Fragestellung: Die AMPK, ein ubiquitärer zellulärer Energiesensor und das Ziel der Metformintherapie, spielt im Leberstoffwechsel eine zentrale Rolle und reguliert u.a. die Glukoseproduktion und die de novo Lipogenese. In Tiermodellen ist für NAFLD und Diabetes mellitus Typ 2 (DMT2) eine reduzierte Phosphorylierung an Thr172 der katalytischen α Untereinheit der AMPK und eine daraus resultierende Aktivitätsminderung ohne Veränderung der Gesamtproteinmenge gezeigt. Adiponektin gilt als Aktivator der AMPK und vermittelt seine Wirkung zellulär durch die Rezeptoren AdipoR1 und R2. Der Zusammenhang zwischen AMPK und Adiponektin in der humanen NAFLD±DMT2 stand im Fokus dieser Untersuchung.

Thyroid dysfunction has been shown to be associated with insulin resistance (IR). This may involve peripheral thyroid hormone metabolism, which is assumed to be reflected by the ratio triiodothyronine/reverse triiodothyronine (T3/rT3-ratio). To explore a potential association between the T3/rT3-ratio and IR we investigated pairs which differed in IR, but were matched by sex, age, body mass index (BMI), and thyroid stimulating hormone (TSH). For this purpose, matched pair analyses were embedded into a cross sectional study group. 22 pairs were matched from either the first or the third tertile of HOMA%S of a cohort of 353 euthyroid subjects with normal glucose metabolism who did not take any medication. The T3/rT3-ratio was compared in the matched pairs. The T3/rT3-ratio was significantly increased in the insulin resistant subjects compared to their insulin sensitive partners (8.78 ± 0.47 vs. 7.33 ± 0.33, p=0.019). Furthermore the T3/rT3-ratio was lower in men compared to women (p for the within-subject effect=0.046) both in the insulin sensitive and the insulin resistant subjects. Here we show that the T3/rT3-ratio, which is supposed to reflect the tissue thyroid hormone metabolism, is significantly increased in insulin resistant subjects. This further supports a link between thyroid function and IR.

Abstract The incidence of both type 2 diabetes and cardiac events is reported to be higher during winter, indicating a putative annual periodic change in insulin sensitivity (IS). Annual differences in IS – quantified as HOMA-%S and Matsuda-Sensitivity Index – were analyzed using a cosine wave-fitting algorithm in a cross-sectional study group including 2 385 participants. Additionally, semi-annual differences in IS were compared. We found periodicity for HOMA-%S and Matsuda-Sensitivity Index (p=0.02 or 0.006), which was strengthened after restriction to participants without diabetes (p=0.009 or 0.004). The rhythm amplitude of 0.08 indicated moderate changes in IS throughout the year. IS was significantly higher when participants were enrolled during the second vs. the first half of the year (HOMA-%S 112.0±3.0% vs. 97.4±2.4%, p<0.001). The impact of the half-year on IS, which remained significant after adjustment for confounders, was again moderate and explained only 0.5% of the variation. IS showed a significant moderate annual periodicity, which may affect the interpretation of studies reporting small changes in IS.

Einleitung: Inkretine haben neben ihrer bekannten insulinotropen Wirkung auch Einfluss auf den Lipid- und Glucosemetabolismus. Die genauen Vorgänge die durch das Inkretinhormon Glucose-abhängige insulinotrope Polypeptid (GIP) hierbei ausgelöst werden sind bisher nur wenig bekannt. Während eine langfristige Inhibition des GIP-Signals mittels Antagonisten oder im GIP-Rezeptor knockout-Mausmodel vor Adipositas und Insulinresistenz schützen, ist wenig über die akute in-vivo Wirkung von GIP auf Adipozyten bekannt.

Exposure to high vs. low glycemic index (GI) diets increases fat mass and insulin resistance in obesity-prone C57BL/6J mice. However, the longer-term effects and potentially involved mechanisms are largely unknown. We exposed four groups of male C57BL/6J mice (n = 10 per group) to long-term (20 wk) or short-term (6 wk) isoenergetic and macronutrient matched diets only differing in starch type and as such GI. Body composition, liver fat, molecular factors of lipid metabolism, and markers of insulin sensitivity and metabolic flexibility were investigated in all four groups of mice. Mice fed the high GI diet showed a rapid-onset (from week 5) marked increase in body fat mass and liver fat, a gene expression profile in liver consistent with elevated lipogenesis, and, after long-term exposure, significantly reduced glucose clearance following a glucose load. The long-term high-GI diet also led to a delayed switch to both carbohydrate and fat oxidation in the postprandial state, indicating reduced metabolic flexibility. In contrast, no difference in carbohydrate oxidation was observed after short-term high- vs. low-GI exposure. However, fatty acid oxidation was significantly blunted as early as 3 wk after beginning of the high-GI intervention, at a time where most measured phenotypic markers including body fat mass were comparable between groups. Thus long-term high-GI feeding resulted in an obese, insulin-resistant, and metabolically inflexible phenotype in obesity-prone C57BL/6J mice. Early onset and significantly impaired fatty acid oxidation preceded these changes, thereby indicating a potentially causal involvement.

Fragestellung: Dem Lebensstil wird eine große Bedeutung bei der Entstehung des Übergewichtes beigemessen. Wir untersuchen welche Variablen der Lebensgewohnheiten am stärksten assoziiert sind mit dem BMI.

High- vs low-glycaemic index (GI) diets unfavourably affect body fat mass and metabolic markers in rodents. Different effects of these diets could be age-dependent, as well as mediated, in part, by carbohydrate-induced stimulation of glucose-dependent insulinotrophic polypeptide (GIP) signalling.

Objectives: Liver-fatty-acid-binding-protein (L-FABP) is abundantly expressed in hepatocytes and influences lipid transport and metabolism. Amino-acid replacements in L-FABP might affect its function and thus glucose metabolism, as indicated by L-FABP knock-out studies. We hypothesized that hepatic glucose metabolism is altered in lipid-exposed homozygous carriers of the only common Thr94Ala amino-acid replacement.

Hintergrund: Die Inzidenz des Typ 2 Diabetes-Mellitus (T2DM) nimmt weltweit zu mit einem Trend zu einem verringerten Manifestationsalter. Der T2DM ist charakterisiert durch Insulinresistenz, einen zunächst relativen, peripheren Insulinmangel und einen progressiven Verlust der β-Zellfunktion. Dieser führt schließlich zu einem absoluten Insulinmangel. Chronisch erhöhte Glukosekonzentrationen führen zu einer Schädigung von β-Zellen, unter anderem durch die Produktion reaktiver Sauerstoffspezies (ROS) in Mitochondrien oder aber durch einen in β-Zellen exprimierten Subtyp der NAD(P)H-Oxidase. Ziel der vorliegenden Arbeit war es, die Expression der NAD(P)H-Oxidase in INS-1 Zellen zu bestätigen sowie die Glukose- bzw. CaMKII-Abhängigkeit der Expression und Aktivierung von NAD(P)H-Oxidase zu untersuchen.

Obesity is one of the most relevant health problems in westernized countries, and affects more than 300 million people worldwide [1]. Multiple factors contribute to the obese phenotype, including altered energy intake and fuel dissipation. Recently, impaired mitochondrial metabolism has been suggested as playing a possible role in the obese phenotype; specifically, in silico analyses of published literature on obesity and energy metabolism revealed a putative role for mitochondrial aconitase, the enzyme that converts citrate into isocitrate, in aberrant storage of exogenous nutrients [2]. The authors suggest that reduced activity of mitochondrial aconitase would cause impaired oxidative phosphorylation of nutrient intermediates, and might also lead to increased de novo synthesis of fatty acids due to excess citrate accumulation subsequent to reduced mitochondrial conversion into isocitrate.

Diabetes mellitus is one of the most frequent health problems in westernized countries [1]. Type 2 diabetes mellitus is caused by a combination of impaired insulin secretion and decreased insulin sensitivity [2]. Recently, it was suggested that impaired mitochondrial metabolism precedes the development of diabetes mellitus, and may be found in insulin-resistant but otherwise healthy offspring of parents with type 2 diabetes [3]. Furthermore, impaired expression of mitochondrial and mitochondria-related genes has been observed in muscle biopsies from patients with type 2 diabetes [4] [5]. Impaired activity of mitochondrial aconitase (Aco-2) has been hypothetically linked with obesity [6], and hence might as well contribute to a diabetic phenotype.

We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals have a reduced life span and develop multiple hepatic tumors. Livers also show increased oxidative stress, impaired respiration and reduced ATP levels paralleled by reduced activity of iron-sulfur cluster (Fe/S) containing proteins (ISP), which all leads to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin. Taken together, these findings indicate that frataxin may act as a mitochondrial tumor suppressor protein in mammals.