This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Increments in glucagon, in concert with decrements in insulin, play a key role in the prevention, as well as the correction, of clinical (i.e., symptomatic) hypoglycemia when plasma glucose concetration fall below the physiological range. The role of glucagon in maintenance of the postabsorptive plasma glucose concentration within the physiological range is less clear-cut. The prevalent view is that the postabsorptive plasma glucose concentration is maintained within the physiological range (70 to 110 mg/dL in humans) by the interplay of the glucose-lowering action of insulin and the glucose-raising action of glucagon. However, as detailes in the attached protocol, much of the evidence that seemingly supports that view, including our own, is open to alternative interpretations. Therfore, we plan to re-examine this issue - by testing the hypothesis that glucagon does not support the postabsorptive plasma glucose concentration in healthy humans - using the islet clamp technique, somatostatin (octreotide) infusion to suppress endogenous insulin and glucagon (and growth hormone) secretion alone, with insulin replacement, with glucagon replacement. We plan to first critically assess the components of the islet clamp technique and then to use it to test our hypothesis.
In Aim 8. 1 we will determine the glycemic effects, if any, and the plasma concentrations of the hormone doses selected (from the literature, from our experience and in view of our hypothesis) for basal replacement during islet clamps in healthy humans. Then, in Aim 8.2, we expect to confirm the glycemic responses to somastatin (here with the somatostatin analogue octreotide) alone and with insulin replacement and test our hypothesis further by also replacing glucagon and insulin plus glucagon. While the prevalent view may be correct, we believe that the alternative view that the postabsorptive plasma glucose concentration is maintained within the physiological range by insulin alone is plausible and, therefore, that this issue needs more definitive evidence in humans.
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