The Thrifty Phenotype Hypothesis of Diabetes Mellitus Type 2
The Thrifty Phenotype Hypothesis of Diabetes Mellitus Type 2
Previous work by one of us (DJPB) has led to the conclusion that cardiovascular disease in adult life results from restraint of growth during foetal life and infancy. Cardiovascular disease is viewed as a 'programmed' effect of interference with early growth and development. (Programming may be defined as a permanent or long-term change in the structure or function of an organism resulting from a stimulus or insult acting at a critical period of early life. The first evidence for this came from geographical studies which showed that differences in death rates from cardiovascular disease in different areas of England and Wales were closely related to differences in neonatal mortality (deaths before one month of age) 70 and more years ago. Since most neonatal deaths were associated with low birthweight these findings suggest that cardiovascular disease is linked to impaired foetal growth.
This link was subsequently demonstrated in studies of individual men and women whose foetal and infant growth was recorded at the time. The first study was carried out in the county of Hertfordshire, England, where since 1911 all babies born have been weighed at birth and at one year. Among 5654 men those who had the lowest weight at birth and at one year had the highest death rates from ischaemic heart disease as adults. The differences in death rates were large, around three-fold. This posed the question of what processes link lower rates of foetal and infant growth with cardiovascular disease. Subsequent studies in Hertfordshire and in the city of Preston showed that lower birthweight, especially if associated with disproportionately high placental weight, is linked to raised blood pressure in adult life and to elevated plasma levels of fibrinogen. It was concluded that these long-term associations reflect restraint of growth of certain tissues, including blood vessels and the liver, by an adverse environment during a critical period of foetal or infant development. Poor maternal nutrition was suggested as an important environmental influence.
The known associations of Type 2 diabetes and IGT with ischaemic heart disease and hypertension plus awareness of the rapid growth of Beta cells during foetal life suggested to us that reduced glucose tolerance may be another outcome of early growth restraint.
Of the Hertfordshire men who still live in the county 468 attended for venous blood sampling in the fasting state. Of these men 370 agreed to have a full 75 g oral glucose tolerance test. From this study some strong relationships have emerged. The percentage of men with impaired glucose tolerance or Type 2 diabetes fell progressively with increasing birth weight and weight at one year. Forty percent of men with birth weights of 2.5 kg (5.5 pounds) or less had a 2–4 h plasma glucose of 7.8 mmol/l or over compared with 14% of men with birthweights over 4.3 kg (9.5 pounds). Forty three percent of men with weights at one year of 8.2 kg (18 pounds) or less had a 2-h plasma glucose of 7.8 mmol/l or over compared with 13% of men with weights at one year of 12.3 kg (27 pounds) or more. It is possible that some infants with heavier birth weights were the outcome of pregnancies complicated by gestational diabetes. However, the number of such babies would have been small and their survival 60 or more years ago would probably have been poor. Though there is evidence that gestational diabetes predisposes to diabetes in the offspring, this could not explain our findings that the largest babies are those least likely to develop diabetes.
Analysis of the effects of obesity, measured as body-mass index, showed that its diabetogenic effect adds to that of poor early growth. The mean 2-h glucose concentration ranged from 5.8 mmol/l in men who were in the highest tertile of weight at one year but the lowest tertile of current BMI (≤25.4), to 7.7 mmol/l in men in the lowest tertile of weight at one and the highest tertile of current BMI (>28). Interestingly there was a similar addition of the effects of obesity and low weight at one year on current fasting 32–33 split proinsulin concentration. The extremes of the range defined as above were 2.1 and 4.8 pmoI\l respectively. When the subjects were divided into quintiles according to the fasting 32–33 split proinsulin concentration this measurement was highly correlated with systolic blood pressure (Table 1). This association is consistent with earlier findings linking 32–33 split proinsulin and risk factors for ischaemic heart disease and requires an explanation.
The concentrations of 32–33 split proinsulin measured in the Hertfordshire study are in the low pmolar range. Any biological activity of this derivative at these low concentrations has yet to be described. It seems to us that a more likely explanation of its association with blood pressure is that the pathogenic mechanisms leading to changes in both measurements are linked This is reminiscent of the proposal by Reaven in relation to what he termed 'Syndrome X' which includes glucose intolerance, hypertension and some types of hyperlipidaemia. He has hypothesised that insulin resistance is the underlying factor linking these phenomena.
Our data suggests a different interpretation. Consistent with previous findings blood pressure in the Hertfordshire men was inversely related to birth weight though unlike 2-h plasma glucose it was not related to weight at one year. Factors affecting early growth may therefore lead to either high blood pressure or impaired glucose tolerance/Type 2 diabetes, or a mixture of hypertension and glucose intolerance, depending on the exact timing of the growth impairment during foetal or infant life. Our working hypothesis is that the varying components and combinations of Syndrome X, possibly including insulin resistance, are late outcomes of abnormal growth and development processes occurring in foetal and early infant life.
At first sight it may seem improbable that events occurring in the first 2 years of existence could produce changes 50–70 years later. However looked at in another way it is perhaps less surprising. It has been calculated that the fertilised ovum in developing into a full-term infant goes through some 42 rounds of cell division. After birth there need be only a further 5 cycles of division. The number of these divisions and their timing in development varies widely between different tissues. For example at birth a virtually full complement of brain neurons and of renal glomeruli are present and, available data suggest, at the age of 1 year at least half the adult complement of Beta cells is present. Adverse influences, in particular poor nutrition, acting at this early time could permanently impair the size and structure of organs and tissues. Poor intrauterine nutrition may lead either to generalised growth retardation, or growth of the brain may be protected at the expense of the viscera. Evidence for selective growth retardation comes from the studies of blood pressure in Preston, UK where one group of people with high blood pressure as adults was characteristed at birth by their shortness in relation to their head circumference. There is good reason to believe that development of Beta cells, which proceeds rapidly during foetal life and early infancy, would be vulnerable to poor nutrition. Poor foetal nutrition may be caused by poor maternal nutrition A link with poor maternal nutrition would explain the high rates of impaired glucose tolerance and diabetes in parts of the third world and is also consistent with the occurrence of Type 2 diabetes in more affluent countries. A recent survey in Oxford, UK, for example, found evidence of iron deficiency in 47% of all pregnant women.
Thus we propose that poor nutrition of the foetus and infant leads to permanent changes of the structure and function of certain organs and tissues. The timing and precise nature of the deficiencies determine the pattern of metabolic and functional abnormalities seen in later life, including diabetes and hypertension and possibly also including some hyperlipidaemias and even insulin resistance. We suggest that poor early development of islets of Langerhans and Beta cells is a major factor in the aetiology of Type 2 diabetes.
In referring to poor early development we do not at this stage consider this necessarily to be a solely quantitative deficiency of Beta cells but include the possibility that the cells themselves may be altered, or that the more complex aspects of islet structure and function, such as vasculature and innervation may be abnormally developed. There is a disproportionately large flow of blood to the islets (10–20%) compared to that of the pancreas as a whole. Therefore major changes in islet vasculature such as have been described could make a large contribution to changes in islet and particularly Beta cell function.
Foetal and Infant Growth and Type 2 Diabetes
Previous work by one of us (DJPB) has led to the conclusion that cardiovascular disease in adult life results from restraint of growth during foetal life and infancy. Cardiovascular disease is viewed as a 'programmed' effect of interference with early growth and development. (Programming may be defined as a permanent or long-term change in the structure or function of an organism resulting from a stimulus or insult acting at a critical period of early life. The first evidence for this came from geographical studies which showed that differences in death rates from cardiovascular disease in different areas of England and Wales were closely related to differences in neonatal mortality (deaths before one month of age) 70 and more years ago. Since most neonatal deaths were associated with low birthweight these findings suggest that cardiovascular disease is linked to impaired foetal growth.
This link was subsequently demonstrated in studies of individual men and women whose foetal and infant growth was recorded at the time. The first study was carried out in the county of Hertfordshire, England, where since 1911 all babies born have been weighed at birth and at one year. Among 5654 men those who had the lowest weight at birth and at one year had the highest death rates from ischaemic heart disease as adults. The differences in death rates were large, around three-fold. This posed the question of what processes link lower rates of foetal and infant growth with cardiovascular disease. Subsequent studies in Hertfordshire and in the city of Preston showed that lower birthweight, especially if associated with disproportionately high placental weight, is linked to raised blood pressure in adult life and to elevated plasma levels of fibrinogen. It was concluded that these long-term associations reflect restraint of growth of certain tissues, including blood vessels and the liver, by an adverse environment during a critical period of foetal or infant development. Poor maternal nutrition was suggested as an important environmental influence.
The known associations of Type 2 diabetes and IGT with ischaemic heart disease and hypertension plus awareness of the rapid growth of Beta cells during foetal life suggested to us that reduced glucose tolerance may be another outcome of early growth restraint.
Of the Hertfordshire men who still live in the county 468 attended for venous blood sampling in the fasting state. Of these men 370 agreed to have a full 75 g oral glucose tolerance test. From this study some strong relationships have emerged. The percentage of men with impaired glucose tolerance or Type 2 diabetes fell progressively with increasing birth weight and weight at one year. Forty percent of men with birth weights of 2.5 kg (5.5 pounds) or less had a 2–4 h plasma glucose of 7.8 mmol/l or over compared with 14% of men with birthweights over 4.3 kg (9.5 pounds). Forty three percent of men with weights at one year of 8.2 kg (18 pounds) or less had a 2-h plasma glucose of 7.8 mmol/l or over compared with 13% of men with weights at one year of 12.3 kg (27 pounds) or more. It is possible that some infants with heavier birth weights were the outcome of pregnancies complicated by gestational diabetes. However, the number of such babies would have been small and their survival 60 or more years ago would probably have been poor. Though there is evidence that gestational diabetes predisposes to diabetes in the offspring, this could not explain our findings that the largest babies are those least likely to develop diabetes.
Analysis of the effects of obesity, measured as body-mass index, showed that its diabetogenic effect adds to that of poor early growth. The mean 2-h glucose concentration ranged from 5.8 mmol/l in men who were in the highest tertile of weight at one year but the lowest tertile of current BMI (≤25.4), to 7.7 mmol/l in men in the lowest tertile of weight at one and the highest tertile of current BMI (>28). Interestingly there was a similar addition of the effects of obesity and low weight at one year on current fasting 32–33 split proinsulin concentration. The extremes of the range defined as above were 2.1 and 4.8 pmoI\l respectively. When the subjects were divided into quintiles according to the fasting 32–33 split proinsulin concentration this measurement was highly correlated with systolic blood pressure (Table 1). This association is consistent with earlier findings linking 32–33 split proinsulin and risk factors for ischaemic heart disease and requires an explanation.
The concentrations of 32–33 split proinsulin measured in the Hertfordshire study are in the low pmolar range. Any biological activity of this derivative at these low concentrations has yet to be described. It seems to us that a more likely explanation of its association with blood pressure is that the pathogenic mechanisms leading to changes in both measurements are linked This is reminiscent of the proposal by Reaven in relation to what he termed 'Syndrome X' which includes glucose intolerance, hypertension and some types of hyperlipidaemia. He has hypothesised that insulin resistance is the underlying factor linking these phenomena.
Our data suggests a different interpretation. Consistent with previous findings blood pressure in the Hertfordshire men was inversely related to birth weight though unlike 2-h plasma glucose it was not related to weight at one year. Factors affecting early growth may therefore lead to either high blood pressure or impaired glucose tolerance/Type 2 diabetes, or a mixture of hypertension and glucose intolerance, depending on the exact timing of the growth impairment during foetal or infant life. Our working hypothesis is that the varying components and combinations of Syndrome X, possibly including insulin resistance, are late outcomes of abnormal growth and development processes occurring in foetal and early infant life.
At first sight it may seem improbable that events occurring in the first 2 years of existence could produce changes 50–70 years later. However looked at in another way it is perhaps less surprising. It has been calculated that the fertilised ovum in developing into a full-term infant goes through some 42 rounds of cell division. After birth there need be only a further 5 cycles of division. The number of these divisions and their timing in development varies widely between different tissues. For example at birth a virtually full complement of brain neurons and of renal glomeruli are present and, available data suggest, at the age of 1 year at least half the adult complement of Beta cells is present. Adverse influences, in particular poor nutrition, acting at this early time could permanently impair the size and structure of organs and tissues. Poor intrauterine nutrition may lead either to generalised growth retardation, or growth of the brain may be protected at the expense of the viscera. Evidence for selective growth retardation comes from the studies of blood pressure in Preston, UK where one group of people with high blood pressure as adults was characteristed at birth by their shortness in relation to their head circumference. There is good reason to believe that development of Beta cells, which proceeds rapidly during foetal life and early infancy, would be vulnerable to poor nutrition. Poor foetal nutrition may be caused by poor maternal nutrition A link with poor maternal nutrition would explain the high rates of impaired glucose tolerance and diabetes in parts of the third world and is also consistent with the occurrence of Type 2 diabetes in more affluent countries. A recent survey in Oxford, UK, for example, found evidence of iron deficiency in 47% of all pregnant women.
Thus we propose that poor nutrition of the foetus and infant leads to permanent changes of the structure and function of certain organs and tissues. The timing and precise nature of the deficiencies determine the pattern of metabolic and functional abnormalities seen in later life, including diabetes and hypertension and possibly also including some hyperlipidaemias and even insulin resistance. We suggest that poor early development of islets of Langerhans and Beta cells is a major factor in the aetiology of Type 2 diabetes.
In referring to poor early development we do not at this stage consider this necessarily to be a solely quantitative deficiency of Beta cells but include the possibility that the cells themselves may be altered, or that the more complex aspects of islet structure and function, such as vasculature and innervation may be abnormally developed. There is a disproportionately large flow of blood to the islets (10–20%) compared to that of the pancreas as a whole. Therefore major changes in islet vasculature such as have been described could make a large contribution to changes in islet and particularly Beta cell function.
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