Johan G. Eriksson

Prevention of Type 2 Diabetes Mellitus by Changes in Lifestyle among Subjects with Impaired Glucose Tolerance

BACKGROUND Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known. METHODS We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years. RESULTS The mean (+/-SD) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group (P<0.001 for both comparisons between the groups). The cumulative incidence of diabetes after four years was 11 percent (95 percent confidence interval, 6 to 15 percent) in the intervention group and 23 percent (95 percent confidence interval, 17 to 29 percent) in the control group. During the trial, the risk of diabetes was reduced by 58 percent (P<0.001) in the intervention group. The reduction in the incidence of diabetes was directly associated with changes in lifestyle. CONCLUSIONS Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects.

Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study.

BACKGROUND Lifestyle interventions can prevent the deterioration of impaired glucose tolerance to manifest type 2 diabetes, at least as long as the intervention continues. In the extended follow-up of the Finnish Diabetes Prevention Study, we assessed the extent to which the originally-achieved lifestyle changes and risk reduction remain after discontinuation of active counselling. METHODS Overweight, middle-aged men (n=172) and women (n=350) with impaired glucose tolerance were randomly assigned to intensive lifestyle intervention or control group. After a median of 4 years of active intervention period, participants who were still free of diabetes were further followed up for a median of 3 years, with median total follow-up of 7 years. Diabetes incidence, bodyweight, physical activity, and dietary intakes of fat, saturated fat, and fibre were measured. FINDINGS During the total follow-up, the incidence of type 2 diabetes was 4.3 and 7.4 per 100 person-years in the intervention and control group, respectively (log-rank test p=0.0001), indicating 43% reduction in relative risk. The risk reduction was related to the success in achieving the intervention goals of weight loss, reduced intake of total and saturated fat and increased intake of dietary fibre, and increased physical activity. Beneficial lifestyle changes achieved by participants in the intervention group were maintained after the discontinuation of the intervention, and the corresponding incidence rates during the post-intervention follow-up were 4.6 and 7.2 (p=0.0401), indicating 36% reduction in relative risk. INTERPRETATION Lifestyle intervention in people at high risk for type 2 diabetes resulted in sustained lifestyle changes and a reduction in diabetes incidence, which remained after the individual lifestyle counselling was stopped.

Catch-up growth in childhood and death from coronary heart disease: longitudinal study

Abstract Objective: To examine whether catch-up growth during childhood modifies the increased risk of death from coronary heart disease that is associated with reduced intrauterine growth. Design: Follow up study of men whose body size at birth was recorded and who had an average of 10 measurements taken of their height and weight through childhood. Setting: Helsinki, Finland. Subjects: 3641 men who were born in Helsinki University Central Hospital during 1924-33 and who went to school in Helsinki. Main outcome measures: Hazard ratios for death from coronary heart disease. Results: Death from coronary heart disease was associated with low birth weight and, more strongly, with a low ponderal index at birth. Men who died from coronary heart disease had an above average body mass index at all ages from 7 to 15 years. In a simultaneous regression the hazard ratio for death from the disease increased by 14% (95% confidence interval 8% to 19%; P<0.0001) for each unit (kg/m3) decrease in ponderal index at birth and by 22% (10% to 36%; P=0.0001) for each unit (kg/m2) increase in body mass index at 11 years of age. Body mass index in childhood was strongly related to maternal body mass index, which in turn was related to coronary heart disease. The extent of crowding in the home during childhood, although related to body mass index in childhood, was not related to later coronary heart disease. Conclusion: The highest death rates from coronary heart disease occurred in boys who were thin at birth but whose weight caught up so that they had an average or above average body mass from the age of 7 years. Death from coronary heart disease may be a consequence of poor prenatal nutrition followed by improved postnatal nutrition.

Early growth and coronary heart disease in later life: longitudinal study

Abstract Objective: To determine how growth during infancy and childhood modifies the increased risk of coronary heart disease associated with small body size at birth. Design: Longitudinal study. Setting: Helsinki, Finland. Subjects: 4630 men who were born in the Helsinki University Hospital during 1934–44 and who attended child welfare clinics in the city. Each man had on average 18.0 (SD 9.5) measurements of height and weight between birth and age 12 years. Main outcome measures: Hospital admission or death from coronary heart disease. Results: Low birth weight and low ponderal index (birth weight/length3) were associated with increased risk of coronary heart disease. Low height, weight, and body mass index (weight/height2) at age 1 year also increased the risk. Hazard ratios fell progressively from 1.83 (95% confidence interval 1.28 to 2.60) in men whose body mass index at age 1 year was below 16 kg/m2 to 1.00 in those whose body mass index was >19 (P for trend=0.0004). After age 1 year, rapid gain in weight and body mass index increased the risk of coronary heart disease. This effect was confined, however, to men with a ponderal index <26 at birth. In these men the hazard ratio associated with a one unit increase in standard deviation score for body mass index between ages 1 and 12 years was 1.27 (1.10 to 1.47; P=0.001). Conclusion: Irrespective of size at birth, low weight gain during infancy is associated with increased risk of coronary heart disease. After age 1 year, rapid weight gain is associated with further increase in risk, but only among boys who were thin at birth. In these boys the adverse effects of rapid weight gain on later coronary heart disease are already apparent at age 3 years. Improvements in fetal, infant, and child growth could lead to substantial reductions in the incidence of coronary heart disease. What is already known on this topic Coronary heart disease is associated with low birth weight One study has shown that irrespective of size at birth, low weight gain in infancy is also associated with increased risk of the disease among men Rapid weight gain after age 6 years is associated with further increase in risk What this study adds The association with low weight gain in infancy is confirmed The adverse effects of rapid childhood weight gain on risk of coronary heart disease are already apparent at age 3 years and occur only in boys who were thin at birth

Early Metabolic Defects in Persons at Increased Risk for Non-Insulin-Dependent Diabetes Mellitus

To identify early metabolic abnormalities in non-insulin-dependent diabetes mellitus (NIDDM), we measured sensitivity to insulin and insulin secretion in 26 first-degree relatives of patients with NIDDM and compared these subjects both with 14 healthy control subjects with no family history of NIDDM and with 19 patients with NIDDM. The euglycemic insulin-clamp technique, indirect calorimetry, and infusion of [3-3H]glucose were used to assess insulin sensitivity. Total-body glucose metabolism was impaired in the first-degree relatives as compared with the controls (P less than 0.01). The defect in glucose metabolism was almost completely accounted for by a defect in nonoxidative glucose metabolism (primarily the storage of glucose as glycogen). The relatives with normal rates of metabolism (mean +/- SEM, 1.81 +/- 0.27 mg per kilogram of body weight per minute) and impaired rates (1.40 +/- 0.22 mg per kilogram per minute) in oral glucose-tolerance tests had the same degree of impairment in glucose storage as compared with healthy control subjects (3.76 +/- 0.55 mg per kilogram per minute; P less than 0.01 for both comparisons). During hyperglycemic clamping, first-phase insulin secretion was lacking in patients with NIDDM (P less than 0.01) and severely impaired in their relatives with impaired glucose tolerance (P less than 0.05) as compared with control subjects; insulin secretion was normal in the relatives with normal glucose tolerance. We conclude that impaired glucose metabolism is common in the first-degree relatives of patients with NIDDM, despite their normal results on oral glucose-tolerance tests. Both insulin resistance and impaired insulin secretion are necessary for the development of impaired glucose tolerance in these subjects.

Birth weight and risk of type 2 diabetes: A systematic review

CONTEXT Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined. OBJECTIVE To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults. DATA SOURCES AND STUDY SELECTION Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included. DATA EXTRACTION Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations. DATA SYNTHESIS Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight-type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I(2) = 66%; 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight-type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias. CONCLUSION In most populations studied, birth weight was inversely related to type 2 diabetes risk.

The Fetal and Childhood Growth of Persons Who Develop Type 2 Diabetes

Men and women who had low birthweight as a result of slow fetal growth have increased rates of type 2 diabetes and the metabolic syndrome (1-4). This finding has led to the hypothesis that diabetes is one of a group of related disorders, including coronary heart disease and hypertension, that originate through adaptations that occur when the fetus is undernourished. These adaptations include reduced growth (5, 6). Insulin plays a central role in the regulation of fetal growth, and one fetal adaptation to undernutrition is alteration of insulin and glucose metabolism. Both insulin resistance and insulin deficiency are found in patients with type 2 diabetes and may be initiated by fetal adaptations (7). Adult obesity adds to the effects of low birthweight in increasing the risk for type 2 diabetes (2, 3). A recent study has shown that obesity established in childhood has a greater effect on the development of the metabolic syndrome than does obesity that occurs in adulthood (8). We do not yet know whether, or to what extent, the increased risk for type 2 diabetes associated with reduced prenatal growth is modified by particular patterns of growth throughout childhood. We recently reported the occurrence of coronary heart disease in a cohort of 7086 men and women who were born in Helsinki, Finland, for whom detailed records of body size at birth and height and weight throughout childhood are available (9-11). We describe here the associations between body size at birth, childhood growth, and the risk for type 2 diabetes. Methods Study Cohort The study cohort consisted of 7086 persons who were born between 1924 and 1933 at the Helsinki University Central Hospital, went to school in Helsinki, resided in Finland in 1971, and remained in Finland thereafter. Each member of the study cohort had both a detailed birth record and a school health record. The details of these records have been described previously (9-11). Data on the mothers included age, parity, height, date of the last menstrual period, and body weight measured on admission for labor. Data on the newborn babies included birthweight, length, head circumference, and placental weight. The school health records include a mean (SD) of 10 4 measurements of height and weight between the ages of 6 and 16 years. These records also include the number of persons living in the childs home, recorded at the time of the first examination, and the number of rooms. Using the fathers occupation, which was recorded on the birth records, we grouped the men and women according to a social classification used by the Central Statistical Office. Overall, 78% of the fathers were laborers and 10% were classified as lower middle class. These groups constituted the lower social class. The upper social class was subdivided into upper middle class (2%) and self-employed (2%). Eight percent of the cohort was unclassified. Study Design We linked the birth and school records to a national database of all persons receiving medication for type 2 diabetes. Antidiabetic drugs prescribed by a physician are free in Finland, subject to the approval of a physician who reviews each case history. The physician confirms the diagnosis of diabetes on the basis of the World Health Organization criteria (12). All patients receiving free medication (either oral antidiabetic agents or insulin) are entered into a register maintained by the Social Insurance Institute. In 1971, every Finnish citizen was assigned a unique personal identifier. We used this number to ascertain the 513 persons in the cohort who received diabetic medication at any time from 1964 to 1997. The register does not distinguish between patients with type 1 and type 2 diabetes. However, all hospital admissions in Finland are recorded in the national hospital discharge register. We used this register to identify 331 patients who had been admitted to the hospital with a diagnosis of diabetes among the 513 persons who received diabetic medication. We were able to review the records of 291 (88%) of these patients and thereby identified 42 persons who had type 1 diabetes. This is consistent with other studies showing that about 10% of patients with diabetes have type 1 disease. We excluded these 42 persons, leaving 471 patients with type 2 diabetes, although this number could still include a few patients with type 1 diabetes. Our study did not include patients with type 2 diabetes who do not require medication. Of the estimated 150 000 patients with diagnosed diabetes in Finland, 113 000 (75%) are treated with medication (13). The study was approved by the Ethical Committee of the National Public Health Institute, Helsinki. Statistical Analysis Tests for trends were based on multivariate logistic regression by using continuous variables, which included year of birth to adjust for the effects of age. The occurrence of type 2 diabetes was the dependent variable. We converted each measurement of height, weight, and body mass index (BMI) (weight/height 2) for each person to a Z score by using the method of Royston (14). Interpolation between successive Z scores by using a piecewise linear function was performed, and a Z score was obtained for each birthday from 7 to 15 years of age. These Z scores were back-transformed to obtain the corresponding height, weight, and BMI at these ages. The use of Z scores allowed us to make comparisons across ages, across measurements made in childhood, and between boys and girls. At each age, the mean Z score for height or weight or BMI in the 7086 persons in the cohort is set at 0, and the SD is set at 1. Role of the Funding Source This study was funded by British Heart Foundation, Novo Nordisk Foundation, and Finska Lkaresllskapet, which took no part in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results The maternal, neonatal, and childhood characteristics of the 7086 men and women in the cohort have already been published (9-11). Of this group, 471 persons286 men and 185 womenwere receiving medication for type 2 diabetes. The cumulative incidence of type 2 diabetes was 6.6% (7.9% in men and 5.4% in women). Size at Birth Table 1 shows the associations between the cumulative incidence of type 2 diabetes and size at birth. The incidence increased with decreasing birthweight for both men and women. The odds ratio for type 2 diabetes was 1.38 (95% CI, 1.15 to 1.66; P <0.001) for each 1-kg decrease in birthweight. The trend was stronger in men than in women, in whom it was not statistically significant (Table 1). Type 2 diabetes was not significantly related to the length of gestation; thus, we did not adjust for it in analyses of birth size. The incidence of type 2 diabetes also increased with decreasing birth length, ponderal index (birthweight/length 3), and placental weight. The odds ratios for type 2 diabetes were 1.07 (CI, 1.03 to 1.12; P =0.002) for each 1-cm decrease in length, 1.04 (CI, 1.01 to 1.09; P =0.03) for each kg/m3 decrease in ponderal index, and 1.13 (CI, 1.04 to 1.22; P =0.002) for each 100-g decrease in placental weight. On average, the birthweight of men who developed type 2 diabetes was 0.17 SD below that of all the men. They were also 0.15 SD shorter and 0.10 SD lower in ponderal index. The corresponding SDs for the women who developed type 2 diabetes, compared with all the women, were 0.13, 0.12, and 0.10, respectively. Table 1. Cumulative Incidence of Type 2 Diabetes according to Size at Birth Growth in Childhood The Figure shows the childhood growth of men and women with type 2 diabetes by using mean Z scores for height, weight, and BMI at each year from 7 to 15 years of age. The mean values for all persons in the study cohort are 0; the SD is 1. The mean weights and heights of the boys who later developed type 2 diabetes were about average at 7 years of age, whereas the weights and heights of the girls were above average at that age. Thus, body size of both sexes had caught up since birth. When we allowed for weight at 7 years, the effects of birthweight on the risk for type 2 diabetes were increased: The odds ratio for type 2 diabetes was 1.48 (CI, 1.23 to 1.79; P <0.001) for each 1-kg decrease in birthweight in a multiple logistic regression that included weight at 7 years. The odds ratio was 1.09 (CI, 1.04 to 1.14; P <0.001) for each 1-cm decrease in birth length in a multiple logistic regression that included height at 7 years. Figure. Height, weight, and body mass index during childhood in 286 men and 185 women who later developed type 2 diabetes. Z Z In comparison with other children, the boys and girls who later developed type 2 diabetes had faster growth rates in height, weight, and BMI between the ages of 7 and 15 years (Figure). We calculated the difference between their Z scores for body size at 7 and 15 years of age. The odds ratio for the subsequent development of type 2 diabetes was 1.44 (CI, 1.20 to 1.72; P <0.001) for each unit increase in height between 7 and 15 years. The corresponding figure was 1.39 (CI, 1.21 to 1.61; P <0.001) for weight and 1.24 (CI, 1.10 to 1.41; P <0.001) for BMI. The findings were similar when we analyzed boys and girls separately. We evaluated the interaction between childhood growth and size at birth. We found that the effects of childhood weight gain differed between persons whose birthweight was less than 3000 g and those whose birthweight exceeded 3000 g. For each unit increase in SD for weight between 7 and 15 years of age for those with birthweight less than 3000 g, the odds ratio was 1.83 (CI, 1.37 to 2.45; P <0.001); for those with birthweight greater than 3000 g, the odds ratio was 1.25 (CI, 1.06 to 1.48; P =0.008). This difference in odds ratios was statistically significant (P =0.02). Findings for gains in height and BMI were similar. The BMI at any age in childhood was not significantly related to the risk for developing type 2 diabetes among men. In contrast, am

Concordance for Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland

SummaryWe studied the cumulative incidence, concordance rate and heritability for diabetes mellitus in a nationwide cohort of 13,888 Finnish twin pairs of the same sex. The twins were born before 1958 and both co-twins were alive in 1967. Data on diabetes were derived through computerized record linkage from death certificates, the National Hospital Discharge Register and the National Drug Register. Records were reviewed in order to assign a diagnostic category to the 738 diabetic patients identified. Of these patients 109 had Type 1 (insulin-dependent) diabetes, 505 Type 2 (non-insulin-dependent) diabetes, 46 gestational diabetes, 24 secondary diabetes, 38 impaired glucose tolerance and 16 remained unclassified. The cumulative incidence of diabetes was 1.4 % in men and 1.3 % in women aged 28–59 years and 9.3 % and 7.0 % in men and women aged 60 years and over, respectively. The cumulative incidence did not differ between monozygotic and dizygotic twins. The concordance rate for Type 1 diabetes was higher among monozygotic (23 % probandwise and 13 % pairwise) than dizygotic twins (5 % probandwise and 3 % pairwise). The probandwise and pairwise concordance rates for Type 2 diabetes were 34% and 20% among monozygotic tiwns and 16% and 9 % in dizygotic twins, respectively. Heritability for Type 1 diabetes was greater than that for Type 2 where both genetic and environmental effects seemed to play a significant role.

Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion

Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in β cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal β cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on β cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.

Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study

Abstract Objective: To examine whether women who develop coronary heart disease have different patterns of fetal and childhood growth from men in the same cohort who develop the disease. Design: Follow up study of women whose body size at birth was recorded and who had an average of 10 measurements of height and weight during childhood. Setting: Helsinki, Finland. Subjects: 3447 women who were born in Helsinki University Central Hospital during 1924-33 and who went to school in Helsinki. Main outcome measures: Hazard ratios for hospital admission for or death from coronary heart disease. Results Coronary heart disease among women was associated with low birth weight (P=0.08 after adjustment for gestation, P=0.007 after adjustment for placental weight) and was more strongly associated with short body length at birth (P=0.001 and P>0.0001, respectively). The hazard ratio for women developing coronary heart disease increased by 10.2% (95% confidence interval 4.3 to 15.7) for each cm decrease in length at birth. The effect of short length at birth was greatest in women whose height “caught up” after birth so that as girls they were tall. Such girls tended to have tall mothers. In contrast, men in the same cohort who developed the disease were thin at birth rather than short, showed “catch up” growth in weight rather than height, and their mothers tended to be overweight rather than tall. Conclusions: Coronary heart disease among both women and men reflects poor prenatal nutrition and consequent small body size at birth combined with improved postnatal nutrition and “catch up” growth in childhood. The disease is associated with reductions in those aspects of body proportions at birth that distinguish the two sexes—short body length in women and thinness in men. Key messages Coronary heart disease in women is associated with low birth weight but more strongly with short body length at birth Among men in the same cohort coronary heart disease is also associated with low birth weight but more strongly with thinness at birth In the whole cohort body proportions at birth differed in the two sexes: the girls were short and the boys were thin These differences may reflect intrinsic sex differences in rates of fetal growth at similar levels of maternal nutrition The slower fetal growth of females may underlie their lower rates of coronary heart disease