The pancreatic islet beta-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mellitus (IDDM) has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). Pancreatic beta cells and a subpopulation of central nervous system neurons express high levels of this enzyme. Autoantibodies against glutamic acid decarboxylase with a higher titre and increased epitope recognition compared with those usually associated with IDDM are found in stiff-man syndrome, a rare neurological disorder characterized by a high coincidence with IDDM.

Diabetes mellitus is associated to an increased risk of cardiovascular diseases. Hyperglycemia is an important factor in cardiovascular damage, working through different mechanisms such as activation of protein kinase C, polyol and hexosamine pathways, advanced glycation end products production. All of these pathways, in association to hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress, promote reactive oxygen species (ROS) accumulation that, in turn, promote cellular damage and contribute to the diabetic complications development and progression. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression and, therefore, irreversible oxidative modifications. Hyperglycemia-induced oxidative stress induces endothelial dysfunction that plays a central role in the pathogenesis of micro- and macro-vascular diseases. It may also increase pro-inflammatory and pro-coagulant factors expression, induce apoptosis and impair nitric oxide release. Oxidative stress induces several phenotypic alterations also in vascular smooth-muscle cell (VSMC). ROS is one of the factors that can promote both VSMC proliferation/migration in atherosclerotic lesions and VSMC apoptosis, which is potentially involved in atherosclerotic plaque instability and rupture. Currently, there are contrasting clinical evidences on the benefits of antioxidant therapies in the prevention/treatment of diabetic cardiovascular complications. Appropriate glycemic control, in which both hypoglycemic and hyperglycemic episodes are reduced, in association to the treatment of dyslipidemia, hypertension, kidney dysfunction and obesity, conditions which are also associated to ROS overproduction, can counteract oxidative stress and, therefore, both microvascular and macrovascular complications of diabetes mellitus.

Stiff-man syndrome is a rare disorder of the central nervous system of unknown pathogenesis. We have previously reported the presence of autoantibodies against glutamic acid decarboxylase (GAD) in a patient with stiff-man syndrome, epilepsy, and insulin-dependent diabetes mellitus. GAD is an enzyme selectively concentrated in neurons secreting the neurotransmitter gamma-aminobutyric acid (GABA) and in pancreatic beta cells. We subsequently observed autoantibodies to GABA-ergic neurons in 20 of 33 patients with stiff-man syndrome. GAD was the principal autoantigen. In the group of patients positive for autoantibodies against GABA-ergic neurons, there was a striking association with organ-specific autoimmune diseases, primarily insulin-dependent diabetes mellitus. These findings support the hypothesis that stiff-man syndrome is an autoimmune disease and suggest that GAD is the primary autoantigen involved in stiff-man syndrome and the associated insulin-dependent diabetes mellitus. Our findings also indicate that autoantibodies directed against GABA-ergic neurons are a useful marker in the diagnosis of the disease.

GABA, a major inhibitory neurotransmitter of the brain, is also present at high concentration in pancreatic islets. Current evidence suggests that within islets GABA is secreted from beta‐cells and regulates the function of mantle cells (alpha‐ and delta‐cells). In the nervous system GABA is stored in, and secreted from, synaptic vesicles. The mechanism of GABA secretion from beta‐cells remains to be elucidated. Recently the existence of synaptic‐like microvesicles has been demonstrated in some peptide‐secreting endocrine cells. The function of these vesicles is so far unknown. The proposed paracrine action of GABA in pancreatic islets makes beta‐cells a useful model system to explore the possibility that synaptic‐like microvesicles, like synaptic vesicles, are involved in the storage and release of non‐peptide neurotransmitters. We report here the presence of synaptic‐like microvesicles in beta‐cells and in beta‐cells. Some beta‐cells in culture were found to extend neurite‐like processes. When these were present, synaptic‐like microvesicles were particularly concentrated in their distal portions. The GABA synthesizing enzyme, glutamic acid decarboxylase (GAD), was found to be localized around synaptic‐like microvesicles. This was similar to the localization of GAD around synaptic vesicles in GABA‐secreting neurons. GABA immunoreactivity was found to be concentrated in regions of beta‐cells which were enriched in synaptic‐like microvesicles. These findings suggest that in beta‐cells synaptic‐like microvesicles are storage organelles for GABA and support the hypothesis that storage of non‐peptide signal molecules destined for secretion might be a general feature of synaptic‐like microvesicles of endocrine cells.