Hypoglycemia remains the major factor limiting the use of the intensified insulin therapy shown to prevent or delay the long-term complications in type 1 diabetes (T1DM). This proposal seeks continued support of a grant with the long-term goal of developing novel strategies to minimize the risk of hypoglycemia in T1DM patients.
The specific aims outlined below use functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) in conjunction with the glucose clamp technique to assess the changes in brain function, neurotransmission and fuel metabolism causing the syndrome of hypoglycemia unawareness in T1DM. The protocols rely heavily, where possible, on human investigation involving non-diabetic and T1DM subjects exposed to experimental hypoglycemia. However, we also take advantage of the power of rodent models to test specific mechanistic hypotheses. The primary hypothesis of this proposal is that hypoglycemia unaware T1DM patients not only have impaired hormonal responses, but also lack another key hypoglycemia defense mechanism, i.e. the capacity to activate motivation/reward circuits stimulating the drive to eat. Furthermore, we test the hypothesis that these changes are mediated by adaptive increases in brain lactate metabolism induced by antecedent hypoglycemia that directly or indirectly increase GABA tone. The result is inhibition of neural circuits driving glucose counterregulation and motivation for food during hypoglycemia, while reducing the ability to act in accordance with internal drives.
The specific aims are to: 1) determine if T1DM patients with hypoglycemia unawareness (vs. T1DM and non-diabetic controls) lose the capacity to normally activate both striatal and hypothalamic neurocircuits and deactivate pre-frontal and anterior cingulate cortex (ACC) executive control in response to food cues during mild and moderate hypoglycemia. Follow-up studies will explore whether closed-loop insulin delivery can reverse these changes in brain activation in unaware T1DM patients;2) determine if patients with T1DM and hypoglycemia unawareness display increased GABA concentration in the striatum, and ACC in the basal state and following acute hypoglycemia using proton MRS and if this is accompanied by increased brain lactate levels during hypoglycemia. We will also develop MRS methods at 7 Tesla to assess GABA levels in the hypothalamus in hypoglycemia unaware T1DM patients;and 3) examine the specific changes in brain fuel metabolism responsible for increased brain GABA concentration in T1DM patients. For this purpose, rats exposed to recurrent hypoglycemia will be studied using a hyperinsulinemic hypoglycemic clamp, MRS, and 3-13C-lactate to measure rates of lactate transport and metabolism, GABA synthesis as well as GABA and lactate concentrations in high-powered microwave irradiated tissue (to stop metabolism) in striatum, hypothalamus, and frontal cortex derived from awake rats. Follow-up studies test if, by decreasing or increasing brain lactate delivery, we alter GABA synthesis.
The benefits of intensified insulin therapy in T1DM are limited by higher rates of severe hypoglycemia, often occurring without warning symptoms and the failure of patients to take corrective action by eating. As a result, many patients do not achieve target glycemic goals, because their immediate fear of hypoglycemia exceeds their fear of long-term complications. Thus, understanding the pathophysiological mechanisms underlying hypoglycemia unawareness is essential both for prevention of brain injury and more effective T1DM treatment.
|Szepietowska, Barbara; Horvath, Tamas L; Sherwin, Robert S (2014) Role of synaptic plasticity and EphA5-ephrinA5 interaction within the ventromedial hypothalamus in response to recurrent hypoglycemia. Diabetes 63:1140-7|
|Sun, Xue; Veldhuizen, Maria G; Wray, Amanda E et al. (2014) The neural signature of satiation is associated with ghrelin response and triglyceride metabolism. Physiol Behav 136:63-73|
|Belfort-Deaguiar, Renata; Constable, R Todd; Sherwin, Robert S (2014) Functional MRI signal fluctuations: a preclinical biomarker for cognitive impairment in type 2 diabetes? Diabetes 63:396-8|
|Paranjape, S A; Chan, O; Zhu, W et al. (2013) Improvement in hepatic insulin sensitivity after Roux-en-Y gastric bypass in a rat model of obesity is partially mediated via hypothalamic insulin action. Diabetologia 56:2055-8|
|Gulanski, Barbara I; De Feyter, Henk M; Page, Kathleen A et al. (2013) Increased brain transport and metabolism of acetate in hypoglycemia unawareness. J Clin Endocrinol Metab 98:3811-20|
|Lebastchi, Jasmin; Deng, Songyan; Lebastchi, Amir H et al. (2013) Immune therapy and *-cell death in type 1 diabetes. Diabetes 62:1676-80|
|Chan, Owen; Sherwin, Robert (2013) Influence of VMH fuel sensing on hypoglycemic responses. Trends Endocrinol Metab 24:616-24|
|Page, Kathleen A; Chan, Owen; Arora, Jagriti et al. (2013) Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA 309:63-70|
|Beall, Craig; Haythorne, Elizabeth; Fan, Xiaoning et al. (2013) Continuous hypothalamic K(ATP) activation blunts glucose counter-regulation in vivo in rats and suppresses K(ATP) conductance in vitro. Diabetologia 56:2088-92|
|McNay, Ewan C; Teske, Jennifer A; Kotz, Catherine M et al. (2013) Long-term, intermittent, insulin-induced hypoglycemia produces marked obesity without hyperphagia or insulin resistance: a model for weight gain with intensive insulin therapy. Am J Physiol Endocrinol Metab 304:E131-8|
Showing the most recent 10 out of 93 publications