Insulin Resistance In Adult Life Research Articles

Relationship between asymmetric dimethylarginine in umbilical cord plasma and birth weight follows a U-shaped curve.

Asymmetric dimethylarginine (ADMA) is a nonselective nitric oxide (NO) synthase inhibitor associated with cardiovascular and metabolic disorders. NO regulates placental blood flow, which plays an important role in fetal growth. Many epidemiological studies have disclosed that restricted fetal growth is associated with an increased risk of insulin resistance in adult life. We studied the relationship between ADMA in cord blood and birth size. Nine small for gestational age (SGA) and 32 appropriate for gestational age (AGA) infants were studied. Their cord plasma ADMA, insulin, insulin-like growth factor-1 (IGF-1), and adipocytokine levels were determined using enzyme-linked immunosorbent assays. The relationship between birth weight and ADMA levels followed a U-shaped curve rather than inverse linear associations expected over a full range of birth weight distribution. ADMA positively correlated with birth weight in the AGA group (p<0.001, R=0.590), and inversely correlated with birth weight in the SGA group (p<0.05, R=-0.741). ADMA inversely correlated with adiponectin (p<0.05, R=-0.289) and quantitative insulin sensitivity check index (QUICKI) (p<0.05, R=-0.294) in all subjects, and did not correlate with nitrogen oxides (NOX). Insulin, IGF-1, leptin, adiponectin and QUICKI were lower in the SGA than the AGA group. Plasma ADMA levels in cord blood may be a marker of fetal growth and insulin resistance.

Periconceptional undernutrition programs changes in insulin-signaling molecules and microRNAs in skeletal muscle in singleton and twin fetal sheep.

Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We determined the effect of maternal undernutrition in the periconceptional period (PCUN, i.e., 60 days prior to 6 days after conception) and the preimplantation period (PIUN, i.e., 0-6 days after conception) on mRNA expression and protein abundance of key insulin-signaling molecules as well as the global microRNA expression in quadriceps muscle of singleton and twin fetal sheep in late gestation. In singleton fetuses, exposure to PCUN resulted in lower protein abundance of PIK3CB (P < 0.01), PRKCZ (P < 0.05), and pPRKCZ (Thr410) (P < 0.05) in skeletal muscle compared to controls. In PIUN singletons, there was a higher protein abundance of IRS1 (P < 0.05), PDPK1 (P < 0.05), and SLC2A4 (P < 0.05) compared to controls. In twins, PCUN resulted in higher protein abundance of IRS1 (P < 0.05), AKT2 (P < 0.05), PDPK1 (P < 0.05), and PRKCZ (P < 0.001), while PIUN also resulted in higher protein abundance of IRS1 (P < 0.05), PRKCZ (P < 0.001), and SLC2A4 (P < 0.05) in fetal muscle compared to controls. There were specific patterns of the types and direction of changes in the expression of 22 microRNAs in skeletal muscle after exposure to PCUN or PIUN and clear differences in these patterns between singleton and twin pregnancies. These findings provide evidence that maternal undernutrition around the time of conception induces changes in the expression of microRNAs, which may play a role in altering the abundance of the key insulin-signaling molecules in skeletal muscle and in the association between PCUN undernutrition and insulin resistance in adult life.

Does Cardiorespiratory Fitness Modify the Association between Birth Weight and Insulin Resistance in Adult Life?

ObjectiveLower birth weight is associated with higher insulin resistance in later life. The aim of this study was to determine whether cardiorespiratory fitness modifies the association of birth weight with insulin resistance in adults.MethodsThe subjects were 379 Japanese individuals (137 males, 242 females) aged 20–64 years born after 1943. Insulin resistance was assessed using a homeostasis model assessment of insulin resistance (HOMA-IR), which is calculated from fasting blood glucose and insulin levels. Cardiorespiratory fitness (maximal oxygen uptake, VO2max) was assessed by a maximal graded exercise test on a cycle ergometer. Birth weight was reported according to the Maternal and Child Health Handbook records or the subject’s or his/her mother’s memory.ResultsThe multiple linear regression analysis revealed that birth weight was inversely associated with HOMA-IR (β = −0.141, p = 0.003), even after adjustment for gender, age, current body mass index, mean blood pressure, triglycerides, HDL cholesterol, and smoking status. Further adjustments for VO2max made little difference in the relationship between birth weight and HOMA-IR (β = −0.148, p = 0.001), although VO2max (β = −0.376, p<0.001) was a stronger predictor of HOMA-IR than birth weight.ConclusionsThe results showed that the association of lower birth weight with higher insulin resistance was little modified by cardiorespiratory fitness in adult life. However, cardiorespiratory fitness was found to be a stronger predictor of insulin resistance than was birth weight, suggesting that increasing cardiorespiratory fitness may have a much more important role in preventing insulin resistance than an individual’s low birth weight.

The effect of placental restriction on insulin signaling and lipogenic pathways in omental adipose tissue in the postnatal lamb.

Intrauterine growth restriction (IUGR) followed by accelerated growth after birth is associated with an increased risk of abdominal (visceral) obesity and insulin resistance in adult life. The aim of the present study was to determine the impact of IUGR on mRNA expression and protein abundance of insulin signaling molecules in one of the major visceral fat depots, the omental adipose depot. IUGR was induced by placental restriction, and samples of omental adipose tissue were collected from IUGR (n = 9, 5 males, 4 females) and Control (n = 14, 8 males, 6 females) neonatal lambs at 21 days of age. The mRNA expression of the insulin signaling molecules, AMP-kinase (AMPK) and adipogenic/lipogenic genes was determined by qRT-PCR, and protein abundance by Western Blotting. AMPKα2 mRNA expression was increased in male IUGR lambs (0.015 ± 0.002 v. 0.0075 ± 0.0009, P < 0.001). The proportion of the AMPK pool that was phosphorylated (%P-AMPK) was lower in IUGR lambs compared with Controls independent of sex (39 ± 9% v. 100 ± 18%, P < 0.001). The mRNA expression and protein abundance of insulin signaling proteins and adipogenic/lipogenic genes was not different between groups. Thus, IUGR is associated with sex-specific alterations in the mRNA expression of AMPKα2 and a reduction in the percentage of the total AMPK pool that is phosphorylated in the omental adipose tissue of neonatal lambs, before the onset of visceral obesity. These molecular changes would be expected to promote lipid accumulation in the omental adipose depot and may therefore contribute to the onset of visceral adiposity in IUGR animals later in life.

Feeding Preterm Infants Today for Later Metabolic and Cardiovascular Outcomes

Preterm birth continues to contribute disproportionately to neonatal morbidity and subsequent physical and neurodevelopmental disabilities. Epidemiologic studies have described additional long-term health consequences of preterm birth such as an increased risk of hypertension and insulin resistance in adult life. It is not known whether the influence of infant and childhood growth rates and early nutrition on long-term outcomes is the same or different among preterm infants and neonates with intrauterine growth restriction. Our goal is to review the effects of fetal growth, postnatal growth, and early nutrition on long-term cardiovascular and metabolic outcomes in preterm infants. Present evidence suggests that even brief periods of relative undernutrition during a sensitive period of development have significant adverse effects on later development. Our review suggests that growth between birth and expected term and 12-18 months post-term has no significant effect on later blood pressure and metabolic syndrome, whereas reduced growth during hospitalization significantly impacts later neurodevelopment. In contrast, growth during late infancy and childhood appears to be a major determinant of later metabolic and cardiovascular well being, which suggests that nutritional interventions during this period are worthy of more study. Our review also highlights the paucity of well-designed, controlled studies in preterm infants of the effects of nutrition during hospitalization and after discharge on development, the risk of developing hypertension, or insulin resistance.

Small for Gestational Age and Magnesium in Cord Blood Platelets: Intrauterine Magnesium Deficiency May Induce Metabolic Syndrome in Later Life

Magnesium deficiency in pregnancy frequently occurs because of inadequate or low intake of magnesium. Magnesium deficiency during pregnancy can induce not only maternal and fetal nutritional problems, but also consequences that might last in offspring throughout life. Many epidemiological studies have disclosed that small for gestational age (SGA) is associated with an increased risk of insulin resistance in adult life. We reported that intracellular magnesium of cord blood platelets is lower in SGA groups than that in appropriate for gestational age groups, suggesting that intrauterine magnesium deficiency may result in SGA. Taken together, intrauterine magnesium deficiency in the fetus may lead to or at least program insulin resistance after birth. In this review, we propose that intrauterine magnesium deficiency may induce metabolic syndrome in later life. We discuss the potential contribution of aberrant magnesium regulation to SGA and to the pathogenesis of metabolic syndrome.

Mechanisms involved in the developmental programming of adulthood disease.

There are many instances in life when the environment plays a critical role in the health outcomes of an individual, yet none more so than those experienced in fetal and neonatal life. One of the most detrimental environmental problems encountered during this critical growth period are changes in nutrition to the growing fetus and newborn. Disturbances in the supply of nutrients and oxygen to the fetus can not only lead to adverse fetal growth patterns, but they have also been associated with the development of features of metabolic syndrome in adult life. This fetal response has been termed developmental programming or the developmental origins of health and disease. The present review focuses on the epidemiological studies that identified this association and the importance that animal models have played in studying this concept. We also address the potential mechanisms that may underpin the developmental programming of future disease. It also highlights (i) how developmental plasticity, although beneficial for short-term survival, can subsequently programme glucose intolerance and insulin resistance in adult life by eliciting changes in key organ structures and the epigenome, and (ii) how aberrant mitochondrial function can potentially lead to the development of Type 2 diabetes and other features of metabolic syndrome.

The transition from fetal growth restriction to accelerated postnatal growth: a potential role for insulin signalling in skeletal muscle

A world-wide series of epidemiological and experimental studies have demonstrated that there is an association between being small at birth, accelerated growth in early postnatal life and the emergence of insulin resistance in adult life. The aim of this study was to investigate why accelerated growth occurs in postnatal life after in utero growth restriction. Samples of quadriceps muscle were collected at approximately 140 days gestation (term approximately 150 days gestation) from normally grown fetal lambs (Control, n = 7) and from growth restricted fetal lambs (placentally restricted: PR, n = 8) and from Control (n = 14) and PR (n = 9) lambs at 21 days after birth. The abundance of the insulin and IGF1 receptor protein was higher in the quadriceps muscle of the PR fetus, but there was a lower abundance of the insulin signalling molecule PKC, and GLUT4 protein in the PR group. At 21 days of postnatal age, insulin receptor abundance remained higher in the muscle of the PR lamb, and there was also an up-regulation of the insulin signalling molecules, PI3Kinase p85, Akt1 and Akt2 and of the GLUT4 protein in the PR group. Fetal growth restriction therefore results in an increased abundance of the insulin receptor in skeletal muscle, which persists after birth when it is associated with an upregulation of insulin signalling molecules and the glucose transporter, GLUT4. These data provide evidence that the origins of the accelerated growth experienced by the small baby after birth lie in the adaptive response of the growth restricted fetus to its low placental substrate supply.

Markers of insulin sensitivity in placentas and cord serum of intrauterine growth‐restricted newborns

Intrauterine growth restriction (IUGR) has been related to a higher incidence of insulin resistance in adult life, which is associated with low adiponectin and high resistin, insulin and interleukin (IL)-6 serum concentrations. This study assessed cortisol, insulin, total insulin receptor, resistin, adiponectin and IL-6 concentrations, as markers of insulin sensitivity, in placental lysates and cord serum of IUGR and appropriate for gestational age (AGA) newborns, to establish relationships among peptides and with growth parameters at birth. Whole villous tissue and cord serum at birth were collected from 24 AGA and 18 IUGR newborns of comparable gestational age. Hormonal and peptide concentrations were assayed in placental lysates and cord serum using specific commercial kits. Concentrations in lysates were adjusted per mg of total protein content. Cortisol, insulin and resistin concentrations and the total amount of insulin receptor were similar in both groups. IL-6 concentration in lysates was significantly higher in IUGR compared with AGA newborns. Adiponectin was significantly lower in lysates from IUGR compared with AGA newborns. Placental insulin and resistin concentrations were positively correlated. Placental adiponectin concentration was positively correlated with the weight of the placenta, birthweight and head circumference. IL-6 concentration in lysates was negatively correlated with birth length, birthweight and head circumference. This study evaluated the markers of insulin sensitivity in the placentas of subjects born IUGR, showing new potential roles for adiponectin and IL-6 in particular, and suggesting a role for the placenta in the programming of these hormones.

Intrauterine Growth Restriction and the Sex Specific Programming of Leptin and Peroxisome Proliferator-Activated Receptor γ (PPARγ) mRNA Expression in Visceral Fat in the Lamb

Being born small is associated with an increased risk of visceral obesity and insulin resistance in adult life. We have investigated the effect of IUGR on adipogenic and lipogenic gene expression in visceral fat in the lamb at 3 wk of age. Perirenal fat mass, but not adipocyte size was greater in females than males, independent of birth weight. Plasma insulin concentrations during the first 24 h after birth predicted the size of the adipocytes and expression of adiponectin in visceral adipose tissue in both males and females. In females, plasma nonesterified fatty acids (NEFA) concentrations during the first 24 h after birth were directly related to peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA expression in the perirenal fat depot at 3 wk of age. In the males, in contrast to the females, PPARgamma and leptin expression in perirenal visceral fat were significantly lower in IUGR compared with control lambs. Thus, the early nutritional environment programs adipocyte growth and gene expression in visceral adipose tissue. The differential effect of sex and IUGR on PPARgamma and leptin expression in visceral fat may be important in the subsequent development of visceral obesity and the insulin resistant phenotype in later life.

Fetus and magnesium

Chronic magnesium deficiency in pregnant women is frequently seen because of inadequate or low intake of magnesium. Magnesium deficiency during pregnancy can induce not only maternal and fetal nutritional problem, but also pediatric consequences that might last throughout life. Many epidemiological studies have disclosed that restricted fetal growth, i.e., intrauterine growth retardation (IUGR) is associated with an increased risk of insulin resistance in adult life. We previously postulated that intracellular magnesium of cord blood platelets is lower in the small for gestational age than in the appropriate for gestational age group, suggesting chronic intrauterine magnesium deficiency may result in IUGR. Taken together, chronic intrauterine magnesium deficiency in the fetus may lead to or program the insulin resistance after birth. Prospective study whether the children born with magnesium induced IUGR are at high-risk for metabolic syndrome in childhood or adulthood is currently undertaken.

Relationship of intracellular magnesium of cord blood platelets to birth weight

Magnesium (Mg2+) has an important role in insulin action, and insulin stimulates Mg2+ uptake in insulin-sensitive tissues. Impaired biologic responses to insulin are referred to as insulin resistance. Diabetic patients and obese subjects are reported to have intracellular magnesium ([Mg2+]i) deficiency. Many epidemiologic studies have disclosed that restricted fetal growth has been associated with increased risk of insulin resistance in adult life. We studied the relationship of [Mg2+]i in cord blood platelets to birth weight. The subjects were 19 infants who were small for gestational age (SGA) and 45 who were appropriate for gestational age (AGA). By using a fluorescent probe, mag-fura-2, we examined the basal and insulin-stimulated [Mg2+]i of platelets in the cord blood. Cord plasma insulin-like growth factor-1 (IGF-1)and leptin levels were determined with the use of enzyme-linked immunosorbent assay (ELISA). Birth weight was correlated with cord plasma IGF-1 (P < .001) and leptin (P < .005). Mean basal [Mg2+]i, but not plasma Mg2+, was lower in the SGA than in the AGA group (291 ± 149 μmol/L v 468 ± 132 μmol/L, P < .001). The basal [Mg2+]i was significantly correlated with the birth weight (P < .001) as well as birth length (P < .001). At 60 seconds after stimulation with insulin, there was no significant difference in stimulated [Mg2+]i between the SGA and AGA groups. Although the SGA group had low [Mg2+]i, the platelets had good potentiality to compensate for low [Mg2+]i. [Mg2+]i reflects the extent of fetal growth. Decreased [Mg2+]i in SGA might underlie the initial pathophysiologic events leading to insulin resistance.

Is taurine beneficial in reducing risk factors for diabetes mellitus?

Taurine is a semiessential amino acid, and its deficiency is involved in retinal and cardiac degenerations. In recent years, it was found that diabetes mellitus (DM) is associated with taurine, and many in vivo experimental studies showed that taurine administration is able to reduce the alterations induced by DM in the retina, lens, and peripheral nerve, although its effects on diabetic kidney are dubious. Interestingly, long-term taurine supplementation reduces the mortality rate in diabetic rats. The mechanisms by which taurine exerts beneficial effects in DM are discussed below. Recently, it has been suggested that taurine deficiency may alter the endocrine pancreas "fetal programming," increasing the risk of insulin resistance in adult life. The bulk of experimental data suggests that taurine administration could be useful in the treatment of type 1 DM and in the prevention of insulin resistance.

The association between birth weight and capillary recruitment is independent of blood pressure and insulin sensitivity: a study in prepubertal children

Alterations in microvascular function have been hypothesized as a possible mechanism explaining the negative association of weight at birth with blood pressure and insulin resistance in adult life. However, these variables are closely associated, so that it has been difficult to establish whether microvascular dysfunction is a cause or a consequence of increased blood pressure or insulin resistance. Cohort study. VU University Medical Center, Amsterdam, The Netherlands. Twenty-one prepubertal healthy children showing a wide range in birth weight. Birth weight data were obtained from hospital records. Blood pressure was measured with an ambulatory 24-h blood pressure monitor, and insulin sensitivity was assessed with the hyperinsulinaemic euglycaemic clamp technique. Microvascular function (i.e. capillary recruitment during post-occlusive reactive hyperaemia and endothelium (in)dependent vasodilatation of the skin) was evaluated by videomicroscopy and iontophoresis of acetylcholine and sodium nitroprusside. Birth weight was positively and significantly associated with capillary recruitment [slope, 22%/kg birth weight; 95% confidence interval (CI), 0.1-43; 0.05]. Birth weight was not associated with insulin sensitivity and systolic blood pressure (slope, -0.11 mg/kg per min per pmol/l; 95% CI, -2.4 to 2.2; = 0.9; and slope, 1.4 mmHg; 95% CI, -5.0 to 7.7/kg birth weight; = 0.7, respectively). The association between low birth weight and impaired capillary recruitment was not affected by adjustment for blood pressure and insulin sensitivity. Birth weight was not associated with endothelium-(in)dependent vasodilatation. These results suggest that the association between birth weight and capillary recruitment is independent of blood pressure and insulin sensitivity. These findings are consistent with the hypothesis that an impaired capillary recruitment plays a mechanistic role in the association of birth weight with blood pressure and insulin resistance in adult life.

Familial, anthropometric, and metabolic associations of intramyocellular lipid levels in prepubertal males.

The cause of skeletal muscle insulin resistance is unclear, but high levels of intramyocellular lipids are often present in affected individuals. We aimed to establish the metabolic, familial, and anthropometric associations of intramyocellular lipid in a pediatric population. We studied 41 boys aged 6.9-9.9 y and 23 of their mothers by proton magnetic resonance spectroscopy. We related muscle lipid levels to important factors that define an increased risk of developing insulin resistance in adult life. There were significant associations between the boys' intramyocellular lipid and their waist circumference (r = 0.42, p = 0.007), body mass index SD score (r = 0.32, p = 0.04), weight SD score (r = 0.32, p = 0.04), glucose:insulin ratio (r= -0.59, p = 0.04), maternal log fasting insulin levels (r = 0.44, p = 0.04), maternal body mass index (r = 0.46, p = 0.03), and maternal intramyocellular lipid (r = 0.62, p = 0.003). In the 41 boys, waist circumference explained 19% of the variance in the boys' intramyocellular lipid. Maternal intramyocellular lipid explained 39% of the variance in the boys' intramyocellular lipid in the sub-group of 23 boys. Intramyocellular lipid levels have both metabolic and anthropometric associations in childhood. Before puberty, children develop or inherit muscle metabolic characteristics that are associated both with insulin resistance and risk factors for the development of insulin resistance syndrome in adult life.

Association between birth weight and insulin sensitivity in healthy young men in Korea: role of visceral adiposity

Recent studies have demonstrated decreased insulin sensitivity in individuals with low birth weight. This study was performed to examine whether abdominal obesity is a link between insulin resistance and low birth weight. We studied the relationships between birth weight and insulin secretion, insulin sensitivity, and various anthropometric indices including visceral fat area in 22 healthy young Korean adults. Birth weight correlated significantly with diastolic blood pressure ( r=−0.47, P<0.05) and insulin sensitivity index ( S I) measured by a frequently sampled intravenous glucose tolerance test (FSIGT) ( r=0.54, P<0.05), but not with insulin secretory indices such as acute insulin responses during FSIGT ( r=−0.35, NS) or hyperglycemic clamp ( r=0.17, NS) and submaximum insulin response during hyperglycemic clamp ( r=0.10, NS). S I correlated significantly with abdominal obesity measurements such as waist circumference ( r=−0.48, P<0.05), waist-to-hip ratio ( r=−0.53, P<0.05) and visceral fat area ( r=−0.58, P<0.01). However, we could not find significant correlation between birth weight and any of the abdominal obesity measurements ( r=−0.35 for waist-to-hip ratio, r=−0.22 for visceral fat area, and r=−0.24 for visceral-to-subcutaneous fat ratio; NS for all). The present data confirm that low birth weight is associated with insulin resistance in adult life. However, our data suggest that the association between low birth weight and insulin resistance is not mediated by abdominal obesity.

The fetal insulin hypothesis: an alternative explanation of the association of low bir thweight with diabetes and vascular disease

Low birthweight is associated with insulin resistance, hypertension, coronary-artery disease, and non-insulin-dependent diabetes (NIDDM). A suggested explanation for this association is intrauterine programming in response to maternal malnutrition. We propose, however, that genetically determined insulin resistance results in impaired insulin-mediated growth in the fetus as well as insulin resistance in adult life. Low birthweight, measures of insulin resistance in life, and ultimately glucose intolerance, diabetes, and hypertension could all be phenotypes of the same insulin-resistant genotype. There is evidence to support this hypothesis. Insulin secreted by the fetal pancreas in response to maternal glucose concentrations is a key growth factor. Monogenic diseases that impair sensing of glucose, lower insulin secretion, or increase insulin resistance are associated with impaired fetal growth. Polygenic influences resulting in insulin resistance in the normal population are therefore likely to result in lower birthweight. Abnormal vascular development during fetal life and early childhood, as a result of genetic insulin resistance, could also explain the increased risk of hypertension and vascular disease. The predisposition to NIDDM and vascular disease is likely to be the result of both genetic and fetal environmental factors.

Glucose tolerance and resistance to insulin-stimulated glucose uptake in men aged 70 years in relation to size at birth.

Although several studies have shown that reduced size at birth predicts glucose intolerance and insulin resistance in adult life, the relation has been inconsistent and usually stronger for ponderal index than for birthweight. We examined glucose tolerance and insulin sensitivity (by the euglycaemic clamp method) in relation to size at birth in 709 men aged 69-73 years in Uppsala, Sweden. After adjusting for adult body mass index, prevalence of glucose intolerance (defined as diabetes or impaired glucose tolerance) was inversely related to birthweight. In men born at term, there was a positive monotonic relation of insulin sensitivity with birthweight, strongest in those who were overweight at age 70. This relation was reversed in men born before term (p = 0.005 for interaction between pre-term birth and birthweight effect). Glucose intolerance and insulin resistance showed inverted U-shaped relations with ponderal index, in contrast with the monotonic inverse relation seen in this cohort at earlier ages. This change in form of the relations was partly accounted for by selective loss to follow-up between ages 60 and 70 years. These results confirm that the association between reduced fetal growth and glucose intolerance is mediated through insulin resistance and depends upon an interaction with obesity in adult life. This relation is obscured when pre-term births are included. Failure to stratify by gestational age in previous studies could account for inconsistencies in the relations of insulin resistance and glucose intolerance to size at birth and for the detection of stronger associations with ponderal index than with birthweight.

A common mitochondrial DNA variant is associated with insulin resistance in adult life.

Mitochondrial DNA is maternally inherited. Mitochondrial DNA mutations could contribute to the excess of maternal over paternal inheritance of non-insulin-dependent diabetes mellitus (NIDDM). We therefore investigated the relationship between this variant, insulin resistance and other risk factors in a cohort which had been well characterised with respect to diabetes. Blood DNA was screened from 251 men born in Hertfordshire 1920-1930 in whom an earlier cohort study had shown that glucose tolerance was inversely related to birthweight. The 16189 variant (T--> C transition) in the first hypervariable region of mitochondrial DNA was detected using the polymerase chain reaction and restriction digestion. DNA analysis showed that 28 of the 251 men (11%) had the 16189 variant. The prevalence of the 16189 variant increased progressively with fasting insulin concentration (p < 0.01). The association was independent of age and body mass index and was present after exclusion of the patients with NIDDM or impaired glucose tolerance. We found that insulin resistance in adult life was associated with the 16189 variant. This study provides the first evidence that a frequent mitochondrial variant may contribute to the phenotype in patients with a common multifactorial disorder.

Fetal growth and insulin resistance in adult life: role of skeletal muscle morphology.

1. Thinness at birth is associated with insulin resistance in adult life and an apparent delay in activation of glycolysis/glycogenolysis in exercising skeletal muscle. As developmental abnormalities of skeletal muscle histology or metabolism may explain this association we examined muscle histology, biochemistry and blood flow in a group of 27 adult women whose birth details were known. 2. Subjects were examined by near-infrared spectroscopy to determine forearm muscle oxygen supply, and by muscle biopsy and forearm plethysmography. Those with a ponderal index at birth < 23 kg/m3 were insulin resistant (assessed by the short insulin-tolerance test-mean rate constants for glucose disappearance = 4.14 compared with 4.83%/min, P = 0.045) and had significantly more rapid muscle reoxygenation than the remainder of the subjects (13 compared with 22 s, P = 0.004). 3. Thinness at birth did not influence muscle capillary density, muscle glycogen content, glycogen synthase activity, citrate synthase activity or resting forearm blood flow. 4. Insulin resistance seen after fetal malnutrition was not associated with abnormal muscle histology, resting muscle blood flow, mitochondrial volume or glycogen content. 5. The increase in muscle reoxygenation rate in adult subjects who were thin at birth could occur to promote oxidative ATP synthesis in compensation for the delay in activation of glycolysis/glycogenolysis. It suggests altered regulation rather than structure of the muscle microcirculation. These changes appear to antedate the structural and biochemical changes seen in muscle from patients with established diabetes.