Interaction of a selective serotonin reuptake inhibitor with insulin in the control of hepatic glucose uptake in conscious dogs

Abstract

Whether hyperinsulinemia is required for stimulation of net hepatic glucose uptake (NHGU) by a selective serotonin reuptake inhibitor (SSRI) was examined in four groups of conscious 42-h-fasted dogs, using arteriovenous difference and tracer ([3-3 H]glucose) techniques. Experiments consisted of equilibration (Ϫ120 to Ϫ30 min), basal (Ϫ30 to 0 min), and experimental periods (Exp; 0 -240 min). During Exp, somatostatin, intraportal insulin [at basal (Ins groups) or 4-fold basal rates (INS groups)], basal intraportal glucagon, and peripheral glucose (to double hepatic glucose load) were infused. In the Fluv-Ins (n ϭ 7) and Fluv-INS groups (n ϭ 6), saline was infused intraportally from 0 to 90 min (P1), and fluvoxamine was infused intraportally at 2 g ⅐ kg Ϫ1 ⅐ min Ϫ1 from 90 to 240 min (P2). Sal-Ins (n ϭ 9) and Sal-INS (n ϭ 8) received intraportal saline in P1 and P2. NHGU during P2 was 8.4 Ϯ 1.4 and 6.9 Ϯ 2.3 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 in Sal-Ins and Fluv-Ins, respectively (not significant), and 13.3 Ϯ 2.2 and 20.9 Ϯ 3.1 mol ⅐ kg (20) enhanced net hepatic glucose uptake (NHGU) in conscious dogs during a hyperinsulinemic hyperglycemic clamp. Although the exact mechanism for this action is unclear, it suggests that SSRIs or 5-HT agonists might provide a tool for reducing postprandial glycemia in individuals with diabetes. This raises the question of whether SSRI treatment would be effective in the presence of a relative deficiency of insulin. Therefore, we examined NHGU and total body glucose disposal (R d ) in conscious dogs during intraportal infusion of fluvoxamine under conditions of hyperglycemia and either euinsulinemia or hyperinsulinemia. Fluvoxamine was effective in bringing about a significant enhancement of NHGU and hepatic carbon storage in the presence of hyperinsulinemia but not euinsulinemia. RESEARCH DESIGN AND METHODSAnimals and surgical procedures. Studies were carried out on conscious 42-h-fasted mongrel dogs of either sex with a mean weight of 22.8 Ϯ 0.4 kg. Diet and housing were as previously described (29), and the protocol was approved by the Vanderbilt University Institutional Animal Care and Use Committee. The 42-h fast is well tolerated by the dog, which exhibits little change in blood glucose (⌬ 0.2-0.3 mM) and only a 10% increase in plasma glucagon between 18 and 42 h of fasting (24). However, it reduces the hepatic glycogen to a stable concentration, which decreases the variability of NHGU in response to hyperglycemia and hyperinsulinemia. The dog, as well as the human, exhibits marked variability in hepatic glycogen content during a fast shorter than 40 h (8,32).Approximately 16 days before study, each dog underwent a laparotomy for placement of ultrasonic flow probes (Transonic Systems, Ithaca, NY) around the portal vein and the hepatic artery, as well as for insertion of silicone rubber catheters for sampling in a hepatic vein, the portal vein, and a femoral artery and for infusion into a splenic and a jejunal vein, as described in detail elsewhere (25,29). Criteria for inclusion in the stu...

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

“…Studies were carried out in conscious 42-h-fasted dogs of either sex (20 -23 kg). This length of fast in the canine does not induce hypoglycemia, raise the plasma levels of stress hormones, or exhaust liver glycogen (38,39). In addition, after a 42-h fast approximately two-thirds of hepatic glucose production is accounted for by gluconeogenic flux (48), comparable with overnight-fasted humans.…”

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

“…Physiological studies by Moore and colleagues demonstrated increased hepatic glucose uptake after intraportal infusion of 5-HT or selective 5-HT uptake inhibitors [12][13][14][15]. This raised the question whether these effects are mediated by a direct effect of 5-HT on hepatocytes or by indirect mechanisms involving haemodynamic changes or altered transmission of afferent signals.…”

“…For the determination of phosphorylase a, the cells were extracted as described by Aiston et al [23] and phosphorylase a was assayed spectrometrically in the 13,000 g supernatant [15]; activity is expressed as mU/mg protein. For determination of glycogen synthase, cells were extracted and enzyme activity was determined radiochemically from the incorporation of UDP-[6-3 H]-glucose, as described by Aiston et al [23].…”

“…However, in the liver, intraportal infusion of 5-HT or its precursor, 5-hydroxytryptophan, stimulated glucose uptake during a hyperinsulinaemic clamp [12,13]. Stimulation of hepatic glucose uptake with concomitant glycogen storage also occurred during infusion of a selective 5-HT reuptake inhibitor during a hyperinsulinaemic clamp but not during euinsulinaemic clamps [14,15]. This could be due to a direct effect of 5-HT on hepatocytes or to indirect mechanisms involving either haemodynamic changes or decreased afferent signalling.…”

Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog

“…Experiments were conducted on twenty-one 42-h-fasted conscious mongrel dogs of either sex (18 -25 kg). This length of fast does not induce hypoglycemia, raise the plasma levels of stress hormones, or exhaust liver glycogen in the dog (42,43). Housing and diet have been described previously (21).…”