EXCEED THE SPACE PROVIDED. latrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes. The Pi's focus will ontinue to be on the mechanisms of hypoglycemia-associated autonomic failure (HAAF) in diabetes as we extend the findings from Original Aims 1-4 to Aims 5-8. The concept of HAAF posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to subsequent hypoglycemia in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the sympathoadrenal and the resulting neurogenic symptom responses to subsequent hypoglycemia) and, thus, a vicious cycle of recurrent hypoglycemia. We now plan to test four hypotheses:
Aim 5. A decrease in intraislet insulin is a signal for the normal glucagon response to hypoglycemia. If so, the absence of that signal would plausibly explain the loss of the glucagon response to hypoglycemia in insulin deficient diabetes.
Aim 6. Hypoglycemia sufficient to activate glucose counterregu- latory systems is a signal to glucose-sensitive brain neurons rather than a manifestation of brain metabolic fuel deprivation and, specifically, increased brain synaptic activity (rCBF measured with [15O]water and PET) is demonstrable in the medial prefrontal cortex, thalamus and periaqueductal grey at an arterial plasma glucose concentration of 65 mg/dL before but not after -24 hours of interprandialhypoglycemia. If so, wide- spread brain regions would be implicated in the pathogenesis of HAAF.
Aim 7. The epinephrine simulating p2-adrenergic agonist terbutaline more effectively prevents nocturnal hypoglycemia than a conventional bed- time snack or a commercially available bedtime snack containing uncooked cornstarch in type 1 diabetes.
Aim 8. Glucagon supports the postabsorptive plasma glucose concentration. If so, it may be key to the prevention of hypoglycemia. Insight into these basic issues in human pathophysiology can be expected to lead to clinical strategies that will improve the lives of people with diabetes in both the short- and long-term. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37DK027085-25
Application #
6965102
Study Section
Special Emphasis Panel (NSS)
Program Officer
Arreaza-Rubin, Guillermo
Project Start
1980-07-01
Project End
2010-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
25
Fiscal Year
2005
Total Cost
$382,500
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Cryer, Philip E (2015) Hypoglycemia-Associated Autonomic Failure in Diabetes: Maladaptive, Adaptive, or Both? Diabetes 64:2322-3
Cryer, Philip E (2013) Hypoglycemia-associated autonomic failure in diabetes. Handb Clin Neurol 117:295-307
Cryer, Philip E; Axelrod, Lloyd; Grossman, Ashley B et al. (2013) Diagnostic accuracy of an ""amended"" insulin-glucose ratio for the biochemical diagnosis of insulinomas. Ann Intern Med 158:500-1
Arbeláez, Ana María; Rutlin, Jerrel R; Hershey, Tamara et al. (2012) Thalamic activation during slightly subphysiological glycemia in humans. Diabetes Care 35:2570-4
Cryer, Philip E (2012) Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology 153:1039-48
Cryer, Philip E (2011) Death during intensive glycemic therapy of diabetes: mechanisms and implications. Am J Med 124:993-6
Cryer, Philip E (2011) Elimination of hypoglycemia from the lives of people affected by diabetes. Diabetes 60:24-7
Ramanathan, Ranjani; Cryer, Philip E (2011) Adrenergic mediation of hypoglycemia-associated autonomic failure. Diabetes 60:602-6
Cooperberg, Benjamin A; Cryer, Philip E (2010) Glucagon supports postabsorptive plasma glucose concentrations in humans with biologically optimal insulin levels. Diabetes 59:2941-4
Cryer, Philip E (2010) Hypoglycemia in type 1 diabetes mellitus. Endocrinol Metab Clin North Am 39:641-54

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