Exercise in Type 1 Diabetes Mellitus
Exercise in Type 1 Diabetes Mellitus
Background: During and after exercise there is a twofold stimulation of glucose transporter
 type 4 in type 1 diabetes mellitus (T1DM) caused by an exogenous insulin injection and muscle
 contraction. In case of no insulin reduction before exercise and/or an additional
 carbohydrate supplement patients with T1DM would become hypoglycemic. There are no specific
 data dependent on individual exercise intensities and strategies of bolus insulin reduction.
 The aim of the present study is to avoid hypoglycemia during and after exercise and to
 calculate a critical time where blood glucose would decrease to 50% of baseline by a pre
 exercise standardized insulin regimen during standardized cycle ergometer exercises dependent
 on different modes, intensities and energy expenditures as well as counter regulatory
 hormones.

 Methods/design: Participants consist of 7 male subjects aged 18 to 35 years with T1DM
 (fasting C-peptide (≤ 0.3 nmol/l), HbA1c ≤ 64 mmol/mol). After a four-weeks basal insulin
 adaptation of ultralong-acting basal insulin (Novo Nordisk) each subject will perform a
 maximal incremental cycle ergometer exercise test with a reduction of short time insulin of
 40% to determine the individual aerobic/anaerobic threshold called first/second lactate turn
 point (LTP1, LTP2). Four constant load and three high intensity intermittent cycle ergometer
 exercise tests (30min) will be performed at 5% Pmax below and above LTP1 and LTP2 (at 5%
 above LTP2 no high intensity intermittent cycle ergometer exercise test) with a reduction of
 short time insulin doses (standardized breakfast-four hours before each test) of 25% at 5%
 Pmax below LTP1 and 50% at 5% Pmax above LTP1 and 75% at 5% Pmax below and above LTP2 with
 one week interception between testing. 24h before testing subjects will be fitted with a
 continuous glucose monitoring system for at least 48h. Primary outcomes include blood glucose
 decrease from baseline during constant load tests, energy expenditure during testing, 24h
 CGMS measurements and hormones catecholamines, cortisol, glucagon and insulin growth factor
 1. Secondary outcome measurements include heart rate, lactate and respiratory gas exchange
 values.

 Discussion: If the results confirm the hypothesis, this study could be one of the first
 recommendations for T1DM patients, how to adapt bolus insulin dose individually before
 defined exercises without the risk hypoglycemia during and after exercise.
1.1. Pathophysiology of type 1 diabetes mellitus

 Type 1 diabetes mellitus (T1DM) is an metabolic disease with insulin deficiency and a
 dysfunctional release of counter regulatory hormone glucagon. In the pathogenesis of T1DM
 autoantibodies to insulin (IAA), Glutamic Acid Decarboxylase Antibody (GADA) , islet
 antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) can be detected. In absence of endogen
 produced insulin the translocating glucose transporters (GLUT) cannot be activated (excepted
 insulin insensitive GLUT-2 in liver, β-cells of pancreas, kidneys and small intestine and
 GLUT-4 while muscle contraction) (Jensen & Richter 2012). The GLUT translocate to the cell
 surface and import glucose into the cell for metabolism or glycogen storage by
 glucose-6-phosphatase (G-6-P). For that reason in patients with T1DM exogenous insulin must
 be injected by intensified insulin therapy or insulin pump therapy. This exogenous insulin
 docks on the insulin receptor, the insulin receptor substrate (IRS) reacts with G-proteins
 (guanine nucleotide-binding proteins) on the phosphatidylinositide-3 kinase (PI-3 kinase) and
 activates GLUT. Furthermore without insulin there is a deficient carbohydrate metabolism
 while glycogen synthesis, glycogenolysis, gluconeogenesis and glycolysis.

 Dependent on dysfunctional insulin release there is also failure in counter regulatory
 glucagon reaction. In T1DM is no decrease of insulin release while hypoglycemia and thus no
 increase of α-cell glucagon secretion. So in T1DM there are less endogenous opportunities to
 avoid hypoglycemia.

 1.2. Physiology of type 1 diabetes mellitus in sports

 It's already known that in T1DM and non type 1 diabetes mellitus (nT1DM) during and after
 physical activity the glucose utilization increases. During exercise glucose degradation rate
 in blood plasma increases by enhanced translocating GLUT-4 through skeletal muscles
 contractions caused by an increase of calcium (Ca2+), adenosine triphosphate (ATP) turnover,
 AMP-activated protein kinase (AMPK), founding member of a family of proteins sharing a 180-
 to 200-amino acid (TBC1D1/4), endothelial nitric oxide synthase (eNOS), p38 mitogen-activated
 protein kinases (p38 MAPK) and sucrose nonfermenting AMPK-related kinase (SNARK).

 In place of endogenous insulin in nT1DM and exogenous insulin in T1DM muscle contractions
 activate the GLUT-4 during exercise and as a result glucose consumption increases. In
 contrast to T1DM patients in healthy subjects endogenous insulin secretion decreases during
 exercise according to mode, intensity and duration. Therefore in T1DM is a twofold GLUT-4
 increase and a high risk of hypoglycemia during exercise.

 Furthermore the risk of hypoglycemia exists also post exercise. Several studies have shown
 that one bout of exercise increases insulin sensitivity for hours which often causes
 difficulties in insulin regimen.

 1.3. Adaptation of carbohydrate intake and insulin injection before an exercise in type 1
 diabetes mellitus

 Based on these physiological aspects guidelines describe how to reduce the risk of
 hypoglycemia during and after exercise. However, these recommendations are usually very
 general and unspecific. Several studies have shown, that the regular insulin dose before an
 exercise leads to hypoglycemia due to the above mentioned mechanisms. Therefore patients with
 T1DM have to increase carbohydrate intake and/or to reduce insulin injection dose before and
 after performing exercise The mode of exercise is an influencing factor, which impacts blood
 glucose levels during and especially after exercise. Some studies demonstrated, that high
 intensity intermittent exercises lead to a lower decrease in blood glucose level than
 constant load exercise However, there is a lack in the guidelines to which amount to reduce
 insulin or increase carbohydrate intake related to different exercise intensities and modes.

 2. Pilot study

 Objective: To perform sports and exercise in patients with type I diabetes they need to
 reduce insulin dose or increase carbohydrate intake to avoid hypoglycemia. There is a lack in
 the guidelines how to reduce insulin or increase carbohydrate intake related to different
 exercise intensities and modes. The purpose of the present study was to investigate the
 relationship between the blood glucose concentration and the intensity and the duration of
 the work load applying a standardized pre exercise glucose and insulin regimen. As a
 hypothesis we expect an energy expenditure and intensity dependent decrease of blood glucose
 concentration which offers the opportunity to calculate a critical time.

 Research Design and Methods: One trained male subject with type I diabetes (age: 25 years;
 weight: 72 kg; high: 1.8 m; maximal oxygen uptake (VO2max): 55.4 ml.kg-1.min-1; insulin:
 NovoRapid/Levemir; C-peptide positive, HbA1c 48 mmol.mol-1) performed 4 hours after the last
 insulin/carbohydrate supplement, with a reduction of short time insulin to 40%, a maximal
 incremental cycle ergometer exercise test (40 W start; 20 W.min-1 increments) to determine
 the first (LTP1) and the second lactate turn point (LTP2) by means of computer based linear
 regression break point analysis. Three phases of energy supply can be detected and separated
 by LTP1 and LTP2. The LTP1 is characterized as the first increase in blood lactate
 concentration above baseline. The LTP2 is detected as the second abrupt increase in lactate
 between LTP1 and Pmax which defines the highest constant workload to give still a lactate
 steady state. Four constant load ergometer exercise tests (30 min) were performed at 5% Pmax
 below and above LTP1 and LTP2 with a reduction of short time insulin doses of 25% at 5% Pmax
 below and above LTP1 and 50% at 5% Pmax below LTP2 and 75% at 5% Pmax above LTP2 according to
 the literature. Heart rate and gas exchange variables were determined continuously, blood
 lactate concentration (La) and blood glucose concentration were determined at rest, at the
 end of every workload step, every 5 min in constant load ergometer exercise as well as during
 3 and 6 min of active and passive recovery.

 Results: Linear declines of blood glucose were found in all tests. At 5% < LTP1 glucose
 decreased from 191 mg/dl to 149 mg/dl, 5% > LTP1 from 131 md/dl to 96 mg/dl, 5% < LTP2 from
 169 mg/dl to 91 mg/dl and 5% > LTP2 from 187 mg/dl to 144 mg/dl (early stop because of work
 load acidosis above LTP2). The decline of the blood glucose concentrations were calculated by
 a linear interpolation to 50% rest of the baseline value without any other supply of
 carbohydrates. time critical: 5 % < LTP1 - 77 min; 5 % > LTP1 - 31 min; 5% < LTP2 - 31 min;
 5% > LTP2 - 29 min.

 Conclusion: The results show a linear reduction of glucose concentration in relation to the
 intensity and duration of the work load. We suggest that it is possibly to calculate a
 critical time for a certain glucose threshold in type I diabetes patients to avoid
 hypoglycemia during sports and exercise.

 3. Study goal and hypothesis

 We do know that patients with T1DM must adapt insulin and carbohydrate intake before
 exercise, but we don't know the specific individual amount. Therefore we have shown in our
 pilot study a model how to adapt insulin injection dose (while constant basal insulin use)
 with respect to standardized intensities and how to calculate a critical time where glucose
 level in T1DM patients with insulin therapy would fall into hypoglycemia during sports and
 exercise. Now we have to verify those data with a group of subjects and additional hormonal
 markers while using a ultralong-acting basal insulin (Novo Nordisk).

 The aim of the present study is to calculate a critical time by a pre exercise standardized
 insulin regimen during standardized cycle ergometer exercises dependent on different modes,
 intensity, duration and energy expenditure as well as counter regulatory hormones. As a
 hypothesis we expect no hypoglycemia during the cycle ergometer exercises dependent on an
 standardized pre exercise standardized insulin regimen in relation to the intensity, duration
 and the energy expenditure of the exercise and no post exercise hypoglycemia.

 If the results confirm the hypothesis, this study could be the first recommendation for T1DM
 patients, how to individually adapt insulin dose before defined exercises without
 hypoglycemia during and after exercise.

 4. Methods

 4.1. General study design

 This project is a proof of concept study. After the recruitment by the Medical University of
 Graz (Division of Endocrinology and Metabolism), at the first screening visit control of the
 inclusion and exclusion criteria will be done and subjects will give their signed informed
 consent. Before testing a 4-week adaptation of ultralong-acting basal insulin (Novo Nordisk)
 will be done. Each subject will perform a maximal incremental cycle ergometer exercise test
 to determine exercise markers to prescribe constant load and intermittent exercise tests.
 Four constant load and three intermittent ergometer exercise tests (30 min) will be performed
 at 5% Pmax below and above LTP1 and LTP2 with a reduction of short time insulin doses
 (breakfast-four hours before each test) of 25% at 5% Pmax below LTP1 and 50% at 5% Pmax above
 LTP1 and 75% at 5% Pmax below and above LTP2. 24 h before testing subjects will be fitted
 with a continuous glucose monitoring system (CGMS) for at least 48 h. At 5% Pmax above LTP2
 there will be no intermittent ergometer exercise test. The same reduction of bolus insulin
 before testing while be done 15min after testing.

 4.2. Subjects recruitment

 Inclusion criteria:

 -  Subjects must give their signed and dated informed consent before any trial-related
 activities. Trial-related activities are any procedure that would not have been
 performed during normal management of the subject

 -  Male subjects with type 1 diabetes with duration ≥12 month

 -  Age ≥ 18 to ≤ 35 years, both inclusive

 -  HbA1c ≤ 64 mmol/mol

 -  Fasting C-peptide (≤ 0.3 nmol/l)

 -  Treatment with intensified insulin therapy or insulin pump therapy

 -  No diabetic long term complications

 -  No other physical and/or mental disease

 Exclusion criteria:

 -  Previous participation in this trial

 -  History of any illness or disease that, in the opinion of the Investigator might
 confound the results of the trial

 -  Use of drugs, which may interfere with the interpretation of trial results or are known
 to cause clinically relevant interference with insulin action, glucose utilisation, or
 recovery from hypoglycemia

 -  Current addiction to alcohol or substances of abuse as determined by the investigator

 -  Known or suspected allergy to trial products or related products

 -  Any condition that the investigator feels would interfere with the trial participation
 or evaluation of data

 Testing day inclusion criteria:

 -  48h before testing no hypoglycemia

 -  24h before testing no alcohol

 Testing day exclusion criteria:

 -  Illness on and/or before testing day

 -  Low glucose level immediately before testing (< 80 mg/dl)

 -  Defect CGMS

 -  Incorrect time of bolus insulin injection (4 hours before testing)

 -  Mental incapacity, unwillingness, or language barriers precluding adequate understanding
 or co-operation

 -  Incorrect amount of bolus insulin injection (last before testing)

 4.3. Screening visit

 Subjects will receive a subject's number in ascending order. The following will be assessed
 and recorded in the case report form (CRF):

 -  Subjects get informed of study design and will give informed consent

 -  Assessment of inclusion and exclusion criteria

 -  Demography

 -  Abuse of drugs, alcohol and smoking habits

 -  Diagnosis of diabetes

 -  Body measurements: height (m), weight (kg) and body mass index (BMI)

 -  Determination of total daily dose (TDD) (through diabetes diary. 4.4. Adaptation of
 ultralong-acting basal insulin (Novo Nordisk) Insulin is indicated to be administered
 once-daily subcutaneous at the same time every day. In T1DM ultralong-acting basal
 insulin (Novo Nordisk)have to be combined with bolus insulin to cover mealtime
 requirements, so there will be no adaptation in bolus insulin amount. The dosage of
 insulin the ultralong-acting basal insulin (Novo Nordisk) will be adjusted every three
 days individually, with a starting dosage of 70% of the TDD of insulin.

 4.5. Calculation of carbohydrate factor and correction factor

 To determine the amount of carbohydrate exchanges, which increases blood glucose level, we
 will calculate the carbohydrate factor (CarbF) and the glucose correction factors (CorrF).

 The carbohydrate factor indicates how many grams of carbohydrates 1 unit of insulin covers
 and the correction factor measures how far glucose concentration will fall per 1 unit of
 insulin.

 4.6. Install of CGMS and edition carbohydrate supplement

 Subjects will be fitted with the CGMS 24h before exercise testing. A hypoglycemic alarm
 function will be set at 80 mg/dl to avoid hypoglycemia below baseline (70 mg/dl). Standard
 glucose measurements will be done in a usual way to calibrate the CGMS. Also carbohydrate
 supplement (Fortimel complete) will be handed out for the standardized breakfast with the
 individual amount calculated for each test.

 4.7. Maximal incremental cycle ergometer exercise test

 Four hours after the last insulin/carbohydrate supplement with a reduction of short time
 insulin to 40% and constant basal insulin (calculated amount of carbohydrate intake and dose
 of insulin injection of the CarbF and CorrF), subjects will perform a maximal incremental
 cycle ergometer exercise test (40 W start; 20 W.min-1 increments) to determine the first
 (LTP1) and the second lactate turn point (LTP2). Three phases of energy supply can be
 detected and separated by LTP1 and LTP2. The LTP1 is characterized as the first increase in
 blood lactate concentration above baseline. The LTP2 is detected as the second abrupt
 increase in lactate between LTP1 and Pmax which defines the highest constant workload to give
 still a lactate steady state. Heart rate and gas exchange variables will be determined
 continuously, blood lactate concentration and blood glucose concentration will be determined
 at rest at the end of every workload step, every 5 min in constant load ergometer exercise as
 well as during 3 and 6 min of active and passive recovery. We decided to choose intensities
 for the constant load tests and the high intensity intermittent exercise tests related to
 defined phases of energy supply representing common activities. 5% < LTP1 is like daily
 activity at low intensity. 5% > LTP1 is like fast walking at low to moderate intensity. 5% <
 LTP2 is equivalent to moderate to high intensity activity or sports below the maximal lactate
 steady state. 5% > LTP2 is a high intensity activity with no more lactate steady state. To
 simulate sports games we decided to do those high intensity intermittent exercise tests,
 which are very similar to this type of physical activity.

 4.8. Constant load test

 In all constant load tests heart rate and gas exchange variables will be determined
 continuously, blood lactate concentration and blood glucose concentration will be determined
 at rest, at the end of every workload step, every 5 min in constant load ergometer exercise
 as well as during 3 and 6 min of active and passive recovery. Gas exchange variables will be
 processed to calculate the energy expenditure and the distribution of glucose and fat
 metabolism (glucose and fat g/min). Furthermore, at the start, in the middle and at the end
 of exercise venous will be drawn to determine adrenaline, noradrenaline, cortisol, glucagon
 and somatropin. Every 10 minutes blood glucose will be measured additionally from fingertip
 blood samples to determine the actual blood glucose level to provide hypoglycemia during the
 exercises and to calibrate CGMS. After the tests glucose concentration will be measured
 autonomously four times every full hour to avoid post exercise hypoglycemia also by fingertip
 measures.

 The constant load ergometer exercises tests will be performed for 30 min at 5% Pmax below and
 above LTP1 and for 30min at 5% Pmax below and above LTP2 with a standardized reduction of
 short time insulin and constant basal insulin (calculated amount of carbohydrate intake and
 dose of insulin injection of the CarbF and CorrF).

 4.9. High intensity intermittent exercise tests

 In all high intensity intermittent exercise tests heart rate and gas exchange variables will
 be determined continuously, blood lactate concentration and blood glucose concentration will
 be determined at rest, at the end of every workload step, every 5 min in constant load
 ergometer exercise as well as during 3 and 6 min of active and passive recovery. Gas exchange
 variables will be processed to calculate the energy expenditure and the distribution of
 glucose and fat metabolism (glucose and fat g/min). Furthermore at the start, in the middle
 and at the end of exercise adrenaline, noradrenaline, cortisol, glucagon and somatropin will
 be determined from venous blood samples. Every 10 minutes, blood glucose will be measured
 additionally from fingertip blood samples to determine the actual blood glucose level to
 provide hypoglycemia during the exercises and to calibrate CGMS. After the tests glucose
 concentration will be measured autonomously four times every full hour to avoid post exercise
 hypoglycemia.

 The high intermittent exercise tests will be performed for 30 min at 5% Pmax below and above
 LTP1 and for 30min at 5% Pmax below LTP2 with a standardized reduction of short time insulin
 and constant basal insulin (calculated amount of carbohydrate intake and dose of insulin
 injection of the CarbF and CorrF). The high intermittent exercise tests will be performed
 with the same mean work load like in the constant load exercise tests which can be calculated
 by the following equation:

 Intervals will be set at Pmax from 20 sec interspersed by active recovery at 80 % power of
 LTP1 whereas the recovery time will be calculated.

 Measurements 4.9.1. Anthropometric data and TDD

 At the screening visit we will determine body measurements: height (m), weight (kg) and body
 mass index (BMI) and TDD (U).

 4.9.2. Blood glucose, gas exchange, heart rate variables and lactate

 In all tests blood glucose and lactate will be measured form blood samples from the earlobe
 and heart rate and gas exchange variables will be determined continuously. Blood lactate
 concentration and blood glucose concentration will be determined at rest, at the end of every
 workload step, every 5 min in constant load ergometer exercise as well as during 3 and 6 min
 of active and passive recovery. Lactate and glucose concentration will be determined by
 system EKFDiagnostic, GER). Heart rate will be determined through a 12-lead ECG (ZAN, AUT)
 and also by Polar (Polar Electro, FIN). Gas exchange variables will be determined by an open
 spiro-ergometry-system (ZAN, AUT). LTP1 and LTP2 will be assessed by means of computer based
 linear regression break point analysis Pro Sport (AUT). Additional fingertip glucose measures
 will be performed by the subjects own glucose measurement device.

 4.9.3. Continuous glucose monitoring system (CGMS)

 CGMS sensor will be inserted into subcutaneous tissue (postural-lateral abdominal region) 24h
 prior to each test for 48h, to get a permanent glucose recording pre, during and post
 exercise and to minimize the risk of hypoglycemia. Blood glucose readings will be stored in
 the memory of the monitor, which is connected to the sensor. Glucose data will be processed
 computer based 4.9.4. Hormones

 Adrenaline, noradrenaline, cortisol, glucagon and somatropin will be determined from venous
 blood samples obtained from a cubital vene at the start, in the middle and at the end of each
 exercise test. Adrenaline and noradrenaline will be quantified by DRGDiagnostics, USA and
 glucagon by ICNDiagnostics, USA. Somatropin will be measured using CLIASiemens Healthcare
 Diagnostics, USA and cortisol by CENTAUR Siemens Healthcare Diagnostics, USA).

 5. Statistics

 A repeated-measures ANOVA design (number of repetitions = 4) was calculated a priori with a
 medium effect size of 0.5 and an alpha-error of 0.05 based on pilot data. Correlations
 between repetitions were assumed to equal 0.5. With a sample size of 6 patients the achieved
 power (beta-1) is greater than 0.95 and is therefore appropriate for a high risk study. In
 case of dropout we decided to do our study with 7 subjects.

 Results will be assessed by analysis of variance (ANOVA) for repeated measures with the
 paired or unpaired t test, Wilcoxon's rank.-sum test for paired data, or Friedman's repeated
 measures by ANOVA on ranks when applicable (GraphPad Prism Software version 4.0, USA).
Inclusion Criteria:

 -  Subjects must give their signed and dated informed consent before any trial-related
 activities. Trial-related activities are any procedure that would not have been
 performed during normal management of the subject

 -  Male subjects with T1DM with duration ≥12 month

 -  Age ≥ 18 to ≤ 35 years, both inclusive

 -  HbA1c ≤ 64 mmol/mol

 -  Fasting C-peptide ≤ 0.3 nmol/l

 -  Treatment with intensified insulin therapy or insulin pump therapy

 -  No diabetic long term complications

 -  No other physical and/or mental disease

 Exclusion Criteria:

 -  Previous participation in this trial

 -  History of any illness or disease that, in the opinion of the Investigator might
 confound the results of the trial

 -  Use of drugs, which may interfere with the interpretation of trial results or are
 known to cause clinically relevant interference with insulin action, glucose
 utilization, or recovery from hypoglycemia

 -  Current addiction to alcohol or substances of abuse as determined by the investigator

 -  Known or suspected allergy to trial products or related products

 -  Any condition that the investigator feels would interfere with the trial participation
 or evaluation of data