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Henrik U Andersen, Dídac Mauricio, Allan E Karlsen, Thomas Mandrup-Poulsen, Jens H Nielsen, and Jørn Nerup

Andersen HU, Mauricio D, Karlsen AE, Mandrup-Poulsen T, Nielsen JH, Nerup J. Interleukin-nitric oxide production from isolated rat islets is modulated by d-glucose and 3-isobutyl-1-methyl xanthine. Eur J Endocrinol 1996:134:251–9. ISSN 0804–4643

Interleukin-1β has been proposed to cause selective β-cell destruction via the induction of nitric oxide synthesis. The cytotoxic effect of interleukin-1β is modulated by the concentration of d-glucose in the medium. The aim of this study was to investigate if d-glucose-mediated modulation of interleukin-1β effects on insulin release from isolated rat islets was related to modulation of nitric oxide production. Further, we wished to investigate the effects of agents increasing the intracellular concentration of cAMP on interleukin-1β-induced nitrite production. We demonstrated that d-glucose potentiated interleukin-1β-induced nitrite production in rat islets without affecting the mRNA level of the inducible nitric oxide synthase. This effect was dissociated from interleukin-1β action on insulin release, since a relative protection against interleukin-1β effects on acute insulin release was found at high (28 mmol/l) concentrations of d-glucose, and blocking nitrite production by the L-arginine analog aminoguanidine, which selectively inhibits the cytokine-inducible nitric oxide synthase, did not result in protection against the inhibitory action of interleukin-1β Neither l-glucose nor the secretagogues l-leucine, tolbutamide and β-isobutyl-1-methyl xanthine shared the potentiating effect of d-glucose, The phosphodiesterase inhibitor β-isobutyl-1-methyl xanthine reduced interleukin-1β-induced nitrite production at 3.3 mmol/l d-glucose, an effect that could be reproduced by the cAMP analog dibutyryl cAMP. Addition of 3-isobutyl-1-methyl xanthine resulted in a threefold reduction in the mRNA level of interleukin-1β-induced inducible nitric oxide synthase. We conclude that interleukin-1β-induced islet nitric oxide synthesis is augmented by d-glucose but not by non-substrate secretagogues, and that secretagogues that elevate cAMP inhibit islet nitric oxide production.

Jørn Nerup, Steno Diabetes Center, Niels Steensens vej 2, DK-2820 Gentofte, Denmark

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Olga Giménez-Palop, Gabriel Giménez-Pérez, Dídac Mauricio, Eugenio Berlanga, Neus Potau, Carme Vilardell, Jaume Arroyo, José-Miguel González-Clemente, and Assumpta Caixàs

Objective: Ghrelin is a gastric peptide that plays a role in appetite stimulation, energy balance and possibly in insulin resistance. Hyperthyroidism is a situation where negative energy balance and insulin resistance coexist, while in hypothyroidism a positive energy balance and normal insulin sensitivity predominate. We investigated ghrelin levels and their relationship with hunger, food intake and both anthropometric and insulin resistance parameters in patients with thyroid dysfunction.

Design and methods:We studied 24 hyperthyroid and 17 hypothyroid patients before and after normalisation of thyroid hormone levels and their respective body mass index (BMI)-matched control group. We measured plasma ghrelin levels, homeostasis model assessment of insulin resistance (HOMA-IR) index, a hunger score, mean three-day calorie intake and anthropometric parameters.

Results: In hyperthyroidism, HOMA-IR index was higher (3.21 ± 0.60 vs 1.67 ± 0.15mMmU/l; P = 0.014, t test for independent data) and ghrelin levels were lower (463.6 ± 36.4 vs 561.1 ± 32.1 pg/ml; P = 0.041, Mann–Whitney U-test) than in its control group and both normalised after treatment (HOMA-IR: 2.28 ± 0.38mMmU/l; P = 0.106, t test for independent data, and ghrelin: 539.7 ± 45.4 pg/ml; P = 0.549, Mann–Whitney U-test). Glucose, as a component of HOMA-IR index was the only predictor for ghrelin levels (β = −0.415, P = 0.044, stepwise multiple regression analysis). In hypothyroidism, HOMA-IR index and ghrelin levels were similar to those in its control group both before and after treatment. In both thyroid dysfunction states, no correlations were observed between changes in ghrelin levels and in free T4, free T3, anthropometric parameters, total calorie intake and hunger score.

Conclusions: In thyroid dysfunction states, ghrelin levels seemed to be in relation to insulin resistance and not to energy balance and food intake regulation, as seen in other physiological and pathological states.

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María Teresa Julián, Guillem Pera, Berta Soldevila, Llorenç Caballería, Josep Julve, Carlos Puig-Jové, Rosa Morillas, Pere Torán, Carmen Expósito, Manel Puig-Domingo, Esmeralda Castelblanco, Josep Franch-Nadal, Kenneth Cusi, Didac Mauricio, and Nuria Alonso

Objective: To investigate the prevalence and risks factors associated with the presence of significant liver fibrosis in subjects with nonalcoholic fatty liver disease (NAFLD) with and without type 2 diabetes mellitus (T2D).

Design and methods: This study was part of a population-based study conducted in the Barcelona metropolitan area among subjects aged 18-75 years old. Secondary causes of steatosis were excluded. Moderate-to-advanced liver fibrosis was defined as a liver stiffness measurement (LSM) ≥ 8.0 kPa assessed by transient elastography.

Results: Among 930 subjects with NAFLD, the prevalence of moderate-to-advanced liver fibrosis was higher in subjects with T2D compared those without (30.8% vs. 8.7%). By multivariable analysis, one of the main factors independently associated with increased LSM in subjects with NAFLD was atherogenic dyslipidemia, but only in those with T2D. The percentage of subjects with LSM ≥ 8.0 kPa was higher in subjects with T2D and atherogenic dyslipidemia than in those with T2D without atherogenic dyslipidemia, both for the cut-off point of LSM ≥8.0 kPa (45% vs 24%, p=0.002) and 13 kPa (13% vs 4%, p=0.020). No differences were observed in the prevalence of LSM ≥8.0 kPa regarding glycemic control among NAFLD-diabetic subjects.

Conclusions: Factors associated with moderate-to-advanced liver fibrosis in NAFLD are different in subjects with and without T2D. Atherogenic dyslipidemia was associated with the presence of moderate-to-advanced liver fibrosis in T2D with NAFLD but not in non-diabetic subjects. These findings highlight the need for an active search for liver fibrosis in subjects with T2D, NAFLD and atherogenic dyslipidemia.