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This narrative non-systematic review addresses the sex-specific differences observed both in prenatal period and, subsequently, in early childhood. Indeed, gender influences the type of birth and related complications. The risk of preterm birth, perinatal diseases, and differences on efficacy for pharmacological and non-pharmacological therapies, as well as prevention programs, will be evaluated. Although male newborns get more disadvantages, the physiological changes during growth and factors like social, demographic, and behavioural reverse this prevalence for some diseases. Therefore, given the primary role of genetics in gender differences, further studies specifically targeted neonatal sex-differences will be needed to streamline medical care and improve prevention programs. [ABSTRACT FROM AUTHOR]

Uncoupling protein‐3 (UCP3) is a mitochondrial transmembrane protein highly expressed in the muscle that has been implicated in regulating the efficiency of mitochondrial oxidative phosphorylation. Increasing UCP3 expression in skeletal muscle enhances proton leak across the inner mitochondrial membrane and increases oxygen consumption in isolated mitochondria, but its precise function in vivo has yet to be fully elucidated. To examine whether muscle‐specific overexpression of UCP3 modulates muscle mitochondrial oxidation in vivo, rates of ATP synthesis were assessed by 31P magnetic resonance spectroscopy (MRS), and rates of mitochondrial oxidative metabolism were measured by assessing the rate of [2‐13C]acetate incorporation into muscle [4‐13C]‐, [3‐13C]‐glutamate, and [4‐13C]‐glutamine by high‐resolution 13C/1H MRS. Using this approach, we found that the overexpression of UCP3 in skeletal muscle was accompanied by increased muscle mitochondrial inefficiency in vivo as reflected by a 42% reduction in the ratio of ATP synthesis to mitochondrial oxidation. [ABSTRACT FROM AUTHOR]

Obese adolescents are at risk of developing NAFLD and type 2 diabetes. We measured noninvasively the IHF content of obese adolescents to ascertain whether it is associated with insulin resistance and abnormal energy homeostasis. IHF content, whole body energy homeostasis, insulin sensitivity, and body composition were measured using localized hepatic [sup.1]H-MRS, indirect calorimetry, fasting-derived and 3-h-OGTT-derived surrogate indexes (HOMA2 and WBISI), and DEXA, respectively, in 54 obese adolescents (24 female and 30 male, age 13 [+ or -] 2 yr, BMI >99th percentile for their age and sex). NAFLD (defined as IHF content >5 % wet weight) was found in 16 individuals (30%) in association with higher ALT (P < 0.006), Hb [A.sub.1c] (P = 0.021), trunk fat content (P < 0.03), and lower HDL cholesterol (P < 0.05). Individuals with NAFLD had higher fasting plasma glucose (89 [+ or -] 8 vs. 83 [+ or -] 9 mg/dl, P = 0.01) and impaired insulin sensitivity (HOMA2 and WBISI, P < 0.05). Meanwhile, parameters of insulin secretion were unaffected. Their reliance on fat oxidation in the fasting state was lower (RQ 0.83 [+ or -] 0.08 vs. 0.77 [+ or -] 0.05, P < 0.01), and their ability to suppress it during the oral glucose challenge was impaired (P < 0.05) vs. those with normal IHF content. When controlling for trunk fat content, the correlation between IHF content and insulin sensitivity was weakened, whereas the correlation with fasting lipid oxidation was maintained. In conclusion, NAFLD is common in childhood obesity, and insulin resistance is present in association with increased trunk fat content. In contrast, the rearrangement of whole body substrate oxidation in these youngsters appeared to be an independent feature. nonalcoholic fatty liver disease; fat oxidation; 1H magnetic resonance spectroscopy; indirect calorimetry; oral glucose tolerance test.

To fulfill its preeminent function of regulating glucose metabolism, insulin secretion must not only be quantitatively appropriate but also have qualitative, dynamic properties that optimize insulin action on target tissues. This review focuses on the importance of the first-phase insulin secretion to glucose metabolism and attempts to illustrate the relationships between the first-phase insulin response to an intravenous glucose challenge and the early insulin response following glucose ingestion. A clear-cut first phase occurs only when the [beta]-cell is exposed to a rapidly changing glucose stimulus, like the one induced by a brisk intravenous glucose administration. In contrast, peripheral insulin concentration following glucose ingestion does not bear any clear sign of biphasic shape. Coupling data from the literature with the results of a [beta]-cell model simulation, a close relationship between the first-phase insulin response to intravenous glucose and the early insulin response to glucose ingestion emerges. It appears that the same ability of the [beta]-cell to produce a pronounced first phase in response to an intravenous glucose challenge can generate a rapidly increasing early phase in response to the blood glucose profile following glucose ingestion. This early insulin response to glucose is enhanced by the concomitant action of incretins and neural responses to nutrient ingestion. Thus, under physiological circumstances, the key feature of the early insulin response seems to be the ability to generate a rapidly increasing insulin profile. This notion is corroborated by recent experimental evidence that the early insulin response, when assessed at the portal level with a frequent sampling, displays a pulsatile nature. Thus, even though the classical first phase does not exist under physiological conditions, the oscillatory behavior identified at the portal level does serve the purpose of rapidly exposing the liver to elevated insulin levels that, also in virtue of their up-and-down pattern, are particularly effective in restraining hepatic glucose production. insulin pulsatile secretion; mathematical models; early-phase insulin secretion

Extrahepatic glucose release was evaluated during the anhepatic phase of liver transplantation in 14 recipients for localized hepatocarcinoma with mild or absent cirrhosis, who received a bolus of [6,6-[sup.2][H.sub.2]]glueose and L-[3-[sup.3]C]alanine or L-[1,2-[sup.13][C.sub.2]]glutamine to measure glucose kinetics and to prove whether gluconeogenesis occurred from alanine and glutamine. Twelve were studied again 7 mo thereafter along with seven healthy subjects. At the beginning of the anhepatic phase, plasma glucose was increased and then declined by 15%/h. The right kidney released glucose, with an arteriovenous gradient of -3.7 mg/dl. Arterial and portal glucose concentrations were similar. The glucose clearance was 25% reduced, but glucose uptake was similar to that of the control groups. Glucose production was 9.5 [+ or -] 0.9 [micro]mol * [kg.sup.-1] * [min.sup.-1], 30% less than in controls. Glucose became enriched with [sup.13]C from alanine and especially glutamine, proving the extrahepatic gluconeogenesis. The gluconeogenic precursors alanine, glutamine, lactate, pyruvate, and glycerol, insulin, and the counterregulatory hormones epinephrine, cortisol, growth hormone, and glucagon were increased severalfold. Extrahepatic organs synthesize glucose at a rate similar to that of postabsorptive healthy subjects when hepatic production is absent, and gluconeogenic precursors and counterregulatory hormones are markedly increased. The kidney is the main, but possibly not the unique, source of extrahepatic glucose production. kidney; intestines; amino acids

Insulin resistance is a key pathogenic factor of type 2 diabetes (T2DM); in contrast, in type 1 diabetes (T1DM) it is considered a secondary alteration. Increased intramyocellular lipid (IMCL) content accumulation and reduced plasma adiponectin were suggested to be pathogenic events of insulin resistance in T2DM. This study was designed to assess whether IMCL content and plasma adiponectin were also associated with the severity of insulin resistance in T1DM. We studied 18 patients with T1DM, 7 older and overweight/obese patients with T2DM, and 15 nondiabetic, insulin-resistant offspring of T2DM parents (OFF) and 15 healthy individuals (NOR) as appropriate control groups matched for anthropometric features with T1DM patients by means of the euglycemic hyperinsulinemic clamp combined with the infusion of [6,6-[sup.2][H.sub.2]]glucose and [sup.1]H magnetic resonance spectroscopy of the calf muscles. T1DM and T2DM patients showed reduced insulin-stimulated glucose metabolic clearance rate (MCR: 5.1 [+ or -] 0.6 and 3.2 [+ or -] 0.8 ml*[kg.sup.-1]*[min.sup.-1]) similar to OFF (5.3 [+ or -] 0.4 ml*[kg.sup.-1]*[min.sup.-1]) compared with NOR (8.5 [+ or -] 0.5 ml*[kg.sup.-1]*[min.sup.-1], P < 0.001). Soleus IMCL content was increased in T1DM (112 [+ or -] 15 AU), T2DM (108 [+ or -] 10 AU) and OFF (82 [+ or -] 13 AU) compared with NOR (52 [+ or -] 7 AU, P < 0.05) and the result was inversely proportional to the MCR ([R.sup.2] = 0.27, P < 0.001); an association between IMCL content and Hb [A.sub.1c] was found only in T1DM ([R.sup.2] = 0.57, P < 0.001). Fasting plasma adiponectin was reduced in T2DM (7 [+ or -] 1 [micro]g/ml, P = 0.01) and OFF (11 [+ or -] 1 [micro]g/ml, P = 0.03) but not in T1DM (25 [+ or -] 6 [micro]g/ml), whose plasma level was increased with respect to both OFF (P = 0.03) and NOR (16 [+ or -] 2 [micro]g/ml, P = 0.05). In conclusion, in T1DM, T2DM, and OFF, IMCL content was associated with insulin resistance, demonstrating that IMCL accretion is a marker of insulin resistance common to both primary genetically determined and secondary metabolic (chronic hyperglycemia) alterations. The increased adiponectin levels in insulin-resistant patients with T1DM, in contrast to the reduced levels found in patients with T2DM and in OFF, demonstrated that the relationship of adiponectin to insulin resistance in humans is still unclear. intramyocellular triglyceride content; leptin; magnetic resonance spectroscopy

Insulin resistance in acromegaly causes glucose intolerance and diabetes, but it is unknown whether it involves protein metabolism, since both insulin and growth hormone promote protein accretion. The effects of acromegaly and of its surgical cure on the insulin sensitivity of glucose and amino acid/protein metabolism were evaluated by infusing [6,[6.sup.-2][H.sub.2]]glucose, [[1.sup.-13]C]leucine, and [[2.sup.-15]N]glutamine during a euglycemic insulin (1 mU*[kg.sup.-1]*[min.sup.-1]) clamp in 12 acromegalic patients, six studied again 6 mo after successful adenomectomy, and eight healthy controls. Acromegalic patients, compared with postsurgical and control subjects, had higher postabsorptive glucose concentration (5.5 [+ or -] 0.3 vs. 4.9 [+ or -] 0.2 [micro]mol/l, P < 0.05, and 5.1 [+ or -] 0.1 [micro]mol/l) and flux (2.7 [+ or -] 0.1 vs. 2.0 [+ or -] 0.2 [micro]mol*[kg.sup.-1]*[min.sup.-1], P < 0.01, and 2.2 [+ or -] 0.1 [micro]mol*[kg.sup.-1]*[min.sup.-1], P < 0.05) and reduced insulin-stimulated glucose disposal (+15 [+ or -] 9 vs. +151 [+ or -] 18%, P < 0.01, and 219 [+ or -] 58%, P < 0.001 from basal). Postabsorptive leucine metabolism was similar among groups. In acromegalic and postsurgical subjects, insulin suppressed less than in controls the endogenous leucine flux(-9 [+ or -] 1 and -12 [+ or -] 2vs. -18 [+ or -] 2%, P < 0.001 and P < 0.05), the nonoxidative leucine disposal (-4 [+ or -] 3 and -1 [+ or -] 3 vs. -18 [+ or -] 2%, P < 0.01 and P < 0.05), respectively, indexes of proteolysis and protein synthesis, and leucine oxidation (-17 [+ or -] 6% in postsurgical patients vs. -26 [+ or -] 6% in controls, P < 0.05). Within 6 mo, surgery reverses insulin resistance for glucose but not for protein metabolism. After adenomectomy, more leucine is oxidized during hyperinsulinemia. acromegaly; glucose metabolism; growth hormone; leucine metabolism

Antiretroviral therapy in human immunodeficiency virus (HIV)-positive patients can induce a lipodystrophy syndrome of peripheral fat wasting and central adiposity, dyslipidemia, and insulin resistance. To test whether in this syndrome insulin resistance is associated with abnormal muscle handling of fatty acids, 12 HIV-1 patients (8 females/4 males, age = 26 [+ or -] 2 yr, HIV duration = 8 [+ or -] yr, body mass index = 22.0 [+ or -] 1.0 kg/[m.sup.2], on protease inhibitors and nucleoside analog RT inhibitors) and 12 healthy subjects were studied. HIV-1 patients had a total body fat content (assessed by dual-energy X-ray absorptiometry) similar to that of controls (22 [+ or -] 1 vs. 23 [+ or -] 2%; P = 0.56), with a topographic fat redistribution characterized by reduced fat content in the legs (18 [+ or -] 2 vs. 32 [+ or -] 3%; P < 0.01) and increased fat content in the trunk (25 [+ or -] 2 vs. 19 [+ or -] 2%; P = 0.03). In HIV-positive patients, insulin sensitivity (assessed by QUICKI) was markedly impaired (0.341 [+ or -] 0.011 vs. 0.376 [+ or -] 0.007; P = 0.012). HIV-positive patients also had increased total plasma cholesterol (216 [+ or -] 20 vs. 174 [+ or -] 9 mg/dl; P = 0.05) and triglyceride (298 [+ or -] 96 vs. 87 [+ or -] 11 mg/dl; P = 0.03) concentrations. Muscular triglyceride content assessed by means of [sup.1]H NMR spectroscopy was higher in HIV patients in soleus [92 [+ or -] 12 vs. 42 [+ or -] 5 arbitrary units (AU); P < 0.01] and tibialis anterior (26 [+ or -] 6 vs. 11 [+ or -] 3 AU; P = 0.04) muscles; in a stepwise regression analysis, it was strongly associated with QUICKI ([R.sup.2] = 0.27; P < 0.0093). Even if the basal metabolic rate (assessed by indirect calorimetry) was comparable to that of normal subjects, postabsorptive lipid oxidation was significantly impaired (0.30 [+ or -] 0.07 vs. 0.88 [+ or -] 0.09 mg * [kg.sup.-1] * [min.sup.-1]; P < 0.01). In conclusion, lipodystrophy in HIV-1 patients in antiretroviral treatment is associated with intramuscular fat accumulation, which may mediate the development of the insulin resistance syndrome. human immunodeficiency virus

Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat 30% (n = 7) and 14 young, nonobese men with body fat 25% (n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized [sup.1]H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal (P = 0.80), IMCL content in both soleus (P = 0.22) and tibialis anterior (P = 0.75) muscles, and plasma free fatty acid levels (P = 0.075) compared with leaner subjects in association with increased lipid oxidation (P < 0.05), resting energy expenditure (P = 0.046), resting oxygen consumption (P = 0.049), and plasma leptin levels (P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain. intramyocellular lipid content; lipid oxidation; insulin resistance; leptin; tumor necrosis factor-[alpha]; nuclear magnetic resonance spectroscopy