Michel Hochuli

Low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: a randomized controlled trial

BACKGROUND Sugar-sweetened beverages (SSBs) have unfavorable effects on glucose and lipid metabolism if consumed in high quantities by obese subjects, but the effect of lower doses in normal-weight subjects is less clear. OBJECTIVE The aim was to investigate the effects of SSBs consumed in small to moderate quantities for 3 wk on LDL particle distribution and on other parameters of glucose and lipid metabolism as well as on inflammatory markers in healthy young men. DESIGN Twenty-nine subjects were studied in a prospective, randomized, controlled crossover trial. Six 3-wk interventions were assigned in random order as follows: 600 mL SSBs containing 1)40 g fructose/d [medium fructose (MF)], 2) 80 g fructose/d [high fructose (HF)], 3) 40 g glucose/d [medium glucose (MG)], 4) 80 g glucose/d [high glucose (HG)], 5) 80 g sucrose/d [high sucrose (HS)], or 6) dietary advice to consume low amounts of fructose. Outcome parameters were measured at baseline and after each intervention. RESULTS LDL particle size was reduced after HF by -0.51 nm (95% CI: -0.19, -0.82 nm) and after HS by -0.43 nm (95% CI: -0.12, -0.74; P < 0.05 for both). Similarly, a more atherogenic LDL subclass distribution was seen when fructose-containing SSBs were consumed (MF, HF, and HS: P < 0.05). Fasting glucose and high-sensitivity C-reactive protein (hs-CRP) increased significantly after all interventions (by 4-9% and 60-109%, respectively; P < 0.05); leptin increased during interventions with SSBs containing glucose only (MG and HG: P < 0.05). CONCLUSION The present data show potentially harmful effects of low to moderate consumption of SSBs on markers of cardiovascular risk such as LDL particles, fasting glucose, and hs-CRP within just 3 wk in healthy young men, which is of particular significance for young consumers. This trial was registered at clinicaltrials.gov as NCT01021969.

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100-000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness. To achieve these goals, the guidelines were developed using the SIGN methodology by having professionals on MMA/PA across twelve European countries and the U.S. gather all the existing evidence, score it according to the SIGN evidence level system and make a series of conclusive statements supported by an associated level of evidence. Although the degree of evidence rarely exceeds level C (evidence from non-analytical studies like case reports and series), the guideline should provide a firm and critical basis to guide practice on both acute and chronic presentations, and to address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Furthermore, these guidelines highlight gaps in knowledge that must be filled by future research. We consider that these guidelines will help to harmonize practice, set common standards and spread good practices, with a positive impact on the outcomes of MMA/PA patients.

Moderate Amounts of Fructose Consumption Impair Insulin Sensitivity in Healthy Young Men A randomized controlled trial

OBJECTIVE Adverse effects of hypercaloric, high-fructose diets on insulin sensitivity and lipids in human subjects have been shown repeatedly. The implications of fructose in amounts close to usual daily consumption, however, have not been well studied. This study assessed the effect of moderate amounts of fructose and sucrose compared with glucose on glucose and lipid metabolism. RESEARCH DESIGN AND METHODS Nine healthy, normal-weight male volunteers (aged 21–25 years) were studied in this double-blind, randomized, cross-over trial. All subjects consumed four different sweetened beverages (600 mL/day) for 3 weeks each: medium fructose (MF) at 40 g/day, and high fructose (HF), high glucose (HG), and high sucrose (HS) each at 80 g/day. Euglycemic-hyperinsulinemic clamps with [6,6]-2H2 glucose labeling were used to measure endogenous glucose production. Lipid profile, glucose, and insulin were measured in fasting samples. RESULTS Hepatic suppression of glucose production during the clamp was significantly lower after HF (59.4 ± 11.0%) than HG (70.3 ± 10.5%, P < 0.05), whereas fasting glucose, insulin, and C-peptide did not differ between the interventions. Compared with HG, LDL cholesterol and total cholesterol were significantly higher after MF, HF, and HS, and free fatty acids were significantly increased after MF, but not after the two other interventions (P < 0.05). Subjects’ energy intake during the interventions did not differ significantly from baseline intake. CONCLUSIONS This study clearly shows that moderate amounts of fructose and sucrose significantly alter hepatic insulin sensitivity and lipid metabolism compared with similar amounts of glucose.

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial.

Sugar-sweetened beverages with moderate amounts of fructose, but not sucrose, induce Fatty Acid synthesis in healthy young men: a randomized crossover study.

CONTEXT The impact of sugar-sweetened beverages (SSB) on lipid metabolism when consumed in moderate amounts by normal weight subjects is debated. OBJECTIVE The objective of the study was to investigate the effect of different types of sugars in SSB on fatty acid metabolism (ie, fatty acid synthesis and oxidation) in healthy young men. DESIGN Thirty-four normal-weight men were studied in a randomized crossover study. Four isocaloric 3-week interventions with SSB were performed in random order: medium fructose (MF; 40 g/d); high fructose (HF; 80 g/d), high sucrose (HS; 80 g/d), and high glucose (HG; 80g/d). Fasting total plasma fatty acid composition was measured after each intervention. Acylcarnitines were measured in the fasting state and after a euglycemic hyperinsulinemic clamp in nine subjects. RESULTS The relative abundance of palmitate (16:0) and the molar fatty acid ratio of palmitate to linoleic acid (16:0 to18:2) as markers of fatty acid synthesis were increased after HF [relative abundance of palmitate: 22.97% ± 5.51% (percentage of total fatty acids by weight ±SD)] and MF (26.1% ± 1.7%) compared with HS (19.40% ± 2.91%, P < .001), HG (19.43% ±3.12 %, P < .001), or baseline (19.40% ± 2.79%, P < .001). After HS and HG, the relative abundance of palmitate was equal to baseline. Fasting palmitoylcarnitine was significantly increased after HF and HS (HF and HS vs. HG: P = .005), decreasing after inhibition of lipolysis by insulin in the clamp. CONCLUSIONS When consumed in moderate amounts, fructose but not sucrose or glucose in SSB increases fatty acid synthesis (palmitate), whereas fasting long-chain acylcarnitines are increased after both fructose and sucrose, indicating an impaired β-oxidation flux.

A new alpha-globin variant with increased oxygen affinity in a Swiss family: Hb Frauenfeld [alpha 138(H21)Ser-->Phe, TCC>TTC (alpha 2)].

A new α-globin mutation [α138(H21)Ser→Phe] was found in a 55-year-old male proband with an erythrocytosis known since his youth. Cation exchange high performance liquid chromatography (HPLC) revealed an additional peak eluting slightly before Hb A indicating the presence of a variant. The peak area of the variant was approximately one-third that of Hb A suggesting an α-globin variant. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analysis confirmed the mutation at the protein level. The variant is also detectable with isoelectric focusing and reversed phase HPLC. DNA analysis revealed a heterozygous sequence mutation at codon 138 of the α2 gene. A C>T transition at the second nucleotide of the codon indicated a Ser→Phe exchange. The variant showed increased oxygen affinity and was named Hb Frauenfeld.

Disturbed sphingolipid metabolism with elevated 1-deoxysphingolipids in glycogen storage disease type I – A link to metabolic control

BACKGROUND 1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids. They are formed during sphingolipid de novo synthesis by the enzyme serine palmitoyltransferase, due to the alternate use of alanine over its canonical substrate serine. Pathologically elevated 1-deoxySL are involved in several neurological and metabolic disorders. The objective of this study was to investigate the role of 1-deoxySL in glycogen storage disease type I (GSDI). METHODS In this prospective, longitudinal observational study (median follow-up 1.8y), the plasma 1-deoxySL profile was analyzed in 15 adult GSDI patients (12 GSDIa, 3 GSDIb), and 31 healthy controls, along with standard parameters for monitoring GSDI. RESULTS 1-Deoxysphinganine (1-deoxySA) concentrations were elevated in GSDI compared to controls (191 ± 129 vs 35 ± 14 nmol/l, p < 0.0001). Concordant with the mechanism of 1-deoxySL synthesis, plasma alanine was higher (625 ± 182 vs 398 ± 90 μmol/l, p < 0.0001), while serine was lower in GSDI than in controls (88 ± 22 vs 110 ± 18 μmol/l. p < 0.001). Accordingly, serine, alanine and triglycerides were determinants of 1-deoxySA in the longitudinal analysis of GSDIa. 1-deoxySA concentrations correlated with the occurrence of low blood glucose (area under the curve below 4 mmol/l) in continuous glucose monitoring. The 1-deoxySL profile in GSDIb was distinct from GSDIa, with a different ratio of saturated to unsaturated 1-deoxySL. CONCLUSION In addition to the known abnormalities of lipoproteins, GSDI patients also have a disturbed sphingolipid metabolism with elevated plasma 1-deoxySL concentrations. 1-DeoxySA relates to the occurrence of low blood glucose, and may constitute a potential new biomarker for assessing metabolic control. GSDIa and Ib have distinct 1-deoxySL profiles indicating that both GSD subtypes have diverse phenotypes regarding lipid metabolism.

Islet transplantation as safe and efficacious method to restore glycemic control and to avoid severe hypoglycemia after donor organ failure in pancreas transplantation

The aim of this study was to assess safety and efficacy of islet transplantation after initial pancreas transplantation with subsequent organ failure. Patients undergoing islet transplantation at our institution after pancreas organ failure were compared to a control group of patients with pancreas graft failure, but without islet transplantation and to a group receiving pancreas retransplantation. Ten patients underwent islet transplantation after initial pancreas transplantation failed and were followed for a median of 51 months. The primary end point of HbA1c <7.0% and freedom of severe hypoglycemia was met by nine of 10 patients after follow‐up after islet transplantation and in all three patients in the pancreas retransplantation group, but by none of the patients in the group without retransplantation (n = 7). Insulin requirement was reduced by 50% after islet transplantation. Kidney function (eGFR) declined with a rate of ‐1.0 mL ± 1.2 mL/min/1.73 m2 per year during follow‐up after islet transplantation, which tended to be slower than in the group without retransplantation (P = .07). Islet transplantation after deceased donor pancreas transplant failure is a method that can safely improve glycemic control and reduce the incidence of severe hypoglycemia and thus establish similar glycemic control as after initial pancreas transplantation, despite the need of additional exogenous insulin.

Effects of Inadequate Amino Acid Mixture Intake on Nutrient Supply of Adult Patients with Phenylketonuria

Background: Adult phenylketonuria (PKU) patients often reduce their intake of amino acid mixture (AAM) to less than the prescribed amounts. Effects of reduced AAM intake on nutrient supply were evaluated. Methods: Nutrient intake was calculated in 20 adult PKU patients based on a structured food record and complemented by laboratory assessment of nutritional status. Patients were classified into 2 groups, (A) regular AAM intake, or (B) AAM intake below calculated requirements. Results: Group B consumed a higher proportion of natural protein (60 ± 23 vs. 33 ± 12%, p = 0.002); however, the total protein intake was below the recommended amounts in 60% of patients in group B versus 7% in group A (p = 0.03). Fat intake was higher in group B (39 ± 9% of energy vs. 31 ± 6%, p = 0.03), mainly from saturated fats. Selenium, folate, and vitamin B12 intake was below the recommended intake in group B. However, serum concentrations of these analytes remained within the normal range in both groups, although vitamin B12 levels were lower in group B. Plasma tyrosine correlated with AAM intake, and hydroxyproline correlated with the amount of natural protein consumed. Conclusion: Relaxed AAM intake resulted in insufficient nutrient supply, despite a compensatory increase in consumption of natural protein. Care needs to be taken to ensure adequate nutrition in adults with PKU.

Response to Comment on: Aeberli et al. Moderate Amounts of Fructose Consumption Impair Insulin Sensitivity in Healthy Young Men: A Randomized Controlled Trial. Diabetes Care 2013;36:150–156

We appreciate the interest in our recent article on the effects of fructose consumption on insulin sensitivity in young men (1), even though we do not agree with White’s (2) view that our data do not support our conclusion. However, considering his affiliations in the sugar-sweetened beverages (SSBs) industry, his critique is neither new nor surprising. Let us first clarify the study design. Subjects received 40 g (medium fructose [MF]) and 80 g (high fructose [HF]) of fructose per day. Assuming an energy intake of a sedentary study population around 2,400–2,500 kcal/day, this represents 6–7% and 13–14% of total energy intake. Dietary intake was assessed to exclude significant …