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Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes

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ABSTRACT

Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal. In protocol 1, a full counterregulatory response was allowed, whereas in protocol 2, glucagon was fixed at basal, mimicking the diminished α-cell response to hypoglycemia seen in T1DM. In protocol 1, glucose fell faster with Pe insulin than with Po insulin, reaching 56 ± 3 vs. 70 ± 6 mg/dL (P = 0.04) at 60 min. The change in area under the curve (ΔAUC) for glucagon was similar between Pe and Po, but the peak occurred earlier in Pe. The ΔAUC for epinephrine was greater with Pe than with Po (67 ± 17 vs. 36 ± 14 ng/mL/180 min). In protocol 2, glucose also fell more rapidly than in protocol 1 and fell faster in Pe than in Po, reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. Without a rise in glucagon, the epinephrine responses were much larger (ΔAUC of 204 ± 22 for Pe vs. 96 ± 29 ng/mL/180 min for Po). In summary, Pe insulin delivery exacerbates hypoglycemia, particularly in the presence of a diminished glucagon response. Po vein insulin delivery, or strategies that mimic it (i.e., liver-preferential insulin analogs), should therefore lessen hypoglycemia.

No MeSH data available.


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Arterial plasma glucose concentrations (A), endogenous Ra (B), Rd (C), net hepatic glucose output (D), nonhepatic glucose uptake (E), net hepatic glycogenolytic flux (F), and net hepatic gluconeogenic flux (G) for Pr2 in 18-h-fasted, conscious dogs during the basal (−20 to 0 min), experimental (0 to 180 min), and recovery (180 to 300 min) periods (mean ± SEM). *P < 0.05 between groups. Inf, infusion; G6P, glucose-6-phosphate.
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Figure 5: Arterial plasma glucose concentrations (A), endogenous Ra (B), Rd (C), net hepatic glucose output (D), nonhepatic glucose uptake (E), net hepatic glycogenolytic flux (F), and net hepatic gluconeogenic flux (G) for Pr2 in 18-h-fasted, conscious dogs during the basal (−20 to 0 min), experimental (0 to 180 min), and recovery (180 to 300 min) periods (mean ± SEM). *P < 0.05 between groups. Inf, infusion; G6P, glucose-6-phosphate.

Mentions: In Pr2, using the same insulin infusion rate as in Pr1 but with glucagon clamped, the fall in glucose was faster regardless of the route of insulin delivery. As in Pr1, however, glucose fell more rapidly with Pe than with Po insulin (Fig. 5A), reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. A nadir of ∼40 mg/dL was reached 60 min into the Pe insulin infusion compared with ∼45 mg/dL at 150 min with the Po insulin infusion. Five dogs in the Pe group versus one in the Po group required a low-rate glucose infusion (average 0.08 mg/kg/min vs. 0.02 mg/kg/min, respectively) to maintain glucose ≥40 mg/dL. Glucose rose more slowly in the recovery period in Pr2 than in Pr1 because the insulin infusion was returned to basal rather than being stopped.


Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes
Arterial plasma glucose concentrations (A), endogenous Ra (B), Rd (C), net hepatic glucose output (D), nonhepatic glucose uptake (E), net hepatic glycogenolytic flux (F), and net hepatic gluconeogenic flux (G) for Pr2 in 18-h-fasted, conscious dogs during the basal (−20 to 0 min), experimental (0 to 180 min), and recovery (180 to 300 min) periods (mean ± SEM). *P < 0.05 between groups. Inf, infusion; G6P, glucose-6-phosphate.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4587648&req=5

Figure 5: Arterial plasma glucose concentrations (A), endogenous Ra (B), Rd (C), net hepatic glucose output (D), nonhepatic glucose uptake (E), net hepatic glycogenolytic flux (F), and net hepatic gluconeogenic flux (G) for Pr2 in 18-h-fasted, conscious dogs during the basal (−20 to 0 min), experimental (0 to 180 min), and recovery (180 to 300 min) periods (mean ± SEM). *P < 0.05 between groups. Inf, infusion; G6P, glucose-6-phosphate.
Mentions: In Pr2, using the same insulin infusion rate as in Pr1 but with glucagon clamped, the fall in glucose was faster regardless of the route of insulin delivery. As in Pr1, however, glucose fell more rapidly with Pe than with Po insulin (Fig. 5A), reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. A nadir of ∼40 mg/dL was reached 60 min into the Pe insulin infusion compared with ∼45 mg/dL at 150 min with the Po insulin infusion. Five dogs in the Pe group versus one in the Po group required a low-rate glucose infusion (average 0.08 mg/kg/min vs. 0.02 mg/kg/min, respectively) to maintain glucose ≥40 mg/dL. Glucose rose more slowly in the recovery period in Pr2 than in Pr1 because the insulin infusion was returned to basal rather than being stopped.

View Article: PubMed Central - PubMed

ABSTRACT

Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal. In protocol 1, a full counterregulatory response was allowed, whereas in protocol 2, glucagon was fixed at basal, mimicking the diminished &alpha;-cell response to hypoglycemia seen in T1DM. In protocol 1, glucose fell faster with Pe insulin than with Po insulin, reaching 56 &plusmn; 3 vs. 70 &plusmn; 6 mg/dL (P = 0.04) at 60 min. The change in area under the curve (&Delta;AUC) for glucagon was similar between Pe and Po, but the peak occurred earlier in Pe. The &Delta;AUC for epinephrine was greater with Pe than with Po (67 &plusmn; 17 vs. 36 &plusmn; 14 ng/mL/180 min). In protocol 2, glucose also fell more rapidly than in protocol 1 and fell faster in Pe than in Po, reaching 41 &plusmn; 3 vs. 67 &plusmn; 2 mg/dL (P &lt; 0.01) by 60 min. Without a rise in glucagon, the epinephrine responses were much larger (&Delta;AUC of 204 &plusmn; 22 for Pe vs. 96 &plusmn; 29 ng/mL/180 min for Po). In summary, Pe insulin delivery exacerbates hypoglycemia, particularly in the presence of a diminished glucagon response. Po vein insulin delivery, or strategies that mimic it (i.e., liver-preferential insulin analogs), should therefore lessen hypoglycemia.

No MeSH data available.


Related in: MedlinePlus