Harald Stingl

Lipid-dependent control of hepatic glycogen stores in healthy humans

Aims/hypothesis. Non-esterified fatty acids and glycerol could stimulate gluconeogenesis and also contribute to regulating hepatic glycogen stores. We examined their effect on liver glycogen breakdown in humans.¶Methods. After an overnight fast healthy subjects participated in three protocols with lipid/heparin (plasma non-esterified fatty acids: 2.2 ± 0.1 mol/l; plasma glycerol: 0.5 ± 0.03 mol/l; n = 7), glycerol (0.4 ± 0.1 mol/l; 1.5 ± 0.2 mol/l; n = 5) and saline infusion (control; 0.5 ± 0.1 mol/l; 0.2 ± 0.02 mol/l; n = 7). Net rates of glycogen breakdown were calculated from the decrease of liver glycogen within 9 h using 13C nuclear magnetic resonance spectroscopy. Endogenous glucose production was measured with infusion of D-[6,6-2H2]glucose.¶Results. Endogenous glucose production decreased by about 25 % during lipid and saline infusion (p < 0.005) but not during glycerol infusion (p < 0.001 vs lipid, saline). An increase of plasma non-esterified fatty acids or glycerol reduced the net glycogen breakdown by about 84 % to 0.6 ± 0.3 μmol · kg–1· min–1 (p < 0.001 vs saline: 3.7 ± 0.5 μmol · kg–1· min–1) and by about 46 % to 2.0 ± 0.4 μmol · kg–1· min–1 (p < 0.01 vs saline and lipid), respectively. Rates of gluconeogenesis increased to 11.5 ± 0.8 μmol · kg–1· min–1 (p < 0.01) and 12.8 ± 1.0 μmol · kg–1· min–1 (p < 0.01 vs saline: 8.2 ± 0.7 μmol · l–1· min–1), respectively.¶Conclusion/interpretation: An increase of non-esterified fatty acid leads to a pronounced inhibition of net hepatic glycogen breakdown and increases gluconeogenesis whereas glucose production does not differ from the control condition. We suggest that this effect is not due to increased availability of glycerol alone but rather to lipid-dependent control of hepatic glycogen stores. [Diabetologia (2001) 44: 48–54]

Elevated Fetuin-A concentrations in morbid obesity decrease after dramatic weight loss.

CONTEXT Morbid obesity (MO) is a risk factor for cardiovascular morbidity, mortality, and diabetes, which can be effectively reduced by bariatric surgery. The liver-secreted protein Fetuin-A is elevated in insulin resistance, is an independent predictor of type 2 diabetes and is associated with atherosclerosis. OBJECTIVE We studied Fetuin-A concentrations in patients with MO before and after weight loss induced by gastric bypass. DESIGN We conducted a cross-sectional study and a 16-month longitudinal study. SETTING This study was performed in secondary care. PATIENTS, SUBJECTS, AND INTERVENTION: We included 75 MO patients [65 women, body mass index (BMI) 45.6 ± 8.1 kg/m(2)] and 38 healthy controls (21 women, BMI 26.0 ± 5.5 kg/m(2)) in a cross-sectional study and investigated them before and about 16 months after gastric bypass surgery. MAIN OUTCOME MEASURES Apart from measurements of blood pressure and routine laboratory parameters, a 75-g oral glucose tolerance test was performed. Insulin resistance was calculated by using homeostatic model assessment (HOMA). RESULTS Fetuin-A levels were significantly higher in MO (877 ± 318 μg/ml) than in controls (295 ± 61 μg/ml; P < 0.001). After surgery-induced weight loss (BMI 31.6 ± 6.8 vs. 45.6 ± 8.1 kg/m(2); P < 0.001), HOMA (2.0 ± 1.2 vs. 6.6 ± 6.3; P < 0.001) and Fetuin-A (710 ± 350 vs. 877 ± 318 μg/ml; P < 0.001) decreased. Delta (Δ) Fetuin-A concentrations correlated with Δfasting insulin (r = 0.710; P = 0.001), Δ2-h insulin (r = 0.693; P = 0.005), and HOMA-insulin resistance (r = 0.684; P = 0.001). CONCLUSIONS Fetuin-A is markedly increased in patients with MO. The reduction of Fetuin-A after weight loss could play an important role in the beneficial effects of gastric bypass surgery.

Elevated serum free fatty acid concentrations inhibit T lymphocyte signaling

Unbound cis‐unsaturated free (i.e., nonesterified) fatty acids (FFA) inhibit T lymphocyte activation in vitro and therefore may exert immunosuppressive effects. However, in blood serum the major proportion of FFA is tightly bound to albumin, whereas unbound FFA are hardly detectable. Since serum FFA elevation occurs under pathological conditions like insulin resistance or cancer, which are often associated with a disturbed immune response, we addressed the question of whether increased serum FFA concentrations could affect T lymphocyte activation under in vivo conditions. Our studies revealed that 1) addition of pure long‐chain cis‐unsaturated FFA in the absence of albumin inhibited calcium response in cultured Jurkat T cells. 2) In healthy volunteers, serum FFA elevation by a lipid/ heparin infusion, including predominantly unsatu‐rated fatty acids, decreased calcium response of cultured T cells in contrast to studies without hepa‐rin. 3) Most notably, stepwise increasing serum FFA by lipid/heparin infusion also inhibited calcium response of simultaneously isolated autologous peripheral blood T lymphocytes as well as their CD4+ and CD8+ subsets. In conclusion, our data emphasize that serum FFA elevation is able to exert immuno‐suppressive effects in vivo.—Stulnig, T. M., Berger, M., Roden, M., Stingl, H., Raederstorff, D., Waldhausl, W. Elevated serum free fatty acid concentrations inhibit T lymphocyte signaling. FASEBJ. 14, 939–947 (2000)

Acute troglitazone action in isolated perfused rat liver

The thiazolidinedione compound, troglitazone, enhances insulin action and reduces plasma glucose concentrations when administered chronically to type 2 diabetic patients. To analyse to what extent thiazolidinediones interfere with liver function, we examined the acute actions of troglitazone (0.61 and 3.15 μM) on hepatic glucose and lactate fluxes, bile secretion, and portal pressure under basal, insulin‐ and/or glucagon‐stimulated conditions in isolated perfused rat livers. During BSA‐free perfusion, high dose troglitazone increased basal (P<0.01), but inhibited glucagon‐stimulated incremental glucose production by ∼75% (10.0±2.5 vs control: 40.0±7.2 μmol g liver−1, P<0.01). In parallel, incremental lactate release rose ∼6 fold (13.1±5.9 vs control: 2.2±0.8 mmol g liver−1, P<0.05), while bile secretion declined by ∼67% [0.23±0.02 vs control: 0.70±0.05 mg g liver−1 min−1), P<0.001]. Low dose troglitazone infusion did not enhance the inhibitory effect of insulin on glucagon‐stimulated glucose production, but rapidly increased lactate release (P<0.0005) and portal venous pressure (+0.17±0.07 vs +0.54±0.07 cm buffer height, P<0.0001). These results indicate that troglitazone exerts both insulin‐like and non‐insulin‐like hepatic effects, which are blunted by addition of albumin, possibly due to troglitazone binding.

Zukünftige Angriffspunkte für die Therapie des Typ-2-Diabetes

Prevention and treatment of type 2 diabetes mellitus (T2DM) and the metabolic syndrome represent a major clinical challenge, because effective strategies such as fat restriction and exercise are difficult to implement into diabetes treatment. Based on the increasing knowledge on the pathogenesis of T2DM, new therapeutic approaches are currently under investigation. Potential targets of new therapeutic approaches include: (i) Inhibition of hepatic glucose production, (ii) stimulation of glucose-dependent insulin secretion, (iii) enhancement of insulin signal transduction, and (iv) reduction of body fat mass. Agonists of glucagon-like-peptide 1 (GLP-1) and antagonists of dipeptidylpeptidase IV, which inactivates GLP-1, stimulate glucose-dependent insulin secretion, improve hyperglycemia and are already tested in clinical trials. In humans, glucagon antagonists and an amylin analogue reduce glucagon-dependent glucose production. The glucose-lowering effect of current modulators of lipid oxidation is not pronounced and their use could be limited by side effects. In addition to clinically approved thiazolidendiones, new agonists of the peroxisome proliferator activator receptor gamma (PPAR gamma) as well as combined PPAR alpha/gamma agonists are developed at present. The direct modulation of insulin signal transduction is still limited to experimental studies.SummaryPrevention and treatment of type 2 diabetes mellitus (T2DM) and the metabolic syndrome represent a major clinical challenge, because effective strategies such as fat restriction and exercise are difficult to implement into diabetes treatment. Based on the increasing knowledge on the pathogenesis of T2DM, new therapeutic approaches are currently under investigation. Potential targets of new therapeutic approaches include: (i) Inhibition of hepatic glucose production, (ii) stimulation of glucose-dependent insulin secretion, (iii) enhancement of insulin signal transduction, and (iv) reduction of body fat mass. Agonists of glucagon-like-peptide 1 (GLP-1) and antagonists of dipeptidylpeptidase IV, which inactivates GLP-1, stimulate glucose-dependent insulin secretion, improve hyperglycemia and are already tested in clinical trials. In humans, glucagon antagonists and an amylin analogue reduce glucagon-dependent glucose production. The glucose-lowering effect of current modulators of lipid oxidation is not pronounced and their use could be limited by side effects. In addition to clinically approved thiazolidendiones, new agonists of the peroxisome proliferator activator receptor γ (PPARγ) as well as combined PPAR α/γ agonists are developed at present. The direct modulation of insulin signal transduction is still limited to experimental studies.ZusammenfassungDie Prävention und Behandlung des Typ-2-Diabetes mellitus (T2DM) und des metabolischen Syndroms stellen eine große klinische Herausforderung dar, da wirksame therapeutische Strategien wie fettarme Diät und körperliche Bewegung derzeit nur unzureichend umgesetzt werden. Aufgrund des zunehmenden Wissens über die Pathogenese des T2DM werden neue Therapieansätze geprüft. Angriffspunkte solcher Therapieformen sind (i) die Hemmung der Glukose-produktion der Leber, (ii) die Stimulation der Glukoseabhängigen Insulinsekretion, (iii) die Verbesserung der Insulin-Signaltransduktion und (iv) die Reduktion der Fettgewebsmasse. Agonisten des Glukagon-like-peptide (GLP-1) und Antagonisten der Dipeptidylpeptidase-IV, die GLP-1 abbauen, stimulieren die Glukose-abhängige Insulinsekretion, verbessern so die Hyperglykämie deutlich und sind bereits in klinischer Prüfung. Beim Menschen reduzieren Glukagon-Antagonisten sowie ein Amylin-Analog die Glukagon-abhängige Glukoseproduktion. Die Blutzucker-senkende Wirkung vorhandener Modulatoren der Lipidoxidation ist nicht ausgeprägt und könnte durch Nebenwirkungen limitiert sein. Neben bereits zugelassenen Thiazolidendion-Präparaten werden weitere Agonisten des peroxisome proliferator activator receptors γ (PPARγ) sowie kombinierte PPARα/γ-Agonisten untersucht. Die direkte Modulation der Insulin-Signaltransduktion ist derzeit noch auf experimentelle Untersuchungen beschränkt.

The Place of Insulin Secretagogues in the Treatment of Type 2 Diabetes in the Twenty-First Century

Development of diabetes mellitus is closely related to development of insulin resistance [1]. However, insulin resistance itself cannot completely explain the development of hyperglycaemia, because impairment of beta-cell function is strongly involved in the pathogenesis of disease [2,3]. As fasting plasma glucose increases, it is overt that insulin secretion decreases progressively [4,5]. In particular, loss of first-phase insulin secretion seems to be the first and most important defect of the beta cell. In the UKPDS, the decline in insulin secretion was strongly associated with disease progression [6]. In Pima Indians, development of diabetes mellitus was associated with only a modest deterioration in insulin sensitivity, but a major decrease in acute insulin response to glucose [7]. In addition, loss of first-phase insulin secretion has been shown to be a predictor of impaired glucose tolerance in the San Antonio Heart Study [8]. Thus, effective treatment of diabetes mellitus will have to include drugs that improve insulin secretion. History