Genetic ablation of synaptotagmin-9 alters tomosyn-1 function to increase insulin secretion from pancreatic ß-cells improving glucose clearance.

Stimulus-coupled insulin secretion from the pancreatic islet ß-cells involves the fusion of insulin granules to the plasma membrane (PM) via SNARE complex formation-a cellular process key for maintaining whole-body glucose homeostasis. Less is known about the role of endogenous inhibitors of SNARE complexes in insulin secretion. We show that an insulin granule protein synaptotagmin-9 (Syt9) deletion in mice increased glucose clearance and plasma insulin levels without affecting insulin action compared to the control mice. Upon glucose stimulation, increased biphasic and static insulin secretion were observed from ex vivo islets due to Syt9 loss. Syt9 colocalizes and binds with tomosyn-1 and the PM syntaxin-1A (Stx1A); Stx1A is required for forming SNARE complexes. Syt9 knockdown reduced tomosyn-1 protein abundance via proteasomal degradation and binding of tomosyn-1 to Stx1A. Furthermore, Stx1A-SNARE complex formation was increased, implicating Syt9-tomosyn-1-Stx1A complex is inhibitory in insulin secretion. Rescuing tomosyn-1 blocked the Syt9-knockdown-mediated increases in insulin secretion. This shows that the inhibitory effects of Syt9 on insulin secretion are mediated by tomosyn-1. We report a molecular mechanism by which ß-cells modulate their secretory capacity rendering insulin granules nonfusogenic by forming the Syt9-tomosyn-1-Stx1A complex. Altogether, Syt9 loss in ß-cells decreases tomosyn-1 protein abundance, increasing the formation of Stx1A-SNARE complexes, insulin secretion, and glucose clearance. These outcomes differ from the previously published work that identified Syt9 has either a positive or no effect of Syt9 on insulin secretion. Future work using ß-cell-specific deletion of Syt9 mice is key for establishing the role of Syt9 in insulin secretion.

Temporal summation of mechanical pain prospectively predicts movement-evoked pain severity in adults with chronic low back pain.

BACKGROUND: Biopsychosocial factors above and beyond pathoanatomical changes likely contribute to the severity of chronic low back pain. A pro-nociceptive endogenous pain modulatory balance (↓inhibition and ↑facilitation) may be an important contributor to chronic low back pain severity and physical function; however, additional research is needed to address this possibility. The objective of this study was to determine whether quantitative sensory tests of endogenous pain inhibition and facilitation prospectively predict movement-evoked pain and cLBP severity self-reported on a validated questionnaire. METHODS: One hundred thirty-four individuals with chronic low back pain were enrolled in this two-session study. During the first study session, temporal summation of mechanical pain and conditioned pain modulation were assessed at the lumbar spine to determine endogenous pain facilitation and inhibition, respectively. One week later, participants returned for a second study session whereby they reported their pain severity and pain interference using the Brief Pain Inventory-Short Form. Movement-evoked pain and physical function capacity were assessed upon completion of the balance, walking, and transition from sit to stand tests of the Short Physical Performance Battery. RESULTS: Temporal summation of mechanical pain, but not conditioned pain modulation, significantly and prospectively predicted greater movement-evoked pain and poorer physical function on the Short Physical Performance Battery. Neither temporal summation nor conditioned pain modulation were significantly related to self-reported pain severity or pain interference on the Brief Pain Inventory-Short Form. CONCLUSIONS: Findings suggest that a pro-nociceptive pain modulatory balance characterized by enhanced pain facilitation may be an important driver of movement-evoked pain severity and poor physical function in individuals with chronic low back pain.

Race, Social Status, and Depressive Symptoms: A Moderated Mediation Analysis of Chronic Low Back Pain Interference and Severity.

BACKGROUND: Chronic low back pain (cLBP) is the leading cause of disability, with a significant societal cost. It disproportionately affects non-Hispanic blacks and individuals of lower socioeconomic status. The biopsychosocial framework has been used to study and manage cLBP, yet disparities persist. OBJECTIVE: The objective of this study was to assess whether self-identified race moderated the relationship between perceived social status and cLBP outcomes (pain interference and pain severity) and investigate whether race moderated the indirect relationship between perceived social status and pain outcomes via depressive symptoms. METHODS: Fifty-seven blacks and 48 whites with cLBP were recruited as part of a large ongoing study. Depressive symptoms, objective and subjective measures of socioeconomic status, and pain outcomes were measured. Hayes' moderated mediation model was used to estimate conditional direct and indirect relationship between these variables. RESULT: On average black participants reported significantly more pain interference (4.12 [SD=2.65] vs. 2.95 [SD=2.13]) and severity (5.57 [SD=2.27] vs. 3.99 [SD=1.99]) than white participants, (P<0.05). Race moderated the association between perceived social status and pain interference: higher social status decreases pain interference for white participants, but that trend was not observed in black participants. Moreover, race moderated association of perceived social status with depressive symptoms (P<0.001); which mediates the effects of perceived social status on pain outcomes. CONCLUSION: Higher perceived social status is associated with less severe depressive symptoms, which in turn is associated with less pain severity and less pain interference for whites but not for blacks with cLBP.

Perceived Injustice Helps Explain the Association Between Chronic Pain Stigma and Movement-Evoked Pain in Adults with Nonspecific Chronic Low Back Pain.

OBJECTIVE: For most patients with chronic low back pain (cLBP), the cause is "nonspecific," meaning there is no clear association between pain and identifiable pathology of the spine or associated tissues. Laypersons and providers alike are less inclined to help, feel less sympathy, dislike patients more, suspect deception, and attribute lower pain severity to patients whose pain does not have an objective basis in tissue pathology. Because of these stigmatizing responses from others, patients with cLBP may feel that their pain is particularly unjust and unfair. These pain-related injustice perceptions may subsequently contribute to greater cLBP severity. The purpose of this study was to examine whether perceived injustice helps explain the relationship between chronic pain stigma and movement-evoked pain severity among individuals with cLBP. METHODS: Participants included 105 patients with cLBP who completed questionnaires assessing chronic pain stigma and pain-related injustice perception, as well as a short physical performance battery for the assessment of movement-evoked pain and physical function. RESULTS: Findings revealed that perceived injustice significantly mediated the association between chronic pain stigma and cLBP severity (indirect effect = 6.64, 95% confidence interval [CI] = 2.041 to 14.913) and physical function (indirect effect = -0.401, 95% CI = -1.029 to -0.052). Greater chronic pain stigma was associated with greater perceived injustice (P = 0.001), which in turn was associated with greater movement-evoked pain severity (P = 0.003). CONCLUSIONS: These results suggest that perceived injustice may be a means through which chronic pain stigma impacts nonspecific cLBP severity and physical function.