low-carbohydrate high-fat diet increases weight gain
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Researchers suggest controlled pulses of glucose may normalize the reduced insulin production characteristic of type 2 diabetes.
Insulin is produced by beta cells in the pancreas. Its primary role is to regulate blood glucose levels and help convert glucose from the carbohydrates we eat into energy.
In healthy individuals, beta cells release regular pulses of the hormone into the bloodstream. These pulses restrict the amount of glucose released by the liver, as well as propel body tissues to absorb the glucose that has been released.
However, in people with high blood glucose - or hyperglycemia, a hallmark of type 2 diabetes - the excess glucose suppresses the "clock" of beta cells that controls the rhythm of insulin pulses, reducing insulin production.
In the new study, McKenna and colleagues show how administering controlled pulses of glucose could normalize the production of insulin.
Controlled glucose pulses restarted insulin clock
Firstly, the team created a mathematical model - the Dual Oscillator Model (DOM) - to simulate experiments with the islets of Langerhans, which are small clusters of pancreatic cells that contain insulin-producing beta cells.The DOM model predicted that pulses of glucose to the bloodstream has the potential to reactivate the insulin clock within beta cells that has been halted by exposure to excess glucose.
The team then tested this theory in non-diabetic mice that had their islets of Langerhans removed.
Using a specially engineered microfluidic device, the researchers then delivered different concentrations of a glucose solution to the mouse islets.
As expected, when a high, steady glucose concentration was administered, the insulin clock within the mouse islets was deactivated.
When controlled pulses of glucose were applied to the islets, however, the insulin clock was restarted. What is more, when the flow of glucose solution followed a feedback loop that simulates the action of the liver, the team found the reactivated islets had the ability to recruit other islets and restart their insulin clock.
According to the researchers, their findings provide insight into the reduced insulin production that occurs in type 2 diabetes.
"This article demonstrates how microfluidics and mathematical modeling can be used together to gain new insights into the mechanisms for hormone secretion," says study co-author Richard Bertram, of the Department of Mathematics and Programs in Neuroscience and Molecular Biophysics at FSU.
Importantly, the authors say their study may also lead to new prevention strategies for type 2 diabetes:
"Here, we demonstrate, with a combined modeling and experimental approach, that the loss of pulsatile insulin release that results from elevated glucose may be recovered by an oscillatory glucose stimulus.In future research, the team plans to apply the microfluidic device to islets from diabetic mice, before studying islets from healthy humans and those with diabetes.
Our results have potential implications for enhancing insulin pulsatility and therefore mitigating the development of type 2 diabetes."
Read about how drinking at least two soft drinks daily could double the risk of diabetes.
Background/Objectives:
Dietary
guidelines for the past 20 years have recommended that dietary fat
should be minimized. In contrast, recent studies have suggested that
there could be some potential benefits for reducing carbohydrate intake
in favor of increased fat. It has also been suggested that
low-carbohydrate diets be recommended for people with type 2 diabetes.
However, whether such diets can improve glycemic control will likely
depend on their ability to improve β-cell function, which has not been
studied. The objective of the study was to assess whether a
low-carbohydrate and therefore high-fat diet (LCHFD) is beneficial for
improving the endogenous insulin secretory response to glucose in
prediabetic New Zealand Obese (NZO) mice.
Methods:
NZO
mice were maintained on either standard rodent chow or an LCHFD from 6
to 15 weeks of age. Body weight, food intake and blood glucose were
assessed weekly. Blood glucose and insulin levels were also assessed
after fasting and re-feeding and during an oral glucose tolerance test.
The capacity of pancreatic β-cells to secrete insulin was assessed in vivo
with an intravenous glucose tolerance test. β-Cell mass was assessed in
histological sections of pancreata collected at the end of the study.
Results:
In NZO mice, an LCHFD reduced plasma triglycerides (P=0.001) but increased weight gain (P<0.0001), adipose tissue mass (P=0.0015), high-density lipoprotein cholesterol (P=0.044) and exacerbated glucose intolerance (P=0.013). Although fasting insulin levels tended to be higher (P=0.08), insulin secretory function in LCHFD-fed mice was not improved (P=0.93) nor was β-cell mass (P=0.75).
Conclusions:
An
LCHFD is unlikely to be of benefit for preventing the decline in β-cell
function associated with the progression of hyperglycemia in type 2
diabetes.
Top of page
Top of pageIntroduction
Low-carbohydrate high-fat diets (LCHFDs) have achieved weight loss in several clinical studies,1, 2, 3, 4 and others have described their potential benefits in patients with diabetes.5, 6, 7 Reducing ingested carbohydrates limits the potential for blood glucose levels to increase following a meal.6, 8
However, as the major contributors to hyperglycemia in type 2 diabetes
include a resistance to insulin action on target tissues, in combination
with an inability of pancreatic β-cells to secrete enough insulin,9 it is important we further consider the impact that LCHFD could have on these important aspects of metabolic regulation.
Insulin-stimulated
glucose uptake into muscle and adipose tissue is significantly improved
by weight loss, such as that achieved in some studies using LCHFDs.3, 4
However, an LCHFD does not necessarily result in weight reduction, and
high dietary fat in animal studies, regardless of effects on body
weight, has been shown to cause an increased accumulation of lipids in
the liver, which negatively affects insulin’s ability to reduce hepatic
glucose production.10, 11, 12, 13
Therefore, the proposed benefits vs potential negative effects of an
LCHFD on blood glucose control need to be seriously considered before
such diets are regarded as a useful option for diabetes management.
Moreover, whether LCHFDs will prove beneficial for improving glucose
control in type 2 diabetes after long-term use will depend on their
impact on glucose-induced insulin secretion from pancreatic β-cells,
which prior to this study has not been carefully examined.
Appropriate
insulin secretion in response to changes in blood glucose is essential
for maintaining normoglycemia. In type 2 diabetes, insulin resistance
places a greater demand on pancreatic β-cells to secrete more insulin.
If β-cell function is maintained at a level that can compensate for
insulin resistance, blood glucose is maintained within the normal range.
However, in susceptible individuals, β-cells are unable to cope with
the extra stresses of increased metabolism and insulin production that
are required. In patients with diabetes, β-cell function is
insufficient, and as it continues to decline over time, blood glucose
control becomes progressively worse. In this setting, an increase in
β-cell apoptosis can also contribute to a loss of β-cell mass.14 It is clear that diabetes therapies that do not address this decline in β-cell function fail to maintain blood glucose control.15
Therefore, the impacts of LCHFDs on β-cell function may determine
whether they could be a useful part of type 2 diabetes management.
A
diet or therapy that reduces the workload of pancreatic β-cells in the
early stages of diabetes might be predicted to have a beneficial effect
for maintaining and perhaps preserving their capacity to respond to
increases in blood glucose. In contrast, chronic hypersecretion of
insulin has been associated with β-cell failure.16 Of potential benefit, reducing dietary carbohydrate reduces postmeal glucose excursions and the need for insulin secretion.6, 8 However, in healthy individuals an LCHFD can result in an impaired response to an oral glucose tolerance.17
Animal studies are able to shed further light on the potential impact
of LCHFDs because they can control dietary and other influences more
tightly than clinical studies. HFDs, in combination with either normal
or high carbohydrate, have generally induced metabolic impairments in
rodents.10, 18, 19, 20, 21, 22 Some studies in normal-weight animals have also shown impairments in glucose tolerance and a reduction in β-cell mass.10, 18 In contrast, some improvements in glucose homeostasis with an LCHFD were observed in leptin-deficient ob/ob mice.23
However, none of these studies specifically examined the effect of an
LCHFD on β-cell function in an animal model that is prone to diabetes.
The New Zealand Obese (NZO) mouse is a polygenic model of obesity, which
develops early in the progression of the disease owing to increased
energy intake, akin to human obesity.24
In NZO mice, which also display glucose intolerance, impaired β-cell
function and develop diabetes from approximately 20 weeks of age, a HFD
worsened obesity and insulin resistance.25 Interestingly, in these mice, a high-fat carbohydrate-free diet prevented hyperglycemia and preserved β-cell mass.25 However, when carbohydrate-naive NZO mice were later exposed to a diet containing carbohydrate (32% of energy), they were highly susceptible and quickly developed diabetes.26, 27
In summary, a life-long completely carbohydrate-free diet is unlikely
to be achievable but an LCHFD, through reducing postmeal glucose
excursions, could potentially have some benefit for improving glucose
control in diabetes. Therefore, we aimed to determine whether feeding
prediabetic NZO mice an LCHFD could positively affect β-cell function
and mass. The results presented herein demonstrate that, although
postmeal glucose excursions were reduced by an LCHFD, there were no
longer-term benefits for β-cell function or glucose metabolism.
Materials and methods
Animal diets and housing conditions
NZO
mice were bred under specific-pathogen-free conditions in the
BioResources Facility at Austin Health (Heidelberg, VIC, Australia).
After weaning, male mice were housed in groups of 2–3 per cage and
maintained under standard laboratory conditions with controlled
temperature (19–22 °C) and 12-h light/dark cycle. All mice were fed ad libitum
with free access to clean drinking water throughout the duration of
this study. Prior to the study, all mice were fed a standard rodent
maintenance diet. At 6 weeks of age, mice were either transferred to an
LCHFD or maintained on the standard diet (chow) for a further 9 weeks.
The LCHFD contained 24 MJ kg−1 digestible energy (3.1 MJ or 13% coming from protein, 1.5 MJ or 6% from carbohydrate and 19.5 MJ or 81% from fat (Supplementary Table S1). The carbohydrate content of the LCHFD was exclusively derived from simple sugar (sucrose: 106 g kg−1). The fat content of this diet was derived from 55% saturated, 37% monounsaturated and 8% polyunsaturated fats, by weight. The chow diet contained 13.5 MJ kg−1 digestible energy, with 2.7 MJ or 20% coming from protein, 9.5 MJ or 70% from carbohydrate and 1.4 MJ or 10% from fat (Supplementary Table S2). Typically, rodent chow carbohydrate is contributed to by 50% starch and approximately 2%
simple sugars (monosaccharides plus disaccharides) as a proportion of
total carbohydrates by weight. The fat content of chow is typically 18% saturated, 37% monounsaturated and 15.4% polyunsaturated fats. All animal procedures were approved by the Austin Health Animal Ethics Committee.
Overview of animal experiments
Random-fed blood glucose (at ≈1400
hours), body weight and food intake were measured weekly. Care was
taken to account for all the food that was left over and crumbled into
the cage. After 6–7 weeks of the diet (at 12–13 weeks of age), mice were
fasted overnight and re-fed their respective diets so that insulin and
glucose levels could be assessed. Body weight and blood glucose
measurements were carried out prior to the removal of food from the
cages at 1700 hours. The next day, following the overnight fast (16 h),
body weight and blood glucose measurements were repeated, and a 100-μl
blood sample was collected from the tail vein. Food was returned, and
after 4 h of ad libitum re-feeding, blood glucose was measured and another 100 μl
of tail blood was collected. After 7–8 weeks, an oral glucose tolerance
test (OGTT) was performed as described below. After 9 weeks, an
intravenous glucose tolerance test (IVGTT) was performed. Immediately
after the IVGTT, animals were killed with a lethal dose of sodium
pentobarbital and tissue samples were excised.
Oral glucose tolerance test
The OGTT was performed in awake mice as previously described.20, 28 After administering a standardized glucose dose (37.5 mg in a volume of 150 μl) to all animals, blood glucose was measured at 0, 10, 20, 30, 60, 90 and 120 min, and blood samples were taken at 0, 10 and 30 min. After centrifugation, plasma was stored at −20 °C for future glucose and insulin analyses.
Intravenous glucose tolerance test
The IVGTT was performed as previously described.21 Following the glucose bolus (1 g kg−1), blood samples were taken at 0, 2, 5, 10, 15 and 30 min. Plasma was stored at −20 °C for later glucose and insulin analyses.
Plasma glucose, insulin, triglyceride and cholesterol measurements
A
GM7 Analox glucose analyzer (Helena Laboratories, Mount Waverley, VIC,
Australia) was used to determine plasma glucose levels via a glucose
oxidase assay. Plasma insulin levels were determined using a Mouse
Insulin ELISA Kit (Alpco, Caringbah, NSW, Australia). Plasma
triglyceride (TRO100) and cholesterol (MAK043) levels were determined
using the commercial assay kits (Sigma-Aldrich, Castle Hill, NSW,
Australia).
Tissue extraction and analysis
At
the end of the 9-week study, following killing of mice, pancreata and
epididymal fat pads were rapidly excised and weighed. Pancreatic tissue
was fixed in 10% neutral buffered formalin for 48 h and stored in 70%
ethanol until further processing and embedding in paraffin. For
assessment of β-cell mass, pancreatic sections were immunostained for
insulin (using a guinea pig anti-insulin primary antibody, 1:100
dilution) as previously described.29 Two sections (separated by 100 μm)
from each pancreas were analyzed. Slides were scanned using the
ScanScope CS system (Aperio Technologies, Vista, CA, USA) at × 40
magnification. Digital images were analyzed with the ScanScope software
(Aperio Technologies). β-Cell mass was calculated as the product of
pancreas weight before fixation and the ratio of insulin positive/total pancreas cross-sectional area.
Statistical analysis
All data are presented as mean±s.e.m. and P<0.05
was deemed significant. GraphPad Prism 6 (GraphPad Software Inc, La
Jolla, CA, USA) was used for statistical analysis. Student’s t-tests were performed to determine statistical significance between the LCHFD and chow groups. When multiple t-tests
were performed, the Holm–Sidak method was used to correct for multiple
comparisons. When data from repeated measures were analyzed, for
example, from weekly blood glucose/body weight
measurements or GTT curves, or fasting and re-fed conditions, two-way
analysis of variance performed and Sidak’s multiple comparison test was
used to analyse multiple comparisons between the two experimental
groups.
If you have pre-diabetes
(impaired glucose tolerance), your blood sugar (glucose) is raised
beyond the normal range but it is not so high that you have diabetes.
However, if you have pre-diabetes, you are at increased risk of
developing diabetes. You are also at increased risk of developing
conditions such as heart disease, peripheral arterial disease and stroke
(cardiovascular diseases). If pre-diabetes is treated, it can help to
prevent the development of diabetes and cardiovascular disease. The most
effective treatment is lifestyle changes, including eating a healthy
balanced diet, losing weight if you are overweight, and doing regular
physical activity.
Understanding blood glucose and insulin
So, when your blood glucose level begins to rise (after you eat), the level of a hormone called insulin should also rise. Insulin works on the cells of your body and makes them take in glucose from the bloodstream. Some of the glucose is used by the cells for energy and some is converted into stores of energy (glycogen or fat).
When the blood glucose level begins to fall (between meals), the level of insulin falls. Some glycogen or fat is then converted back into glucose which is released from the cells into the bloodstream.
Insulin is a hormone that is made by cells called beta cells. These are part of little islands of cells (islets) within the pancreas. Hormones are chemicals that are released into the bloodstream and work on various parts of the body.
What is a normal blood glucose level?
Your blood sugar (glucose) level literally refers to the amount of glucose in your blood. A normal blood glucose level ranges between about 4 and 8 millimoles per litre (mmol/L). Blood glucose levels may be at the higher end of the range after eating and at the lower end of the range first thing in the morning.If your blood glucose is measured by a blood test when you have not been fasting, this is called a random blood glucose level. If your blood glucose is measured after you have been fasting, this is called a fasting blood glucose level. A normal fasting blood glucose level is less than 6 mmol/L.
Note: the terms blood sugar and blood glucose mean the same thing.
What is diabetes mellitus?
Diabetes mellitus (just called diabetes from now on) occurs when the level of glucose in the blood becomes higher than normal. There are two main types of diabetes - type 1 diabetes and type 2 diabetes. Type 2 diabetes is much more common than type 1 diabetes.The World Health Organization (WHO) has said that someone may have diabetes if they have:
- A fasting blood glucose of 7 mmol/L or more; or
- A blood glucose of 11.1 mmol/L or more after a two-hour oral glucose tolerance test (see below).
Type 1 diabetes
In type 1 diabetes the beta cells in the pancreas stop making insulin. The illness and symptoms develop quickly (over days or weeks) because the level of insulin in the bloodstream becomes very low. Type 1 diabetes used to be known as juvenile, early-onset, or insulin-dependent diabetes. It usually first develops in children or in young adults. Type 1 diabetes is treated with insulin injections and diet. See separate leaflet called Type 1 Diabetes for more details.Type 2 diabetes
With type 2 diabetes, the illness and symptoms tend to develop gradually (over weeks or months). This is because in type 2 diabetes you still make insulin (unlike in type 1 diabetes). However, you develop diabetes because:- You do not make enough insulin for your body's needs.
- Or, the cells in your body do not use insulin properly. This is called insulin resistance. The cells in your body become resistant to normal levels of insulin. This means that you need more insulin than you would normally make to keep the blood glucose level down.
- Or, a combination of the above two reasons.
What is pre-diabetes?
If you have pre-diabetes (impaired glucose tolerance), your blood sugar (glucose) is raised beyond the normal range but it is not so high that you have diabetes. However, if you have pre-diabetes you are at risk of developing type 2 diabetes.Between 1 and 3 out of every 4 people with pre-diabetes will develop diabetes within ten years.
It is also thought that having pre-diabetes increases your risk of developing conditions such as heart disease, peripheral arterial disease and stroke (cardiovascular diseases). Also, people who have pre-diabetes are more likely also to have other risk factors for cardiovascular disease, including high blood pressure, raised cholesterol levels, being overweight, etc. See separate leaflets called Preventing Cardiovascular Diseases and Cardiovascular Health Risk Assessment for more details.
The WHO defines someone as having pre-diabetes if they have:
- A fasting blood glucose of less than 7 mmol/L.
- And, a blood glucose of 7.8 mmol/L or more but less than 11.1 mmol/L after a two-hour oral glucose tolerance test (see below).
What is impaired fasting glycaemia?
The WHO has also said that someone has impaired fasting glycaemia if they have:- A fasting blood glucose between 6.1 to 6.9 mmol/L.
- And, a blood glucose of less than 7.8 mmol/L after a two-hour oral glucose tolerance test (see below).
How common is pre-diabetes?
Many people have pre-diabetes (impaired glucose tolerance) and because there are no symptoms, they do not know that they have it. Diabetes UK estimates that around seven million people in the UK have pre-diabetes.What causes pre-diabetes and who develops it?
Pre-diabetes (impaired glucose tolerance) develops for the same reasons as type 2 diabetes (see above). There are various things that can increase your risk of developing pre-diabetes. They are the same risk factors as those for type 2 diabetes. They include:- Being overweight or obese (most people with pre-diabetes are overweight or obese).
- Having a family history of diabetes. This refers to a close family member with diabetes - a mother, father, brother or sister.
- Doing little physical activity.
- Having other risk factors for cardiovascular disease such as high blood pressure or high cholesterol levels.
- If a woman has polycystic ovary syndrome and is also overweight.
- If you developed diabetes during pregnancy (called gestational diabetes).
What are the symptoms of pre-diabetes and how is it diagnosed?
People with pre-diabetes (impaired glucose tolerance) usually have no symptoms. You are often found to have pre-diabetes after blood tests taken for another reason show that you have a raised blood sugar (glucose) level. Sometimes, your doctor may suggest that a screening blood test should be taken to check your blood glucose because they are worried that you may have some risk factors for pre-diabetes or diabetes. For example, if you have high cholesterol levels, are overweight or have high blood pressure, or if you have had a heart attack or stroke, your doctor may suggest that you have a blood test to check your blood glucose.Pre-diabetes is now most often diagnosed using a blood test called HbA1c. See separate leaflet called Tests for Blood Sugar (Glucose) and HbA1c for more details. An HbA1c value of 48 mmol/mol (6.5%) or above is recommended as the blood level for diagnosing diabetes. People with an HbA1c level of 42-47 mmol/mol (6.0-6.5%) are often said to have pre-diabetes because they are at increased risk of diabetes and cardiovascular disease.
Another test to diagnose pre-diabetes is the glucose tolerance but this is much less often used now. See separate leaflet called Glucose Tolerance Test for further details.
How is pre-diabetes treated?
There is increasing evidence that if pre-diabetes (impaired glucose tolerance) is treated, the progression to diabetes can be prevented. Also, it may be possible to prevent cardiovascular disease from developing. So, it is important to know if you have pre-diabetes and to treat it in order to reduce your risk of developing diabetes and cardiovascular disease. Treatments that have been suggested include lifestyle changes and treatments with medicines.It is also very important to have a regular blood test to recheck your blood sugar (glucose) level in case you develop diabetes. The frequency of the blood test will vary but you should discuss this with your doctor. A blood glucose test at least once each year is usually recommended.
Lifestyle changes
Lifestyle changes have been found to be the most effective way to stop pre-diabetes from developing into diabetes. Losing weight if you are overweight, and increasing your levels of physical activity, can help to reduce insulin resistance and therefore make the insulin that is produced more effective at controlling your blood glucose levels.If you have pre-diabetes, you should:
- Eat a healthy balanced diet. Your practice nurse and/or a dietician will give details on how to eat a healthy diet. The diet is the same as recommended for everyone. The idea that you need special foods if you have pre-diabetes or diabetes is a myth. Basically, you should aim to eat a diet low in fat, high in fibre and with plenty of starchy foods, fruit and vegetables. See separate leaflet called Healthy Eating.
- Lose weight if you are overweight. Getting to a perfect weight is unrealistic for many people. However, if you are overweight or obese then losing some weight will help to reduce your blood glucose level (and have other health benefits too). See separate leaflet called Weight Reduction - How to Lose Weight.
- Do some physical activity regularly. If you are able, a minimum of 30 minutes of physical activity at least five times a week is advised. For example, walking, swimming, cycling, jogging, dancing. Ideally you should do an activity that makes you at least mildly out of breath and mildly sweaty. You can spread the activity over the day. (For example, two 15-minute spells of brisk walking, cycling, dancing, etc per day.) Regular physical activity also reduces your risk of having a heart attack or stroke. Always check with your doctor that it is safe to start exercising if you have been inactive for a long period. See separate leaflet called Physical Activity For Health.
- Stopping smoking if you are a smoker.
- Ensuring that you stick to the recommended alcohol intake. See separate leaflet called Recommended Safe Limits of Alcohol for more details.
Also, discuss with your doctor or practice nurse if you need a cholesterol check and/or treatment to lower your cholesterol level.
Treatments with medicines
A number of medical trials have looked at the use of various treatments with medicines for people with pre-diabetes to see if they can help to prevent diabetes and cardiovascular disease. Medicines that have been trialled include metformin, acarbose, a group of medicines called angiotensin-converting enzyme (ACE) inhibitors and another group of medicines called angiotensin-II receptor antagonists.Lifestyle changes (as indicated above) are the most important thing if you are found to have pre-diabetes. However, the National Institute for Health and Care Excellence (NICE) has recommended that metformin should be used if a lifestyle-change programme isn't successful or isn't possible because of a disability or medical reasons. A medicine called orlistat may also be recommended to help lose weight and therefore reduce the risk of developing diabetes.
What follow-up is needed if you have pre-diabetes?
If you are found to have pre-diabetes (impaired glucose tolerance), it is important that you be followed up regularly by your doctor. This will usually mean a blood test to check your fasting blood sugar (glucose) level at least once a year. This is to make sure that you have not developed diabetes. Your doctor is also likely to keep a check on any other risk factors that you may have for cardiovascular disease. So, they may monitor your weight and your blood pressure and also suggest a blood test to check your cholesterol and triglyceride levels.In the meantime, if you develop any symptoms of diabetes, you should visit your doctor sooner. Symptoms include excess thirst, passing large amounts of urine, tiredness, weight loss and feeling generally unwell. Symptoms tend to develop quite slowly, over weeks or months.
Can pre-diabetes be prevented?
The same things that can help prevent type 2 diabetes can help prevent pre-diabetes (impaired glucose tolerance). These include:- Eating a healthy balanced diet.
- Losing weight if you are overweight.
- Doing some physical activity regularly.
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