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1.
Diabetes ; 53 Suppl 3: S79-83, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15561927

ABSTRACT

Peroxisome proliferator-activated receptor (PPAR)-gamma is expressed in human beta-cells and in the rat beta-cell line INS-1. Previous studies have suggested that PPAR-gamma agonism (e.g., thiazolidinediones) enhances glucose-stimulated insulin secretion (GSIS) from islets or INS-1 cells. We tested the direct effect on insulin release by INS-1e of a PPAR-gamma agonist (Ro4389679-000-001 at 0.2 and 0.4 micromol/l) and a PPAR-gamma antagonist (SR202 at 0.2 and 0.4 mmol/l). Cells were incubated in 11 mmol/l glucose for 96 h and then challenged with 3.3, 7.5, 11.0, and 20.0 mmol/l glucose for 1 h. Under these control conditions, insulin concentrations in the medium rose from 19 +/- 4 ng/ml (mean +/- SE) to 82 +/- 5, 107 +/- 11, and 103 +/- 10 ng/ml (P <0.0001 by ANOVA). Preincubation for 48 h with the PPAR-gamma agonist potentiated GSIS (to 154 +/- 14 and 156 +/- 12 ng/ml at 20 mmol/l glucose, P <0.01). Cell insulin content was not altered by either acute glucose challenge or PPAR-gamma agonist coincubation. Preincubation for 48 h with SR202 at the higher dose caused a 30% inhibition of GSIS, with no change in cell insulin contents. When cells were preincubated with 11 mmol/l glucose plus 1 mmol/l oleate, GSIS was significantly potentiated (by 30%, P <0.0001); adding Ro4389679-000-001 or SR202 to these preincubations reduced GSIS to the respective levels seen in the absence of oleate (P <0.0001 for both effects). In conclusion, INS-1e cells display a PPAR-gamma tone that is symmetrically modulated and competitively stimulated by oleate.


Subject(s)
Glucose/pharmacology , Insulin/metabolism , Islets of Langerhans/metabolism , PPAR gamma/antagonists & inhibitors , PPAR gamma/physiology , Animals , Cell Line , Humans , Insulin Secretion , Islets of Langerhans/drug effects , Kinetics , Rats
3.
J Cardiovasc Pharmacol ; 40(6): 916-21, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12451325

ABSTRACT

Single-drug treatment of essential hypertension (HT) is often insufficient to normalize blood pressure (BP), and high doses of antihypertensive agents can have adverse effects on glucose tolerance (GT) and insulin sensitivity. This study tested whether aggressive BP lowering with combination treatment had any influence on GT or insulin action. In all, 29 nonobese (body mass index [BMI], <30 kg/m ), normolipidemic patients with established HT (159 +/- 3/99 +/- 1 mm Hg) but normal GT were recruited. Eleven normotensive (125 +/- 3/85 +/- 1 mm Hg) subjects were matched to the patients for both anthropometric and metabolic variables. Following baseline studies (serum lipid profile, oral GT, insulin release, and insulin sensitivity assessed by the insulin clamp technique), patients were randomized in a double-blind fashion to two combination regimens (verapamil 180 mg/day + trandolapril 2 mg/day or atenolol 50 mg/day + nifedipine 20 mg/day) and restudied 3 months later. Blood pressure was normalized in both groups (with decrements of 25 +/- 5/17 +/- 2 and 29 +/- 3/15 +/- 2 mm Hg, respectively). Lipid profile, GT, insulin release, and insulin sensitivity of both glucose uptake and lipolysis were unchanged following both treatments. The authors conclude that in nonobese, normolipidemic, glucose-tolerant hypertensive patients, BP normalization with combination therapy is feasible at no cost in terms of undesired effects on glucose and lipid metabolism and insulin sensitivity.


Subject(s)
Antihypertensive Agents/therapeutic use , Hemodynamics/drug effects , Hypertension/drug therapy , Antihypertensive Agents/administration & dosage , Atenolol/administration & dosage , Atenolol/pharmacology , Blood Glucose/drug effects , Cholesterol/blood , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Female , Glucose Tolerance Test , Humans , Indoles/administration & dosage , Indoles/pharmacology , Insulin/metabolism , Insulin Secretion , Male , Middle Aged , Nifedipine/administration & dosage , Nifedipine/pharmacology , Verapamil/administration & dosage , Verapamil/pharmacology
4.
Diabetes ; 51 Suppl 1: S130-3, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11815471

ABSTRACT

First-phase insulin response to intravenous glucose is impaired both in type 2 diabetic patients and in subjects at risk for the disease. Hyperglycemia can modify beta-cell response by either inhibiting or potentiating both first- and second-phase insulin release. In normal subjects, the effect of acute hyperglycemia on insulin secretion is controversial. We measured (in 13 healthy volunteers) insulin secretion (by deconvolution of plasma C-peptide concentrations) during three consecutive 30-min hyperglycemic steps (2.8, 2.8, and 5.6 mmol/l), followed by an intravenous arginine bolus. First-phase insulin secretion in response to the first hyperglycemic step (456 +/- 83 pmol.min(-1).m(-2)) was significantly larger than that in response to the second step (311 +/- 37 pmol.min(-1).m(-2), P < 0.01); the subsequent increase in glycemia failed to stimulate first-phase secretion any further (377 +/- 60 pmol.min(-1).m(-2), NS vs. the previous value). This inhibition was also evident when insulin release rates were corrected for the respective increments (absolute or percentage) in plasma glucose levels and was not due to beta-cell exhaustion because the arginine bolus still elicited a large peak of insulin secretion (4,790 +/- 2,330 pmol.min(-1).m(-2)). In contrast, second-phase insulin secretion was related to the prevailing glucose levels across the three hyperglycemic steps in a direct quasilinear manner. We conclude that first-phase insulin secretion is inhibited by short-term modest hyperglycemia, whereas the second-phase insulin secretion increases linearly with hyperglycemia.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Hyperglycemia/metabolism , Insulin/metabolism , Islets of Langerhans/metabolism , Acute Disease , Adult , Aged , Arginine/administration & dosage , C-Peptide/blood , Glucose/administration & dosage , Humans , Insulin/blood , Insulin Secretion , Middle Aged
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