Glucagon-like peptide-2 (GLP-2) receptor expression in the central nervous system and gastrointestinal tract

grantor: University of TorontoThe gut-brain hormones, glucagon-like peptides-1 (GLP-1) and -2 (GLP-2) are synthesized from proglucagon in enteroendocrine cells and neurons, are secreted from the gut in response to nutrient ingestion and stimulate diverse actions to regulate energy homeostasis. GLP-1 and GLP-2 transduce their action through cognate membrane bound G-protein coupled receptors. GLP-2 induces trophic, anti-apoptotic and transit-modulating events in the gut, but GLP-2 action in the brain remains unexplored. To identify the components of the GLP-2/GLP-2 receptor axis in the CNS we undertook a combinatorial approach using (1) RT-PCR, (2) immunocytochemistry, and (3) transgenic models to study the expression and function of this axis in the brain in vivo. We studied the developing intestine and CNS to determine whether this axis was present and functional during periods of rapid growth and tissue development. We have described the spatial distribution of GLP-2 receptor expression throughout the adult rodent CNS, and identified 5'-regulatory sequences that confer tissue- and cell-specific expression to reporter genes in the CNS. We studied the central actions of GLP-2 on food intake, and demonstrated the satiating effects of a potent GLP-2 analogue, h[Gly2]-GLP-2. We examined the inter-relationship between central GLP-1 and GLP-2 responsive systems, and discovered functional interdependence of GLP-1R and GLP-2R signaling in the brain. In the neonatal rat intestine we detected substantial increases in the relative expression of GLP-2 and the GLP-2 receptor during gut development and demonstrated that GLP-2 is coupled to intestinal growth in the neonate. Both GLP-2 and GLP-2 receptor expression were detected in fetal and neonatal brain, and we demonstrated that cells isolated from the neonatal rat brainstem respond to GLP-2. Taken together, these studies demonstrate the functional expression of the GLP-2/GLP-2 receptor axis in the brain. Our finding of integrated GLP-1 and GLP-2 responsive neuronal systems extends current concepts of central GLP-1 and GLP-2 action and suggests new strategies for manipulating the actions of these two important regulators of energy homeostasis in the brain.Ph.D

Validity of a point-of-care nerve conduction device for polyneuropathy identification in older adults with diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes

<div><p>Objective</p><p>Point-of-care nerve conduction devices (POCD) have been studied in younger patients and may facilitate screening for polyneuropathy in non-specialized clinical settings. However, performance may be impaired with advanced age owing to age-related changes in nerve conduction. We aimed to evaluate the validity of a POCD as a proxy for standard nerve conduction studies (NCS) in older adults with type 1 diabetes (T1D).</p><p>Methods</p><p>Sural nerve amplitude potential (AMP) and sural nerve conduction velocity (CV) was measured in 68 participants with ≥ 50 years T1D duration and 71 controls (from age/sex-matched subgroups) using POCD and NCS protocols. Agreement was determined by the Bland-Altman method, and validity was determined by receiver operating characteristic curves.</p><p>Results</p><p>T1D were 53% female, aged 66±8yr and had diabetes duration 54yr[52,58]. Controls were 56%(p = 0.69) female and aged 65±8yr(p = 0.36). Mean AMP_POCD and CV_POCD for the 139 participants was 7.4±5.8μV and 45.7±11.2m/s and mean AMP_NCS and CV_NCS was 7.2±6.1μV and 43.3±8.3m/s. Mean difference of AMP_POCD−AMP_NCS was 0.3±3.8μV and was 2.3±8.5m/s for CV_POCD−CV_NCS. A AMP_POCD of ≤6μV had 80% sensitivity and 80% specificity for identifying abnormal AMP_NCS, while a CV_POCD of ≤44m/s had 81% sensitivity and 82% specificity to identify abnormal CV_NCS. Abnormality in AMP_POCD or CV_POCD was associated with 87% sensitivity, while abnormality in both measures was associated with 97% specificity for polyneuropathy identification.</p><p>Conclusions</p><p>The POCD has strong agreement and diagnostic accuracy for identification of polyneuropathy in a high-risk subgroup and thus may represent a sufficiently accurate and rapid test for routinely detecting those with electrophysiological dysfunction.</p></div