Insulin Resistance in Children
Editor's Note:
The Insulin Resistance in Children Consensus Conference Group consists of experts representing the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), the International Society for Pediatric and Adolescent Diabetes (ISPAD), the Asia Pacific Pediatric Endocrine Society (APPES), the Australasia Pediatric Endocrine Society (APEG), the Sociedad Latino-Americana de Endocrinologia Pediatrica (SLEP), and the Japanese Society for Pediatric Endocrinology (JSPE). A 2010 report issued by the consensus group, Insulin Resistance in Children: Consensus, Perspective, and Future Directions, summarized the most recent evidence in the areas of definition, measurement, risk factors, and strategies for prevention and treatment. Laurie Scudder, DNP, NP, spoke with Professor Wayne Cutfield, BHB, MB, ChB, MD, Director, Liggins Institute, Professor of Pediatric Endocrinology at The University of Auckland, and an author of the consensus report about the implications of this information for the care of at-risk children and teens.
Medscape: Professor Cutfield, the report clarifies the definition of insulin resistance (IR) noting that it is defined by decreased tissue response to insulin-mediated cellular activity and that this process is a continuum. Can you speak to the impact of physiological conditions, such as puberty, on that process? Are there clinical implications to these physiological processes occurring on top of pre-existing resistance?
Wayne Cutfield, BHB, MB, ChB, MD: Yes, in a child with underlying IR, obesity is likely to add to their IR. Puberty will have an additional additive effect.
We know that IR is a risk factor for type 2 diabetes, though the condition does not automatically progress to type 2 diabetes. The additive effect of lifestyle factors, genetic risk factors, and early-life factors ultimately lead to type 2 diabetes. Some of these factors may be modified. So if this same obese, pubertal child who has IR were then to diet and exercise, and reduce their obesity, their IR would also reduce.
The other important thing to note is that IR is a dynamic state. IR today does not necessarily mean that individual will be just as insulin resistant in 2 years or 5 years. Lifestyle factors can make the condition worse or potentially better.
Medscape: The report discusses the difficulty in IR outside of research settings. As a result, the consensus does not recommend screening children, even those who are obese, for resistance. Are there any circumstances where measurement of IR would be recommended and would subsequently impact decisions regarding management?
Prof. Cutfield: This is an issue that was debated at enormous length. There are several issues around screening children for IR. The first is the lack of any standard for measuring IR. The gold standard is the euglycemic clamp, an intricate test that is only performed in a research setting. It is difficult to perform and requires considerable experience and expertise. It requires a half day to complete and is therefore a significant intrusion on an individual. Additionally, it's very expensive and would be extremely difficult to implement on a large scale.
There are other tools that are crude proxies, if you like, of IR. These include fasting insulin levels and the homeostasis model assessment-estimated insulin resistance (HOMA-IR). There are children who will have IR that is not fairly reflected by these tests.
HOMA-IR is specifically mentioned in the consensus statement. There are many different insulin assays, and all vary in terms of a normal range for that specific assay. Unless you use the exact same essay, comparisons of results are meaningless.
Discussion of screening tests for IR begs the question, "Well, what are you going to do about it?" One of the justifications for screening is that there is an effective treatment available for the condition for which the test is screening. If we look at IR, what is the justification for simply treating the insulin-resistant child? Are there any studies that show if you treat a child who just has IR that you can prevent them from developing type 2 diabetes, or any of the other later consequences of IR, like hypertension or risk for malignancy?. There are no studies conducted in children with IR that demonstrate that treatment reduces a child's risk for diabetes mellitus, metabolic syndrome, hypertension, heart disease, or lipid disorders.
Now, of course there are effective therapies for obesity, but not all children with obesity are insulin resistant. For example, could we justify drug treatment for a nonobese 10-year-old child with IR or reduced insulin sensitivity? What would be the benefits? We couldn't justify treating this child because long-term benefits have not been demonstrated. That may change in time, but right now in 2011, there is no evidence to indicate that treating an insulin-resistant child will prevent long-term disease.
Medscape: In the discussion of risk factors for IR, the report notes ethnicities that are inherently less insulin sensitive. That group includes African American children. Recognizing that this is an international statement, is the correct interpretation that African children are not at similar risk?
Prof. Cutfield: Reference was made to African American children because that is the group that has been studied. Your question, which is a fair one, is what about African children in Africa? In the United States, there are high obesity rates in the African American population. As I noted earlier, IR is the sum of influences that include genetic predisposition but also adiposity or obesity, lifestyle, diet, and activity levels. Obesity is not seen as much in Africa because of the nutritional deprivation often seen in that continent. There are a number of ethnic groups in addition to African Americans, who are less insulin sensitive in comparison to European Caucasians including Pacific Islanders and Indians.
Medscape: Comorbid conditions associated with IR include acanthosis nigricans, polycystic ovary syndrome (PCOS), abdominal visceral adiposity, and nonalcoholic fatty liver disease (NAFLD). How complete are these relationships and should clinicians presume that children with these conditions are also insulin resistant?
Prof. Cutfield: These conditions are often, but not always, strongly associated with IR. They are not, however, diagnostic of IR. The strongest of these associations is with acanthosis nigricans, although not every adolescent or child with acanthosis nigricans will be insulin resistant. However, a child or teenager with several of these conditions does have a strong likelihood of being insulin resistant. However, I come back to my earlier point about treatment -- what do you do? IR, per se, does not lead to symptoms. It is the associations that are the issue.
For example, girls with clinical features of PCOS may be treated with metformin. Data from randomized controlled trials conducted primarily in adults have provided strong evidence of efficacy of this therapy with resultant modification of the symptoms of PCOS. There is no similar evidence for the treatment of NAFLD or abdominal obesity.
It is usually the co-existing obesity that has contributed enormously to the IR. It is that component of the clinical picture, the obesity, where treatment is effective. In disorders in which IR is a component, the treatment is about fixing the other conditions.
Medscape: That is a good segue to my next question. The treatment of IR is a back-to-basics one that includes weight loss and improved fitness through exercise, ideally as part of a multicomponent lifestyle intervention. Are there specific dietary macronutrient recommendations?
Prof. Cutfield: The most difficult dietary approach to the management of obesity is calorie restriction. It is the least palatable of all to humans as we hate not eating. Therefore, micronutrient manipulation, if it works without requiring a dramatic reduction in calories, is more appealing. The issue of whether a manipulation of micro- or macronutrients would be effective is a fundamentally important point. When we think about IR, it appears as if most of the effect from manipulation of dietary components may well be the result of related weight loss.
What is not clear is whether there is an effect independent of weight loss. Clearly that's an area that needs to be better researched, because the simplest approach, a lower-calorie diet that is adhered to, is the most likely to be successful but also the least palatable. There is evidence to indicate that a reduction in saturated fat intake and optimization of dietary fiber intake improves insulin sensitivity. This is in line with diets recommended by dietetic societies. Those diets suggest increasing vegetable intake, reducing saturated fat intake, and reducing glucose intake.
Reduction in calories to balance the energy in and energy out is clearly going to be important.
Weight loss is important to achieve, but can you improve IR without reducing weight? Does correction of insulin sensitivity without improvement in obesity reduce risk for long-term problems like heart disease, hypertension, type 2 diabetes, dyslipidemia, NAFLD, cancer, and the list goes on. That question is unanswered.
Medscape: The report discusses use of metformin as part of this treatment regime. Could you discuss this strategy? Are there specific recommendations to guide clinicians on when to include this agent as part of the broader therapeutic approach?
Prof. Cutfield: There are a number of studies in both adolescents and adults showing the benefit of metformin in correcting the symptoms of PCOS, some of which, like menstrual irregularity, are the result of IR. Beyond PCOS, the question remains as to whether a very obese child or adolescent should be treated with metformin. My sense is that there are quite a few obese children treated with metformin. What is the justification for this therapy and what will be achieved? There is no evidence that treating a child or adolescent with metformin will prevent their long-term risk of developing insulin-resistant consequential diseases, type 2 diabetes, hypertension, heart disease, or dyslipidemia.
If there was clear, unequivocal evidence that the introduction of metformin to obese adolescents and/or children reduced the risk for long-term diseases, then there would be hundreds of thousands of American children treated with this drug. So it's a large-scale problem. The other issue is the side effects, and metformin, while relatively safe, is not completely free of side effects. Potentially treating large numbers of patients increases the risk for rare, but serious, adverse effects. While the use of this agent is discussed in the consensus document, it should be emphasized that there is no evidence to justify the treatment of an obese child who might be insulin resistant with metformin to try and prevent long-term complications of IR, and it is not recommended.
Medscape: The report discusses the importance of prevention. While a number of maternal factors are noted, including addressing maternal obesity, gestational diabetes, undernutrition, and smoking, the strategies for prevention of IR appear to focus on prevention of obesity in infants and children through early identification and intervention of infants and children at risk for obesity. Specifically the report discusses adiposity rebound as a sensitive marker for the risk for obesity. Can you discuss this concept and its recognition in the primary care setting?
Editor's Note: After the first year of life, body mass index (BMI) typically declines and reaches a nadir at approximately 5-7 years of life. In most children, BMI then begins a gradual and sustained increase. There is a large body of evidence that onset of rebound at a younger age is associated with significantly increased risk for obesity in adulthood.
Prof. Cutfield: There are several points to make, some of them well known, to answer this question. The first is the concept of obesity trait: an obese child has a very high likelihood of becoming an obese adolescent, and an obese adolescent has a much higher chance of being an obese adult. The risk that results from obesity during infancy, while still there, is not quite as great. The older a child is at the onset of obesity, the higher is the risk for persistent obesity into adulthood. The best management of obesity is in prevention of the evolutional development of obesity. Those who do become obese usually begin that trajectory early in childhood. There is a cycle that begins with an obese mother who has a large fetus and delivers a large baby, who goes on to be an obese child, who then grows up to become an obese parent who has an obese child, and so on.
Therefore interventions earlier in childhood are potentially easier to implement and more effective than salvage interventions applied after the child becomes morbidly obese. Also more effective are strategic interventions during pregnancy, with attention to maternal diet and weight gain during pregnancy. In fact, childhood obesity may be predetermined based on the mother's diet from conception through pregnancy. However, it is also clearly important to address adiposity rebound that begins during the latter phases of infancy and early childhood and provide interventions and guidance in the areas of food intake and activity at that time.
It should be emphasized that a discussion of IR and its prevention should not be reduced to solely a discussion about obesity. As I have noted, obesity is usually associated with IR, however, not all obese children are insulin resistant.
Medscape: Prof. Cutfield, do you have any final insights or thoughts for primary care providers caring for these children?
Prof. Cutfield: There are several key things to emphasize:
Editor's Note:
The Insulin Resistance in Children Consensus Conference Group consists of experts representing the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), the International Society for Pediatric and Adolescent Diabetes (ISPAD), the Asia Pacific Pediatric Endocrine Society (APPES), the Australasia Pediatric Endocrine Society (APEG), the Sociedad Latino-Americana de Endocrinologia Pediatrica (SLEP), and the Japanese Society for Pediatric Endocrinology (JSPE). A 2010 report issued by the consensus group, Insulin Resistance in Children: Consensus, Perspective, and Future Directions, summarized the most recent evidence in the areas of definition, measurement, risk factors, and strategies for prevention and treatment. Laurie Scudder, DNP, NP, spoke with Professor Wayne Cutfield, BHB, MB, ChB, MD, Director, Liggins Institute, Professor of Pediatric Endocrinology at The University of Auckland, and an author of the consensus report about the implications of this information for the care of at-risk children and teens.
Medscape: Professor Cutfield, the report clarifies the definition of insulin resistance (IR) noting that it is defined by decreased tissue response to insulin-mediated cellular activity and that this process is a continuum. Can you speak to the impact of physiological conditions, such as puberty, on that process? Are there clinical implications to these physiological processes occurring on top of pre-existing resistance?
Wayne Cutfield, BHB, MB, ChB, MD: Yes, in a child with underlying IR, obesity is likely to add to their IR. Puberty will have an additional additive effect.
We know that IR is a risk factor for type 2 diabetes, though the condition does not automatically progress to type 2 diabetes. The additive effect of lifestyle factors, genetic risk factors, and early-life factors ultimately lead to type 2 diabetes. Some of these factors may be modified. So if this same obese, pubertal child who has IR were then to diet and exercise, and reduce their obesity, their IR would also reduce.
The other important thing to note is that IR is a dynamic state. IR today does not necessarily mean that individual will be just as insulin resistant in 2 years or 5 years. Lifestyle factors can make the condition worse or potentially better.
Medscape: The report discusses the difficulty in IR outside of research settings. As a result, the consensus does not recommend screening children, even those who are obese, for resistance. Are there any circumstances where measurement of IR would be recommended and would subsequently impact decisions regarding management?
Prof. Cutfield: This is an issue that was debated at enormous length. There are several issues around screening children for IR. The first is the lack of any standard for measuring IR. The gold standard is the euglycemic clamp, an intricate test that is only performed in a research setting. It is difficult to perform and requires considerable experience and expertise. It requires a half day to complete and is therefore a significant intrusion on an individual. Additionally, it's very expensive and would be extremely difficult to implement on a large scale.
There are other tools that are crude proxies, if you like, of IR. These include fasting insulin levels and the homeostasis model assessment-estimated insulin resistance (HOMA-IR). There are children who will have IR that is not fairly reflected by these tests.
HOMA-IR is specifically mentioned in the consensus statement. There are many different insulin assays, and all vary in terms of a normal range for that specific assay. Unless you use the exact same essay, comparisons of results are meaningless.
Discussion of screening tests for IR begs the question, "Well, what are you going to do about it?" One of the justifications for screening is that there is an effective treatment available for the condition for which the test is screening. If we look at IR, what is the justification for simply treating the insulin-resistant child? Are there any studies that show if you treat a child who just has IR that you can prevent them from developing type 2 diabetes, or any of the other later consequences of IR, like hypertension or risk for malignancy?. There are no studies conducted in children with IR that demonstrate that treatment reduces a child's risk for diabetes mellitus, metabolic syndrome, hypertension, heart disease, or lipid disorders.
Now, of course there are effective therapies for obesity, but not all children with obesity are insulin resistant. For example, could we justify drug treatment for a nonobese 10-year-old child with IR or reduced insulin sensitivity? What would be the benefits? We couldn't justify treating this child because long-term benefits have not been demonstrated. That may change in time, but right now in 2011, there is no evidence to indicate that treating an insulin-resistant child will prevent long-term disease.
Medscape: In the discussion of risk factors for IR, the report notes ethnicities that are inherently less insulin sensitive. That group includes African American children. Recognizing that this is an international statement, is the correct interpretation that African children are not at similar risk?
Prof. Cutfield: Reference was made to African American children because that is the group that has been studied. Your question, which is a fair one, is what about African children in Africa? In the United States, there are high obesity rates in the African American population. As I noted earlier, IR is the sum of influences that include genetic predisposition but also adiposity or obesity, lifestyle, diet, and activity levels. Obesity is not seen as much in Africa because of the nutritional deprivation often seen in that continent. There are a number of ethnic groups in addition to African Americans, who are less insulin sensitive in comparison to European Caucasians including Pacific Islanders and Indians.
Medscape: Comorbid conditions associated with IR include acanthosis nigricans, polycystic ovary syndrome (PCOS), abdominal visceral adiposity, and nonalcoholic fatty liver disease (NAFLD). How complete are these relationships and should clinicians presume that children with these conditions are also insulin resistant?
Prof. Cutfield: These conditions are often, but not always, strongly associated with IR. They are not, however, diagnostic of IR. The strongest of these associations is with acanthosis nigricans, although not every adolescent or child with acanthosis nigricans will be insulin resistant. However, a child or teenager with several of these conditions does have a strong likelihood of being insulin resistant. However, I come back to my earlier point about treatment -- what do you do? IR, per se, does not lead to symptoms. It is the associations that are the issue.
For example, girls with clinical features of PCOS may be treated with metformin. Data from randomized controlled trials conducted primarily in adults have provided strong evidence of efficacy of this therapy with resultant modification of the symptoms of PCOS. There is no similar evidence for the treatment of NAFLD or abdominal obesity.
It is usually the co-existing obesity that has contributed enormously to the IR. It is that component of the clinical picture, the obesity, where treatment is effective. In disorders in which IR is a component, the treatment is about fixing the other conditions.
Medscape: That is a good segue to my next question. The treatment of IR is a back-to-basics one that includes weight loss and improved fitness through exercise, ideally as part of a multicomponent lifestyle intervention. Are there specific dietary macronutrient recommendations?
Prof. Cutfield: The most difficult dietary approach to the management of obesity is calorie restriction. It is the least palatable of all to humans as we hate not eating. Therefore, micronutrient manipulation, if it works without requiring a dramatic reduction in calories, is more appealing. The issue of whether a manipulation of micro- or macronutrients would be effective is a fundamentally important point. When we think about IR, it appears as if most of the effect from manipulation of dietary components may well be the result of related weight loss.
What is not clear is whether there is an effect independent of weight loss. Clearly that's an area that needs to be better researched, because the simplest approach, a lower-calorie diet that is adhered to, is the most likely to be successful but also the least palatable. There is evidence to indicate that a reduction in saturated fat intake and optimization of dietary fiber intake improves insulin sensitivity. This is in line with diets recommended by dietetic societies. Those diets suggest increasing vegetable intake, reducing saturated fat intake, and reducing glucose intake.
Reduction in calories to balance the energy in and energy out is clearly going to be important.
Weight loss is important to achieve, but can you improve IR without reducing weight? Does correction of insulin sensitivity without improvement in obesity reduce risk for long-term problems like heart disease, hypertension, type 2 diabetes, dyslipidemia, NAFLD, cancer, and the list goes on. That question is unanswered.
Medscape: The report discusses use of metformin as part of this treatment regime. Could you discuss this strategy? Are there specific recommendations to guide clinicians on when to include this agent as part of the broader therapeutic approach?
Prof. Cutfield: There are a number of studies in both adolescents and adults showing the benefit of metformin in correcting the symptoms of PCOS, some of which, like menstrual irregularity, are the result of IR. Beyond PCOS, the question remains as to whether a very obese child or adolescent should be treated with metformin. My sense is that there are quite a few obese children treated with metformin. What is the justification for this therapy and what will be achieved? There is no evidence that treating a child or adolescent with metformin will prevent their long-term risk of developing insulin-resistant consequential diseases, type 2 diabetes, hypertension, heart disease, or dyslipidemia.
If there was clear, unequivocal evidence that the introduction of metformin to obese adolescents and/or children reduced the risk for long-term diseases, then there would be hundreds of thousands of American children treated with this drug. So it's a large-scale problem. The other issue is the side effects, and metformin, while relatively safe, is not completely free of side effects. Potentially treating large numbers of patients increases the risk for rare, but serious, adverse effects. While the use of this agent is discussed in the consensus document, it should be emphasized that there is no evidence to justify the treatment of an obese child who might be insulin resistant with metformin to try and prevent long-term complications of IR, and it is not recommended.
Medscape: The report discusses the importance of prevention. While a number of maternal factors are noted, including addressing maternal obesity, gestational diabetes, undernutrition, and smoking, the strategies for prevention of IR appear to focus on prevention of obesity in infants and children through early identification and intervention of infants and children at risk for obesity. Specifically the report discusses adiposity rebound as a sensitive marker for the risk for obesity. Can you discuss this concept and its recognition in the primary care setting?
Editor's Note: After the first year of life, body mass index (BMI) typically declines and reaches a nadir at approximately 5-7 years of life. In most children, BMI then begins a gradual and sustained increase. There is a large body of evidence that onset of rebound at a younger age is associated with significantly increased risk for obesity in adulthood.
Prof. Cutfield: There are several points to make, some of them well known, to answer this question. The first is the concept of obesity trait: an obese child has a very high likelihood of becoming an obese adolescent, and an obese adolescent has a much higher chance of being an obese adult. The risk that results from obesity during infancy, while still there, is not quite as great. The older a child is at the onset of obesity, the higher is the risk for persistent obesity into adulthood. The best management of obesity is in prevention of the evolutional development of obesity. Those who do become obese usually begin that trajectory early in childhood. There is a cycle that begins with an obese mother who has a large fetus and delivers a large baby, who goes on to be an obese child, who then grows up to become an obese parent who has an obese child, and so on.
Therefore interventions earlier in childhood are potentially easier to implement and more effective than salvage interventions applied after the child becomes morbidly obese. Also more effective are strategic interventions during pregnancy, with attention to maternal diet and weight gain during pregnancy. In fact, childhood obesity may be predetermined based on the mother's diet from conception through pregnancy. However, it is also clearly important to address adiposity rebound that begins during the latter phases of infancy and early childhood and provide interventions and guidance in the areas of food intake and activity at that time.
It should be emphasized that a discussion of IR and its prevention should not be reduced to solely a discussion about obesity. As I have noted, obesity is usually associated with IR, however, not all obese children are insulin resistant.
Medscape: Prof. Cutfield, do you have any final insights or thoughts for primary care providers caring for these children?
Prof. Cutfield: There are several key things to emphasize:
Measuring fasting insulin and HOMA doesn't measure IR.
We do need to have better definition of IR and, in part, that requires a unified approach that standardizes insulin assays and methodologies for measurement.
Just as importantly, clinicians need to think about why they wish to measure IR and what will they do with these data.
An area that requires a lot more research is that of diet manipulation in order to gain a better understanding of the impact of specific interventions for IR. While we know a lot, there's a lot more we don't know about the most effective management of IR.
Finally, research also needs to focus on the long-term consequences of resistance.
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