Abstract
BackgroundA distinctive feature of type 2 diabetes is inability of insulin-secreting β-cells to properly respond to elevated glucose eventually leading to β-cell failure. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of β-cell dysfunction.Principal FindingsWe show now that islets of type 2 spontaneous diabetes in GK rats display excessive NO generation associated with abnormal iNOS expression in insulin and glucagon cells, increased ncNOS activity, impaired glucose-stimulated insulin release, glucagon hypersecretion, and impaired glucose-induced glucagon suppression. Pharmacological blockade of islet NO production by the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) greatly improved hormone secretion from GK islets suggesting islet NOS activity being an important target to inactivate for amelioration of islet cell function. The incretin hormone GLP-1, which is used in clinical practice suppressed iNOS and ncNOS expression and activity with almost full restoration of insulin release and partial restoration of glucagon release. GLP-1 suppression of iNOS expression was reversed by PKA inhibition but unaffected by the proteasome inhibitor MG132. Injection of glucose plus GLP-1 in the diabetic rats showed that GLP-1 amplified the insulin response but induced a transient increase and then a poor depression of glucagon.ConclusionThe results suggest that abnormally increased NO production within islet cells is a significant player in the pathogenesis of type 2 diabetes being counteracted by GLP-1 through PKA-dependent, nonproteasomal mechanisms.
Highlights
Diabetes type 2 is a global health problem, characterized of both insulin resistance and impaired insulin response to glucose, defects that are regarded multifactorial in origin and are considered a result of both environmental and undefined genetic factors
The results suggest that abnormally increased nitric oxide (NO) production within islet cells is a significant player in the pathogenesis of type 2 diabetes being counteracted by glucagon-like peptide-1 (GLP-1) through PKA-dependent, nonproteasomal mechanisms
Previous studies have suggested that high amounts of NO derived from inducible NOS (iNOS) activity are cytotoxic and implicated in the autoimmunemediated dysfunction and destruction of islet b-cells during development of type 1 diabetes [25]
Summary
Diabetes type 2 is a global health problem, characterized of both insulin resistance and impaired insulin response to glucose, defects that are regarded multifactorial in origin and are considered a result of both environmental and undefined genetic factors. We have shown [1,2,3,4,5,6,7,8] that islet nitric oxide (NO) derived from neuronal constitutive NO synthase (ncNOS) is a strong negative modulator of glucose-stimulated insulin release This enzyme resides abundantly in b-cells [9]. In healthy animals, that exposure of islets to high concentrations of glucose or lipids induces expression and strong activity of inducible NOS (iNOS) in their b-cells concomitant with reduced insulin response to glucose [2,3,7,11]. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of b-cell dysfunction
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