indinavir-sulfate and Diabetes-Mellitus--Type-1

Pathologies in which insulin is dysregulated, including diabetes, can disrupt central vagal circuitry, leading to gastrointestinal and other autonomic dysfunction. Insulin affects whole body metabolism through central mechanisms and is transported into the brain stem dorsal motor nucleus of the vagus (DMV) and nucleus tractus solitarius (NTS), which mediate parasympathetic visceral regulation. The NTS receives viscerosensory vagal input and projects heavily to the DMV, which supplies parasympathetic vagal motor output. Normally, insulin inhibits synaptic excitation of DMV neurons, with no effect on synaptic inhibition. Modulation of synaptic inhibition in DMV, however, is often sensitive to cAMP-dependent mechanisms. We hypothesized that an effect of insulin on GABAergic synaptic transmission may be uncovered by elevating resting cAMP levels in GABAergic terminals. We used whole cell patch-clamp recordings in brain stem slices from control and diabetic mice to identify insulin effects on inhibitory neurotransmission in the DMV in the presence of forskolin to elevate cAMP levels. In the presence of forskolin, insulin decreased the frequency of inhibitory postsynaptic currents (IPSCs) and the paired-pulse ratio of evoked IPSCs in DMV neurons from control mice. This effect was blocked by brefeldin-A, a Golgi-disrupting agent, or indinavir, a GLUT4 blocker, indicating that protein trafficking and glucose transport were involved. In streptozotocin-treated, diabetic mice, insulin did not affect IPSCs in DMV neurons in the presence of forskolin. Results suggest an impairment of cAMP-induced insulin effects on GABA release in the DMV, which likely involves disrupted protein trafficking in diabetic mice. These findings provide insight into mechanisms underlying vagal dysregulation associated with diabetes.

Topics: Animals; Brain Stem; Brefeldin A; Colforsin; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Electric Stimulation; Female; gamma-Aminobutyric Acid; Glucose Transporter Type 4; Golgi Apparatus; Indinavir; Inhibitory Postsynaptic Potentials; Insulin; Male; Mice; Neural Inhibition; Protein Transport; Synaptic Transmission; Vagus Nerve

Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy.. To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI-associated diabetes.. Cross-sectional evaluation.. 8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir.. Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 microM) on rat pancreatic beta-cell function in vitro.. In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat beta-cells.. The pathogenesis of HIV PI-associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic beta-cell function was not impaired by indinavir. HIV PI-associated diabetes mirrors that of non-insulin-dependent diabetes mellitus and impaired insulin action in the periphery.

Topics: Adult; Animals; Anti-HIV Agents; C-Peptide; Cells, Cultured; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Glucagon; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Insulin; Insulin Resistance; Islets of Langerhans; Male; Phospholipases A; Proinsulin; Rats; Rats, Sprague-Dawley