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. 2008 Sep;57(9):2259-68.
doi: 10.2337/db08-9023.

Bringing light to the dark side of insulin: a journey across the blood-brain barrier

Robert S Sherwin  1
Affiliations

Bringing light to the dark side of insulin: a journey across the blood-brain barrier

Robert S Sherwin. Diabetes. 2008 Sep.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Intensive insulin treatment alters the glucose threshold for epinephrine (EPI) release in response to insulin-induced hypoglycemia in patients with type 1 diabetes (T1DM).
FIG. 2.
FIG. 2.
Changes in VMH KATP channel activity modulate the counterregulatory hormone response to hypoglycemia via the local release of GABA.
FIG. 3.
FIG. 3.
Inhibition of AMPKα2 gene expression in the VMH with AAV RNA interference (AMPK shRNA) reduces glucagon and epinephrine release during hyperinsulinemic hypoglycemia. The upper panel shows the distribution of the virus following bilateral VMH microinjections of a green fluorescent protein (GFP)-tagged AAV-shAMPK; most GFP-positive neurons are located in the VMH rather than arcuate nucleus (ARC). (Please see http://dx.doi.org/10.2337/db08-9023 for a high-quality digital representation of this figure.).
FIG. 4.
FIG. 4.
Working model of VMH glucose sensing. Reciprocal changes in glucose-excited and glucose-inhibited neurons act in concert to stimulate or inhibit glucose counterregulation when blood glucose rises or falls.
FIG. 5.
FIG. 5.
Expanded VMH model for activation of glucose counterregulation to include stimulatory and inhibitory input from the CRF family of neuropeptides. The model posits that hypoglycemia provokes the activation of AMP kinase in VMH glucose-inhibited neurons. Simultaneously, the inhibitory neuronal inputs, urocortin III and GABA, are suppressed, and the CRF metabolic stress pathway is activated. Together, these changes act in concert to fully activate downstream neural pathways to restore glucose homeostasis.
FIG. 6.
FIG. 6.
Delivery of KCOs into the VMH reverses the suppressive effect of antecedent recurrent hypoglycemia on glucagon and epinephrine secretion. Three groups of rats were studied: control (open bars), recurrent hypoglycemic (shaded bars), and recurrent hypoglycemic plus bilateral VMH KCO microinjections (black bars).
FIG. 7.
FIG. 7.
Potential adaptive mechanisms for the development of defective glucose counterregulation based on the proposed VMH glucose-sensing model, including diminished AMP kinase activity in VMH glucose-inhibited neurons as well as increased activation of GABA and CRF2 receptor inhibitory neuronal circuits.
FIG. 8.
FIG. 8.
Influence over time of once weekly bouts of insulin-induced hypoglycemia (3 h) on memory performance in nondiabetic rats. Animals exposed to recurrent hypoglycemia (RH) and those given saline injections (controls) were tested 1 week after their last injection of insulin or saline when they were euglycemic.
FIG. 9.
FIG. 9.
The brain and islet work in concert to regulate glucose homeostasis. During hypoglycemia the brain serves as the dominant control center.
FIG. 10.
FIG. 10.
The brain and islet work in concert to regulate glucose homeostasis. During hyperglycemia the islet serves as the dominant control center.
FIG. 11.
FIG. 11.
The islet and brain see very disparate changes in local insulin levels during insulin-induced hypoglycemia. Although insulin levels rise in the VMH, a paradoxical decrease in insulin levels occurs within the islet due to the suppression of endogenous insulin secretion.
See this image and copyright information in PMC

References

    1. Saccà L, Hendler R, Sherwin RS: Hyperglycemia inhibits glucose production in man independent of changes in glucoregulatory hormones. J Clin Endocrinol Metab 47 :1160 –1163,1978 - PubMed
    1. Saccà, Sherwin RS, Hendler R, Felig P: Influence of continuous physiologic hyperinsulinemia on glucose kinetics and counterregulatory hormones in normal and diabetic humans. J Clin Invest 63 :849 –857,1979 - PMC - PubMed
    1. Tamborlane WV, Sherwin RS, Genel M, Felig P: Reduction to normal of plasma glucose in juvenile diabetes by subcutaneous administration of insulin with a portable infusionpump. N Engl J Med 300 :573 –578,1979 - PubMed
    1. Tamborlane WV, Sherwin RS, Genel M, Felig P: Restoration of normal lipid and amino acid metabolism in diabetic patients treated with a portable insulin pump. Lancet 1 :1258 –1261,1979 - PubMed
    1. Tamborlane WV, Hintz R, Bergman M, Genel M, Felig P, Sherwin RS: Insulin infusion pump treatment of diabetes: influence of improved metabolic control on plasma somatomedin levels. N Engl J Med 305 :303 –307,1981 - PubMed

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