Burak Salgin

Session 7: Early nutrition and later health early developmental pathways of obesity and diabetes risk.

Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the beta-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of beta-cell mass, as demonstrated by recent studies of pancreatic beta-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of beta-cell mass may ultimately be the most important determinants of an individuals ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.

Insulin resistance is an intrinsic defect independent of fat mass in women with Turner's syndrome

Background/Aims: Turner’s syndrome (TS) is associated with increased insulin resistance and adiposity, which might be associated with type 2 diabetes in later life. We aimed to determine whether the defect in insulin sensitivity is a primary intrinsic defect in TS or dependent on variation in body composition. Methods: Sixteen women with TS not on growth hormone replacement but receiving oestrogen replacement therapy [age (mean ± SD): 30.2 ± 8.5 years; height-corrected fat-free mass: 26.1 ± 3.1 kg/height] and a control group of 16 normal healthy women (age: 30.1 ± 8.2 years; height-corrected fat-free mass: 25.9 ± 2.4 kg/height) were studied. Fasting blood samples were obtained for measurement of glucose, insulin, IGF-I, IGFBP-1, IGFBP-3 and lipid levels. The hyperinsulinaemic euglycaemic clamp was performed to assess peripheral insulin sensitivity (M value), and the Homeostasis Model Assessment (HOMA-S) was used to estimate fasting insulin sensitivity. Body composition was assessed using a dual-energy X-ray absorptiometry scan. Results: Fasting insulin sensitivity (HOMA-S 103.2 ± 78.6 vs. 193.9 ± 93.5, p = 0.006) was lower in TS subjects compared to controls as was whole-body insulin sensitivity (M value 2.9 ± 1.9 vs. 5.5 ± 2.6 mg/kg/min, p = 0.003). In a multiple regression analysis the Turner karyotype was significantly related to insulin sensitivity (p = 0.008) independent of any differences in fat-free mass and percent whole-body fat mass. Conclusion: The increased insulin resistance in women with TS is independent of measures of body composition and may represent an intrinsic defect related to their chromosomal abnormality.

Higher Fasting Plasma Free Fatty Acid Levels Are Associated with Lower Insulin Secretion in Children and Adults and a Higher Incidence of Type 2 Diabetes

CONTEXT There are limited data in humans on the association between fasting free fatty acid (FFA) levels and pancreatic β-cell function. OBJECTIVE Our objective was to examine this association in children and adults with normal glucose tolerance and to explore fasting FFA levels in relation to subsequent risk of impaired glucose tolerance (IGT) and type 2 diabetes (T2D). DESIGN We measured FFA, glucose, and insulin levels after an overnight fast and 30 min after an oral glucose load in 797 children aged 8 yr in the Avon Longitudinal Study of Parents and Children and 770 adults aged 44-71 yr in the Medical Research Council Ely Study. We calculated the homeostasis model assessment to estimate fasting insulin sensitivity, the insulinogenic index to estimate insulin secretion, and the disposition index to assess insulin secretion corrected for insulin sensitivity. RESULTS Higher fasting FFA levels were associated with lower insulin secretion in children (boys, P = 0.03; girls, P = 0.001) and adults (men, P = 0.03, women, P = 0.04). Associations with insulin sensitivity were more variable, but after adjustment for insulin sensitivity, higher fasting FFA levels remained associated with lower insulin secretion (disposition index). Compared with adults in the lowest tertile of fasting FFA levels, those in the middle and highest tertiles had a 3-fold higher incidence of IGT or T2D over the following 5-8 yr. CONCLUSIONS Higher fasting FFA levels were consistently associated with lower insulin secretion in children and adults with normal glucose tolerance. Furthermore, higher fasting FFA levels were prospectively associated with a greater risk of subsequent IGT and T2D.

Even transient rapid infancy weight gain is associated with higher BMI in young adults and earlier menarche

Background:Early postnatal rapid ‘catch-up’ weight gain has been consistently associated with subsequent higher obesity risk and earlier pubertal development. In many low- and middle-income countries, infancy catch-up weight gain is transient and often followed by growth faltering. We explored the hypothesis that even transient catch-up weight gain during infancy is associated with later obesity risk and earlier puberty.Methods:A total of 2352 (1151 male, 1201 female) black South African children in the birth to twenty prospective birth cohort study (Johannesburg–Soweto) underwent serial measurements of body size and composition from birth to 18 years of age. At the age of 18 years, whole-body fat mass and fat-free mass were determined using dual-energy X-ray absorptiometry. Pubertal development was assessed by the research team between ages 9 and 10 years, and it was recorded annually from the age of 11 years using a validated self-assessment protocol.Results:Catch-up weight gain from birth to the age of 1 year, despite being followed by growth faltering between ages 1 and 2 years, was associated with greater mid-upper arm circumference (P=0.04) and skinfold thickness (P=0.048) at 8 years of age, and with higher weight (P<0.001) and body mass index (P=0.001) at 18 years of age after adjustment for sex, age, smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status. Infancy catch-up weight gain was also associated with younger age at menarche in girls (P<0.001). This association persisted after adjustment for smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status (P=0.005).Conclusion:Transient catch-up weight gain from birth to the age of 1 year among children born in a low-income area of South Africa was associated with earlier menarche and greater adiposity in early adulthood. This observation suggests that modifiable determinants of rapid infancy weight gain may be targeted in order to prevent later obesity and consequences of earlier puberty in girls.

Effects of prolonged fasting and sustained lipolysis on insulin secretion and insulin sensitivity in normal subjects

Normal beta-cells adjust their function to compensate for any decrease in insulin sensitivity. Our aim was to explore whether a prolonged fast would allow a study of the effects of changes in circulating free fatty acid (FFA) levels on insulin secretion and insulin sensitivity and whether any potential effects could be reversed by the antilipolytic agent acipimox. Fourteen (8 female, 6 male) healthy young adults (aged 22.8-26.9 yr) without a family history of diabetes and a body mass index of 22.6 +/- 3.2 kg/m(2) were studied on three occasions in random order. Growth hormone and FFA levels were regularly measured overnight (2200-0759), and subjects underwent an intravenous glucose tolerance test in the morning (0800-1100) on each visit. Treatment A was an overnight fast, treatment B was a 24-h fast with regular administrations of a placebo, and treatment C was a 24-h fast with regular ingestions of 250 mg of acipimox. The 24-h fast increased overnight FFA levels (as measured by the area under the curve) 2.8-fold [51.3 (45.6-56.9) vs. 18.4 (14.4-22.5) *10(4) micromol/l*min, P < 0.0001], and it led to decreases in insulin sensitivity [5.7 (3.6-8.9) vs. 2.6 (1.3-4.7) *10(-4) min(-1) per mU/l, P < 0.0001] and the acute insulin response [16.3 (10.9-21.6) vs. 12.7 (8.7-16.6) *10(2) pmol/l*min, P = 0.02], and therefore a reduction in the disposition index [93.1 (64.8-121.4) vs. 35.5 (21.6-49.4) *10(2) pmol/mU, P < 0.0001]. Administration of acipimox during the 24-h fast lowered FFA levels by an average of 20% (range: -62 to +49%; P = 0.03), resulting in a mean increase in the disposition index of 31% (P = 0.03). In conclusion, the 24-h fast was accompanied by substantial increases in fasting FFA levels and induced reductions in the acute glucose-simulated insulin response and insulin sensitivity. The use of acipimox during the prolonged fast increased the disposition index, suggesting a partial reversal of the effects of fasting on the acute insulin response and insulin sensitivity.

Insulin Administration and Rate of Glucose Appearance in People With Type 1 Diabetes

OBJECTIVE—To assess whether prandial insulin, in addition to basal insulin, has an effect on the rate of glucose appearance from a meal in people with type 1 diabetes. RESEARCH DESIGN AND METHODS—The rate of glucose appearance from a mixed meal (Rameal) was investigated in six adult (aged 24 ± 2 years), lean (BMI 23.6 ± 1.5 kg/m2) subjects with well-controlled type 1 diabetes (duration 7.9 ± 6.9 years, A1C 7.6 ± 0.9%) with/without prandial insulin. Actrapid was infused to maintain euglycemia before meals were consumed. Subjects consumed two identical meals on separate occasions, and Rameal was measured using a dual isotope method. [6,6-2H2]glucose was incorporated into the meal (0.081 g/kg body wt), and a primed constant/variable rate infusion of [1,2,3,4,5,6,6-2H2]glucose was administered. In the tests with prandial insulin, an additional bolus dose of Actrapid was given 20 min before the meal at 0.1 units/kg body wt. RESULTS—Insulin concentration with prandial insulin was significantly higher than during basal insulin studies (119 ± 16 vs. 66 ± 15 pmol/l, P = 0.03 by paired t test). Despite differences in insulin concentration, there were no differences in total glucose appearance (3,398 ± 197 vs. 3,307 ± 343 μmol/kg) or time taken for 25% (33.1 ± 3.3 vs. 31.7 ± 3.5 min), 50% (54.6 ± 3.5 vs. 54.1 ± 4.7 min), and 75% (82.9 ± 7.1 vs. 82.8 ± 5.8 min) of total glucose appearance. The fraction of the glucose dose appearing in the circulation was the same for basal (73 ± 8%) and prandial (75 ± 4%) study days. CONCLUSIONS—These results suggest that meal glucose appearance is independent of prandial insulin concentration in people with type 1 diabetes.

Effects of Growth Hormone and Free Fatty Acids on Insulin Sensitivity in Patients with Type 1 Diabetes

CONTEXT Because GH stimulates lipolysis, an increase in circulating free fatty acid levels, as opposed to a direct effect of high GH levels, could underlie the development of insulin resistance in type 1 diabetes (T1D). Our aim was to explore the relative contributions of GH and free fatty acids to the development of insulin resistance in patients with T1D. PATIENTS Seven (four females, three males) nonobese patients with T1D aged 21-30 yr were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by octreotide. Three 1-h pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an antilipolytic drug, or a placebo were ingested every 4 h on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a two-step hyperinsulinemic euglycemic clamp on each visit. MAIN OUTCOME rhGH administration led to increases in the insulin infusion rate required to maintain euglycemia overnight (P = 0.008), elevated basal endogenous glucose production (P = 0.007), decreased basal peripheral glucose uptake (P = 0.03), and reduced glucose uptake during step 1 of the clamp (P < 0.0001). Coadministration of rhGH and acipimox reversed these effects and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity. RESULTS GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis.

Baseline IGF-I Levels Determine Insulin Secretion and Insulin Sensitivity during the First Year on Growth Hormone Therapy in Children Born Small for Gestational Age. Results from a North European Multicentre Study (NESGAS)

Objective: Developmental programming alters growth and metabolic outcome in children born small for gestational age (SGA). We explored insulin and glucose metabolism in SGA children treated with a fixed GH dose over 1 year. Methods: In the North European Small for Gestational Age Study (NESGAS), 110 short SGA children received GH at 67 µg/kg/day for 1 year. Insulin secretion was assessed by acute insulin response (AIR), insulin sensitivity (IS) by HOMA and disposition index (DI) by insulin secretion adjusted for IS. Results: First-year GH therapy led to increases in height and IGF-I standard deviation score (SDS), and reductions in IS (p < 0.0001). Compensatory increases in AIR (p < 0.0001) were insufficient and resulted in reduced DI (p = 0.032). Children in the highest IGF-I SDS tertile at baseline were the least insulin sensitive at baseline (p = 0.024) and 1 year (p = 0.006). IGF-I responses after 1 year were positively related to AIR (r = 0.30, p = 0.007) and DI (r = 0.29, p = 0.005). Conclusion: In SGA children treated with a high GH dose for 1 year, baseline IGF-I levels were related to IS whilst gains in height and IGF-I responses were associated with insulin secretion. Defining heterogeneity in IGF-I in SGA children may be useful in predicting growth and metabolic response.

Intramyocellular lipid levels are associated with peripheral, but not hepatic, insulin sensitivity in normal healthy subjects

Increased levels of IMCL (intramyocellular lipid) have been shown to be associated with reduced steady-state glucose infusion rates during a hyperinsulinaemic-euglycaemic clamp (M-value). The aim of the present study was to explore how IMCL levels relate to the insulin-mediated suppression of endogenous glucose production [hepatic SI (insulin sensitivity)] and increase in glucose disposal (peripheral SI). In the present study, 11 healthy young adults (7 male, 4 female; aged 21-31 years) undertook, in random order, an hyperinsulinaemic-euglycaemic clamp combined with stable glucose isotope enrichment to measure peripheral and hepatic SI, a 1H-MRS (proton-magnetic resonance spectroscopy) scan to determine IMCL levels and a DXA (dual-energy X-ray absorptiometry) scan to assess body composition. IMCL levels (range, 3.2-10.7) were associated with whole-body fat mass (r=0.787, P=0.004), fat mass corrected for height (r=0.822, P=0.002) and percentage of central fat mass (r=0.694, P=0.02), but were not related to whole-body FFM (fat-free mass; r=-0.472, P=0.1). IMCL levels correlated closely with the M-value (r=-0.727, P=0.01) and FFM-corrected peripheral SI (r=-0.675, P=0.02), but were not related to hepatic SI adjusted for body weight (r=0.08, P=0.8). The results of the present study suggest that IMCL accumulation may be a sensitive marker for attenuations in peripheral, but not hepatic, SI in normal populations. Given the close relationship of IMCL levels to whole-body and central abdominal fat mass, relative increases in the flux of lipids from adipose tissue to the intramyocellular compartment may be an integral part of the mechanisms underlying reductions in SI.

Health Behaviour in Children and Adolescents with Type 1 Diabetes Compared to a Representative Reference Population

Objective We provide a population-based overview of health behaviours of children and adolescents with type 1 diabetes in comparison to the general population, and analyse their relevance for glycaemic control and self-rated health status. Methods Data from questionnaires of 11- to 17-year-old children and adolescents with diabetes (n = 629) were compared to a representative sample (n = 6,813). Results Children and adolescents with type 1 diabetes had a significantly increased odds of infrequent physical activity (adjusted OR 1.56), short overall duration of physical activity per week (OR 1.55, difference -1.3 hours/week), and high daily computer use (OR 2.51). They had a lower odds of active and passive smoking (OR 0.31 and OR 0.29), and high daily television time (OR 0.68). The odds of an at least good and excellent self-rated health status was increased with intense physical activity, and decreased with active smoking and prolonged daily use of computer and television. Active smoking and prolonged daily use of computer were associated with higher HbA1c. Conclusions Children and adolescents with type 1 diabetes showed a different profile of health behaviour. Their overall health may improve if their education stresses specifically frequent physical activity with longer overall duration and less frequent television or computer use.