Philipp A. Gerber

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.

PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells.

Insulin secretion from pancreatic beta cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1alpha, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1alpha pathway in the control of beta-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in beta cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca(2+) concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1alpha rescued these phenotypes, implying that they are the result of HIF1alpha activation. Together, these results identify pVHL and HIF1alpha as key regulators of insulin secretion from pancreatic beta cells. They further suggest that changes in the metabolic strategy of glucose metabolism in beta cells have profound effects on whole-body glucose homeostasis.

Exercise Prevents Fructose-Induced Hypertriglyceridemia in Healthy Young Subjects

Excess fructose intake causes hypertriglyceridemia and hepatic insulin resistance in sedentary humans. Since exercise improves insulin sensitivity in insulin-resistant patients, we hypothesized that it would also prevent fructose-induced hypertriglyceridemia. This study was therefore designed to evaluate the effects of exercise on circulating lipids in healthy subjects fed a weight-maintenance, high-fructose diet. Eight healthy males were studied on three occasions after 4 days of 1) a diet low in fructose and no exercise (C), 2) a diet with 30% fructose and no exercise (HFr), or 3) a diet with 30% fructose and moderate aerobic exercise (HFrEx). On all three occasions, a 9-h oral [13C]-labeled fructose loading test was performed on the fifth day to measure [13C]palmitate in triglyceride-rich lipoprotein (TRL)-triglycerides (TG). Compared with C, HFr significantly increased fasting glucose, total TG, TRL-TG concentrations, and apolipoprotein (apo)B48 concentrations as well as postfructose glucose, total TG, TRL-TG, and [13C]palmitate in TRL-TG. HFrEx completely normalized fasting and postfructose TG, TRL-TG, and [13C]palmitate concentration in TRL-TG and apoB48 concentrations. In addition, it increased lipid oxidation and plasma nonesterified fatty acid concentrations compared with HFr. These data indicate that exercise prevents the dyslipidemia induced by high fructose intake independently of energy balance.

Hif-2α Promotes Degradation of Mammalian Peroxisomes by Selective Autophagy

Peroxisomes play a central role in lipid metabolism, and their function depends on molecular oxygen. Low oxygen tension or von Hippel-Lindau (Vhl) tumor suppressor loss is known to stabilize hypoxia-inducible factors alpha (Hif-1α and Hif-2α) to mediate adaptive responses, but it remains unknown if peroxisome homeostasis and metabolism are interconnected with Hif-α signaling. By studying liver-specific Vhl, Vhl/Hif1α, and Vhl/Hif2α knockout mice, we demonstrate a regulatory function of Hif-2α signaling on peroxisomes. Hif-2α activation augments peroxisome turnover by selective autophagy (pexophagy) and thereby changes lipid composition reminiscent of peroxisomal disorders. The autophagy receptor Nbr1 localizes to peroxisomes and is likewise degraded by Hif-2α-mediated pexophagy. Furthermore, we demonstrate that peroxisome abundance is reduced in VHL-deficient human clear cell renal cell carcinomas with high HIF-2α levels. These results establish Hif-2α as a negative regulator of peroxisome abundance and metabolism and suggest a mechanism by which cells attune peroxisomal function with oxygen availability.

Glycemic Control in Simultaneous Islet-Kidney Versus Pancreas-Kidney Transplantation in Type 1 Diabetes: A Prospective 13-Year Follow-up

OBJECTIVE In patients with type 1 diabetes and end-stage renal disease, combined transplantation of a kidney together with a pancreas or isolated pancreatic islets are options to improve glycemic control. The aim of this study was to compare their long-term outcome with regard to metabolic control and surgical complication rate, as well as function of the transplanted kidney. RESEARCH DESIGN AND METHODS We conducted a prospective cohort study in consecutive patients receiving either a pancreas or islet transplant simultaneously with or after kidney transplantation (simultaneous pancreas-kidney [SPK]/pancreas-after-kidney [PAK] or simultaneous islet-kidney [SIK]/islet-after-kidney [IAK] transplantation). RESULTS Ninety-four patients who had undergone SPK/PAK transplantation were compared with 38 patients who had undergone SIK/IAK transplantation over a period of up to 13 years. HbA1c levels declined from 7.8 ± 1.3% (62 ± 14 mmol/mol) to 5.9 ± 1.1% (41 ± 12 mmol/mol), and from 8.0 ± 1.3% (64 ± 14 mmol/mol) to 6.5 ± 1.1% (48 ± 12 mmol/mol), respectively, in the SPK/PAK and SIK/IAK groups (P < 0.001 for both) and remained stable during follow-up, despite a reduction in the rate of severe hypoglycemia by >90%. The 5-year insulin independence rate was higher in the SPK/PAK group (73.6 vs. 9.3% in the SIK/IAK group), as was the rate of relaparotomy after transplantation (41.5 vs. 10.5% in the SIK/IAK group). There was no difference in the rate of kidney function decline. CONCLUSIONS During a long-term follow-up, SPK/PAK transplantation as well as SIK/IAK transplantation resulted in a sustained improvement of glycemic control with a slightly higher glycated hemoglobin level in the SIK/IAK group. While insulin independence is more common in whole-organ pancreas recipients, islet transplantation can be conducted with a much lower surgical complication rate and no difference in kidney function decline.

Small, Dense LDL Particles Predict Changes in Intima Media Thickness and Insulin Resistance in Men with Type 2 Diabetes and Prediabetes – A Prospective Cohort Study

The association of small, dense low-density lipoprotein (sdLDL) particles with an increased cardiovascular risk is well established. However, its predictive value with regard to glucose metabolism and arterial disease in patients with type 2 diabetes has not been thoroughly investigated. We conducted a prospective longitudinal cohort study in patients with (pre)diabetes who were seen at baseline and after two years. sdLDL particles were determined by gradient gel electrophoresis. Insulin resistance was estimated by using the homeostatic model assessment 2 (HOMA2). Intima media thickness (IMT) and flow-mediated dilation (FMD) were assessed by ultrasound measurements. Fifty-nine patients (mean age 63.0 ± 12.2 years) were enrolled and 39 were seen at follow-up. IMT increased in the whole cohort during follow-up. The change in IMT was predicted by the proportion of sdLDL particles at baseline (p=0.03), and the change in FMD was predicted by LDL-cholesterol levels at baseline (p=0.049). HOMA2 and changes in HOMA2 correlated with the proportion of sdLDL particles and changes in this proportion, respectively (p<0.05 for both). Serum resistin levels increased in parallel with the increasing sdLDL particle number, while serum adiponectin increased only in patients with unaltered sdLDL particle number at follow-up (p<0.01 for both). In conclusion, the proportion of small, dense LDL particles and changes in this proportion are predictive of changes in intima media thickness and insulin resistance, and are closely associated with other determinants of an adverse metabolic status. Thus, this parameter extends the individual risk assessment beyond the limitations of traditional risk markers in patients with dysglycemia.

Effects of Acute Exposure to Moderate Altitude on Vascular Function, Metabolism and Systemic Inflammation

Background Travel to mountain areas is popular. However, the effects of acute exposure to moderate altitude on the cardiovascular system and metabolism are largely unknown. Objectives To investigate the effects of acute exposure to moderate altitude on vascular function, metabolism and systemic inflammation. Methods In 51 healthy male subjects with a mean (SD) age of 26.9 (9.3) years, oxygen saturation, blood pressure, heart rate, arterial stiffness, lipid profiles, low density lipoprotein (LDL) particle size, insulin resistance (HOMA-index), highly-sensitive C-reactive protein and pro-inflammatory cytokines were measured at 490 m (Zurich) and during two days at 2590 m, (Davos Jakobshorn, Switzerland) in randomized order. The largest differences in outcomes between the two altitudes are reported. Results Mean (SD) oxygen saturation was significantly lower at 2590 m, 91.0 (2.0)%, compared to 490 m, 96.0 (1.0)%, p<0.001. Mean blood pressure (mean difference +4.8 mmHg, p<0.001) and heart rate (mean difference +3.3 bpm, p<0.001) were significantly higher at 2590 m, compared to 490 m, but this was not associated with increased arterial stiffness. At 2590 m, lipid profiles improved (median difference triglycerides −0.14 mmol/l, p = 0.012, HDL +0.08 mmol/l, p<0.001, total cholesterol/HDL-ratio −0.25, p = 0.001), LDL particle size increased (median difference +0.45 nm, p = 0.048) and hsCRP decreased (median difference −0.18 mg/l, p = 0.024) compared to 490 m. No significant change in pro-inflammatory cytokines or insulin resistance was observed upon ascent to 2590 m. Conclusions Short-term stay at moderate altitude is associated with increased blood pressure and heart rate likely due to augmented sympathetic activity. Exposure to moderate altitude improves the lipid profile and systemic inflammation, but seems to have no significant effect on glucose metabolism. Trial Registration ClinicalTrials.gov NCT01130948

Omega-3 Fatty Acids: Role in Metabolism and Cardiovascular Disease

The inverse association of cardiovascular risk with intake of omega-3 polyunsaturated fatty acids was suspected early in populations that are known to have a high consumption of fish and fish oil. Subsequent cohort studies confirmed such associations in other populations. Further evidence of possible beneficial effects on metabolism and cardiovascular health was provided by many studies that were able to show specific mechanisms that may underlie these observations. These include improvement of the function of tissues involved in the alterations occurring during the development of obesity and the metabolic syndrome, as adipose tissue, the liver and skeletal muscle. Direct action on the cardiovascular system was not only shown regarding vascular function and the formation of atherosclerotic plaques, but also by providing antiarrhythmic effects on the heart. Data on these effects come from in vitro as well as in vivo studies that were conducted in animal models of disease, in healthy humans and in humans suffering from cardiovascular disease. To define prophylactic as well as treatment options in primary and secondary prevention, large clinical trial assessed the effect of omega-3 polyunsaturated fatty acids on end points as cardiovascular morbidity and mortality. However, so far these trials provided ambiguous data that do allow recommendations regarding the use of omega-3 polyunsaturated fatty acids in higher dosages and beyond the dietary advice of regular fish intake only in few clinical situations, such as severe hypertriglyceridemia.

Regulation of low-density lipoprotein subfractions by carbohydrates

Purpose of reviewThis article aims at reviewing the recent findings that have been made concerning the crosstalk of carbohydrate metabolism with the generation of small, dense low-density lipoprotein (LDL) particles, which are known to be associated with an adverse cardiovascular risk profile. Recent findingsStudies conducted during the past few years have quite unanimously shown that the quantity of carbohydrates ingested is associated with a decrease of LDL particle size and an increase in its density. Conversely, diets that aim at a reduction of carbohydrate intake are able to improve LDL quality. Furthermore, a reduction of the glycaemic index without changing the amount of carbohydrates ingested has similar effects. Diseases with altered carbohydrate metabolism, for example, type 2 diabetes, are associated with small, dense LDL particles. Finally, even the kind of monosaccharide the carbohydrate intake consists of is important concerning LDL particle size: fructose has been shown to alter the LDL particle subclass profile more adversely than glucose in many recent studies. SummaryLDL particle quality, rather than its quantity, is affected by carbohydrate metabolism, which is of clinical importance, in particular, in the light of increased carbohydrate consumption in todays world.

Improved physiological properties of gravity-enforced reassembled rat and human pancreatic pseudo-islets.

Previously we demonstrated the superiority of small islets vs large islets in terms of function and survival after transplantation, and we generated reaggregated rat islets (pseudo‐islets) of standardized small dimensions by the hanging‐drop culture method (HDCM). The aim of this study was to generate human pseudo‐islets by HDCM and to evaluate and compare the physiological properties of rat and human pseudo‐islets. Isolated rat and human islets were dissociated into single cells and incubated for 6–14 days by HDCM. Newly formed pseudo‐islets were analysed for dimensions, morphology, glucose‐stimulated insulin secretion (GSIS) and total insulin content. The morphology of reaggregated human islets was similar to that of native islets, while rat pseudo‐islets had a reduced content of α and δ cells. GSIS of small rat and human pseudo‐islets (250 cells) was increased up to 4.0‐fold (p < 0.01) and 2.5‐fold (p < 0.001), respectively, when compared to their native counterparts. Human pseudo‐islets showed a more pronounced first‐phase insulin secretion as compared to intact islets. GSIS was inversely correlated to islet size, and small islets (250 cells) contained up to six‐fold more insulin/cell than large islets (1500 cells). Tissue loss with this new technology could be reduced to 49.2 ± 1.5% in rat islets, as compared to the starting amount. With HDCM, pseudo‐islets of standardized size with similar cellular composition and improved biological function can be generated, which compensates for tissue loss during production. Transplantation of small pseudo‐islets may represent an attractive strategy to improve graft survival and function, due to better oxygen and nutrient supply during the phase of revascularization. Copyright