Melvin K. Dea

Université de Montréal

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Richard N. Bergman

Cedars-Sinai Medical Center

Marianthe Hamilton-Wessler

University of Southern California

Steven D. Mittelman

Mattel Children's Hospital

Marilyn Ader

Cedars-Sinai Medical Center

G. W. van Citters

University of Southern California

Stella P. Kim

Cedars-Sinai Medical Center

Stephan Quessy

Université de Montréal

Numa Dancause

Université de Montréal

Jan Markussen

Novo Nordisk (Denmark)

Donna Moore

University of Pittsburgh

Cooperative Institutions

University of Southern California

McGill University

Cedars-Sinai Medical Center

Université de Montréal

Novo Nordisk (Denmark)

Montreal Neurological Institute and Hospital

National Institutes of Health

Keck Hospital of USC

Canadian Institutes of Health Research

University of California, San Francisco

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Different Patterns of Cortical Inputs to Subregions of the Primary Motor Cortex Hand Representation inCebus apella

Cerebral Cortex (2016)

Melvin K. Dea Adjia Hamadjida Guillaume Elgbeili Stephan Quessy Numa Dancause

The primary motor cortex (M1) plays an essential role in the control of hand movements in primates and is part of a complex cortical sensorimotor network involving multiple premotor and parietal areas. In a previous study in squirrel monkeys, we found that the ventral premotor cortex (PMv) projected mainly to 3 regions within the M1 forearm representation [rostro-medial (RM), rostro-lateral (RL), and caudo-lateral (CL)] with very few caudo-medial (CM) projections. These results suggest that projections from premotor areas to M1 are not uniform, but rather segregated into subregions. The goal of the present work was to study how inputs from diverse areas of the ipsilateral cortical network are organized within the M1 hand representation. In Cebus apella, different retrograde neuroanatomical tracers were injected in 4 subregions of the hand area of M1 (RM, RL, CM, and CL). We found a different pattern of input to each subregion of M1. RM receives inputs predominantly from dorsal premotor cortex, RL from PMv, CM from area 5, and CL from area 2. These results support that the M1 hand representation is composed of several subregions, each part of a unique cortical network.

Premotor cortex

Representation

Supplementary motor area

Motor area

10.1093/cercor/bhv324

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Citations (49)

Mechanism of protracted metabolic effects of fatty acid acylated insulin, NN304, in dogs: retention of NN304 by albumin

Diabetologia (1999)

Marianthe Hamilton-Wessler Marilyn Ader Melvin K. Dea Donna Moore P N Jørgensen

Interstitial fluid

Basal (medicine)

NEFA

Human albumin

10.1007/s001250051301

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Citations (66)

Parallel Cortical Networks Formed by Modular Organization of Primary Motor Cortex Outputs

Current Biology (2016)

Adjia Hamadjida Melvin K. Dea Joan Deffeyes Stephan Quessy Numa Dancause

Premotor cortex

Supplementary motor area

Motor area

10.1016/j.cub.2016.04.068

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Citations (28)

Mechanism of Action in Dogs of Slow-Acting Insulin Analog O346

The Journal of Clinical Endocrinology & Metabolism (2003)

Martin Ellmerer Marianthe Hamilton-Wessler Stella P. Kim Melvin K. Dea Erlinda L. Kirkman

We compared metabolic effects as well as plasma and interstital fluid kinetics of fatty acid-acylated insulin, LysB29(Nε-ω-carboxynonadecanoyl)-des(B30) human insulin (O346), with previously determined kinetics of native insulin and insulin detemir. Euglycemic clamps with iv injection of O346 (90 pmol/kg) or saline control were performed in 10 male mongrel dogs under inhalent anesthesia. The t1/2 for the clearance of O346 from plasma was 375.7 ± 26.7 min; the t1/2 for the appearance of O346 in interstital fluid was 137 ± 20 min (mean ± sem). Glucose disposal with O346 injection was increased 4-fold (t = 480 min, 8.3 ± 1.42 mg/min/kg) compared with preinjection (t = 0 min, 2.1 ± 0.13 mg/min/kg; P < 0.05) or saline control (t = 480 min, 2.09 ± 0.22 mg/min/kg; P < 0.05). O346 plasma elimination and transendothelial transport were 0.3% and 3.5% of regular insulin and 3% and 50% of insulin detemir, respectively. Combination of in vivo results and compartmental modeling suggests that the duration of action of O346 after iv injection is about 25-fold and 10-fold longer compared with regular human insulin and insulin detemir, respectively. This study demonstrates that O346 stimulates glucose disposal very slowly, but when injected iv, its effect may be maintained for as long as 48 h as estimated from simulation analysis. The data suggest that O346 bound to albumin in plasma acts as a storage compartment for O346 from which the analog is slowly released to insulin-sensitive tissues. Reduced liver clearance of O346 is suggested to be the major mechanism for the protracted action.

Interstitial fluid

10.1210/jc.2002-021102

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Rapid oscillations in omental lipolysis are independent of changing insulin levels in vivo

Journal of Clinical Investigation (2000)

Lisa Getty Antonios E. Panteleon Steven D. Mittelman Melvin K. Dea Richard N. Bergman

Abnormal fat metabolism plays an important role in the pathogenesis of obesity-related type 2 diabetes mellitus. This study examined whether free fatty acid levels (FFAs), like insulin levels, oscillate rapidly in plasma. Peripheral and portal blood samples from dogs were assayed for FFA, glycerol, glucose, and insulin. FFA and glycerol showed correlated oscillatory profiles, with about 8 pulses/hour. Omental lipolysis was also pulsatile, with about 10 pulses/hour, and insulin levels oscillated rapidly in plasma with about 7 pulses/hour. We applied an insulin clamp, β-adrenergic blockade, or both together, to determine the driving force behind the FFA oscillation, and we analyzed our findings by approximate entropy (ApEn) for which lower values suggest regular pulses and higher values suggest disorder. Under basal conditions, ApEn was 0.3 ± 0.2. With insulin not oscillating, FFA still cycled at about 9 pulses/hour and the ApEn was 0.2 ± 0.1. In contrast, β-blockade, either in the presence or absence of an insulin clamp, removed the FFA oscillation in three of nine dogs. In the other six dogs, the oscillatory profile was unchanged, but ApEn was significantly higher than basal values, suggesting that the regularity of the profile was disrupted. These results suggest that the FFA oscillation is driven by the central nervous system, not by insulin.

Pulsatile flow

Basal (medicine)

10.1172/jci7815

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Citations (54)

Lack of hepatic “interregulation” during inhibition of glycogenolysis in a canine model

AJP Endocrinology and Metabolism (2001)

Keld Fosgerau Steven D. Mittelman Agneta L. Sunehag Melvin K. Dea K. Lundgren

It has been proposed that the glycogenolytic and gluconeogenic pathways contributing to endogenous glucose production are interrelated. Thus a change in one source of glucose 6-phosphate might be compensated for by an inverse change in the other pathway. We therefore investigated the effects of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), a potent glycogen phosphorylase inhibitor, on glucose production in fasted conscious dogs. When dogs were treated acutely with high glucagon, glucose production rose from 1.93 ± 0.14 to 3.07 ± 0.37 mg · kg −1 · min −1 ( P < 0.01). When dogs were treated acutely with DAB in addition to high glucagon infusion, the stimulation of the glycogenolytic rate was completely suppressed. Glucose production rose from 1.85 ± 0.20 to 2.41 ± 0.17 mg · kg −1 · min −1 ( P < 0.05), which was due to the increase in gluconeogenesis from 0.93 ± 0.09 to 1.54 ± 0.08 mg · kg −1 · min −1 ( P < 0.001). In conclusion, infusion of DAB inhibited glycogenolysis; however, the absolute contribution of gluconeogenesis to glucose production was not affected. These results suggest that inhibition of glycogenolysis could be an effective antidiabetic treatment.

Glycogenolysis

Gluconeogenesis

10.1152/ajpendo.2001.281.2.e375

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Citations (11)

Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1

Cerebrovascular Diseases (2016)

Ralf Schirrmacher Melvin K. Dea Wolf‐Dieter Heiss Alexey Kostikov Thomas Funck

Background: Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction. Methods: Multitracer micro-PET of ET1 focal ischemia in rats was performed using [11C]-flumazenil ([11C]FMZ) as a flow- and viability tracer and [18F]-fluoromisonidazole ([18F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [11C]FMZ-binding and [18F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex. Results: CBF in the hypoperfused cortex was significantly reduced (p < 0.01) at 5 h (0.58 ± 0.025), 6 h (0.54 ± 0.043) and 23 h (0.66 ± 0.024) compared to controls (1.00 ± 0.011) and moderately reduced (p < 0.05) in the remainder of the affected hemisphere at 5 h (0.93 ± 0.036). [11C]FMZ-binding was within the control range at all time points. Significant [18F]FMISO-retention (1.16 ± 0.091, p < 0.05) was observed only after 6 h in the ischemic core that later turned into infarct. Conclusion: ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology.

Penumbra

10.1159/000442997

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Citations (14)

Albumin Binding of Acylated Insulin (NN304) Does Not Deter Action to Stimulate Glucose Uptake

Diabetes (2002)

Melvin K. Dea Marianthe Hamilton-Wessler Marilyn Ader Donna Moore Lauge Schäffer

NN304 [LysB29-tetradecanoyl des(B30) human insulin] is a potentially therapeutic insulin analog designed to exhibit protracted glucose-lowering action. In dogs with infusion rates similar to insulin itself, NN304 exhibits similar glucose uptake (Rd) stimulation with delayed onset of action. This compartmental modeling study was to determine if NN304 action could be accounted for by the ∼2% unbound NN304 concentration. NN304 (or human insulin) (n = 6 each) was infused at 10.2 pmol · min−1 · kg−1 under euglycemic clamp conditions in anesthetized dogs. NN304 appearance in lymph, representing interstitial fluid (ISF), was slow compared with insulin (t1/2 = 70 ± 7 vs. 14 ± 1 min, P < 0.001). Rd was highly correlated with the ISF concentration for insulin and NN304 (r = 0.86 and 0.93, respectively), suggesting that slow transendothelial transport (TET) is responsible for sluggish NN304 action. Insulin and NN304 concentration data were fit to a two-compartment (plasma and ISF) model. NN304 plasma elimination and TET were reduced to 10 and 7% of insulin, respectively. Thus, there was reduction of NN304 transport, but not to the degree expected. In ISF, there was no reduction in NN304 elimination. Thus, this acylated insulin analog demonstrates blunted kinetics in plasma, and full efficacy in the compartment of action, ISF.

Interstitial fluid

Compartment (ship)

10.2337/diabetes.51.3.762

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Citations (70)

Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance

AJP Endocrinology and Metabolism (2004)

Morvarid Kabir Karyn J. Catalano Suchitra Ananthnarayan Stella P. Kim G. W. van Citters

The mechanism by which increased central adiposity causes hepatic insulin resistance is unclear. The "portal hypothesis" implicates increased lipolytic activity in the visceral fat and therefore increased delivery of free fatty acids (FFA) to the liver, ultimately leading to liver insulin resistance. To test the portal hypothesis at the transcriptional level, we studied expression of several genes involved in glucose and lipid metabolism in the fat-fed dog model with visceral adiposity vs. controls (n = 6). Tissue samples were obtained from dogs after 12 wk of either moderate fat (42% calories from fat; n = 6) or control diet (35% calories from fat). Northern blot analysis revealed an increase in the ratio of visceral to subcutaneous (v/s ratio) mRNA expression of both lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor-gamma (PPARgamma). In addition, the ratio for sterol regulatory element-binding transcription factor-1 (SREBP-1) tended to be higher in fat-fed dogs, suggesting enhanced lipid accumulation in the visceral fat depot. The v/s ratio of hormone-sensitive lipase (HSL) increased significantly, implicating a higher rate of lipolysis in visceral adipose despite hyperinsulinemia in obese dogs. In fat-fed dogs, liver SREBP-1 expression was increased significantly, with a tendency for increased fatty acid-binding protein (FABP) expression. In addition, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat-fed animals vs. controls. Moreover, insulin receptor binding was 50% lower in fat-fed dogs. Increased gene expression promoting lipid accumulation and lipolysis in visceral fat, as well as elevated rate-limiting gluconeogenic enzyme expression in the liver, is consistent with the portal theory. Further studies will need to be performed to determine whether FFA are involved directly in this pathway and whether other signals (either humoral and/or neural) may contribute to the development of hepatic insulin resistance observed with visceral obesity.

Hyperinsulinemia

Adipose triglyceride lipase

Gluconeogenesis

Hormone-sensitive lipase

Hepatic lipase

10.1152/ajpendo.00203.2004

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Citations (315)

Paradoxical effect of troglitazone in normal animals: enhancement of adipocyte but reduction of liver insulin sensitivity.

Diabetes (2000)

Melvin K. Dea G. W. van Citters Marilyn Ader Steven D. Mittelman Agneta L. Sunehag

Troglitazone is an antidiabetic agent that improves the ability of adipocytes to store triglycerides by enhancing their insulin sensitivity. Although potent in insulin-resistant states, the effect of troglitazone on lipid and glucose turnover in normal animals has not been assessed. Euglycemic clamps were performed as an insulin dose response in normal mongrel dogs (n = 6). Somatostatin was infused without hormone replacement (zero insulin) for 90 min. Insulin was then either portally replaced (1.8 pmol x min(-1) x kg(-1), overreplaced (5.4 pmol x min(-1) x kg(-1)), or overreplaced peripherally to match the systemic levels of the portal overreplacement dose (2.3 pmol x min(-1) x kg(-1)) for 180 min. A total of 600 mg troglitazone was then given orally each day for 3 weeks and continued throughout a second experimental phase, at which point the euglycemic clamps were repeated. In concordance with previous studies, endogenous glucose production (EGP) was similar whether insulin was delivered portally or peripherally, both before and during troglitazone treatment. Although free fatty acids (FFAs) at zero insulin were not affected, there was a leftward shift of the insulin-FFA dose response curve secondary to a suppression of FFA release into plasma. EGP was paradoxically elevated by troglitazone treatment because of an elevation of both gluconeogenesis and glycogenolysis. In conclusion, troglitazone reduced hepatic sensitivity to FFAs. Because EGP is a primary determinant of fasting blood glucose, we hypothesize that a protective mechanism exists in normal animals, preventing hypoglycemia during insulin sensitization with troglitazone.

Troglitazone

Glycogenolysis

10.2337/diabetes.49.12.2087

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Citations (6)