Insulin Sensitivity in De Novo Parkinson's Disease: A Hyperinsulinemic‐Euglycemic Clamp Study

Yang Hyun Lee, MD, Takashi Ando, MD, Jae Jung Lee, MD, Min Seok Baek, MD, Chul Hyoung Lyoo, MD, PhD, Sang Jin Kim, MD, PhD, Minkyeong Kim, MD, Jin Whan Cho, MD, PhD, Young H. Sohn, MD, PhD, Masahisa Katsuno, MD, PhD, Hirohisa Watanabe, MD, PhD, Mari Yoshida, MD, PhD,* and Phil Hyu Lee, MD, PhD* Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan Department of Neurology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, South Korea Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea Department of Neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, South Korea Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea Department of Neurology, Fujita Health University, Toyoake, Japan Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan Severance Biomedical Science Institute, Yonsei University, Seoul, Korea


Supporting Data
Additional Supporting Information may be found in the online version of this article at the publisher's web-site.

Insulin Sensitivity in De Novo
Parkinson's Disease: A Hyperinsulinemic-Euglycemic Clamp Study A recent clinical trial found that exenatide, an antidiabetic drug, could slow down the rate of decline in motor performance in patients with Parkinson's disease (PD). 1 A higher prevalence of diabetes mellitus (DM) has been reported in PD patients, 2 whereas an increased incidence of PD was found in patients with DM. [3][4][5] Although these findings suggest that peripheral insulin resistance might be involved in PD pathogenesis, 6 systemic substrate metabolism and its responsiveness to insulin stimulation have not been rigorously assessed before in de novo, medication-free PD patients. Therefore, using the hyperinsulinemic-euglycemic clamp technique, the most accurate and precise method available for quantifying insulin sensitivity, we aimed to assess whether insulin resistance is an inherent feature of PD.
We performed a hyperinsulinemic-euglycemic clamp with stable isotopes ([6,6-2 H 2 ]-glucose and [ 2 H 5 ]-glycerol), as    Table S1). The diagnosis of PD was made by a movement disorders specialist (R.A.C.R.) according to the UK Parkinson's Disease Society Brain Bank criteria. The study was approved by the local ethics committee. Intergroup differences were assessed using the unpaired t test, with the significance threshold set at P < 0.05. Given the exploratory nature of the study, we did not apply multiple comparison adjustments. Data are presented as mean AE standard error. During basal steady-state conditions, peripheral glucose disposal rate and endogenous glucose production rate were similar between PD patients and controls (21.9 AE 0.5 vs. 21.0 AE 0.5 μmol/kg FatFreeMass(FFM) /min, respectively; P = 0.26). In PD and control subjects, insulin stimulation increased whole-body glucose disposal rate (57.5 AE 8.5 vs. 48.0 AE 4.9 μmol/kg FFM /min; P = 0.35) and suppressed glucose production rate (14.4 AE 1.6 vs. 12.3 AE 1.0 μmol/kg FFM /min; P = 0.30) to a similar extent, although with a slightly higher hepatic insulin resistance index in PD patients (3,829 AE 227 vs. 3,020 AE 265 μmol kg FFM /min/ pmol × L; P = 0.04; Table 1). Both plasma glycerol levels and its rate of appearance, a measure of lipolysis, were similar between the two groups, with a similar degree of suppression of lipolysis by hyperinsulinemia (Table 1).
We found that whole-body glucose disposal rate, the gold standard for quantification of peripheral insulin resistance, was remarkably similar between newly diagnosed, medication-free PD patients and age-, sex-, and body composition-matched controls. In addition, other physiological responses of systemic glucose and fat metabolism to insulin challenge were unaltered in PD patients. These findings thus indicate that PD is not associated with insulin resistance. Our results therefore also suggest that the putative neuroprotective action of antidiabetic drugs, including exenatide, may originate from their effect at the neuronal level rather than on systemic metabolism. 1 However, given the increased risk of developing PD and a more aggressive course of PD in those with DM, [3][4][5] it remains possible that treatment of the systemic metabolic disturbances in PD patients with hyperglycemia and insulin resistance may affect disease progression.

Supporting Data
Additional Supporting Information may be found in the online version of this article at the publisher's web-site. EGP, endogenous glucose production; FFM, fat free mass; FM, fat mass; HIR, hepatic insulin resistance; MCR I , metabolic clearance rate of insulin; R a , rate of appearance; R d , rate of disappearance; HbA1c, glycosylated hemoglobin; TSH, thyroid-stimulating hormone.