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Background & Aims: Excessive fructose intake is associated with increased de novo lipogenesis, blood triglycerides, and hepatic insulin resistance. We aimed to determine whether fructose elicits specific effects on lipid metabolism independently of excessive caloric intake., Methods: A total of 94 healthy men were studied in this double-blind, randomized trial. They were assigned to daily consumption of sugar-sweetened beverages (SSBs) containing moderate amounts of fructose, sucrose (fructose-glucose disaccharide) or glucose (80 g/day) in addition to their usual diet or SSB abstinence (control group) for 7 weeks. De novo fatty acid (FA) and triglyceride synthesis, lipolysis and plasma free FA (FFA) oxidation were assessed by tracer methodology., Results: Daily intake of beverages sweetened with free fructose and fructose combined with glucose (sucrose) led to a 2-fold increase in basal hepatic fractional secretion rates (FSR) compared to control (median FSR %/day: sucrose 20.8 (p = 0.0015); fructose 19.7 (p = 0.013); control 9.1). Conversely, the same amounts of glucose did not change FSR (median of FSR %/day 11.0 (n.s.)). Fructose intake did not change basal secretion of newly synthesized VLDL-triglyceride, nor did it alter rates of peripheral lipolysis, nor total FA and plasma FFA oxidation. Total energy intake was similar across groups., Conclusions: Regular consumption of both fructose- and sucrose-sweetened beverages in moderate doses - associated with stable caloric intake - increases hepatic FA synthesis even in a basal state; this effect is not observed after glucose consumption. These findings provide evidence of an adaptative response to regular fructose exposure in the liver., Lay Summary: This study investigated the metabolic effects of daily sugar-sweetened beverage consumption for several weeks in healthy lean men. It revealed that beverages sweetened with the sugars fructose and sucrose (glucose and fructose combined), but not glucose, increase the ability of the liver to produce lipids. This change may pave the way for further unfavorable effects on metabolic health., Clinical Trial Registration Number: NCT01733563., Competing Interests: Conflict of interest The authors have declared that no conflicts of interest exist with regard to this study. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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]-(2)H(2) 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.

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.

Protein kinase B (PKB)/Akt is considered to be a key target downstream of insulin receptor substrate 2 (IRS2) in the regulation of beta-cell mass. However, while deficiency of IRS2 in mice results in diabetes with insulin resistance and severe failure of beta-cell mass and function, only loss of the PKBbeta isoform leads to a mild metabolic phenotype with insulin resistance. Other isoforms were reported not to be required for metabolic regulation. To clarify the roles of the three PKB isoforms in the regulation of islet mass and glucose homeostasis, we assessed the metabolic and pancreatic phenotypes of Pkbalpha, Pkbbeta, and Pkbgamma-deficient mice. Our study uncovered a novel role for PKBalpha in the regulation of glucose homeostasis, whereas it confirmed that Pkbbeta(-/)(-) mice are insulin resistant with compensatory increase of islet mass. Pkbalpha(-/)(-) mice displayed an opposite phenotype with improved insulin sensitivity, lower blood glucose, and higher serum glucagon concentrations. Pkbgamma(-/)(-) mice did not show metabolic abnormalities. Additionally, our signaling analyses revealed that PKBalpha, but not PKBbeta or PKBgamma, is specifically activated by overexpression of IRS2 in beta-cells and is required for IRS2 action in the islets.

The Per-ARNT-Sim (PAS) domain serine/threonine kinase PASKIN, or PAS kinase, links energy flux and protein synthesis in yeast and regulates glycogen synthase in mammals. A recent report suggested that PASKIN mRNA, protein, and kinase activity are increased in pancreatic islet beta-cells under hyperglycemic conditions and that PASKIN is necessary for insulin gene expression. We previously generated Paskin knockout mice by targeted replacement of the kinase domain with the beta-geo fusion gene encoding beta-galactosidase reporter activity. Here we show that no 5-bromo-4-chloro-3-indolyl-ss-d-galactopyranoside (X-gal) staining was observed in islet beta-cells derived from Paskin knockout mice, irrespective of the ambient glucose concentration, whereas adenoviral expression of the lacZ gene in beta-cells showed strong X-gal staining. No induction of PASKIN mRNA could be detected in insulinoma cell lines or in islet beta-cells. Increasing glucose concentrations resulted in PASKIN-independent induction of insulin mRNA levels and insulin release. PASKIN mRNA levels were high in testes but undetectable in pancreas and in islet beta-cells. Finally, blood glucose levels and glucose tolerance after intraperitoneal glucose injection were indistinguishable between Paskin wild-type and knockout mice. These results suggest that Paskin gene expression is not induced by glucose in pancreatic beta-cells and that glucose-stimulated insulin production is independent of PASKIN.

Glucotoxicity and lipotoxicity contribute to the impaired beta-cell function observed in type 2 diabetes. Here we examine the effect of saturated and monounsaturated fatty acids at different glucose concentrations on human beta-cell turnover and secretory function. Exposure of cultured human islets to saturated fatty acid and/or to an elevated glucose concentration for 4 days increased beta-cell DNA fragmentation and decreased beta-cell proliferation. In contrast, the monounsaturated palmitoleic acid or oleic acid did not affect DNA fragmentation and induced beta-cell proliferation. Moreover, each monounsaturated fatty acid prevented the deleterious effects of both palmitic acid and high glucose concentration. The cell-permeable ceramide analogue C(2)-ceramide mimicked both the palmitic acid-induced beta-cell apoptosis and decrease in proliferation. Furthermore, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on beta-cell turnover. In addition, palmitic acid decreased Bcl-2 expression and induced release of cytochrome c from the mitochondria into the cytosol, which was prevented by fumonisin B1 and by oleic acid. Finally, each monounsaturated fatty acid improved beta-cell secretory function that was reduced by palmitic acid and by high glucose. Thus, in human islets, the saturated palmitic acid and elevated glucose concentration induce beta-cell apoptosis, decrease beta-cell proliferation, and impair beta-cell function, which can be prevented by monounsaturated fatty acids. The deleterious effect of palmitic acid is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway, whereas Bcl-2 may contribute to the protective effect of monounsaturated fatty acids.

In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.

Type 2 diabetes mellitus results from an inadequate adaptation of the functional pancreatic beta cell mass in the face of insulin resistance. Changes in the concentration of glucose play an essential role in the regulation of beta cell turnover. In human islets, elevated glucose concentrations impair beta cell proliferation and induce beta cell apoptosis via up-regulation of the Fas receptor. Recently, it has been shown that the caspase-8 inhibitor FLIP may divert Fas-mediated death signals into those for cell proliferation in lymphatic cells. We observed expression of FLIP in human pancreatic beta cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro exposure of islets from nondiabetic organ donors to high glucose levels decreased FLIP expression and increased the percentage of apoptotic terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL)-positive beta cells; FLIP was no longer detectable in such TUNEL-positive beta cells. Up-regulation of FLIP, by incubation with transforming growth factor beta or by transfection with an expression vector coding for FLIP, protected beta cells from glucose-induced apoptosis, restored beta cell proliferation, and improved beta cell function. The beneficial effects of FLIP overexpression were blocked by an antagonistic anti-Fas antibody, indicating their dependence on Fas receptor activation. The present data provide evidence for expression of FLIP in the human beta cell and suggest a novel approach to prevent and treat diabetes by switching Fas signaling from apoptosis to proliferation.

Human fibroblast growth factor 21 (FGF21) is a multifaceted metabolic regulator considered to control sugar intake and to exert beneficial effects on glucose and lipid metabolism. Elevated serum FGF21 levels are associated with metabolic syndrome, suggesting a state of FGF21 resistance. Further, given the evidence of a hepatic ChREBP and FGF21 signaling axis, it can be assumed that SSBs containing fructose would possibly increase FGF21 concentrations. We investigated the effects of sugar-sweetened beverage (SSB) consumption on fasting FGF21 levels in healthy, lean men, discriminating the effects of glucose, fructose, and their disaccharide sucrose by secondary data analysis from a randomized controlled trial. Seven weeks of daily SSB consumption resulted in increased fasting FGF21 in healthy, lean men, irrespective of the sugar type. Medians of ΔFGF21 between post-SSB intervention values (week 7) and no-intervention period values (IQR) in pg/mL were: glucose 17.4 (0.4–45.8), fructose 22.9 (−8.6–35.1), and sucrose 13.7 (2.2–46.1). In contrast, this change in FGF21 concentration was only 6.3 (−20.1–26.9) pg/mL in the control group. The lack of a fructose-specific effect on FGF21 concentrations is contrary to our assumption. It is concluded that SSB intake may impact FGF21 concentrations and could contribute to the increased FGF21 concentrations observed in subjects suffering from metabolic syndrome that is possibly associated with decreased FGF21 responsiveness. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To compare the effect of acute psychosocial stress on glucose concentrations in the fasting state and following food intake in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS -- In study 1, 20 patients were exposed to moderate psychosocial stress by means of the Trier Social Stress Test (TSST) in the fasting state. In study 2, the TSST was applied to 20 additional patients 75 min after intake of a standard meal. Glucose concentrations (by continuous glucose monitoring system), blood pressure, and heart rate were monitored on the control day and on the stress testing day. RESULTS -- In both studies, blood pressure increased in response to TSST from 122/77 ± 14/9 mmHg at baseline to a maximum of 152/93 ± 21/13 mmHg (P < 0.001), and heart rate increased from 80 ± 11 to 99 ± 19 bpm (P < 0.001). In the fasting state (study 1), glucose concentrations remained unchanged during the control day as well as during the stress testing day. In study 2, glucose concentrations were similar on both days before and up to 75 min after the intake of the standard meal. However, a significant delay (of 45 min) in the decrease of glucose concentrations was induced by psychological stress. A two-factor repeated-measures ANOVA revealed a significant difference of glucose concentrations over time (F = 646.65/P < 0.001). CONCLUSIONS -- In the postprandial period, acute psychological stress induced a significantly delayed decrease of glucose concentrations, whereas in the fasting state, no effect on poststress glucose concentrations was observed. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that a progressive decrease in the functional β-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, β-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1β and/or high-glucose-induced β-cell production of IL-1β. Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel potassium channel opener NN414, selective for the β-cell potassium channel SUR1/Kir6.2, on glucose- and IL-1β-induced apoptosis and impaired function in human β-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1β, or 10 and 100 µmol/l of the sulfonylurea tolbutamide induced β-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1β were blocked by 200 µmol/l diazoxide as well as by 3 and 30 µmol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1β were shown to activate the extracellular signal-regulated kinase (ERK) ½, an effect that was abrogated by 3 µmol/l NN414. Similarly, 1 µmol/l of the mitogen-activated protein kinase/ERK kinase ½ inhibitor PD098059 or 1 µmol/l of the L-type Ca[sup2+] channel blocker nimodipine prevented glucose- and IL-1β-induced ERK activation, β-cell apoptosis, and impaired function. Finally, islet release of IL-1β in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1β-induced β-cell secretory dysfunction and apoptosis are Ca[sup2+] influx and ERK dependent and can be prevented by the β-cell selective potassium channel opener NN414. Diabetes 53:1706-1713, 2004 [ABSTRACT FROM AUTHOR]

Examines the genetic expression of FLIP in human pancreatic β cells of nondiabetic and diabetic patients. Role of glucose in the regulation of FLIP expression; Information on Fas receptor activation by FLIP; Inhibition of the beneficial effects of FLIP overexpression.

Several studies support the concept of a diabetic cardiomyopathy in the absence of discernible coronary artery disease, although its mechanism remains poorly understood. We investigated the role of glucose and palmitic acid on cardiomyocyte apoptosis and on the organization of the contractile apparatus. Exposure of adult rat cardiomyocytes for 18 h to palmitic acid (0.25 and 0.5 mmol/l) resulted in a significant increase of apoptotic cells, whereas increasing glucose concentration to 33.3 mmol/l for up to 8 days had no influence on the apoptosis rate. However, both palmitic acid and elevated glucose concentration alone or in combination had a dramatic destructive effect on the myofibrillar apparatus. The membrane-permeable C2-ceramide but not the metabolically inactive C2-dihydroceramide enhanced apoptosis of cardiomyocytes by 50%, accompanied by detrimental effects on the myofibrils. The palmitic acid-induced effects were impaired by fumonisin B1, an inhibitor of ceramide synthase. Sphingomyelinase, which activates the catabolic pathway of ceramide by metabolizing sphingomyeline to ceramide, did not adversely affect cardiomyocytes. Palmitic acid-induced apoptosis was accompanied by release of cytochrome c from the mitochondria. Aminoguanidine did not prevent glucose-induced myofibrillar degeneration, suggesting that formation of nitric oxide and/or advanced glycation end products play no major role. Taken together, these results suggest that in adult rat cardiac cells, palmitic acid induces apoptosis via de novo ceramide formation and activation of the apoptotic mitochondrial pathway. Conversely, glucose has no influence on adult cardiomyocyte apoptosis. However, both cell nutrients promote degeneration of myofibrils. Thus, gluco- and lipotoxicity may play a central role in the development of diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Presents a study which assessed the effects of glucose, arginine and glucagon on beta-cell function as well as on the alpha-cell response to arginine in a family with mitochondrial diabetes. Research design and methods; Results; Conclusions.

Regular carbohydrate intake to avoid hypoglycemia is the mainstay of dietary treatment in glycogen storage disease type I (GSDI). The aim of this study was to evaluate the quality of dietary treatment and glycemic control in a cohort of GSDI patients, in relation to the presence of typical long-term complications. Data of 25 patients (22 GSD subtype Ia and 3 GSDIb, median age 20y) from the Swiss hepatic glycogen storage disease registry was analyzed cross-sectionally. Frequency and type of hypoglycemia symptoms were assessed prospectively using a structured questionnaire. Diagnostic continuous glucose monitoring (CGM) was performed as part of usual clinical care to assess glycemic control in 14 patients, usually once per year with a mean duration of 6.2 ± 1.1 consecutive days per patient per measurement. Although maintenance of euglycemia is the primary goal of dietary treatment, few patients (n = 3, 13%) performed capillary blood glucose measurements regularly. Symptoms possibly associated with hypoglycemia were present in 13 patients (57%), but CGM revealed periods of low glucose (<4 mmol/l) in all patients, irrespective of the presence of symptoms. GSDIa patients with liver adenomas (n = 9, 41%) showed a higher frequency and area under the curve (AUC) of low blood glucose than patients without adenomas (frequency 2.7 ± 0.8 vs. 1.5 ± 0.7 per day, AUC 0.11 ± 0.08 vs. 0.03 ± 0.02 mmol/l/d; p < 0.05). Similarly, the presence of microalbuminuria was also associated with the frequency of low blood glucose. Z -Scores of bone density correlated negatively with lactate levels. The quality of glucose control is related to the presence of typical long-term complications in GSDI. Many patients experience episodes of asymptomatic low blood glucose. Regular assessment of glucose control is an essential element to evaluate the quality of treatment, and increasing the frequency of glucose self-monitoring remains an important goal of patient education and motivation. CGM devices may support patients to optimize dietary therapy in everyday life. [ABSTRACT FROM AUTHOR]

Focuses on a study that tested the hypothesis that IL-β may mediate the deleterious effects of high glucose on human β cells. Procedures used in the isolation and culture of islets; ELISA kits used in the evaluation of cytokine release; Identification of the islet cellular source of glucose-dependent IL-1β production.

A correction to the article "Glucose-induced B cell production of IL-1B contributes to glucotoxicity in human pancreatic islets" in the previous issue is presented.