EXPERIMENTAL AND THERAPEUTIC MEDICINE 19: 3069-3075, 2020 Effectiveness and safety of pulsatile intravenous insulin therapy for the improvement of respiratory quotient in Chinese patients with diabetes mellitus NAN GU1, AIMEI DONG1, LEI GAO2, CHENYING XIE1, PEIYI HOU1, WENBO WANG3, SAINAN ZHU4, CHEN YAO4, JUNQING ZHANG1 and XIAOHUI GUO1 1Department of Endocrinology, 2Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100034; 3Department of Endocrinology, Peking University Shougang Hospital, Beijing 100144; 4Department of Biostatistics, Peking University First Hospital, Beijing 100034, P.R. China Received May 31, 2019; Accepted December 20, 2019 DOI: 10.3892/etm.2020.8563 Abstract. Pulsatile intravenous insulin therapy (PIVIT) is a Registry (http://www.chictr.org.cn) on November 13th 2019 means of imitating naturally occurring insulin pulses arti- (registration no. ChiCTR1900027510). ficially. It is thought to improve carbohydrate metabolism, which can be assessed using the respiratory quotient (RQ). Introduction The aim of this present study was to assess the efficacy and safety of PIVIT for the improvement of RQ in Chinese patients Insulin secretion occurs in a pulsatile manner into the circula- with diabetes mellitus (DM). This 12‑week, multi‑center, tion of humans and animals, with fast pulses occurring every prospective, randomized, open‑label, parallel‑group study 5‑15 min (1,2). Insulin is secreted into the portal vein and involved 110 DM patients (both type 1 and type 2) whose RQ undergoes partial (40‑80%) hepatic extraction, before being was <0.8. Of these, 53 patients formed the control group, in diluted into the systemic insulin pool. Peripheral insulin which standard anti‑diabetic therapy was maintained, and concentrations oscillate because of the pulsatility of insulin 54 patients formed the treatment group, which underwent secretions (3). Pulsatile insulin concentrations are important weekly PIVIT in addition to the administration of standard to achieve optimal insulin action, especially the metabolic anti‑diabetic therapy. RQ was evaluated monthly in control effects of insulin, such as the suppression of hepatic glucose subjects, and before and after every PIVIT treatment in the output and overall insulin secretion (4). However, insulin treatment group. After weekly PIVIT for 12 weeks, the mean pulsatility is disrupted in patients with type 2 diabetes mellitus RQ increased from 0.70 to 0.90 in the treatment group, but did (T2DM) (5), first‑degree relatives who lack significant meta- not change in the control group. The percentage of subjects bolic abnormalities (4), and patients with early type 1 diabetes reporting adverse events (AEs) was 31.5% (17/54) in the treat- mellitus (T1DM) (6). ment group and 9.43% (5/53) in the control group (P=0.0053). Pulsatile infusion and multiple daily subcutaneous injec- The most frequently reported AE (by 12 subjects) was a tions have been reported to have a greater hypoglycemic effect gastroenteric reaction when these individuals were receiving than continuous delivery (7), and also to prevent metabolic and 50% glucose during the PIVIT treatment. The majority of AEs microvascular complications in T1DM (6,8‑10). Whereas the were mild and did not interfere with the ongoing treatment. commonly used methods of therapeutic insulin administration Thus, PIVIT can be viewed as tolerated and effective for the are not pulsatile in nature, several well‑known classes of phar- improvement of RQ in Chinese DM patients. This study was macological agents that are used to treat patients with T2DM retrospectively registered with the Chinese Clinical Trial increase plasma insulin in a pulsatile manner in both humans and animals, but without significantly modifying insulin pulse frequency (11,12). Using an artificial pancreas system to replicate the physio- logical insulin pulse patterns could be one approach to providing Correspondence to: Professor Xiaohui Guo, Department of effective intravenous insulin infusion in patients with DM for Endocrinology, Peking University First Hospital, 8 Xishiku Street, whom traditional therapy is insufficient (13,14). Pulsatile intra- Beijing 100034, P.R. China venous insulin therapy (PIVIT) involves once‑weekly sessions E‑mail: [email protected] during which pulsatile intravenous insulin and concurrent oral glucose or quantified amounts of carbohydrate are admin- Key words: pulsatile intravenous insulin therapy, respiratory istered, according to a standard protocol and under medical quotient, diabetes supervision (15). Respiratory quotient (RQ) is the ratio of the volume of carbon dioxide produced to the volume of oxygen consumed, 3070 GU et al: EFFECTIVENESS AND SAFETY OF PULSATILE INTRAVENOUS INSULIN THERAPY IN DIABETES and is an excellent indicator of substrate oxidation (16). continued their standard anti‑diabetic therapy, and had their Oxygen consumption (VO2) and carbon dioxide produc- RQ evaluated every 4 weeks, while 54 patients formed the tion (VCO2) occur during the oxidation of carbohydrate, treatment group (the PIVIT group) and underwent weekly protein and fat, but the associated RQ values differ according PIVIT in addition to their standard anti‑diabetic therapy. to the substrate being metabolized.; the RQ values are 0.7 for RQ, the ratio of the mean CO2 produced to the mean O2 fat, 0.8 for protein and 1.0 for glucose (16,17). Low RQ has consumed/minute, was automatically calculated using a been frequently observed in patients with DM (18), because in VacuMed® (VacuMed YD 17590; Vacumetrics, Inc.). Patients diabetes, fat replaces glucose as the main source of energy, and fasted for at least 8 h overnight, after which indirect calorimetry this increase in fat consumption, alongside that of protein, is a was performed the following morning. The humidity of the contributing factor to hypermetabolism. testing room was maintained at 45‑60% and the temperature The purpose of the present study was to assess the efficacy at 24‑26˚C. and safety of PIVIT for the improvement of RQ in Chinese The initial PIVIT treatment was carried out three times a patients with DM. day, at 30 min intervals for 2 days, and was then continued once weekly, three times a day. The PIVIT protocol was Subjects and methods performed as previously described (6). RQ was evaluated before and after every treatment, and the fasting blood of Ethics statement. The present study was retrospectively regis- all patients was collected for the measurement of glucose tered in the research registry (www.chictr.org.cn; registration and lipid levels. Glucose and lipid levels were measured no. ChiCTR1900027510; November 13th 2019). The study using Beckman Coulter AU chemistry analyzers obtained protocol and informed written consent forms were approved from commercially available kits (Beckman Coulter, Inc.) by the research ethics committee of Peking University according to manufacturer's protocol. A standard question- First Hospital [approval no. (2012)‑Instrument Registration naire was completed, which included general information, No. (15)], and the study was carried out in accordance with family history, medical history and details of the medica- the principles of the Declaration of Helsinki. All patients gave tion being used. During the evaluation, height, body mass, their informed written consent to participate in the study. blood pressure and pulse were measured. Blood and urine were collected at the baseline stage and after 12 weeks to Study population. The inclusion criteria were a diagnosis determine the levels of glucose and glycated hemoglobin of DM that was made according to the 1999 World Health (HbA1c), as well as the lipid profile and urinary protein Organization diagnostic criteria, and a measured RQ of <0.8. excretion. A total of 110 patients with DM were recruited from July 2012 The procedures undertaken for the PIVIT group were to September 2013 from Peking University First Hospital as follows: i) Capillary blood glucose was measured and Peking University Shougang Hospital, and were enrolled using an Accu-CHEK® Performa Blood Glucose Meter in the present study (Fig. 1). Specific anti‑diabetic therapies, (Roche Diagnostics). If the blood glucose was <8 mmol/l, including the use of any oral anti‑diabetic agents and insulin, oral glucose (50% glucose injection, 20 ml, 10 g; Otsuka were recorded in a questionnaire. Pharmaceutical Co., Ltd.) was administered to increase The exclusion criteria were as follows: The presence of the blood concentration. ii) An ambulatory infusion pump hypokalemia; pregnancy or intended pregnancy; or a history of (10 pulses/h; Microdose®; Bionica Corp.) was used. A volume unstable cardiac disease (including new or worsening signs or of 1 ml insulin (Novolin R®; 3 ml/300 IU; Novo Nordisk A/S) symptoms of coronary heart disease within 3 months of study and 9 ml normal saline (0.9% saline; Baxter International, Inc.) entry). Additional exclusion criteria were any of the following were mixed in a 10‑ml syringe, and the syringe was loaded within 6 months of study entry: Acute coronary syndrome, into the syringe driver on the left of the pump. iii) The infu- stroke or ischemic event; coronary artery intervention or sion pump was then connected to a hand or forearm vein. RQ New York Heart Association Class II‑IV congestive heart was evaluated before connecting the pump to a vein. iv) The failure; significant renal impairment (creatinine clearance rate capillary blood glucose of patients was then monitored every <50 ml/min); high (>2X the upper limit of normal) plasma 30 min by nurses. If blood glucose levels were <8 mmol/l, alanine aminotransferase or aspartate aminotransferase patients were administered oral 50% glucose therapy and their activities; or high plasma triglycerides (>600 mg/dl). blood glucose concentration was measured every 15 min until The key withdrawal criteria were intolerance of the study it reached 8 mmol/l. v) Resting VO2 and VCO2 were measured drugs, an inability to continue adherence to the protocol and after the treatment. vi) The patients left the hospital when unwillingness to continue in the study. they had completed the treatment and their blood glucose was >8 mmol/l.