Although of small sample size, the study confirms prior results that continuous glucose monitoring helps avoid hypoglycemia in type 1 diabetes. Authors propose that improved endogenous glucose production during hypoglycemia is a partial molecular mechanism for a such benefit.
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J C E M
longitudinal
January 2018
Context
Patients with long-standing type 1 diabetes (T1D) are at increased risk for severe hypoglycemia because of defects in glucose counterregulation and recognition of hypoglycemia symptoms, in part mediated through exposure to hypoglycemia.
Objective
To determine whether implementation of real-time continuous glucose monitoring (CGM) as a strategy for hypoglycemia avoidance could improve glucose counterregulation in patients with long-standing T1D and hypoglycemia unawareness.
Design
Eleven patients with T1D disease duration of ∼31 years were studied longitudinally in the Clinical & Translational Research Center of the University of Pennsylvania before and 6 and 18 months after initiation of CGM and were compared with 12 nondiabetic control participants.
Main Outcome Measure
Endogenous glucose production (EGP) response derived from paired hyperinsulinemic stepped-hypoglycemic and euglycemic clamps with infusion of 6,6-2H2-glucose.
Results
In patients with T1D, hypoglycemia awareness (Clarke score) and severity (HYPO score and severe events) improved (P < 0.01 for all) without change in hemoglobin A1c (baseline, 7.2%).
In response to insulin-induced hypoglycemia, endogenous glucose production (EGP) did not change from before to 6 months (0.42, 0.54) but improved after 18 months (0.84), albeit remaining less than in controls (1.39).
Conclusions
Real-time CGM can improve awareness and reduce the burden of problematic hypoglycemia in patients with long-standing T1D, but with only modest improvement in the endogenous glucose production response that is required to prevent or correct low blood glucose.
More from the publication:
Patients with long-standing type 1 diabetes (T1D) are at increased risk for severe hypoglycemia because of defects in glucose counterregulation and recognition of hypoglycemia symptoms. This increased risk for severe hypoglycemia is related to the progressive development of compromised physiologic defense mechanisms against a falling plasma glucose concentration in the setting of therapeutic hyperinsulinemia.
The near-total destruction of insulin-producing β cells produces an associated defect in glucagon secretion from α cells in response to hypoglycemia, which leaves activation of the sympathoadrenal system as the only defense against hypoglycemia; epinephrine secretion contributes to endogenous (primarily hepatic) glucose production (EGP), and autonomic symptoms alert the individual to ingest food. Unfortunately, recurrent episodes of hypoglycemia blunt sympathoadrenal activation and produce a syndrome of hypoglycemia unawareness, also known as hypoglycemia-associated autonomic failure (HAAF). Once established, hypoglycemia unawareness in T1D is associated with a 20-fold increased risk for experiencing severe hypoglycemia, which contributes significantly to disease-related morbidity and mortality.
Real-time CGM is increasingly being used as a tool to help avoid hypoglycemia in T1D. CGM use in adults with T1D has been associated with modest reductions in hemoglobin A1c (HbA1c) (∼0.5%) from baseline levels >7.5%, especially for patients >25 years of age who use their glucose sensor at least 6 days per week. Although the demonstrated reductions in HbA1c seen with use of CGM have not been associated with increases in severe hypoglycemia, rates of severe hypoglycemic events were low in these trials, which were not designed to assess hypoglycemia in patients at increased risk for experiencing a severe episode.
Nevertheless, time spent in the hypoglycemic range by CGM has been shown to be significantly shorter with real-time use compared with self-monitoring of blood glucose (SMBG), and so CGM may help achieve hypoglycemia avoidance in patients with T1D complicated by hypoglycemia unawareness. In the current study, we sought to determine whether implementation of real-time CGM as a strategy for hypoglycemia avoidance could improve glucose counterregulation measured by the EGP response to insulin-induced hypoglycemia in patients with long-standing T1D complicated by hypoglycemia unawareness.
These results demonstrate that use of real-time CGM may be associated with reduction of problematic hypoglycemia in patients with long-standing T1D complicated by hypoglycemia unawareness, without deterioration in glycemic control.
Reductions in hypoglycemia unawareness, hypoglycemia severity, and the incidence of severe hypoglycemia events were documented after 6 months of intensive implementation of CGM and remained lower, in fact, during the subsequent 12 months of standard follow-up.
The current study supports recent guidelines to consider use of real-time CGM subsequent to educational intervention to address problematic hypoglycemia in T1D, and referring for consideration of pancreas or islet transplantation those patients in whom hypoglycemia unawareness and severe hypoglycemia events persist.
In conclusion, patients with long-standing T1D experiencing problematic hypoglycemia despite current intensive insulin management may benefit from effects of real-time CGM on improving awareness while reducing the burden and severity of hypoglycemia. These effects may in part be related to improvement in the EGP response to insulin-induced hypoglycemia, which is required to prevent or correct low blood glucose, but substantial residual defects in glucose counterregulation remain and will require alternative approaches to achieve more thorough recovery of defense mechanisms against the development of low blood glucose.