Project Details
Description
Project Summary:
Integrated Approach to Close the Loop in Type 1 diabetes
We have established in the current grant cycle, that early prandial hyper-glucagonemia is a feature in
individuals with type 1 diabetes (T1D) contributing to prandial hyperglycemia. Likewise, plasma glucagon
concentrations do not rise appropriately in response to declining glucose concentrations in T1D, placing them
at risk for hypoglycemia. However, the causes of these abnormalities are speculated, but not proven to be due
to concomitant α cell dysfunction leading to abnormal glucagon secretion/kinetics. From a network-control
view-point, this effect amounts to a disruption of the intra-islet β-α cell feedback control, which we have
described in previous work. Therefore, our overarching goal in this application is to apply a novel isotope
dilution method we have recently developed, to measure in vivo glucagon kinetics in T1D subjects
across clinically relevant scenarios. This will allow quantifying the network deficiencies observed in T1D,
and will in turn enable the development of a sophisticated multi-hormonal closed loop artificial pancreas (AP)
taking into account the specifics of intra-islet functioning in health and in T1D. At any given time, plasma
glucagon concentrations reflect a net balance between the rates of glucagon secretion, its’ clearance and it’s
volume of distribution (VD). Unlike the C-peptide model that is used to measure insulin secretion, no such
model is available to measure glucagon kinetics. Hence, it has not been possible to directly and reliably
estimate these parameters in humans. Existing control algorithms utilizing glucagon in response to declining
glucose concentrations are based on indirect estimations of glucagon kinetics. To directly measure these
parameters, we will use novel tracer methods combined with organ catheterization technique, to determine
whether, and if so, how glucagon appearance, hepatic extraction, clearance and/or VD is altered in T1D during
post absorptive and postprandial states. Thereafter, we will determine systemic glucagon kinetics during
subcutaneous (sq) administration of glucagon in T1D, as that is after all, the clinically germane route of
administration of glucagon for multi-hormonal AP systems. These data will be used to estimate the parameters
of our intra-islet network model and a glucagon secretion model, which will then enable computer simulation
and AP algorithm design based on glucagon physiology in T1D. The algorithm will be designed to restore
physiological glucagon profiles by using inhibitors of glucagon secretion to prevent excessive early prandial
rise in glucagon and subsequent sq. glucagon infusions to restore apt late prandial rise in glucagon levels.
Status | Active |
---|---|
Effective start/end date | 9/30/09 → 4/30/24 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $717,961.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.