Differing physiological effects of epinephrine in type 1 diabetes and nondiabetic humans

Guy, Deanna Aftab; Sandoval, Darleen A.; Richardson, M. Antoinette; Tate, Donna B.; Flakoll, Paul J.

doi:10.1152/ajpendo.00310.2004

Cited by 19 publications

(15 citation statements)

References 48 publications

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“…Our data demonstrated that patients with T1DM have decreased neuroendocrine (glucagon and norepinephrine), metabolic [endogenous glucose production (EGP), glucose uptake (R d ), and glucose oxidation], cardiovascular (mean arterial pressure), and symptomatic responses but increased lipolytic responses to moderately elevated physiological levels of epinephrine compared with nondiabetic subjects (2).…”

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confidence: 71%

“…Previously, we (2) have investigated the integrated physiological effects of epinephrine independently of the confounding variable of hyperglycemia in a group of T1DM with average control and healthy nondiabetic subjects. Our data demonstrated that patients with T1DM have decreased neuroendocrine (glucagon and norepinephrine), metabolic [endogenous glucose production (EGP), glucose uptake (R d ), and glucose oxidation], cardiovascular (mean arterial pressure), and symptomatic responses but increased lipolytic responses to moderately elevated physiological levels of epinephrine compared with nondiabetic subjects (2).…”

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confidence: 99%

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Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes

Guy¹,

Sandoval²,

Richardson³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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Severe hypoglycemia occurs in intensively treated patients with type 1 diabetes mellitus (T1DM) due in part to deficient epinephrine counterregulatory responses. Previously, we have found that T1DM patients demonstrated a spectrum of altered responses to epinephrine at a variety of target organs compared with nondiabetic healthy subjects. What is not known is whether intensive glycemic control further modifies target organ responses in individuals with T1DM. Therefore, the aim of this study is to assess whether there is tissue specific (liver, muscle, adipose tissue, pancreas and cardiovascular) resistance to epinephrine in intensively controlled (IC) T1DM compared with those with conventional control (CC). Eight IC patients (age 33 ± 4 yr, BMI 24 ± 2 kg/m2, Hb A1C6.7 ± 0.1%), and 11 CC patients (age 35 ± 3 yr, BMI 25 ± 1 kg/m2, Hb A1C9.6 ± 0.1%) underwent two separate randomized, single-blind, 2-h hyperinsulinemic euglycemic clamp studies with (EPI) and without (NO EPI) epinephrine infusion. Epinephrine levels during EPI were similar in all groups (5,197 ± 344 pmol/l). Glucose (5.3 ± 0.1 mmol/l) and insulin levels (515 ± 44 pmol/l) were similar in all groups during the glucose clamps. Endogenous glucose production (EGP) and glucose uptake (Rd) were determined using [3-H3]glucose. Muscle biopsy was performed at the end of each study. IC had a significantly reduced EGP and Rdresponses to EPI compared with CC. Glucagon responses to EPI were similarly blunted in both IC and CC. Free fatty acid and glycerol response to EPI was greater in CC compared with IC. There was a significantly greater systolic blood pressure response to EPI in CC. We conclude that, despite similar epinephrine, insulin, and glucose levels, intensively treated T1DM patients had reduced cardiovascular, skeletal muscle, hepatic, and adipose target organ responses to EPI compared with conventionally treated T1DM patients.

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confidence: 71%

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confidence: 99%

Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes

Guy¹,

Sandoval²,

Richardson³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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“…Although evidence of hepatic resistance to the effects of counterregulatory hormones is not strong, a recent report suggests attenuation of the effects of infused epinephrine on EGP in poorly controlled type 1 diabetes (32). In contrast to these findings, Berk et al (33) demonstrated enhanced glycemic responsiveness to epinephrine in type 1 diabetic subjects compared with nondiabetic subjects.…”

Section: Discussionmentioning

confidence: 97%

Role of Hepatic Glycogen Breakdown in Defective Counterregulation of Hypoglycemia in Intensively Treated Type 1 Diabetes

et al. 2006

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Impairment of hypoglycemic counterregulation in intensively treated type 1 diabetes has been attributed to deficits in counterregulatory hormone secretion. However, because the liver plays a critical part in recovery of plasma glucose, abnormalities in hepatic glycogen metabolism per se could also play an important role. We quantified the contribution of net hepatic glycogenolysis during insulininduced hypoglycemia in 10 nondiabetic subjects and 7 type 1 diabetic subjects (HbA 1c 6.5 ؎ 0.2%) using 13 C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma glucose 92 ؎ 4 mg/dl) or hypoglycemia (plasma glucose 58 ؎ 3 mg/dl). In nondiabetic subjects, hypoglycemia was associated with a brisk counterregulatory hormone response (plasma epinephrine 246 ؎ 38 vs. 2,785 ؎ 601 pmol/l during hypoglycemia, plasma norepinephrine 1.9 ؎ 0.2 vs. 2.5 ؎ 0.3 nmol/l, and glucagon 38 ؎ 7 vs. 92 ؎ 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous glucose production (EGP 0.83 ؎ 0.14 mg ⅐ kg ؊1 ⅐ min ؊1 during euglycemia yet ϳ50% higher with hypoglycemia [1.30 ؎ 0.20 mg ⅐ kg ؊1 ⅐ min ؊1 ], P < 0.001). Net hepatic glycogen content declined progressively during hypoglycemia to 22 ؎ 3% below baseline (P < 0.024). By the final 30 min of hypoglycemia, hepatic glycogen fell from 301 ؎ 14 to 234 ؎ 10 mmol/l (P < 0.001) and accounted for ϳ100% of EGP. In marked contrast, after an overnight fast, hepatic glycogen concentration in type 1 diabetic subjects (215 ؎ 23 mmol/l) was significantly lower than in nondiabetic subjects (316 ؎ 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to hypoglycemia was significantly reduced with small increments in plasma epinephrine and norepinephrine (126 ؎ 22 vs. 448 ؎ 16 pmol/l in hypoglycemia and 0.9 ؎ 0.3 vs. 1.6 ؎ 0.3 nmol/l, respectively, P < 0.05 for both) and no increase in plasma glucagon. EGP decreased during hypoglycemia with no recovery (1.3 ؎ 0.5 vs.

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“…Rates of glucose uptake were unchanged during the series of hypoglycemic clamps. Previous studies have demonstrated that the doseresponse effects of epinephrine to inhibit glucose uptake are relatively flat (33,34) in association with increasing the concentrations of the catecholamines from 600 to 1,000 pg/ml, producing limited actions. Similar to the findings in healthy humans, fluoxetine resulted in an increased response of cortisol during hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Counterregulatory Responses to Hypoglycemia in Individuals With Type 1 Diabetes

et al. 2008

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OBJECTIVE-Previous work has demonstrated that chronic administration of the serotonin reuptake inhibitor (SSRI) fluoxetine augments counterregulatory responses to hypoglycemia in healthy humans. However, virtually no information exists regarding the effects of fluoxetine on integrated physiological counterregulatory responses during hypoglycemia in type 1 diabetes. Therefore, the specific aim of this study was to test the hypothesis that 6-week use of the SSRI fluoxetine would amplify autonomic nervous system (ANS) counterregulatory responses to hypoglycemia in individuals with type 1 diabetes. )-hypoglycemic clamp studies before and after 6 weeks of fluoxetine administration (n ϭ 8) or identical placebo (n ϭ 10). Glucose kinetics was determined by 3-tritiated glucose. Muscle sympathetic nerve activity (MSNA) was determined by microneurography. RESEARCH DESIGN AND METHODS-EighteenRESULTS-Hypoglycemia (2.8 Ϯ 0.1 mmol/l) and insulinemia (646 Ϯ 52 pmol/l) were similar during all clamp studies. ANS, neuroendocrine, and metabolic counterregulatory responses remained unchanged in the placebo group. However, fluoxetine administration significantly (P Ͻ 0.05) increased key ANS (epinephrine, norepinephrine, and MSNA), metabolic (endogenous glucose production and lipolysis), and cardiovascular (systolic blood pressure) counterregulatory responses during hypoglycemia.CONCLUSIONS-This study has demonstrated that 6-week administration of the SSRI fluoxetine can amplify ANS and metabolic counterregulatory mechanisms during moderate hypoglycemia in patients with type 1 diabetes. These data also suggest that the use of fluoxetine may be useful in increasing epinephrine responses during hypoglycemia in clinical practice. Diabetes 57:3315-3322, 2008 S elective serotonin reuptake inhibitors (SSRIs) are effective drugs for the treatment of depressive disorders associated with reduced serotonergic function. Serotonergic neurons play an important role in the regulation of neuroendocrine function carried out via both sympathoadrenal and hypothalamic-pituitaryadrenal (HPA) pathways.Two studies have reported increased hypoglycemia and loss of awareness to hypoglycemia related to the use of SSRIs in depressed patients with type 1 diabetes (1,2). Although SSRIs are potent inhibitors of neuronal serotonin uptake, they also have the ability to block norepinephrine transport (3,4). This would be predicted to increase sympathetic outflow activity (4 -7). Supporting this, previous studies by a number of investigators have demonstrated that SSRIs can modulate sympathetic nervous system activity and increase counterregulation in rats (8).Two recent studies in healthy humans (9) and conscious rats (10) have provided further insight into the effects of SSRIs on counterregulatory physiology during hypoglycemia. Briscoe et al. (9) investigated the effects of 6 weeks of high-dose fluoxetine administration on physiological responses to hypoglycemia in a group of healthy, nondepressed humans. Key sympathetic nervous system (epinephrine, norepinephrine,...

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Differing physiological effects of epinephrine in type 1 diabetes and nondiabetic humans

Cited by 19 publications

References 48 publications

Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes

Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes

Role of Hepatic Glycogen Breakdown in Defective Counterregulation of Hypoglycemia in Intensively Treated Type 1 Diabetes

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Counterregulatory Responses to Hypoglycemia in Individuals With Type 1 Diabetes

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