Stephanie Wiesenthal | University of Toronto (original) (raw)
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Papers by Stephanie Wiesenthal
Diabetes, 1999
Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impai... more Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether F FAs impair hepatic insulin extraction (E H ) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml · kg -1 · m i n -1 ) plus heparin (0.44 U · kg -1 · min -1 ) (IH) was infused into normal dogs to elevate FFA levels. Insulin was infused intraportally at 18 pmol · kg -1 · min -1 for 150 min (period A, high insulin dose), and then at 2.4 pmol · kg -1 · min -1 for another 150 min (period B, low insulin dose). After the low portal insulin dose, additional insulin was infused peripherally at 8.4 pmol · k g -1 · min -1 for 120 min (period C) to assess the clearance of insulin from the peripheral plasma. In 16 paired experiments, FFA levels were 1,085 ± 167, 1,491 ± 240, 1,159 ± 221 µmol/l (IH) and 221 ± 44, 329 ± 72, 176 ± 44 µmol/l (SAL) in periods A, B, and C, respectively. Peripheral insulin levels were greater with IH (P < 0.001) than with SAL in all periods (1,620 ± 114, 126 ± 12, 1,050 ± 72 pmol/l for IH vs. 1,344 ± 168, 96 ± 4.2, 882 ± 60 pmol/l for SAL). Glucose clearance was impaired by IH in all periods (P < 0.05), whereas glucose production was slightly increased by IH during period B. Peripheral insulin clearance (Cl) and E H were calculated from the insulin infusion rate and insulin concentration data in each period by taking into account the nonlinearity of insulin kinetics. Cl was lower (P < 0.01) with IH (9.6 ± 0.6, 12.0 ± 0.9, 10.2 ± 0.6 ml · kg -1 · min -1 ) than with SAL (11.2 ± 1, 13.6 ± 0.7, 11.9 ± 0.9 ml · kg -1 · min -1 ) in periods A, B, and C. E H was also lower (P < 0.05) with IH (25 ± 4, 40 ± 5, 32 ± 5%) than with SAL (30 ± 2.8, 47 ± 3, 38 ± 3%). We conclude that FFAs can impair hepatic insulin extraction in vivo at high and low insulin levels, an effect that may contribute to the peripheral hyperinsulinemia of obesity. Diabetes 48:766-774, 1999
Diabetes, 1999
To determine whether glucagon-like peptide (GLP)-1 increases insulin sensitivity in addition to s... more To determine whether glucagon-like peptide (GLP)-1 increases insulin sensitivity in addition to stimulating insulin secretion, we studied totally depancreatized dogs to eliminate GLP-1's incretin effect. Somatostatin was infused (0.8 µg · kg -1 · min -1 ) to inhibit extrapancreatic glucagon in dogs, and basal glucagon was restored by intraportal infusion (0.65 ng · kg -1 · min -1 ) . To simulate the residual intraportal insulin secretion in type 2 diabetes, basal intraportal insulin infusion was given to obtain plasma glucose concentrations of ~10 mmol/l. Glucose was clamped at this level for the remainder of the experiment, which included peripheral insulin infusion (high dose, 5.4 pmol · kg -1 · min -1 , or low dose, 0.75 pmol · kg -1 · min -1 ) with or without GLP-1(7-36) amide (1.5 pmol · kg -1 · min -1 ). Glucose production and utilization were measured with 3-[ 3 H]glucose, using radiolabeled glucose infusates. In 12 paired experiments with six dogs at the high insulin dose, GLP-1 infusion resulted in higher glucose requirements than saline (60.9 ± 11.0 vs. 43.6 ± 8.3 µmol · kg -1 · min -1 , P < 0.001), because of greater glucose utilization (72.6 ± 11.0 vs. 56.8 ± 9.7 µmol · kg -1 · min -1 , P < 0.001), whereas the suppression of glucose production was not a ffected by GLP-1. Free fatty acids (FFAs) were significantly lower with GLP-1 than saline (375.3 ± 103.0 vs. 524.4 ± 101.1 µmol/l, P < 0.01), as was glycerol (77.9 ± 17.5 vs. 125.6 ± 51.8 µmol/l, P < 0.05). GLP-1 receptor gene expression was found using reverse transcriptase-polymerase chain reaction of poly(A)-selected RNA in muscle and adipose tissue, but not in liver. Low levels of GLP-1 receptor gene expression were also found in adipose tissue using Northern blotting. In 10 paired experiments with five dogs at the low insulin dose, GLP-1 infusion did not affect glucose utilization or FFA and glycerol suppression when compared with saline, suggesting that GLP-1's effect on insulin action was dependent on the insulin dose. In conclusion, in depancreatized dogs, GLP-1 potentiates insulin-stimulated glucose utilization, an effect that might be contributed in part by GLP-1 potentiation of insulin's antilipolytic action. D i a b e t e s 48:. S.E. is a member on advisory boards for Eli Lilly and the Nordic Research Foundation, has served as a consultant to Eli Lilly, and has received grants from Eli Lilly, Novo Nordisk, and Hoechst Marion Roussel.
Biochemical and Biophysical Research Communications, 2006
We have previously shown that free fatty acids (FFA) impair hepatic insulin extraction in vivo an... more We have previously shown that free fatty acids (FFA) impair hepatic insulin extraction in vivo and thus generate hyperinsulinemia, a suspected risk factor for atherosclerosis and cancer. Hepatic insulin extraction is a receptor-mediated event, which is initiated by hepatocyte insulin binding. In the present study, we investigated the effect of FFA on insulin binding in freshly isolated rat hepatocytes maintained at 10 mM glucose. Hepatocyte insulin binding decreased after 1 h exposure to oleate in a concentration-dependent manner reaching a maximum (35-40%) at 125 lM. Inhibition of FFA oxidation by >90% with the carnitine palmitoyltransferase I (CPT-I) inhibitor methylpalmoxirate (MP, 30 lM) did not prevent the effect of oleate. However, when hepatocytes were treated with the PKC inhibitor bisindolylmaleimide (BIM, 1 lM) the effect of oleate was abolished. Subcellular fractionation and immunoblotting of specific PKC isoforms revealed that oleate-induced hepatic PKC-d membrane translocation, but did not translocate-e, -h, -a, -bI and -bII. These results indicate that PKC-d activation mediated the FFA-induced decrease in hepatocyte insulin binding under our conditions, and thus provides a mechanistic basis for FFA-induced hyperinsulinemia.
Academic Psychiatry, 2006
Objective: To examine the influence of initial interest, pre-clerkship experiences, clerkship exp... more Objective: To examine the influence of initial interest, pre-clerkship experiences, clerkship experiences, and enrichment activities on choosing a career in psychiatry.
Diabetes, 1999
Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impai... more Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether F FAs impair hepatic insulin extraction (E H ) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml · kg -1 · m i n -1 ) plus heparin (0.44 U · kg -1 · min -1 ) (IH) was infused into normal dogs to elevate FFA levels. Insulin was infused intraportally at 18 pmol · kg -1 · min -1 for 150 min (period A, high insulin dose), and then at 2.4 pmol · kg -1 · min -1 for another 150 min (period B, low insulin dose). After the low portal insulin dose, additional insulin was infused peripherally at 8.4 pmol · k g -1 · min -1 for 120 min (period C) to assess the clearance of insulin from the peripheral plasma. In 16 paired experiments, FFA levels were 1,085 ± 167, 1,491 ± 240, 1,159 ± 221 µmol/l (IH) and 221 ± 44, 329 ± 72, 176 ± 44 µmol/l (SAL) in periods A, B, and C, respectively. Peripheral insulin levels were greater with IH (P < 0.001) than with SAL in all periods (1,620 ± 114, 126 ± 12, 1,050 ± 72 pmol/l for IH vs. 1,344 ± 168, 96 ± 4.2, 882 ± 60 pmol/l for SAL). Glucose clearance was impaired by IH in all periods (P < 0.05), whereas glucose production was slightly increased by IH during period B. Peripheral insulin clearance (Cl) and E H were calculated from the insulin infusion rate and insulin concentration data in each period by taking into account the nonlinearity of insulin kinetics. Cl was lower (P < 0.01) with IH (9.6 ± 0.6, 12.0 ± 0.9, 10.2 ± 0.6 ml · kg -1 · min -1 ) than with SAL (11.2 ± 1, 13.6 ± 0.7, 11.9 ± 0.9 ml · kg -1 · min -1 ) in periods A, B, and C. E H was also lower (P < 0.05) with IH (25 ± 4, 40 ± 5, 32 ± 5%) than with SAL (30 ± 2.8, 47 ± 3, 38 ± 3%). We conclude that FFAs can impair hepatic insulin extraction in vivo at high and low insulin levels, an effect that may contribute to the peripheral hyperinsulinemia of obesity. Diabetes 48:766-774, 1999
Diabetes, 1999
To determine whether glucagon-like peptide (GLP)-1 increases insulin sensitivity in addition to s... more To determine whether glucagon-like peptide (GLP)-1 increases insulin sensitivity in addition to stimulating insulin secretion, we studied totally depancreatized dogs to eliminate GLP-1's incretin effect. Somatostatin was infused (0.8 µg · kg -1 · min -1 ) to inhibit extrapancreatic glucagon in dogs, and basal glucagon was restored by intraportal infusion (0.65 ng · kg -1 · min -1 ) . To simulate the residual intraportal insulin secretion in type 2 diabetes, basal intraportal insulin infusion was given to obtain plasma glucose concentrations of ~10 mmol/l. Glucose was clamped at this level for the remainder of the experiment, which included peripheral insulin infusion (high dose, 5.4 pmol · kg -1 · min -1 , or low dose, 0.75 pmol · kg -1 · min -1 ) with or without GLP-1(7-36) amide (1.5 pmol · kg -1 · min -1 ). Glucose production and utilization were measured with 3-[ 3 H]glucose, using radiolabeled glucose infusates. In 12 paired experiments with six dogs at the high insulin dose, GLP-1 infusion resulted in higher glucose requirements than saline (60.9 ± 11.0 vs. 43.6 ± 8.3 µmol · kg -1 · min -1 , P < 0.001), because of greater glucose utilization (72.6 ± 11.0 vs. 56.8 ± 9.7 µmol · kg -1 · min -1 , P < 0.001), whereas the suppression of glucose production was not a ffected by GLP-1. Free fatty acids (FFAs) were significantly lower with GLP-1 than saline (375.3 ± 103.0 vs. 524.4 ± 101.1 µmol/l, P < 0.01), as was glycerol (77.9 ± 17.5 vs. 125.6 ± 51.8 µmol/l, P < 0.05). GLP-1 receptor gene expression was found using reverse transcriptase-polymerase chain reaction of poly(A)-selected RNA in muscle and adipose tissue, but not in liver. Low levels of GLP-1 receptor gene expression were also found in adipose tissue using Northern blotting. In 10 paired experiments with five dogs at the low insulin dose, GLP-1 infusion did not affect glucose utilization or FFA and glycerol suppression when compared with saline, suggesting that GLP-1's effect on insulin action was dependent on the insulin dose. In conclusion, in depancreatized dogs, GLP-1 potentiates insulin-stimulated glucose utilization, an effect that might be contributed in part by GLP-1 potentiation of insulin's antilipolytic action. D i a b e t e s 48:. S.E. is a member on advisory boards for Eli Lilly and the Nordic Research Foundation, has served as a consultant to Eli Lilly, and has received grants from Eli Lilly, Novo Nordisk, and Hoechst Marion Roussel.
Biochemical and Biophysical Research Communications, 2006
We have previously shown that free fatty acids (FFA) impair hepatic insulin extraction in vivo an... more We have previously shown that free fatty acids (FFA) impair hepatic insulin extraction in vivo and thus generate hyperinsulinemia, a suspected risk factor for atherosclerosis and cancer. Hepatic insulin extraction is a receptor-mediated event, which is initiated by hepatocyte insulin binding. In the present study, we investigated the effect of FFA on insulin binding in freshly isolated rat hepatocytes maintained at 10 mM glucose. Hepatocyte insulin binding decreased after 1 h exposure to oleate in a concentration-dependent manner reaching a maximum (35-40%) at 125 lM. Inhibition of FFA oxidation by >90% with the carnitine palmitoyltransferase I (CPT-I) inhibitor methylpalmoxirate (MP, 30 lM) did not prevent the effect of oleate. However, when hepatocytes were treated with the PKC inhibitor bisindolylmaleimide (BIM, 1 lM) the effect of oleate was abolished. Subcellular fractionation and immunoblotting of specific PKC isoforms revealed that oleate-induced hepatic PKC-d membrane translocation, but did not translocate-e, -h, -a, -bI and -bII. These results indicate that PKC-d activation mediated the FFA-induced decrease in hepatocyte insulin binding under our conditions, and thus provides a mechanistic basis for FFA-induced hyperinsulinemia.
Academic Psychiatry, 2006
Objective: To examine the influence of initial interest, pre-clerkship experiences, clerkship exp... more Objective: To examine the influence of initial interest, pre-clerkship experiences, clerkship experiences, and enrichment activities on choosing a career in psychiatry.