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Cold
As a consequence of the increasing prevalence of obesity, type 2 diabetes (T2D) and its associated cardiovascular complications have emerged as one of the leading causes of death in Western countries. Although more common lifestyle interventions such as exercise training programs and dietary regimes are effective, novel intervention options and treatment targets to improve insulin sensitivity, a major hallmark of T2D, are warranted to counter this epidemic.
Cold exposure is a novel lifestyle intervention with a great therapeutic potential which is increasingly gaining attention among the scientific community. Our observations thus far indicate that skeletal muscle activation during cold exposure, i.e. shivering, is a key pre-requisite for cold-induced improvements in glucose homeostasis in patients with T2D and overweight/obese individuals. In this regard, we have observed that prolonged (10-day), intermittent (6h/day), mild cold acclimation resulted in a marked ~40% increase in peripheral insulin sensitivity in type 2 diabetes patients (1). When, however, in a follow-up study we took measures to minimize/eliminate shivering, we failed to observe changes in insulin sensitivity (2). Based on these observations, our current research within DMRG exclusively focuses on the effects of shivering thermogenesis on metabolic health parameters in patients with T2D and individuals at risk of developing the disease. Important questions we aim to address through our research include ‘Can we use cold exposure as a lifestyle method to prevent and treat diabetes and co-morbidities linked to the disease?’, ‘How much cold exposure is enough to see clinically relevant results?’, ‘Do all individuals respond optimally to cold therapy?’ and ‘What are the underlying mechanisms of cold-induced improvements in metabolic health?’. Ultimately, we aim to unravel the therapeutic potential of cold in the management of type 2 diabetes and its co-morbidities, as well as to set a firm ground for further research into this topic.
- Hanssen MJ, Hoeks J, Brans B, van der Lans AA, Schaart G, van den Driessche JJ, et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat Med. 2015;21(8):863-5.
- Remie CME, Moonen MPB, Roumans KHM, Nascimento EBM, Gemmink A, Havekes B, et al. Metabolic responses to mild cold acclimation in type 2 diabetes patients. Nat Commun. 2021;12(1):1516.
Liver metabolism
Non-alcoholic fatty liver (NAFL), the excessive accumulation of fat in the liver in the absence of excessive alcohol consumption, is the most common liver disorder in western society and is strongly associated with insulin resistance and increases the risk for the development of type 2 diabetes mellitus. NAFL is thought to be the result of an imbalance between lipid storage (due to increased delivery and synthesis), and disposal. Little is known about how hepatic fat causes insulin resistance and knowledge on the importance of delivery, synthesis and disposal pathways in causing NAFL in humans is sparse. Gaining a better understanding of the mechanisms underlying hepatic fat accumulation and its relation to insulin resistance is crucial in the development of effective treatment and prevention strategies for type 2 diabetes and NAFL.
To this end, we develop and apply state-of-the art Magnetic Resonance Spectroscopy (MRS) techniques, including 1H-MRS for quantification of hepatic fat content and composition (fatty acid saturation) and determination of hepatic acetylcarnitine, 13C-MRS for quantification of hepatic glycogen levels, and 31P-MRS for determination of hepatic energy metabolites, such as ATP and inorganic phosphate. In our research, we combine this MR-methodology with other state-of-the art techniques, such as stable isotope methods, including the use of D2O for measurements of de novo lipogenesis (DNL) and gluconeogenesis, hyperinsulinemic-euglycemic clamp methodology to assess insulin sensitivity and PET-methodology to measure organ-specific glucose uptake.
In this research line we use lifestyle interventions and pharmaceutical interventions as tools to study the etiology of insulin resistance and type 2 diabetes focusing on the role of the liver. Our current research goals on liver metabolism are:
- Investigate the relation between hepatic fat storage and insulin-stimulated hepatic glucose uptake
- Investigate the metabolic effects of ketohexokinase inhibition in individuals with NAFL
- Investigate the importance of hepatic saturated fatty acid content and DNL in determining hepatic insulin resistance
- Investigate the role of overnight hepatic gluconeogenesis in prediabetes