDL
particle size, not measured in this study, there is no evidence to suggest a major harmful
effect on overall lipid profile. This supports the findings of Davis et al who demonstrated
a greater rise in HDL cholesterol with a low-carbohydrate diet compared with a low-fat
diet, but no difference in other lipid parameters [26]. The reduction in triglycerides was
non-significant unlike most reduced carbohydrate diets [22-24], but not seen by Davis
[26], and probably reflects the small study cohort and the effect of non-adherence. Some
individuals had a deterioration in their overall lipid profile raising caution that lowcarbohydrate high-fat diet may worsen lipid profiles. This effect can be particularly
exacerbated if individuals are unsuccessful in losing weight, and as in an individual in
this study, may be linked with further weight gain and risk of adverse health outcomes.
This study has confirmed that in people with type 2 diabetes an “Atkins style” low
carbohydrate diet can achieve short-term weight loss through reduction in total energy
intake, associated improvements in glucose metabolism without significant adverse
effects. However, caution must remain over the long-term effects of a low carbohydrate
diet, particularly if the source of protein and fat is animal based rather than vegetable
based [21]. This concern is firstly whether individuals are able to maintain weight loss
and health benefits by maintaining a low carbohydrate intake, and second whether
adverse effects not seen in the short-term become apparent over a longer-term if
individuals do maintain the diet. The findings of this small study support the need for
large randomised trials, specifically in those with diabetes, over a minimum of 2 years to
examine the relative benefits and compliance of a low carbohydrate diet compared with
the currently advised low fat diet.
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Acknowledgments
This study was supported through grants from the New Zealand Society for the Study of
Diabetes (NZSSD) Novo-Nordisk grant scheme and from the Wellington Medical
Research Foundation.