Healthy Offspring Of Patients Research Articles

Disrupted functional connectivity of the locus coeruleus in healthy adults with parental history of Alzheimer's disease

Prevention and early treatment strategies for Alzheimer's disease (AD) are hampered by the lack of research biomarkers. Neuropathological changes in the Locus Coeruleus (LC) are detected early in AD, and noradrenaline plays a neuroprotective role in LC projecting areas. We assessed functional connectivity (FC) of the brainstem in asymptomatic individuals at familial risk for AD hypothesizing that FC of the LC will be decreased in relation to not-at-risk individuals. Thirty-one offspring of patients with late-onset AD (O-LOAD) (22 females; mean age ± SD = 50.36 ± 8.32) and 28 healthy controls (HC) (20 females; mean age ± SD = 53.90 ± 8.44) underwent a neurocognitive evaluation and a resting-state functional magnetic resonance imaging acquisition. In FC analyses we evaluated whole-brain global connectivity of the brainstem area, and subsequently assessed seed-to-voxel FC patterns from regions showing between-group differences. O-LOAD individuals scored worse in neurocognitive measures of memory and overall functioning (pFDR<0.05). In imaging analyses, we observed that O-LOAD individuals showed decreased global connectivity in a cluster encompassing the left LC (peak = −4, −34, −32, pTFCE<0.05). Seed-to-voxel analyses revealed that this finding was largely explained by decreased connectivity between the LC and the cerebellar cortex. Moreover, FC between the LC and the left cerebellum correlated positively with delayed recall scores. FC between the LC and the cerebellar cortex is decreased in the healthy offspring of patients with LOAD, such connectivity measurements being associated with delayed memory scores. The assessment of FC between the LC and the cerebellum may serve as a biomarker of AD vulnerability.

Fructose overfeeding in first-degree relatives of type 2 diabetic patients impacts energy metabolism and mitochondrial functions in skeletal muscle.

The aim of the study was to assess the effects of a high-fructose diet (HFrD) on skeletal muscle transcriptomic response in healthy offspring of patients with type 2 diabetes, a subgroup of individuals prone to metabolic disorders. Ten healthy normal weight first-degree relatives of type 2 diabetic patients were submitted to a HFrD (+3.5 g fructose/kg fat-free mass per day) during 7 days. A global transcriptomic analysis was performed on skeletal muscle biopsies combined with in vitro experiments using primary myotubes. Transcriptomic analysis highlighted profound effects on fatty acid oxidation and mitochondrial pathways supporting the whole-body metabolic shift with the preferential use of carbohydrates instead of lipids. Bioinformatics tools pointed out possible transcription factors orchestrating this genomic regulation, such as PPARα and NR4A2. In vitro experiments in human myotubes suggested an indirect action of fructose in skeletal muscle, which seemed to be independent from lactate, uric acid, or nitric oxide. This study shows therefore that a large cluster of genes related to energy metabolism, mitochondrial function, and lipid oxidation was downregulated after 7 days of HFrD, thus supporting the concept that overconsumption of fructose-containing foods could contribute to metabolic deterioration in humans.

Untargeted mass spectrometric approach in metabolic healthy offspring of patients with type 2 diabetes reveals medium-chain acylcarnitine as potential biomarker for lipid induced glucose intolerance (LGIT)

Offspring of type 2 diabetes (T2D) patients have increased risk to develop diabetes, due to inherited genetic susceptibility that directly interferes with the individual adaption to environmental conditions. We characterise T2D offspring (OSP) to identify metabolic risk markers for early disease prediction. Plasma of metabolically healthy OSP individuals (n = 43) was investigated after an oral lipid tolerance test (oLTT) by an untargeted mass spectrometric approach for holistic metabolome analyses. Two subgroups of OSP probands can be separated by oLTT, although not differing in general clinical parameters. Analyses of the plasma metabolome revealed mainly medium-chain acylcarnitines and very long-chain fatty acids with differential abundance in the subgroups. The study presented indicates that metabolically healthy OSP of T2D patients differ upon metabolic challenging in serum metabolite composition, especially medium-chain acylcarnitines. The difference suggest that postprandial lipid induced glucose intolerance (LGIT) may serve as a further valuable marker for early diabetes prediction.

Lipoprotein(a) concentration does not differ between sexes in healthy offspring of patients with premature myocardial infarction

Although a family history of coronary artery disease (CAD) is an established factor influencing lipoprotein(a) [Lp(a)] levels, the effect of sex on Lp(a) concentration remains unclear. A potential cause of the conflicting findings regarding the effect of sex on this novel CAD risk factor is the limited ability of the studies, to date, to adequately control for the potential confounding effect of CAD familial predisposition. Our purpose was to evaluate the influence of sex on Lp(a) concentration in healthy young individuals by controlling for family history of CAD. In order to achieve our goal, we compared Lp(a) levels in pairs of brothers and sisters with a positive parental history of premature myocardial infarction (PHPMI). We measured Lp(a) concentration in 77 healthy brother-sister pairs with PHPMI (mean age: brothers: 18.4 ± 6.2 years and sisters: 18.1 ± 5.8 years). Total cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol, triglycerides, apolipoprotein (Apo) A-I and B were also measured. Lp(a) levels did not differ between siblings of different sex (male vs. female sex: 0.994 ± 1.29 vs. 0.860 ± 0.82 μmol/l, P = 0.940); moreover, the prevalence of elevated (>1.071 μmol/l) Lp(a) concentrations between sexes was the same (29.9%). As expected, compared to female sex, male sex showed higher total/HDL-cholesterol ratio (3.642 ± 0.99 vs. 3.329 ± 0.89, P = 0.017) and lower HDL-cholesterol (1.221 ± 0.24 vs. 1.343 ± 0.28 mmol/l, P = 0.001), Apo A-I (1.390 ± 0.20 vs. 1.474 ± 0.23 g/l, P = 0.003) concentrations and Apo A-I/Apo B ratio (1.632 ± 0.49 vs. 1.830 ± 0.66, P = 0.016). Our results show that healthy young men with PHPMI have a similar Lp(a) levels but worse lipid profile than women.

Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes

Background: Both nutritional and genetic factors are involved in the pathogenesis of nonalcoholic fatty liver disease and insulin resistance.Objective: The aim was to assess the effects of fructose, a potent stimulator of hepatic de novo lipogenesis, on intrahepatocellular lipids (IHCLs) and insulin sensitivity in healthy offspring of patients with type 2 diabetes (OffT2D)—a subgroup of individuals prone to metabolic disorders.Design: Sixteen male OffT2D and 8 control subjects were studied in a crossover design after either a 7-d isocaloric diet or a hypercaloric high-fructose diet (3.5 g · kg FFM–1 · d–1, +35% energy intake). Hepatic and whole-body insulin sensitivity were assessed with a 2-step hyperinsulinemic euglycemic clamp (0.3 and 1.0 mU · kg–1 · min–1), together with 6,6-[2H2]glucose. IHCLs and intramyocellular lipids (IMCLs) were measured by 1H-magnetic resonance spectroscopy.Results: The OffT2D group had significantly (P < 0.05) higher IHCLs (+94%), total triacylglycerols (+35%), and lower whole-body insulin sensitivity (–27%) than did the control group. The high-fructose diet significantly increased IHCLs (control: +76%; OffT2D: +79%), IMCLs (control: +47%; OffT2D: +24%), VLDL-triacylglycerols (control: +51%; OffT2D: +110%), and fasting hepatic glucose output (control: +4%; OffT2D: +5%). Furthermore, the effects of fructose on VLDL-triacylglycerols were higher in the OffT2D group (group × diet interaction: P < 0.05).Conclusions: A 7-d high-fructose diet increased ectopic lipid deposition in liver and muscle and fasting VLDL-triacylglycerols and decreased hepatic insulin sensitivity. Fructose-induced alterations in VLDL-triacylglycerols appeared to be of greater magnitude in the OffT2D group, which suggests that these individuals may be more prone to developing dyslipidemia when challenged by high fructose intakes. This trial was registered at clinicaltrials.gov as NCT00523562.

Letter to the Editor

To the Editor: Endothelial nitric oxide synthase (eNOS) deficiency was found to affect insulin sensitivity and vascular homeostasis in animal models.1,2 Blood flow regulation by endothelial NO was suggested to modulate glucose uptake in the skeletal muscle.3 Therefore, it is possible that also in human subjects defects in eNOS activation or levels could affect insulin sensitivity.3 The D298D eNOS variant reduces eNOS protein half-life under stress conditions4 and it has been associated to increased cardiovascular disease (CVD) risk.5 The aim of present study was to assess whether among healthy offspring of patients with type 2 diabetes mellitus (T2DM) carriers of the D298D genotype are characterized by insulin resistance and early signs of atherosclerosis. We recruited 142 young white offspring of T2DM with these inclusion criteria: age <45 years, 1 parent affected by T2DM, normal glucose tolerance (fasting plasma glucose <110 mg/dL; …

Insulin receptor number is reduced in healthy offspring of patients with essential hypertension

Epidemiologic studies have shown that healthy offspring of hypertensive patients exhibit many features of the metabolic syndrome, such as hyperinsulinemia, insulin resistance, and lipid disorders. Patients with essential hypertension have reduced numbers of insulin receptors. The aim of this study was to examine whether the number of insulin receptors is reduced in the erythrocytes of healthy offspring of hypertensive patients in comparison to the offspring of healthy normotensive subjects. The study population consisted of 25 healthy offspring of patients with essential hypertension (group A) and 28 healthy offspring of healthy normotensive individuals (group B). The two groups were matched for sex, age, and body mass index. Systolic blood pressure (SBP) and diastolic blood pressure (DBP), resting heart rate (HR), plasma insulin levels, and human insulin receptor (hINR) number in erythrocytes were determined in each participant. Mean SBP, DBP, and resting HR were significantly higher in group A than in group B (121 +/- 13 v 110 +/- 10 mm Hg, 78 +/- 6 v 73 +/- 8 mm Hg, and 76 +/- 4 v 72 +/- 6 beats/min; P < .01, P < .05, and P < .01, respectively). Plasma insulin levels were significantly higher, whereas hINR density was significantly lower, in group A than in group B (21 +/- 7 v 15 +/- 6 pIU/mL, P < .01, and 5.6 +/- 1.4 v 6.8 +/- 1.3 receptors x 10(3)/red cell, P < .01, respectively). Our findings suggest that increased SBP, DBP, HR, plasma insulin levels, and decreased erythrocyte hINR density preexist in healthy offspring of patients with essential hypertension.

Higher carotid-radial pulse wave velocity in healthy offspring of patients with Type 2 diabetes.

To determine whether carotid-radial pulse wave velocity (crPWV), a simple non-invasive measurement of muscular artery structure and function, is increased in offspring of patients with Type 2 diabetes compared with well-matched controls with no family history of diabetes. Serum levels of intercellular adhesion molecule-1 (sICAM-1) were also examined. Offspring (n = 19, M = 8) were recruited via contact with patients attending clinics. Controls (n = 19, M = 8) were recruited by advertisement. crPWV was measured using COMPLIOR. Blood pressure and heart rate were determined and fasting blood taken for measurement of metabolic and endothelial parameters. Offspring and controls were well matched [mean (sd)] for age [33.1 (9.6) vs. 32.8 (9.5) years], body mass index [24.8 (4.9) vs. 24.3 (3.4) kg/m2], waist circumference [78.3 (2.3) vs. 76.3 (2.5) cm], and systolic blood pressure [120 (9.3) vs. 119 (14.2) mmHg]. crPWV was 10% higher in the offspring [9.94 (1.3) m/s] compared with controls [9.01 (1.2) m/s, P = 0.02] despite similar pulse pressure [52 (10.5) vs. 53.5 (9.3) mmHg] and resting heart rate [71 (8.7) vs. 69 (14.0) beats/min]. They also showed a trend toward higher sICAM-1 [217 (55) vs. 188 (40) ng/ml, P = 0.07] concentrations which were also strongly correlated to crPWV in offspring (r = 0.63, P = 0.004). Vascular dysfunction in the form of increased muscular artery stiffness is present from an early stage in subjects at higher risk of developing diabetes. This may be secondary to impaired activation of endothelial signalling pathways in the context of inherited insulin resistance.

Elevated plasma immunoreactive leptin levels preexist in healthy offspring of patients with essential hypertension

Background: Plasma leptin levels and plasma insulin levels have been found to be elevated in patients with essential hypertension (EH) and have been suggested to be components of the metabolic syndrome. Increased heart rate (HR) may predict the development of EH in normal or borderline-hypertensive individuals. The aim of our study was to test the hypothesis that elevated plasma leptin and insulin levels as well as systolic blood pressure (SBP) and diastolic blood pressure (DBP) and increased resting HR preexist in the healthy offspring of patients with EH. Methods and Results: Twenty-six (12 male, 14 female) healthy offspring of hypertensive patients, mean age 16 ± 2.5 years and body mass index (BMI) of 21.5 ± 2.8 kg/m2 (group A), and 30 (14 male, 16 female) healthy offspring of normotensive patients, mean age 17 ± 2.3 years and BMI of 21.9 ± 2.4 kg/m2 (group B), were studied. (The two groups were matched for sex, age, and BMI). Mean SBP, DBP, resting HR, plasma leptin, and plasma insulin levels (radioimmunoassay method) were determined in the whole study population. Mean SBP, DBP, and resting HR were significantly higher in group A than in group B (120 ± 12 vs 112 ± 9.5 mm Hg, 77 ± 9 vs 72 ± 7 mm Hg, 79 ± 8 vs 75 ± 5 beats/min, P < .01, P < .05, and P < .05, respectively). Plasma leptin and insulin levels were significantly higher in group A than in group B (9 ± 5.06 vs 5.6 ± 2.5 ng/mL and 20.11 ± 11.3 vs 14.8 ± 5.2 μIU/mL, P < .01 and P < .05, respectively). Conclusions: Our findings support the hypothesis that hyperleptinemia, hyperinsulinemia, and elevated blood pressure and resting HR preexist in the healthy offspring of patients with EH. (Am Heart J 1999;138:922-5.)

Impaired respiratory response to resistive loading during sleep in healthy offspring of patients with obstructive sleep apnea.

To evaluate the possibility that healthy offspring of patients with obstructive sleep apnea syndrome (OSAS) may have covert signs of sleep disordered breathing, we compared the respiratory response to inspiratory resistive loads (IRL) in 10 adult offspring of fathers previously diagnosed with OSAS with that of 14 offspring of healthy parents. None of the offspring in either group had any sign of OSAS, and groups were age, weight, and body mass index matched. Both ventilatory response to progressively increasing levels of IRL and the IRL required to produce severe hypopnea (tidal volume [V(T)] < 20% of unloaded magnitude) were determined, during NREM sleep. Offspring of patients with OSAS (OSAS offspring) responded to all levels of IRL with greater decreases in V(T). Their V(T) decreased in the second breath on IRL of 23 cm H2O/l/s by 39 +/- 10%, as compared with a decrease of 19 +/- 4% (mean +/- SD) in the control group (p < 0.05). Severe hypopnea occurred in the OSAS offspring in response to smaller IRL compared to controls (79 +/- 20 and 153 +/- 14 cm H2O/l/s, respectively, p < 0.005). Total upper airway occlusion in response to IRL occurred in three of the OSAS offspring, but in none of the controls. We conclude that apparently healthy offspring of patients with OSAS may inherit subtle defects that reduce their ability to compensate for increased loads and maintain upper airway patency during sleep. We speculate that offspring of OSAS patients with decreased tolerance to IRL may be prone to developing OSAS later on in life.