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Bringing Light to the Dark Side of Insulin

A Journey Across the Blood-Brain Barrier

From the Department of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, Connecticut

Corresponding author: Robert S. Sherwin, robert.sherwin@yale.edu

The first 300 words of the full text of this article appear below.

I think it's remarkable that only a few months after Banting introduced insulin to the world of diabetes, on the heels of one of medicine's greatest discoveries, Elliot Joslin wrote, "insulin is not a cure for diabetes, but a potent preparation alike . . . for evil and for good." Today, 85 years later, with all the advances in insulin therapy, there is still a dark side to this potent preparation, and it is hypoglycemia. Hypoglycemia is the major barrier preventing insulin from achieving its full, therapeutic promise.

My story begins 30 years ago. Bill Tamborlane came to me with a portable, battery-powered pump being used in pediatrics to infuse the iron-chelating drug desferrioxamine continuously via the subcutaneous route into children with thalassemia major. He hoped to use it to treat children with glycogen storage disease, a study we never performed. This relatively small pump, the Autosyringe Model AS2C, was at that time relatively unique. It had an "instant dose" button that allowed for bolus dose administration as well as the ability to deliver solutions continuously. In short, it was a "perfect" vehicle to infuse insulin in diabetes. Improved glucose control had been demonstrated earlier in the inpatient setting in type 1 diabetic patients given continuous intravenous insulin delivered at preprogrammed basal rates with increments before meals. Such systems were not practical outside of a controlled environment. This device, however, was small enough to be used for continuous subcutaneous insulin delivery.

My enthusiasm for this idea was based on experiments Luigi Sacca and I performed 2 years earlier in the mid 1970s. We demonstrated that overnight basal insulin infusion in doses sufficient to normalize fasting glucose the next morning restored the ability of hyperglycemia to suppress hepatic glucose production in type 1 diabetic patients, despite their failure to release insulin . . . [Full Text of this Article]

	WHERE IN THE BRAIN IS THE GLUCOSE SENSOR?

 

	WHAT MECHANISMS DOES THE VMH USE TO ACTIVATE COUNTERREGULATION?

 
K_ATP channel activity.

	HOW DO CHANGES IN VMH KATP CHANNEL ACTIVITY MODULATE GLUCOSE COUNTEREGULATION?

 
AMP kinase activity.

	HOW DO THESE STUDIES ALL FIT TOGETHER?

 
Corticotropin-releasing factor receptors.

	WHY DOES HYPOGLYCEMIA BEGET MORE HYPOGLYCEMIA?

 
Reduced VMH K_ATP channel activity.
Increased VMH GABAergic inhibitory tone.
Increased VMH CRF2 receptor activity.
Suppressed VMH AMP kinase activity.

	WHY DOES HYPOGLYCEMIA BEGET HYPOGLYCEMIA?

 
Lessons learned from my journey.

	WHY WOULD THE BRAIN ADAPT TO RECURRENT HYPOGLYCEMIA BY BECOMING MORE VULNERABLE TO IT?

 

	DO HYPOGLYCEMIA-INDUCED ADAPTATIONS IN BRAIN FUEL METABOLISM PROTECT IT FROM INJURY?

 

	VIEW OF GLUCOSE HOMEOSTASIS FROM ACROSS THE BLOOD-BRAIN BARRIER

 

	POSTSCRIPT

 

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