Acute noradrenergic activation induces insulin resistance in human skeletal muscle

We assessed in normal subjects the effects of an acute increase in forearm norepinephrine (NE) release, evoked by -20 mmHg lower body negative pressure (LBNP), on insulin-mediated muscle glucose uptake. Seven normal subjects underwent the following two insulin euglycemic clamps in random sequence: one during application of LBNP and the other without LBNP (control study). In the control study, hyperinsulinemia (approximately 60 microU/ml) produced a significant increment in forearm NE release, measured by using the forearm perfusion technique combined with infusion of tritiated NE (from 4.91 +/- 1 to 7.94 +/- 1.33 ng.l-1.min-1; P < 0.05). Forearm glucose uptake rose from 0.97 +/- 0.13 to 5.2 +/- 0.2 mg.l-1.min-1 in response to insulin infusion. When the insulin clamp was performed during LBNP, forearm NE release rose to significantly higher values than those of the control study (from 4.33 +/- 0.52 to 12.7 +/- 1.46 ng.l-1.min-1; P < 0.01 vs. control). Under these conditions, the stimulatory effect of insulin on forearm glucose uptake was markedly reduced (from 0.78 +/- 0.10 to 3.2 +/- 0.7 mg.l-1.min-1; P < 0.02 vs. control). Forearm blood flow and plasma epinephrine and free fatty acid concentrations were comparable in the two study sessions. These data demonstrate that an acute activation of endogenous NE release antagonizes insulin-mediated glucose uptake in forearm skeletal muscle, probably accounted for by a direct metabolic effect of NE.We assessed in normal subjects the effects of an acute increase in forearm norepinephrine (NE) release, evoked by -20 mmHg lower body negative pressure (LBNP), on insulin-mediated muscle glucose uptake. Seven normal subjects underwent the following two insulin euglycemic clamps in random sequence: one during application of LBNP and the other without LBNP (control study). In the control study, hyperinsulinemia (≃60 μU/ml) produced a significant increment in forearm NE release, measured by using the forearm perfusion technique combined with infusion of tritiated NE (from 4.91 ± 1 to 7.94 ± 1.33 ng · l -1 · min -1 ; P < 0.05). Forearm glucose uptake rose from 0.97 ± 0.13 to 5.2 ± 0.2 mg · l -1 · min -1 in response to insulin infusion. When the insulin clamp was performed during LBNP, forearm NE release rose to significantly higher values than those of the control study (from 4.33 ± 0.52 to 12.7 ± 1.46 ng · l -1 · min -1 ; P < 0.01 vs. control). Under these conditions, the stimulatory effect of insulin on forearm glucose uptake was markedly reduced (from 0.78 ± 0.10 to 3.2 ± 0.7 mg · l -1 · min -1 ; P < 0.02 vs. control). Forearm blood flow and plasma epinephrine and free fatty acid concentrations were comparable in the two study sessions. These data demonstrate that an acute activation of endogenous NE release antagonizes insulin-mediated glucose uptake in forearm skeletal muscle, probably accounted for by a direct metabolic effect of NE

Molecular analysis has allowed the definitive diagnosis of multiple acyl-CoA dehydrogenase deficiency (MADD)

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a rare autosomal recessive disorder due to defects in the electron transfer flavoprotein (ETF) or in the electron transfer flavoprotein dehydrogenase (ETFDH) enzymes, involved in the mitochondrial electron transport chain. Patients with MADD fall into different clinical phenotypes, ranging from a severe neonatal presentation, with metabolic acidosis, cardiomyopathy and liver disease to a mild childhood/adult disease, with episodic metabolic decompensation, muscle weakness and respiratory failure.Nowadays, the MADD diagnosis is established by the presence of dicarboxylic organic acids and acylglycine derivatives in the urine and increased levels of medium-and long-chain acylcarnitines in the blood. Mutations in ETFA, ETFB, ETFDH genes, encoding for alpha and beta subunits of ETF and for ETF-dehydrogenase are associated with MADD. We report the case of a three years old child, affected by lethargy and asthenia associated with anorexia. Biochemical analyses showed hypoketotic hypoglycemia with remarkable increments in transaminases, lactic dehydrogenase, aldolase and creatine kinase. The chromatographic layout of urinary organic acids showed a typical dicarboxylic aciduria. Thus, based on these features, MADD was suspected. Fifteen years later, at the age of 19, MADD diagnosis was confirmed by molecular analysis, showing a compound heterozygosity for the mutations c.1074G>C (p.R358S; HGMD: CM031670 in HGMD database) and c.1073G>A (p.R358K) in the ETFDH gene. The c.1073G>A (p.R358K; rs796051959) mutation is reported in ClinVar database as pathogenic allele, although lacking link to a specific clinical condition. However, familial segregation study and in silico analysis, performed by bioinformatics tools, confirmed that this substitution is likely pathogenetic. Her parents were healthy carriers of one of the two mutations. It is known that the severity of the clinical phenotype of MADD may be related to the type of mutation in the ETFA/ETFB/ETFDH genes. Particularly, missense mutations in the ETFDH gene, leaving a detectable residual enzyme activity, may account for the milder form of the disease, as is the case here. In conclusion we suggest that molecular analysis is essential to the definitive diagnosis of MADD and to direct the adequate therapeutic management. Thus, through a close nutritional follow up, a few months ago the patient gave birth to a healthy boy. References Olsen et al. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum Mutat. 2003; 22:12–23

Muscle sympathetic nerve activity in patients with acromegaly

Muscle sympathetic nerve activity was measured in nine acromegalic patients (age, 35 +/- 4 yr; body mass index, 28 +/- 2 kg/m2) and eight healthy subjects (age, 32 +/- 3 yr; body mass index, 25 +/- 2 kg/m2) by combining the forearm arterial-venous difference technique with the tracer method [infusion of tritiated norepinephrine (NE)]. Muscle NE release was quantified both at rest and during physiological hyperinsulinemia while maintaining euglycemia (approximately 90 mg/dL) by means of the euglycemic clamp. Arterial plasma NE was similar in the two groups at rest (197 +/- 28 and 200 +/- 27 pg/mL (-1) and slightly increased during insulin infusion. Forearm NE release was 2.33 +/- 0.55 ng x liter(-1) x min(-1) in healthy subjects and 2.67 +/- 0.61 ng x liter(-1) x min(-1) in acromegalic subjects in the basal state and increased to a similar extent during insulin infusion in both groups (3.13 +/- 0.71 and 3.32 +/- 0.75 ng x L(-1) x min(-1), P < 0.05 vs. basal), indicating a normal stimulatory effect of insulin on muscle sympathetic activity. In contrast, insulin-stimulated forearm glucose uptake was markedly lower in acromegalic patients (2.3 +/- 0.4 mg x L(-1) x min(-1)) than in control subjects (7.9 +/- 1.3 mg x L(-1) x min(-1), P < 0.001), indicating the presence of severe insulin resistance involving glucose metabolism. Our data demonstrate that patients with long-term acromegaly have normal sympathetic activity in the skeletal muscle in the basal, postabsorptive state and normal increments in NE spillover in response to the sympatho-excitatory effect of insulin. Thus, the presence of severe insulin resistance in acromegaly is not accounted for by adrenergic mechanisms

Photoinduced Halogen-Atom Transfer by N-Heterocyclic Carbene-Ligated Boryl Radicals for C(sp³)-C(sp³) Bond Formation

Herein, we present a comprehensive study on the use of N-heterocyclic carbene (NHC)-ligated boryl radicals to enable C(sp3)–C(sp3) bond formation under visible-light irradiation via Halogen-Atom Transfer (XAT). The methodology relies on the use of an acridinium dye to generate the boron-centered radicals from the corresponding NHC-ligated boranes via single-electron transfer (SET) and deprotonation. These boryl radicals subsequently engage with alkyl halides in an XAT step, delivering the desired nucleophilic alkyl radicals. The present XAT strategy is very mild and accommodates a broad scope of alkyl halides, including medicinally relevant compounds and biologically active molecules. The key role of NHC-ligated boryl radicals in the operative reaction mechanism has been elucidated through a combination of experimental, spectroscopic, and computational studies. This methodology stands as a significant advancement in the chemistry of NHC-ligated boryl radicals, which had long been restricted to radical reductions, enabling C–C bond formation under visible-light photoredox conditions

Impact of Sleeve Gastrectomy on Weight Loss, Glucose Homeostasis, and Comorbidities in Severely Obese Type 2 Diabetic Subjects

This study was undertaken to assess medium-term effects of laparoscopic sleeve gastrectomy (LSG) on body weight and glucose homeostasis in severely obese type 2 diabetic (T2DM) subjects. Twenty-five obese T2DM subjects (10 M/15 F, age 45 ± 9 years, BMI 48 ± 8 kg/m2, M ± SD) underwent evaluation of anthropometric/clinical parameters and glucose homeostasis before, 3 and 9–15 months after LSG. Mean BMI decreased from 48 ± 8 kg/m2 to 40 ± 9 kg/m2 (P < .001) at 3 months and 34 ± 6 kg/m2 (P < .001) at 9–15 months after surgery. Remission of T2DM (fasting plasma glucose < 126 mg/dL and HbA1c < 6.5% in the absence of hypoglycemic treatment) occurred in all patients but one. There was a remarkable reduction in the percentage of patients requiring antihypertensive and hypolipidemic drugs. Our study shows that LSG is effective in producing a significant and sustained weight loss and improving glucose homeostasis in severely obese T2DM patients

Evaluation of cardiovascular risk in adults with type 1 diabetes: Poor concordance between the 2019 ESC risk classification and 10-year cardiovascular risk prediction according to the Steno Type 1 Risk Engine

Background: Patients with type 1 diabetes (T1D) have higher mortality risk compared to the general population; this is largely due to increased rates of cardiovascular disease (CVD). As accurate CVD risk stratification is essential for an appropriate preventive strategy, we aimed to evaluate the concordance between 2019 European Society of Cardiology (ESC) CVD risk classification and the 10-year CVD risk prediction according to the Steno Type 1 Risk Engine (ST1RE) in adults with T1D. Methods: A cohort of 575 adults with T1D (272F/303M, mean age 36 ± 12 years) were studied. Patients were stratified in different CVD risk categories according to ESC criteria and the 10-year CVD risk prediction was estimated with ST1RE within each category. Results: Men had higher BMI, WC, SBP than women, while no difference was found in HbA1c levels between genders. According to the ESC classification, 92.5% of patients aged 20 years) alone identified few patients (< 30%) among those aged ≥35 years, who were at very high risk according to ESC, in whom this condition was confirmed by ST1RE; conversely, the coexistence of two or more of these criteria identified about half of the patients at high/very high risk also according to this predicting algorithm. When only patients aged ≥ 50 years were considered, there was greater concordance between ESC classification and ST1RE prediction, since as many as 78% of those at high/very high risk according to ESC were confirmed as such also by ST1RE. Conclusions: Using ESC criteria, a large proportion (45%) of T1D patients without CVD are classified at very high CVD risk; however, among them, none of those < 35 years and only 12% of those ≥ 35 years could be confirmed at very high CVD risk by the ST1RE predicting algorithm. More studies are needed to characterize the clinical and metabolic features of T1D patients that identify those at very high CVD risk, in whom a very aggressive cardioprotective treatment would be justified

Dietary fat differentially modulate the mRNA expression levels of oxidative mitochondrial genes in skeletal muscle of healthy subjects.

Background and aims: Different types of dietary fats exert differential effects on glucose and lipid metabolism. Our aim was to evaluate the impact of different dietary fats on the expression of skeletal muscle genes regulating mitochondrial replication and function in healthy subjects. Methods and results: Ten healthy subjects (age 29±3 years; BMI 25.0±3kg/m2) received in a random order a test meal with the same energy content but different composition in macronutrients and quality of fat: Mediterranean (MED) meal, SAFA meal (Lipid 66%, saturated 36%) and MUFA meal (Lipid 63%, monounsaturated 37%). At fast and after 180min, a fine needle aspiration was performed from the vastus lateralis for determination of mitochondrial gene expression by quantitative PCR. No difference in glucose and triglyceride response was observed between the three meals, while NEFA levels were significantly higher following fat-rich meals compared to MED meal (p<0.002-0.0001). MED meal was associated with an increased expression, albeit not statistically significant, of some genes regulating both replication and function. Following MUFA meal, a significant increase in the expression of PGC1β (p=0.02) and a reduction in the transcription factor PPARδ (p=0.006) occurred with no change in the expression of COX and GLUT4 genes. In contrast, SAFA meal was associated with a marked reduction in the expression of COX (p<0.001) PFK (p<0.003), LPL (p=0.002) and GLUT4 (p=0.009) genes. Conclusion: Dietary fats differentially modulate gene transcriptional profile since saturated, but not monounsaturated fat, downregulate the expression of genes regulating muscle glucose transport and oxidation

Grape pomace polyphenols improve insulin response to a standard meal in healthy individuals: A pilot study

Dietary polyphenols have beneficial effects on glucose/lipid metabolism in subjects at high risk to develop type 2 diabetes; however, the underlying mechanisms are not clear. We aimed to evaluate: 1) the acute effects of the consumption of a drink rich in polyphenols from red grape pomace (RGPD) on glucose/insulin and triglyceride responses to a standard meal in healthy individuals, and, 2) the relationship between plasma levels of phenolic metabolites and metabolic parameters