The Role of Endogenous Lactate in Brain Preservation and Counterregulatory Defenses Against Hypoglycemia
The Effect of Exercise-induced Hyperlacticacidemia on Counterregulatory Responses, Symptoms, Cognitive Function and Brain Lactate Accumulation During Hypoglycemia in (Hypoglycemic Unaware)Type I Diabetes Patients and Normal Controls
Iatrogenic hypoglycemia is the most frequent acute complication of insulin therapy in people with type 1 diabetes (T1DM). Recurrent hypoglycemic events initiate a process of habituation, characterized by suppression of hypoglycemic symptoms, eventually leading to hypoglycemia unawareness, which creates a particularly high risk of severe hypoglycemia. Recent evidence suggest a pivotal role for (brain) lactate in the pathogenesis of hypoglycemia unawareness. Indeed, exogenous lactate administration may preserve brain function and attenuate counterregulatory responses to and symptomatic awareness of hypoglycemia. It is unknown whether endogenous elevation of plasma lactate produces the same effects and whether such effects differ between patients with T1DM with and without hypoglycemia unawareness and healthy controls.
Objective: To investigate the effect of elevated levels of endogenous lactate on brain lactate accumulation and on counterregulatory responses to, symptomatic awareness of and cognitive function during hypoglycemia in patients with T1DM with and without hypoglycemia unawareness and normal controls.
Hypothesis: The investigators hypothesize first that endogenous lactate, when raised through high intensity exercise, preserves neuronal metabolism during subsequent hypoglycemia, which in turn will attenuate counterregulatory hormone responses, appearance of symptoms and deterioration of cognitive function. Second, the investigators posit that these effects will be augmented in patients with hypoglycemia unawareness compared to healthy subjects and T1DM patients with normal awareness as a consequence of greater transport capacity of lactate into the brain.
調査の概要
研究の種類
入学 (実際)
段階
- 適用できない
連絡先と場所
研究場所
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Nijmegen、オランダ
- Radboud UMC
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion criteria for healthy subjects
- Age: 18-40 years
- Body-Mass Index: 18-30 kg/m2
- Blood pressure: <160/90 mmHg
- Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week.
Inclusion criteria T1DM patients with normal hypoglycemic awareness
- Diabetes duration ≥ 1 year
- Age: 18-40 years
- Body-Mass Index: 18-30 kg/m2
- HbA1c: 42-75 mmol/mol (6-9%)
- Outcome Clarke questionnaire: 0-1
- Blood pressure: <160/90 mmHg
- Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week
Inclusion criteria T1DM patients with hypoglycemia unawareness
- Diabetes duration ≥ 1 year
- Age: 18-40 years
- Body-Mass Index: 18-30 kg/m2
- HbA1c: 42-75 mmol/mol (6-9%)
- Outcome Clarke questionnaire: =>3
- Blood pressure: <160/90 mmHg
- Recreationally active
Exclusion criteria:
- Inability to provide informed consent
- Presence of any medical condition that might interfere with the study protocol, such as brain injuries, epilepsy, a major cardiovascular disease event or anxiety disorders
- Use of any medication, except for oral contraceptives
- MR(I) contraindications (pregnancy, severe claustrophobia, metal parts in body)
- Orthopedic and/or neurological diseases that impair exercise
- Cardiopulmonary disease as stated in the 2001 American heart association and 2002 American college of cardiology/American heart association guidelines
Additional exclusion criteria for all T1DM patients:
- Use of any other medication than insulin, except for oral contraceptives or stable thyroxine supplementation therapy
- complications of T1DM, including proliferative retinopathy, neuropathy or nephropathy
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：基礎科学
- 割り当て：ランダム化
- 介入モデル：クロスオーバー割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：High intensity exercise
Subjects will preform a high intensity training exercise (3* 30 seconds all out sprint on a cycle ergometer) to raise plasma lactate levels
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3x30 seconds 'all out' sprints
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偽コンパレータ：Lay down comfortably
As a control conditions, subjects wil lay down comfortably and rest
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rest
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
時間枠 |
|---|---|
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Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma)
時間枠：during 60 m of hypoglycemia
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during 60 m of hypoglycemia
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Plasma levels of other counter-regulatory hormones (Levels of counter-regulatory hormones measured in arterial plasma)
時間枠：During 60 min hypoglycemia
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Levels of counter-regulatory hormones measured in arterial plasma
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During 60 min hypoglycemia
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Glucose infusion rate (Amount of glucose 20% necessary to maintain plasma glucose at steady state values)
時間枠：During 60 min hypoglycemia
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Amount of glucose 20% necessary to maintain plasma glucose at steady state values
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During 60 min hypoglycemia
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Plasma lactate levels (Lactate levels measured in arterial plasma)
時間枠：During 60 min hypoglycemia
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Lactate levels measured in arterial plasma
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During 60 min hypoglycemia
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Cognitive functioning, as measured by cognitive tests
時間枠：During 60 min hypoglycemia
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Cognitive test will be: Dutch State Trait Anxiety Inventory, Digit Span, Stroop color word test, word fluency test, trail making test and Pasat
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During 60 min hypoglycemia
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Plasma levels of inflammatory markers (levels of cytokines)
時間枠：During 60 min hypoglycemia
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levels of cytokines
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During 60 min hypoglycemia
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Brain perfusion measured with ASL-MRI
時間枠：During 60 min hypoglycemia
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Brain perfusion measured with ASL-MRI
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During 60 min hypoglycemia
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Brain lactate accumulation measured with 1H-MRS
時間枠：During 60 min of hypoglycemia
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Brain lactate levels measured with 1H-MRS
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During 60 min of hypoglycemia
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その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Plasma glucose concentration
時間枠：During 60 min hypoglycemia
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Plasma glucose concentration, necessary to adjust glucose infusion rate
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During 60 min hypoglycemia
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Plasma insulin concentration (Insulin levels, measured in arterial plasma)
時間枠：During 60 min hypoglycemia
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Insulin levels, measured in arterial plasma
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During 60 min hypoglycemia
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協力者と研究者
捜査官
- 主任研究者：Bastiaan de Galan, Dr.、Radboud University Medical Center
出版物と役立つリンク
一般刊行物
- van de Ven KC, van der Graaf M, Tack CJ, Klomp DW, Heerschap A, de Galan BE. Optimized [1-(13)C]glucose infusion protocol for 13C magnetic resonance spectroscopy at 3T of human brain glucose metabolism under euglycemic and hypoglycemic conditions. J Neurosci Methods. 2010 Jan 30;186(1):68-71. doi: 10.1016/j.jneumeth.2009.10.025. Epub 2009 Nov 11.
- van de Ven KC, de Galan BE, van der Graaf M, Shestov AA, Henry PG, Tack CJ, Heerschap A. Effect of acute hypoglycemia on human cerebral glucose metabolism measured by (1)(3)C magnetic resonance spectroscopy. Diabetes. 2011 May;60(5):1467-73. doi: 10.2337/db10-1592. Epub 2011 Apr 4.
- van de Ven KC, van der Graaf M, Tack CJ, Heerschap A, de Galan BE. Steady-state brain glucose concentrations during hypoglycemia in healthy humans and patients with type 1 diabetes. Diabetes. 2012 Aug;61(8):1974-7. doi: 10.2337/db11-1778. Epub 2012 Jun 11.
- De Feyter HM, Mason GF, Shulman GI, Rothman DL, Petersen KF. Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. Diabetes. 2013 Sep;62(9):3075-80. doi: 10.2337/db13-0313. Epub 2013 May 28.
- Wiegers EC, Rooijackers HM, van Asten JJA, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Elevated brain glutamate levels in type 1 diabetes: correlations with glycaemic control and age of disease onset but not with hypoglycaemia awareness status. Diabetologia. 2019 Jun;62(6):1065-1073. doi: 10.1007/s00125-019-4862-9. Epub 2019 Apr 19.
- Maddock RJ, Casazza GA, Buonocore MH, Tanase C. Vigorous exercise increases brain lactate and Glx (glutamate+glutamine): a dynamic 1H-MRS study. Neuroimage. 2011 Aug 15;57(4):1324-30. doi: 10.1016/j.neuroimage.2011.05.048. Epub 2011 May 27.
- Wiegers EC, Rooijackers HM, Tack CJ, Groenewoud HJMM, Heerschap A, de Galan BE, van der Graaf M. Effect of Exercise-Induced Lactate Elevation on Brain Lactate Levels During Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia. Diabetes. 2017 Dec;66(12):3105-3110. doi: 10.2337/db17-0794. Epub 2017 Sep 21.
- Rooijackers HM, Wiegers EC, van der Graaf M, Thijssen DH, Kessels RPC, Tack CJ, de Galan BE. A Single Bout of High-Intensity Interval Training Reduces Awareness of Subsequent Hypoglycemia in Patients With Type 1 Diabetes. Diabetes. 2017 Jul;66(7):1990-1998. doi: 10.2337/db16-1535. Epub 2017 Apr 18.
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研究の完了 (実際)
試験登録日
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最終確認日
詳しくは
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