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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK020495-38
Application #
8731860
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Teff, Karen L
Project Start
1977-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
38
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Hwang, Janice Jin; Parikh, Lisa; Lacadie, Cheryl et al. (2018) Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia. J Clin Invest 128:1485-1495
Li, Nina Xiaoyan; Brown, Stacey; Kowalski, Tim et al. (2018) GPR119 Agonism Increases Glucagon Secretion During Insulin-Induced Hypoglycemia. Diabetes 67:1401-1413
Hwang, Janice J; Jiang, Lihong; Hamza, Muhammad et al. (2017) The human brain produces fructose from glucose. JCI Insight 2:e90508
Hwang, Janice J; Jiang, Lihong; Hamza, Muhammad et al. (2017) Blunted rise in brain glucose levels during hyperglycemia in adults with obesity and T2DM. JCI Insight 2:
Naik, Sarita; Belfort-DeAguiar, Renata; Sejling, Anne-Sophie et al. (2017) Evaluation of the counter-regulatory responses to hypoglycaemia in patients with type 1 diabetes during opiate receptor blockade with naltrexone. Diabetes Obes Metab 19:615-621
Jastreboff, Ania M; Sinha, Rajita; Arora, Jagriti et al. (2016) Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents. Diabetes 65:1929-39
Belfort-DeAguiar, R; Seo, D; Naik, S et al. (2016) Food image-induced brain activation is not diminished by insulin infusion. Int J Obes (Lond) 40:1679-1686
Hwang, Janice J; Yeckel, Catherine W; Gallezot, Jean-Dominique et al. (2015) Imaging human brown adipose tissue under room temperature conditions with (11)C-MRB, a selective norepinephrine transporter PET ligand. Metabolism 64:747-55
Jastreboff, Ania M; Sinha, Rajita; Lacadie, Cheryl M et al. (2015) Blunted striatal responses to favorite-food cues in smokers. Drug Alcohol Depend 146:103-6
Belfort-DeAguiar, Renata D; Naik, Sarita; Hwang, Janice et al. (2015) Inhaled Formoterol Diminishes Insulin-Induced Hypoglycemia in Type 1 Diabetes. Diabetes Care 38:1736-41

Showing the most recent 10 out of 118 publications