Caffeine Ingestion to Counter the Exercise-mediated Fall in Glycaemia in Type 1 Diabetes (DE-CAF)

Does Combined Caffeine and Carbohydrate Ingestion Counter the Exercise-mediated Fall in Glycaemia in Individuals With Type 1 Diabetes on Insulin Degludec? The DE-CAF Study

This project will aim to investigate the clinical efficacy and metabolic effects of a pre-exercise dose of caffeine with a low (10g) dose of carbohydrate (CAF+lowCHO) without modification of insulin degludec on exercise metabolism in people with T1D.

Treatment of type 1 diabetes (T1D) involves lifelong use of exogenous insulin to manage blood glucose concentration. As with the rest of the population, people living with T1D are recommended to engage in regular exercise for a variety of health and fitness reasons . However, glycaemic control during exercise remains a particular challenge for this population due to rapid changes in insulin sensitivity and the impact of additional hormones which increase the risk of exercise-related hypoglycaemia. Current guidelines to prevent exercise-induced hypoglycaemia suggest insulin dose reduction and/or ingestion of carbohydrates in the context of the exercise bout. However, these adaptations are often difficult to apply, as insulin dose adjustments require knowledge of insulin pharmacokinetics and advanced planning which is not always possible. None of these strategies provide complete assurance that hypoglycaemia will not occur and high carbohydrate intake can be counterproductive if weight management is the target. Furthermore, modern very long-acting insulin analogues, which are favoured by many people with T1D, do not offer the option to rapidly or transiently reduce insulin before exercise. When using such insulins, dose reductions may take two to three days to achieve an adapted steady state, increasing the risk of inadequate insulin following exercise. Collectively, these factors increase the risk of further deterring patients from exercise. Simple, alternative strategies to reduce the risk of hypoglycaemia, both during and after exercise are needed. Caffeine (1,3,7-trimethylxanthine) is the most commonly consumed chemical stimulant in the world that is naturally found in many foods and is frequently added to sports supplements due to its ergogenic effects in a range of sporting events. Caffeine has numerous physiological effects throughout the body including increased lipolysis in adipose tissues and hepatic glucose production in the liver alongside a decrease in glucose uptake in skeletal muscle. These responses have led to the suggestion that acute caffeine intake may attenuate exercise-associated hypoglycaemia in people with T1D. Ingestion of modest amounts of caffeine (200-250 mg, equivalent to 3-4 cups of coffee each day) has been shown to augment the symptomatic and hormonal responses to hypoglycaemia in participants with and without T1D. Caffeine has also been shown to reduce the frequency of moderate episodes of hypoglycaemia occurring overnight. The paucity of data on caffeine and exercise in individuals with T1D, in conjunction with caffeine's popularity both socially and as a sports supplement, suggests this deserves further attention. A clear example whereby caffeine supplementation may be of use is in patients using an ultra-long acting basal insulin analogue such as insulin degludec. The administration is via subcutaneous injection once daily, and it has a duration of action that lasts up to 42 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as insulin glargine and insulin detemir). On average, the half-life at steady state is approximately 25 hours independent of dose. Compared to the other basal insulin analogues, the risk of hypoglycaemia appears to be lower with insulin degludec, however, hypoglycaemia still occurs. In the case of physical exercise, the inability of the patient using such long-acting insulins to make rapid adjustments can translate to the occurrence of exercise-related hypoglycaemia due to an inability to reduce insulin already onboard, hence the need for new strategies to prevent this undesired phenomenon. When using such insulins, dose reductions may take two to three days to achieve an adapted steady state, increasing the risk of inadequate insulin following exercise. Applying a novel in-house developed lipid chromatography-mass spectrometry (LC-MS) assay, members of our research group observed that a single bout of aerobic exercise increases systemic insulin degludec concentrations in adults on stable basal insulin degludec regimens. Therefore, if these individuals wish to engage in regular exercise, as recommended in international guidelines, current treatment strategies may not be sufficient. For patients treated with modern basal insulin analogues, it seems more adequate not to modify the ultra-long acting insulin doses, as this can often result in more confusion than improvement, but to apply alternative strategies for recreational exercise. Caffeine ingestion pre or post exercise may offer a simple means to better manage glycaemia in the context of exercise in patients using these insulins and have the added benefit of reducing carbohydrate requirements in the context of exercise.

In each of the conditions, participants will receive a taste-matched drink containing either • caffeine and 10 g rapid-acting carbohydrate (CAF+lowCHO); 20 g rapid acting carbohydrate (20g CHO); or placebo. The drink will be made by an independent member of the research team to ensure that neither the investigators or participants know the order of the drinks (double-blind)

A drink containing caffeine and 10 g rapid-acting carbohydrate (glucose) dissolved in 200 mL of tap water

Change in blood glucose concentration, calculated based on the participants' glucose at the start of exercise and the last value measured at the end of exercise. If the exercise is stopped early because of hypoglycaemia, the last exercise glucose value will be used for analysis.

Incidence of hypoglycaemia (≤3.9 mmol/l for 15 min or more) during the 24 hour post exercise recovery period

The % time of glucose sensor measurements < 3.9 mmol/L in the night following the exercise visits will be documented

The % time of glucose sensor measurements > 10.0 mmol/L in the night following the exercise visits will be documented

The sensor glucose in mmol/L within 30 minutes following the exercise visits will be documented and the area under the curve will be calculated

Inclusion Criteria: Type 1 diabetes for ≥1 year and negative C-peptide (<100pmol/l) Male and female aged 18-45 years old HbA1c <8.5% (69 mmol/mol) based on analysis from the central laboratory unit of Bern University Hospital Using multiple daily injections Using insulin degludec (Tresiba; Novo Nordisk A/S, Bagsværd, Denmark) as basal insulin for a minimum of 3 months Written informed consent Able and willing to adhere to safe contraception during the study and for 2 weeks after completion of the study. Safe contraception comprises double barrier methods (hormonal contraception [like: oral contraceptive pills or intrauterine contraceptive devices] together with a mechanical barrier [like: condom, diaphragm]). Exclusion Criteria: Physical or psychological disease likely to interfere with the normal conduct of the study as judged by the investigator Continuous subcutaneous insulin infusion (using an insulin pump) Hypoglycaemic unawareness (Gold likert score ≥4) or having experienced any episode of a severe hypoglycaemic event within the last 6 months (i.e. need of third-party assistance). Current treatment with drugs known to interfere with metabolism e.g. systemic corticosteroids, SGLT2 inhibitors, Glucagon like 1 peptide- receptor agonists, or metformin. Relevant diabetic complications as judged by the investigator and based on medical record check (no cardiovascular disease and no significant microvascular disease) Microalbuminuria (as defined by area under the curve >30 mg/g) Body mass index more than or equal to 30 kg/m2 Uncontrolled hypertension (>180/100 mmHg) Pregnant or planning to become pregnant during the study period (females only) Breastfeeding

Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland

Brazeau AS, Rabasa-Lhoret R, Strychar I, Mircescu H. Barriers to physical activity among patients with type 1 diabetes. Diabetes Care. 2008 Nov;31(11):2108-9. doi: 10.2337/dc08-0720. Epub 2008 Aug 8.

Buzzetti R, Zampetti S, Pozzilli P. Impact of obesity on the increasing incidence of type 1 diabetes. Diabetes Obes Metab. 2020 Jul;22(7):1009-1013. doi: 10.1111/dom.14022. Epub 2020 Mar 24.

Campbell MD, Walker M, Bracken RM, Turner D, Stevenson EJ, Gonzalez JT, Shaw JA, West DJ. Insulin therapy and dietary adjustments to normalize glycemia and prevent nocturnal hypoglycemia after evening exercise in type 1 diabetes: a randomized controlled trial. BMJ Open Diabetes Res Care. 2015 May 12;3(1):e000085. doi: 10.1136/bmjdrc-2015-000085. eCollection 2015.

Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, Horton ES, Castorino K, Tate DF. Physical Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care. 2016 Nov;39(11):2065-2079. doi: 10.2337/dc16-1728. No abstract available.

Costill DL, Dalsky GP, Fink WJ. Effects of caffeine ingestion on metabolism and exercise performance. Med Sci Sports. 1978 Fall;10(3):155-8.

Debrah K, Sherwin RS, Murphy J, Kerr D. Effect of caffeine on recognition of and physiological responses to hypoglycaemia in insulin-dependent diabetes. Lancet. 1996 Jan 6;347(8993):19-24. doi: 10.1016/s0140-6736(96)91557-3.

Dedrick S, Sundaresh B, Huang Q, Brady C, Yoo T, Cronin C, Rudnicki C, Flood M, Momeni B, Ludvigsson J, Altindis E. The Role of Gut Microbiota and Environmental Factors in Type 1 Diabetes Pathogenesis. Front Endocrinol (Lausanne). 2020 Feb 26;11:78. doi: 10.3389/fendo.2020.00078. eCollection 2020.

Francescato MP, Geat M, Fusi S, Stupar G, Noacco C, Cattin L. Carbohydrate requirement and insulin concentration during moderate exercise in type 1 diabetic patients. Metabolism. 2004 Sep;53(9):1126-30. doi: 10.1016/j.metabol.2004.03.015.

Ganio MS, Klau JF, Casa DJ, Armstrong LE, Maresh CM. Effect of caffeine on sport-specific endurance performance: a systematic review. J Strength Cond Res. 2009 Jan;23(1):315-24. doi: 10.1519/JSC.0b013e31818b979a.

Graham TE, Sathasivam P, Rowland M, Marko N, Greer F, Battram D. Caffeine ingestion elevates plasma insulin response in humans during an oral glucose tolerance test. Can J Physiol Pharmacol. 2001 Jul;79(7):559-65.

Greer F, Hudson R, Ross R, Graham T. Caffeine ingestion decreases glucose disposal during a hyperinsulinemic-euglycemic clamp in sedentary humans. Diabetes. 2001 Oct;50(10):2349-54. doi: 10.2337/diabetes.50.10.2349.

Jackman M, Wendling P, Friars D, Graham TE. Metabolic catecholamine, and endurance responses to caffeine during intense exercise. J Appl Physiol (1985). 1996 Oct;81(4):1658-63. doi: 10.1152/jappl.1996.81.4.1658.

Kerr D, Sherwin RS, Pavalkis F, Fayad PB, Sikorski L, Rife F, Tamborlane WV, During MJ. Effect of caffeine on the recognition of and responses to hypoglycemia in humans. Ann Intern Med. 1993 Oct 15;119(8):799-804. doi: 10.7326/0003-4819-119-8-199310150-00005.

Kosinski C, Herzig D, Laesser CI, Nakas CT, Melmer A, Vogt A, Vogt B, Laimer M, Bally L, Stettler C. A Single Load of Fructose Attenuates the Risk of Exercise-Induced Hypoglycemia in Adults With Type 1 Diabetes on Ultra-Long-Acting Basal Insulin: A Randomized, Open-Label, Crossover Proof-of-Principle Study. Diabetes Care. 2020 Sep;43(9):2010-2016. doi: 10.2337/dc19-2250. Epub 2020 Jun 26.

Lane W, Bailey TS, Gerety G, Gumprecht J, Philis-Tsimikas A, Hansen CT, Nielsen TSS, Warren M; Group Information; SWITCH 1. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial. JAMA. 2017 Jul 4;318(1):33-44. doi: 10.1001/jama.2017.7115.

Lascar N, Kennedy A, Hancock B, Jenkins D, Andrews RC, Greenfield S, Narendran P. Attitudes and barriers to exercise in adults with type 1 diabetes (T1DM) and how best to address them: a qualitative study. PLoS One. 2014 Sep 19;9(9):e108019. doi: 10.1371/journal.pone.0108019. eCollection 2014.

Mayer-Davis EJ, Lawrence JM, Dabelea D, Divers J, Isom S, Dolan L, Imperatore G, Linder B, Marcovina S, Pettitt DJ, Pihoker C, Saydah S, Wagenknecht L; SEARCH for Diabetes in Youth Study. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012. N Engl J Med. 2017 Apr 13;376(15):1419-1429. doi: 10.1056/NEJMoa1610187.

Richardson T, Thomas P, Ryder J, Kerr D. Influence of caffeine on frequency of hypoglycemia detected by continuous interstitial glucose monitoring system in patients with long-standing type 1 diabetes. Diabetes Care. 2005 Jun;28(6):1316-20. doi: 10.2337/diacare.28.6.1316.

Riddell MC, Gallen IW, Smart CE, Taplin CE, Adolfsson P, Lumb AN, Kowalski A, Rabasa-Lhoret R, McCrimmon RJ, Hume C, Annan F, Fournier PA, Graham C, Bode B, Galassetti P, Jones TW, Millan IS, Heise T, Peters AL, Petz A, Laffel LM. Exercise management in type 1 diabetes: a consensus statement. Lancet Diabetes Endocrinol. 2017 May;5(5):377-390. doi: 10.1016/S2213-8587(17)30014-1. Epub 2017 Jan 24. Erratum In: Lancet Diabetes Endocrinol. 2017 May;5(5):e3.

Rogers MAM, Kim C, Banerjee T, Lee JM. Fluctuations in the incidence of type 1 diabetes in the United States from 2001 to 2015: a longitudinal study. BMC Med. 2017 Nov 8;15(1):199. doi: 10.1186/s12916-017-0958-6.

Watson JM, Jenkins EJ, Hamilton P, Lunt MJ, Kerr D. Influence of caffeine on the frequency and perception of hypoglycemia in free-living patients with type 1 diabetes. Diabetes Care. 2000 Apr;23(4):455-9. doi: 10.2337/diacare.23.4.455. Erratum In: Diabetes Care 2000 Oct;23(10):1598.

Silink M. Childhood diabetes: a global perspective. Horm Res. 2002;57 Suppl 1:1-5. doi: 10.1159/000053304.

Wysham C, Bhargava A, Chaykin L, de la Rosa R, Handelsman Y, Troelsen LN, Kvist K, Norwood P. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial. JAMA. 2017 Jul 4;318(1):45-56. doi: 10.1001/jama.2017.7117.

Zaharieva DP, Miadovnik LA, Rowan CP, Gumieniak RJ, Jamnik VK, Riddell MC. Effects of acute caffeine supplementation on reducing exercise-associated hypoglycaemia in individuals with Type 1 diabetes mellitus. Diabet Med. 2016 Apr;33(4):488-96. doi: 10.1111/dme.12857. Epub 2015 Aug 18.

Zaharieva DP, Riddell MC. Caffeine and glucose homeostasis during rest and exercise in diabetes mellitus. Appl Physiol Nutr Metab. 2013 Aug;38(8):813-22. doi: 10.1139/apnm-2012-0471. Epub 2013 May 14.