The function of the autonomic nervous system in type 1 diabetes and in response to physiological and pharmacological modulations

Abstract

Type 1 diabetes is a chronic autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic beta cells, whereas type 2 diabetes is characterized by insulin resistance alone or combined with insufficient insulin production. Both types result in hyperglycemia. Prolonged hyperglycemic exposure can lead to several life-impairing microvascular complications, such as diabetic nephropathy, neuropathy, and retinopathy.Diabetic neuropathy is the most common complication of diabetes and can affect both peripheral and autonomic nerves and cause, e.g., distal symmetrical polyneuropathy (DSPN) and diabetic autonomic neuropathy (DAN). Whereas DSPN affects sensorimotor neurons in a "glove and stocking" pattern, DAN results in dysfunction and impaired regulation of several organ systems and autonomically innervated muscles. Diabetic neuropathies can be painful as well as non-painful.Glucagon-like peptide 1 receptor agonists (GLP-1 RA's) are used in the treatment of type 2 diabetes by stimulating insulin secretion and inhibiting glucagon secretion, resulting in a reduction of glucose levels. GLP-1 RA's have several extra-pancreatic effects, including anti-inflammatory, cardioprotective, and neuroprotective effects. In mice, topical administration of a GLP-1 RA has shown to prevent thinning of the neuroretina and promote neurogenesis in retinal cells. In humans, GLP-1 RA's are known to increase heart rate through autonomic stimulation mechanisms not yet fully understood. In this thesis, we investigate the effects of the GLP-1 RA liraglutide in individuals with long-term type 1 diabetes to assess the anti-inflammatory and neuroprotective effects, independently of the anti-hyperglycemic effects.The overall aims of this thesis were to study:1) The effects of long-term type 1 diabetes on autonomic nerves involved in neurocardiac regulation (Study I, III, and IV) 2) The effects of long-term type 1 diabetes on sympathetic nerves innervating the superior and inferior tarsal muscles (Study I) 3) The effects of the GLP-1 RA liraglutide on heart rate variability (HRV) and the retinal nerve fiber layer thickness in individuals with long-term type 1 diabetes and confirmed DSPN (Study II and IV)Paper I investigated the relationship between the sympathetically innervated tarsal muscles' response to phenylephrine (assessed as changes in palpebral fissure height) and HRV measures. The study aimed to examine if the phenylephrine-induced response in palpebral fissure height was associated with HRV measures and thus could be a potential marker of autonomic dysfunction in individuals with type 1 diabetes and DSPN. The phenylephrine-induced changes in palpebral fissure height were associated with autonomic function, diabetic retinopathy stage, and disease duration.