Insulin Causes Weight Gain – Hormonal Obesity IV
In our previous post, we were reviewing the link between insulin and obesity. It appears that insulin is not merely associated with obesity but causes obesity.
Click here for Hormonal Obesity Part I, Part II, and Part III.
For decades we believed the Caloric Reduction as Primary (CRaP) hypothesis of obesity that turned out to be as useful as a half-built bridge. Study after study showed that reducing calories did NOT lead to weight loss. Patient after patient tried to lose weight by restricting calories with consistent failure. But we couldn’t abandon the calorie model so what was left to do? Blame the patient, of course!
Since patients were not losing weight, there was only 2 possibilities. Either the advice to eat a low fat, calorie restricted diet and exercise more was wrong or the patient was not following this advice.
So the doctors and dieticians berated, ridiculed, belittled, rebuked, chided and reprimanded. We said – Eat less, Move more – as if that would cure their problems. After all, the food pyramid couldn’t be wrong, could it? But the excess weight was still as persistent as a nagging tooth.
Doctors, of course, were drawn to this CRaP hypothesis as bathers to a seashore. Obesity was now not our failure to understand it, but their lack of willpower and/or laziness (gluttony or sloth). It was our favourite game – blame the patient.
But, of course, the problem was the CRaP hypothesis. It was just wrong. Increased calories did not cause obesity so reducing calories didn’t cause weight loss. Exercise didn’t work either, as we will see in a future series. So, what was the real aetiology of obesity? Insulin.
What happens when we give high doses of insulin to patients? Insulin makes you gain weight. The more insulin you take, the more weight you gain. It almost doesn’t matter how much you eat or how much you try to exercise. The weight just keeps coming on.
An interesting experiment that demonstrated this exact principle involved intensive treatment of diabetic patients.
Intensive Conventional Insulin Therapy for Type II Diabetes
Diabetes Care 16:23-31 Henry RR
The researchers took 14 diabetics and increased insulin until sugars were almost normal. At the beginning, they were on pills only. Over the 6 months, insulin was increased until the were taking an average of 100 units per day.
Body Weight increased by 8.7 kg (19 lbs). Yet, if we were to look at daily caloric intake, we can see that the average patient decreased by almost 300 calories/ day! In other words, despite eating less patients were gaining weight like crazy. That means that it was not the calories that was driving the weight gain. It was the insulin!
Think about it this way. Insulin is the hormonal signal to the body to increase weight – the Body Set Weight (BSW). If insulin is increased, we increase our BSW. In order to reach this new, higher weight, we will need to eat more or decrease total energy expenditure (TEE). So the insulin makes us fat. In order to get fat, we will eat more or reduce TEE. The behavior of eating more is in response to the hormonal signal to get fat.
In this study, insulin dose was massively increased. Under this hormonal signal, the body tries to gain weight (increase the BSW). As weight increased, patients tried to restrict calories. Since they weren’t eating more, their body is forced to ‘shut down’ in order to conserve energy to increase weight. TEE is lowered. We feel tired, cold, and hungry. And the weight still keeps going up. Sounds like most conventional low fat low calorie diets. Diet, exercise, feel lousy and still can’t lose weight.
There is, in fact, a direct correlation between total dosage and weight gain. The more insulin given, the more weight gained. The higher the insulin levels, the more weight gained. Insulin causes obesity.
A more recent study (N Engl J Med 2007;357:1716-30 Holman RR) showed this exact same effect.
Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes
In this study, 708 diabetics on oral medications got insulin added to their treatment. What happened to weight? It went up. That is really no surprise – every clinician already knows that insulin makes you gain weight.
Those who got the highest doses gained the most weight. Those who got the least, gained the least weight.
Insulin can not only cause generalized obesity, but it can also cause localized fat growth. Those who regularly inject insulin may occasionally experience lipohypertrophy. This just to reinforce the notion that insulin is the signal to gain fat.
There are those who might argue that it is simply the treatment of diabetes that causes weight gain. As we reduce blood sugars, that sugar is taken out of the blood and into the body as fat.
If this were true, then any treatment of diabetes should cause equal weight gain.
We can compare treatment of type 2 diabetes with different agents. Luckily for us, these studies have already been done. This was the large UKPDS (UK Prospective Diabetes Study).
Let me explain here. There are several pills for diabetes (oral hypoglycemics).
Sulphonylureas (SU) are a class of medication that will stimulate the pancreas to produce more insulin. If insulin causes obesity, as the hormonal obesity theory holds, then this class of drugs should indeed increase weight.
Metformin is another class of medication. This is an entirely different kettle of fish. It is considered to be an insulin sensitizer. That is, it helps the insulin in the body work more efficiently. It does not raise serum insulin levels.
This is great. Now we can compare the different effects of the 3 types of drugs – insulin, SU, and metformin. They all have the effect of reducing blood sugars, but the effect on insulin levels in the body are completely different. Insulin will raise blood levels the most, SU will raise levels but not as much as insulin, and metformin not at all.
What are the effects on weight?
As we expected, the insulin group increased weight by the most.
The Chlorpropamide and gliburide (sulphonyureas) increased weight as well, but not as much as insulin.
The metformin group was weight neutral. This group did not gain any more weight than those on diet alone.
So insulin, and gliburide (which raises insulin levels) both increase weight. Metformin, which treats the blood sugar but does NOT raise insulin levels does not raise weight.
Since the publication of the UKPDS there has been the introduction of a new class of drugs to treat diabetes. These are the DPP4 class of medications.
The mechanism of action of these drugs is to increase insulin levels in response to a meal. It does not cause a persistent elevation of insulin levels. As we would expect, the DPP4′s are weight neutral.
In this study, glipizide (a sulphonylurea that raises insulin levels), causes weight gain. Januvia, which does not persistently raise insulin levels does not. This is despite the fact that sugars are treated to the same level.
The results are very consistent. Raising insulin levels causes weight gain. Lowering insulin levels causes weight loss. Increasingly, we are recognizing the importance of these hormonal factors on obesity. Just recently, another study entitled “Insulin resistance and inflammation predict kinetic body weight changes” showed that the strongest predictor of weight regain is insulin resistance. Not willpower. Not caloric intake. Not peer support. Insulin. Insulin. Insulin. It is all about the insulin.
Under the influence of insulin, our body receives instructions to “gain fat”. In response, we eat more and/ or decrease energy expenditure. It is not a voluntary act. Remember this:
The question is NOT how to balance calories, the question is how to balance our hormones. In most cases, the crucial question is not how to reduce calories but how to reduce insulin.
Continue to Hormonal Obesity part V here
Begin here with Calories I
Click here to watch the entire lecture – The Aetiology of Obesity 1/6 – A New Hope
Far from being an innocent response to insulin resistance, hyperinsulinemia drives weight gain and metabolic disruptions, a new study says. Researchers who manipulated mice genes to limit their ability to make insulin found that lowinsulin mice did not become obese on a high-fat diet but actually burned more energy, with their white adipose tissue acting akin to brown fat.
“It’s a very clever experiment,” said C. Ronald Kahn, MD, a prominent insulin and diabetes researcher at Harvard Medical School who was not involved in the study. “I think it is a significant finding because it does challenge our concepts of what is the role of hyperinsulinemia in metabolic syndrome.”
Researchers at the University of British Columbia devised an approach to lowering insulin levels that avoids the pitfalls of previous studies that used drugs, with their unavoidable side effects. Th e researchers exploited the fact that mice have two insulin genes, and therefore four possible alleles. Insulin gene 1 is specific to the pancreas. Insulin gene 2 is like the human insulin gene, present in the pancreas and also in organs such as the brain and thymus.
Mice with both genes knocked out make no insulin and die in infancy, but those with just a single allele function relatively normally. Th e researchers controlled the amount of insulin their mice could make by knocking out the insulin 2 gene entirely, and then creating a line who were missing one allele of gene 1 and therefore genetically limited in the amount of insulin they could produce. Th e researchers then compared how the mice with both alleles vs. a single allele of the pancreas-source gene fared when fed a high-fat diet. That diet normally leads to obesity, hyperinsulinemia, diabetes, and other complications, and the mice with two alleles gained weight as expected.
But the mice with only one allele did not. In addition to avoiding obesity despite consuming a similar amount of calories, they had less inflammation and less liver fat than the other mice. “These mice were healthy across the board; they didn’t accumulate fat in their livers, or any of their other not normally fat-storing tissues, like the regular high-fat mice do,” said lead author James Johnson, PhD, an associate professor of medicine at the University of British Columbia in Vancouver. “Their glucose levels are surprisingly normal given the fact they were missing three of the four insulin genes.”
New Finding on Energy Expenditure
The mice ate similar amounts of food, which raised the question of where the extra calories went in the mice that did not gain weight. To explore the molecular mechanisms involved in this phenomenon, the researchers designed a real-time polymerase chain reaction miniarray of 45 key metabolic, inflammatory, and insulin target genes. They were surprised to find that one of the major sets of genes upregulated in the white adipose tissue of the haploid mice increased the activity of uncoupling proteins—mitochondrial proteins associated with burning energy in brown adipose tissue. This process has been referred to as “browning” of white fat.
“High insulin programs the white fat to really hold onto its nutrients and not burn any of them,” Johnson told Endocrine News. “If you can reduce the hyperinsulinemia, you have an upregulation of these uncoupling proteins, which will burn energy and increase energy expenditure, with no difference in food intake.”
These findings on insulin’s effect on energy balance make the study stand out, said Kahn: “I think they are the first people to say it in quite this way. There are other people who have said that the hyperinsulinemia might be bad because it makes more insulin resistance, but this is something different. that hyperinsulinemia actually changes energy expenditure is very new. Most people would say that high insulin promotes obesity because it causes more fat storage directly. But is saying it’s not causing more fat storage directly, but what it is doing is decreasing energy expenditure, and allowing the energy to be stored.”
Not a New Idea
Th is idea that insulin is a driver of obesity has had its champions since the 1970s, but this is the most direct evidence and clearest demonstration of a mechanism yet, according to Robert Lustig, MD, a pediatric endocrinologist at the University of California San Francisco and member of the Endocrine Society Obesity Task Force. Lustig has been convinced of high insulin’s detrimental role since treating pediatric patients who had obesity caused by hypothalamic tumors. Because the brains of these patients could not sense leptin, their bodies went into a starvation response, and constantly over-released insulin to store energy.
Lustig’s team treated the patients with the acromegaly drug ocreotide, which is used to treat pituitary tumors but also reduces pancreatic insulin secretion. “When we were successful in reducing their insulin release, the patients lost weight and started to feel better. But even more importantly, they started exercising spontaneously and their resting energy expenditure went up, suggesting that energy expenditure was tied to energy intake through insulin,” said Lustig, who has been in the spotlight recently after release of his popular book on obesity (see sidebar).
Insulin Resistance Paradox
Johnson said that his experience in working with the pituitary leads him to question the generally accepted reasoning about insulin resistance: “We were taught as neuroendocrinologists that if there is too much of a certain hormone or neurotransmitter, the receptor for that hormone or neurotransmitter gets desensitized, which is that hormone’s resistance. Diabetes is the only field in endocrinology where they think the opposite, where they think that the resistance happens first.”
He cites research in flies and worms, which has shown that when researchers knock out a cluster of genes that control aging and leanness and stimulate insulin, the animals with reduced insulin are lean and live twice as long. “The people who study worms and flies are tuned in to the idea that you can have excess insulin, and if you bring that down it is beneficial for the organism. But clinical endocrinologists are used to thinking of insulin as a good guy because in the complete absence of insulin you have diabetes. It can be very difficult to think of it as both a good guy and potentially a bad guy when there is too much,” Johnson said.
The study, which Johnson calls “the first evidence that insulin itself is required for weight gain in vivo,” appeared in the December 5 edition of Cell Metabolism.
—Seaborg is a freelance writer in Charlottesville, VA, and a regular contributor to Endocrine News.
According to the work and research of Dr Jason Fung and his phenomenal book The Diabetes Code, insulin is the primary hormone responsible for weight gain. Elevated levels of insulin and insulin resistance are associated with weight gain, so the question that needs to be asked is what causes excess insulin production, how does insulin resistance cause weight gain and what is the connection between overproduction of insulin and weight gain. Before we dive into losing weight with insulin resistance let first take a look at the purpose of insulin in the body.
What does the hormone insulin do?
Insulin is a hormone produced by the beta cells of the pancreas and is secreted when blood sugar (glucose) levels rise. The role of insulin in the body is to transport glucose throughout the body and into the cells so that glucose can then be used as a source of energy once inside the cells. Insulin acts as a key that locks into receptor sites on the cells to allow the entry of glucose from the bloodstream to get inside cells. Without insulin glucose would not be able to enter the cell thus cell starvation would result.
How does insulin cause weight gain if it is just a hormone that transports glucose?
When insulin levels rise in response to eating food insulin tells the body to not burn fat because there is glucose available in the bloodstream for energy. When blood glucose levels rise so will insulin so that glucose can get into our cells and be stored in the liver and muscles as glycogen for later use but when these stores are full the liver will convert any excess glucose into fat to maintain normal blood glucose levels.
How does insulin resistance cause weight gain?
Insulin is the hormone that tells the body to store glucose and not to burn fat thus insulin can be thought of as your fat storage hormone. When insulin levels are elevated the body will be in fat storage mode.
How do sugar and refined carbohydrates cause over production of insulin and weight gain
Refined sugar found in the forms of fruit juice, soda pops, table sugar and refined carbohydrates such as bread, pasta, pastries, sweet treats, breakfast cereals, chips, and refined grains (flours) are broken down and absorbed at a very rapid pace in the body causing what is known as blood sugar spikes.
The body does not like having a fast release of glucose into the bloodstream therefore in response to higher than normal blood glucose levels the pancreas will secrete higher amounts of insulin to bring blood glucose back to balance. Instead of all those calories providing long lasting energy they are quickly stored or turned to fat so that homeostasis of blood sugar can be restored. This is why reducing sugar to lose weight is so important.
The consumption of refined carbohydrates and sugar often leave people on an emotional blood sugar roller coaster experiencing energy spikes along with the dips and weight gain! These energy spikes and dips are also your body’s initial signs of blood sugar imbalances.
What is the connection between sugar and insulin resistance?
When sugar and refined carbohydrates are eaten on a continuous basis and the body is never given the chance to burn through its glycogen stores in the liver and muscles, the body then becomes overwhelmed with the excess amount of glucose in the body. The cells do not want to take in any more glucose, therefore, they become resistant to the hormone insulin. The cells are literally screaming I have enough sugar already and I do not need any more so the cells start to become unresponsive to the signals of insulin.
Are you struggling to lose weight and tired of fad diets? with step by step challenges to lose weight for good.
How does insulin make you gain weight?
The insulin resistance and weight gain problem really starts to show once the cells have become unresponsive to the signals of insulin because the glucose has to go somewhere…. So the pancreas pumps out more insulin hoping that more insulin will get that sugar inside the cells so that blood glucose levels can be maintained. But when the cells are consistently unresponsive to the uptake of new glucose it is then converted to fat resulting in…, you guessed it…weight gain.
How to lose weight with insulin resistance
In order to restore insulin sensitivity, the body needs to be given the opportunity to burn through and utilize all the excess glucose that is already in the body. The cells will not become responsive and sensitive to the hormone insulin until they need more glucose. This means that you have to stop putting more sugar, refined carbohydrates and food into the body.
Refined carbohydrates and sugar in all of its many forms are the foods that increase insulin production, thus raising insulin levels and contributing to insulin resistance which is why reducing sugar to lose weight is key. Sugar and refined carbohydrates are found everywhere from commercial breakfast cereals, pop, fruit juice, bread, pasta, sauces, chips and pretty much everything that comes from a cardboard box. 5 grams of refined carbohydrates equals 1 tsp of sugar….. so ditch all the commercial processed foods and get healthy carbohydrates from non starchy liver cleansing vegetables.
Fats are the best foods that don’t spike insulin levels and signal the satiety hormones that make you feel full and satisfied while offering a slow burning source of energy, therefore healthy fats should be included with every meal. Fats are the foods that increase insulin sensitivity as they have the least impact on signalling insulin. Be mindful that while fats have the least impact on signalling insulin they are still energy dense and some people need to implement intermittent fasting to restore insulin sensitivity and lose weight.
All food that is eaten will signal the hormone insulin to some degree. In some cases in order to restore insulin sensitivity and lower the amounts of insulin present in the body you must implement longer periods of fasting (not consuming any food) to give the body the opportunity to burn through the excess glucose already in the body, such as the glycogen stores in the muscles and liver, so that the next time a person eats those cells will be hungry for glucose and responsive to the signals of insulin. When intermittent fasting is implemented the glycogen stores will be depleted in the liver and muscles so that glucose has somewhere to temporarily be stored and doesn’t need to be converted into fat for storage
Why fasting is not the same as calorie restriction
If weight loss were as simple as counting calories then the answer would be simple, eat less and lose weight…. But that is not the case. The body has the ability to both raise your metabolism and slow down your metabolism. If a person restricts the number of calories consumed the body can just slow down its metabolism to match the number of calories consumed.
But, by extending the time period in which no food is consumed the body will stay in a fat burning mode allowing you to utilize stored and fat for energy without slowing down your metabolism.
Any amount of food eaten, even if it is just a small amount will trigger the fat storage hormone insulin and switch the body out of fat burning mode. The minute insulin levels rise due to food consumption you will not be burning fat or stored glycogen, instead, you will be burning and storing the food that was just eaten.
Losing weight with insulin resistance starts with eliminating/reducing sugar, refined carbohydrates and implementing longer periods of fasting by shortening the eating window in which food is consumed so that insulin sensitivity can be restored and weight loss can be achieved. As everyone is unique and may have different degrees of insulin resistance the fine tuning of the diet and fasting periods can vary for each individual.
Does the insulin pump cause weight gain?
I have been a Type 1 for 19 years now and have been on a pump for about a year. My A1C used to be horrible (13%) and I weighed a normal weight. When I finally got my A1C down to around 7% I put on about 75 pounds in 2 years. I was just wondering if anyone has lost weight while using a pump. If so, what did you do, what do you usually eat everyday, exercise, etc. Any help or suggestions would be greatly appreciated…
Before I address the specific question, I want to educate you about basic physiology regarding glucose (sugar) utilization by our bodies. In someone without diabetes, after eating a meal or snack, the food gets converted to glucose and the brain sends a message to the pancreas requesting insulin to escort the glucose into the cells to be used for energy. The pancreas responds and secretes the appropriate amount of insulin for the food eaten. If this person eats more calories than they burn, they will gain weight. In type 1 diabetes, after eating a meal or snack, the food gets converted to glucose and the brain sends a message to the pancreas requesting insulin to escort the food into the cell. The difference is that in type 1 diabetes, the pancreas does not do its job so instead of the glucose getting put in the cells; it hangs out in the blood and eventually gets sent over to our kidneys which in turn makes us urinate. Each molecule of glucose that we are flushing down our toilets has calories which we are losing through our urine. When people with diabetes begin taking insulin to match their food intake they are holding on to those calories and using them for energy. That is why most people lose weight before being diagnosed with diabetes. Once insulin therapy begins, they can gain that weight back. Insulin itself does not make you gain weight, but instead if you are eating more calories than you burn, you will gain weight.
In your question, this person’s A1C was 13% which means her average blood glucose was around 330mg/dl. In that scenario, her body is not able to use that glucose because there is a deficiency of insulin in her body and she is basically losing those calories via her kidneys and urination. (This is NOT a good idea for weight loss by the way. It has many serious damaging effects on the body.) Once she started on a pump, and her blood sugars were closer to normal as evidenced by the drop in her A1C, she was no longer “flushing” away those calories but holding on to them, thus gaining weight. Then if she was used to eating more calories than what she actually needed but now she is matching her food intake with insulin dose, she may gain more weight.
The question to ask now is how many calories do you need to consume on a daily basis? And are you exercising regularly? As a person with type 1 diabetes, on an insulin pump, assuming you are matching insulin with food intake, you are no different from someone without diabetes meaning that if you are eating more calories than you are burning, you will gain weight.
Insulin pumps do not cause weight gain. People are able to lose weight while using insulin pumps. If you have access to a knowledgeable dietitian or diabetes care team, they should be able to work with you on both calories consumed, and the effect of exercise. You may need to decrease insulin if you begin exercising so that you do not have to eat to control hypoglycemia. If you do not have access to this type of care, you do need to keep food records and evaluate what and how much you are eating. Introduce exercise but recognize that you may need to decrease basal rates and boluses Also keep in mind that a normal A1c is your goal and that you can lose the weight. Good luck!
How to Avoid Insulin-Related Weight Gain
When diet, exercise, and oral diabetes medications aren’t enough to control diabetes, adding insulin can help get your blood sugar under control. Although insulin is an important part of diabetes treatment, some people may have an issue with weight gain after starting on it. If insulin has been prescribed as part of your treatment plan, you may need to pay extra attention to your weight management efforts in addition to blood sugar management.
“Insulin weight gain is a well-known problem and concern for people with type 2 diabetes,” says Amber L. Taylor, MD, an endocrinologist who directs the Diabetes Center at Mercy Medical Center in Baltimore. “This is problematic because weight gain can make managing diabetes more difficult.”
Why Is Weight Gain an Insulin Side Effect?
A study published in the journal Clinical Medicine Insights: Endocrinology and Diabetes focused on 102 people with type 2 diabetes who had recently started taking insulin. After the first year of insulin therapy, both men and women in the study had increased their body weight by about 2.5 percent.
The science behind why this happens is clear. When you’re not managing diabetes well, your body can’t use the glucose (sugar) from your food for energy. That means the sugar builds up in your blood, which can lead to diabetes complications. You may feel hungry because you’re not getting enough energy, and thirsty because your body is trying to flush all that sugar out of your bloodstream. Here’s what happens when you add insulin:
- Insulin helps the sugar in your blood to be absorbed by your cells, where it’s used and stored for energy.
- Because you’re now getting the energy you need, you become less hungry.
- You may retain fluid to make up for the dehydration that was present before taking insulin.
These effects are good for diabetes management, but not so good for weight management. Weight gain from fluid retention doesn’t last long, but weight gain from absorbing more sugar does. This can happen even if you eat the same amount of food as you did before you started taking insulin.
“When your blood sugar is uncontrolled, you lose glucose through your urine,” Dr. Taylor explains. “Once your blood sugar is better controlled, you body will be reabsorbing all that glucose. If your weight was stable before you started taking insulin, this is likely the root of your weight gain and you may need to make appropriate lifestyle changes to compensate.”
How to Avoid Insulin-Related Weight Gain
“Some people with diabetes are afraid to take insulin due to concern about weight gain, but the benefits of better blood sugar control outweigh those risks,” Taylor says. “Talk to your doctor about your diet at each visit, and ask about visits with a dietitian or nutritionist. Discuss healthy eating in general — not just minimizing carbohydrates, but watching sodium and saturated fat, too.”
Here are specific tips to help you manage your weight after adding insulin:
- Eat less. If you continue to eat the same amount of food as you did when your body was craving energy, you’ll be eating too much and will likely gain weight. Work with your doctor or dietitian to find the right amount of daily calories for you.
- Exercise more. The best way to get rid of extra calories is to burn them off through physical activity. As you exercise more and start to lose excess weight, your need for insulin may decrease as well.
- Don’t cut back on insulin on your own. It might be tempting to cut back on insulin for awhile to try to lose some weight, but this is never a good idea. It’s dangerous, can drastically affect your control over diabetes, and when you go back on insulin, you’ll likely gain the weight right back.
- Don’t skip meals. If you’re taking insulin and you skip a meal, your blood sugar can dip too low. This is also dangerous, and can make it harder to get your blood sugar back under control. And skipping meals isn’t a good idea in terms of weight management, either — keeping your metabolism steady with small, frequent meals and snacks is a much smarter approach overall.
- Ask your doctor about different medications. If you’re struggling with insulin-related weight gain, there may be other diabetes medications you can try. Talk to your doctor about all of your options.
Insulin weight gain is a side effect you should know about, but it’s not a reason to avoid insulin completely. The benefits of insulin in managing diabetes far exceed moderate insulin-related weight gain. In most cases, weight management with regular exercise and a healthy diet can keep you at a healthy weight — which is good for managing your diabetes, too. If you’re still struggling with insulin-related weight gain after making lifestyle changes, ask your doctor or dietitian for help.
In the DCCT, the patients randomised to the “intensive” treatment group gained more weight than those randomised to the “conventional” treatment group , . These results confirmed those observed in the “Stockholm Intervention Study” . In the DCCT, weight increased during the whole study in both treatment groups. The excess weight gain in the intensive treatment group was mostly observed during the first years of the study . In this study the excess weight gain was 2.1 kg during the first year, 4.6 kg at 5 years and 4.7 kg at the end of the study , . In the Stockholm study, the excess weight gain of the patients in the “intensive” treatment group was 2.6 kg over a 7.5 years’period. In the “intensive” treatment group of the Stockholm study, glycaemic control was similar to that observed in the intensive group of the DCCT (mean HbA1c level: 7.1%), but glycaemic control was better in the conventional group of the Stockholm study than in the conventional group of the DCCT (mean HbA1c level were 8.5% in the Stockholm study and 9.1% in the DCCT). This suggests that in the DCCT, the poor metabolic control of the “conventional” treatment group prevented weight gain in this group. Indeed, even in the “conventional” treatment group of the DCCT, the mean HbA1c level was significantly higher in the first quartile of weight gain than in the fourth one (Figure 1) , and the weight gain in the fourth quartile of weight gain of the conventional treatment group was greater to that of the first and second quartiles of weight gain of the intensive group, similar to that of the third quartile and only surpassed by the fourth quartile of the intensive treatment group (Figure 1).
The data on the body weight composition analysis in the DCCT have been recently published . In women, the excess weight gain in the intensive group compared to the conventional group was for one-third due to an increase in the fat-free mass, and among patients without major weight gain, intensive therapy was associated with greater fat-free mass but without difference in adiposity , .
What are the causes for this excess weight gain in intensively treated patients? At the end of the trial, the insulin dose was similar in both treatment groups in the Stockholm study (0.71 ± 0.03 vs 0.69 ± 0.3 U • kg –1 • day –1). In the DCCT, patients in the conventional treatment group received 0.62 ± 0.17 vs 0.67 ± 0.21 U • kg –1 • day –1 in the intensive treatment group, and both in the conventional and in the intensive treatment group, the insulin dose of the fourth quartile of weight gain was higher than that of the first quartile . This does not imply that insulin dose was the cause of weight gain, this can also be interpreted as an association of weight gain and greater insulin resistance.
It has been suggested that hypoglycaemic episodes, three times more frequent in the DCCT in the intensive than in the conventional group, were major causes of weight gain. A recent analysis of the DCCT contradicts the previous results reported from this trial, but obtained from a smaller sample of patients followed-up over a shorter period of time: the incidence of hypoglycaemic episodes is not related to changes in BMI. This recent analysis estimates that hypoglycaemic episodes account for only 2% of the weight gain that occurred over the whole duration of the study .
The data on the weight gain in the DCCT have been further analysed in a recently published article . It appears that type 1 diabetic patients with a family history of type 2 diabetes mellitus gained more weight than those without such history (ΔBMI 3.9 ± 2.8 vs 2.9 ± 3.2 kg/m2). At the end of the study, the prevalence of obesity in the intensive group was close to that reported for the general population. Finally, other components of the metabolic syndrome were more likely to be observed in patients with a family history of type 2 diabetes than in those without history, with significant differences for triglycerides, HDL- and LDL-cholesterol, increased waist-to-hip ratio (but neither systolic nor diastolic pressure differences), and the insulin doses were higher in these patients.
The first conclusions of the weight and lipid parameters analysis of the DCCT were negative: “The changes in lipid levels and cholesterol content in the lipoprotein fractions that occur with excessive weight gain (…), along with the findings of higher blood pressures, increased WHR, may over a long follow-up period contribute to an increased risk of macrovascular disease” . These conclusions are now balanced by the recent analysis of the full data, and thus their authors concluded: “These findings supports the hypothesis that intensive therapy permits expression of several components of the central obesity syndrome phenotype in a subset of individuals with a family history of type 2 diabetes” . In agreement with this line of evidence, one has to remember that this is a classic fact that patients with type 1 diabetes may remain leaner than nondiabetic control subjects.
We believe that all the data we summarised here, indicate that as long as they are poorly controlled, patients with type 1 diabetes remain below “their” weight (i.e the weight they would have in the absence of diabetes). Intensive insulin therapy allows them to reach “their” weight. Those who would have been obese without diabetes will become obese with insulin therapy, and may express the full phenotype of the insulin resistance syndrome if they possess the genetic potential for it. The data obtained from the EDIC study, a follow-up study of the DCCT, indicate that as far as macroangiopathy is concerned, the benefits of a good glycaemic control outweigh the risk of obesity and dyslipidemia and their consequences . Only further follow-up of the DCCT cohort will definitively answer this question. Even a meta-analysis of the currently available data was unconclusive, but the number of cardiovascular events collected in this meta-analysis, apart from those of the DCCT, were only 4/150 patients on intensive treatment and 10/140 patients on conventional treatment .