No evidence of tachyphylaxis for insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) in subjects with type 2 diabetes, their first-degree relatives, or in healthy subjects.

BACKGROUND, AIMS: In patients with type 2 diabetes, the lost insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is more apparent after continuous versus bolus administration. To test whether the difference might be explained by rapid tachyphylaxis in response to elevated concentrations of GIP, and whether patients with type 2 diabetes and their relatives are more susceptible to tachyphylaxis than healthy subjects. PATIENTS AND METHODS: In a two-way crossover design, insulinotropic responses to repeated bolus injection (50 pmol/kg body weight at 30 and 120 min) and continuous infusion of GIP (2 pmol.kg-1.min-1 from 30 to 180 min) under hyperglycaemic clamp conditions (8.5 mmol/l) was compared in age- gender- and weight-matched patients with type 2 diabetes, first degree relatives of such patients, and healthy subjects. RESULTS: Insulin secretory responses to the first and second GIP bolus were not significantly different in any of the subject groups. Subjects with type 2 diabetes had a significant relative impairment versus healthy subjects with continuous (C-peptide, -13.2 %, p < 0.05), but not with repeated bolus administration of GIP (+11.1 %, n.s.). First-degree relatives tended to hyper-secrete insulin with bolus or continuous administrations of GIP. CONCLUSIONS: Rapid tachyphylaxis in response to continuous exposure to slightly supraphysiological concentrations of GIP does not explain the reduced insulinotropic response to GIP infusions in patients with type 2 diabetes or their first-degree relatives.

Gender-specific Effects of Treatment with Lifestyle, Metformin or Sulfonylurea on Glycemic Control and Body Weight: A German Multicenter Analysis on 9 108 Patients.

Effects of diabetes treatment are strongly connected to individual factors, but the relevant role of gender has not been addressed so far. This observational study evaluates whether monotherapy with lifestyle, metformin or sulfonylurea has gender-specific effects on glycemic control and/or body weight. Data of 9 108 patients with type 2 diabetes from 129 German diabetes centers were assessed by a standardized, prospective, computer-based diabetes care and outcome documentation system (DPV-Wiss-database; age 63.1±12.8 years, diabetes duration 5.7±7.4 years, HbA1c 55±17.7 mmol/mol [7.2±1.6%], BMI 30.6±6.1 kg/m(2), 49.3% female patients). Antidiabetic concepts included lifestyle intervention (n=5,787), metformin (n=2,180), sulfonylurea (n=943) or other antidiabetic drugs (n=198), respectively. HbA1c and body weight were compared before and after a stable monotherapeutical period of 0.8±0.4 years. Women had a significantly higher reduction of body weight after treatment with lifestyle (women-0.8±0.1 vs. men-0.2±0.1 kg; p<0.05), metformin (women-1.8±0.2 vs. men-1.2±0.2 kg; p<0.05) or sulfonylurea drugs (women-0.9±0.2 vs. men - 0.1±0.2 kg; p<0.05), whereas men displayed significantly higher HbA1c-reductions after treatment with lifestyle (women-6.9±0.2 mmol/mol [- 0.6±0.02%] vs. men-7.5±0.2 mmol/mol [0.7±0.02%]; p<0.05) and metformin only (women-6.3±0.3 mmol/mol [- 0.6±0.03%] vs. men - 7.4±0.3 mmol/mol [- 0.7±0.03%]; p<0.05). No differences were seen for sulfonylurea monotherapy concerning the HbA1c-reduction (women - 5.6±0.5 mmol/mol [- 0.5±0.05%] vs. men-6.4±0.4 mmol/mol [- 0.6±0.04%]; p=0.196). In summary, antidiabetic treatment concepts might result in gender-specific effects on body weight and HbA1c. Gender might therefore represent another important factor in the context of an individualized treatment management of type 2 diabetes.

The effect of different solutions for organ preservation on immediate postischemic pancreatic function in vitro.

The present study compares the effect of organ preservation with Euro-Collins solution, cardioplegic histidine-tryptophan-ketoglutarate solution, and University of Wisconsin solution on immediate pancreatic function after cold storage at 4 degrees C for 24 hr. Postischemic organ quality of a porcine pancreas preparation was tested by quantification of physiological and biomedical parameters in a one-line reperfusion system. During reperfusion with a constant arterial pressure the arteriovenous flow rate was significantly higher for HTK (5.7 +/- 0.91 ml/min, n = 8; P < 0.05 vs. EC) and UW (7.4 +/- 0.81 ml/min, n = 8; P < 0.05 vs. EC) than for EC (3.0 +/- 0.26 ml/min, n = 6). The lowest lactate content in the reperfusate was found after HTK protection (HTK, 64.0 +/- 7.2 mumol/50 ml, n = 8; versus EC, 114.2 +/- 1.7 mumol/50 ml, n = 6, P < 0.001; versus UW, 148.0 +/- 28.6 mumol/50 ml, n = 8, P < 0.05). Amylase in the venous effluent was significantly lower (P < 0.05) for HTK or UW protection than for EC (HTK, 189 +/- 72.6 U/ml; UW, 188 +/- 39.4 U/ml; EC, 416 +/- 71.7 U/ml). Oxygen consumption during reperfusion was significantly higher for HTK (2.15 +/- 0.22 microliters/g/min, P < 0.001) and UW (1.80 +/- 0.52 microliters/g/min, P < 0.05) than for EC (0.47 +/- 0.13 microliters/g/min). We conclude that immediate postischemic organ quality and pancreatic function after protection with HTK is not inferior to preservation with UW.

Preservation of the porcine pancreas with HTK and Euro-Collins solution: studies in a reperfusion system.

The present study compares the preservation of the porcine pancreas by the standard Euro-Collins solution or the cardioplegic histidine-tryptophan-ketoglutarate solution (HTK). The explanted pancreas was stored at 4 degrees C for 6 and 24 h respectively, following which organ quality was assessed in a reperfusion chamber measuring physiological and biomedical parameters. After 6 h ischaemia, the amount of lactate was significantly lower when HTK was used for protection. Other parameters like insulin release, amylase release, vascular resistance and oxygen consumption of the pancreas did not indicate a significant difference. Protection with HTK significantly improved pancreas preservation after 24 h ischaemia: lactate content in the reperfusate was lower (HTK: 64.0 +/- 7.2 mumol 50 ml-1 n = 8, v. EC: 114.2 +/- 1.7 mumol 50 ml-1, n = 6), the arteriovenous flow rate was higher (HTK: 5.7 +/- 0.91 ml min-1 v. EC: 3.0 +/- 0.26 ml min-1), and the pancreatic oxygen consumption was increased (HTK: 2.15 +/- 0.22 microliter O2 min-1 g-1 v. 0.47 +/- 0.08 microliter O2 min-1 g-1). We conclude that pancreas preservation can be improved in vitro by protection with HTK solution.

The perfused porcine pancreas as a model for testing organ protective solutions.

The present study was designed to establish an in vitro perfused porcine pancreas preparation as a model for testing the effect of organ protective solutions on stimulated pancreatic endocrine and exocrine secretion. The pancreas was prepared and perfused for 10 min with Euro Collins solution, thereafter it was stored in the cold (4 degrees C) for various times. After 3-h and 6-h ischemia pancreatic insulin release in response to glucose was not significantly affected. After 12-h ischemia reduced pancreatic insulin secretin, increased perfusion pressure, and increased amylase and lipase release indicated pancreatic damage. Complete pancreatic dysfunction was seen after 24-h and 48-h ischemia with massive increase in perfusion pressure and low insulin secretion which did not follow a glucose-dependent release pattern, while amylase and lipase concentrations in the perfusion medium increased. Stimulated exocrine pancreatic secretion was significantly decreased already after 3-h ischemia and completely lost after 12 h.

Hydroxyethyl starch does not improve pancreas preservation with HTK.

The effect of hydroxyethyl starch on pancreas preservation with cardioplegic histidine-tryptophan-ketoglutarate solution (HTK) was investigated. The study was performed using an in vitro reperfusion system of the porcine pancreas. During organ preservation pancreatic weight, arterial pressure, volume flow, and washout of amylase and lactate were quantified. Addition of hydroxyethyl starch did not affect arteriovenous volume flow or washout of amylase and lactate during protective perfusion after pancreas preparation. However, hydroxyethyl starch in HTK prevented an increase in pancreatic weight at the end of the protective perfusion (102.2 +/- 4.55% vs 127.8 +/- 4.62% in controls; p < 0.005) and after 24 h cold ischemia (72.9 +/- 3.91% vs. 83.5 +/- 3.49% in controls; p < 0.05). Hydroxyethyl starch did not affect postischemic organ quality assessed during reperfusion in a perfusion chamber by pancreatic vascular resistance, amylase and lactate release, insulin secretion, and oxygen consumption. We conclude that hydroxyethyl starch does not bring about any further improvement in immediate postischemic organ quality assessed in an in vitro reperfusion system.