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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 concentrations and ΔAUC for glucagon (A and B), epinephrine (C and D), norepinephrine (E and F), and cortisol (G and H) for Pr1 in 18-h-fasted 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.
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Figure 4: Arterial plasma concentrations and ΔAUC for glucagon (A and B), epinephrine (C and D), norepinephrine (E and F), and cortisol (G and H) for Pr1 in 18-h-fasted 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.

Mentions: The ΔAUC for hepatic sinusoidal plasma glucagon was similar between Pe and Po insulin infusion (2.7 ± 0.8 vs. 2.4 ± 0.4 ng/mL/180 min, P = 0.81) (Fig. 4B), but glucagon peaked earlier with Pe insulin infusion (median [interquartile range] time to peak 60 [60–90] vs. 120 [90–120] min, P = 0.007) (Fig. 4A). The ΔAUC for arterial plasma epinephrine in the Pe insulin infusion group tended to be higher (67 ± 17 vs. 37 ± 14 ng/mL/180 min, Pe vs. Po, P = 0.32) (Fig. 4D) and tended to peak earlier (120 vs. 180 min, P = 0.22) (Fig. 4C). Norepinephrine rose steadily and similarly in both groups (Fig. 4E and F). The arterial plasma cortisol response to hypoglycemia was also similar in both groups (ΔAUC 1,038 ± 185 vs. 860 ± 171 µg/dL/180 min, P = 0.46) and peaked at the same time (90 min) (Fig. 4G and H). The counterregulatory hormone levels returned to baseline during the recovery period.


Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes
Arterial plasma concentrations and ΔAUC for glucagon (A and B), epinephrine (C and D), norepinephrine (E and F), and cortisol (G and H) for Pr1 in 18-h-fasted 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.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4587648&req=5

Figure 4: Arterial plasma concentrations and ΔAUC for glucagon (A and B), epinephrine (C and D), norepinephrine (E and F), and cortisol (G and H) for Pr1 in 18-h-fasted 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.
Mentions: The ΔAUC for hepatic sinusoidal plasma glucagon was similar between Pe and Po insulin infusion (2.7 ± 0.8 vs. 2.4 ± 0.4 ng/mL/180 min, P = 0.81) (Fig. 4B), but glucagon peaked earlier with Pe insulin infusion (median [interquartile range] time to peak 60 [60–90] vs. 120 [90–120] min, P = 0.007) (Fig. 4A). The ΔAUC for arterial plasma epinephrine in the Pe insulin infusion group tended to be higher (67 ± 17 vs. 37 ± 14 ng/mL/180 min, Pe vs. Po, P = 0.32) (Fig. 4D) and tended to peak earlier (120 vs. 180 min, P = 0.22) (Fig. 4C). Norepinephrine rose steadily and similarly in both groups (Fig. 4E and F). The arterial plasma cortisol response to hypoglycemia was also similar in both groups (ΔAUC 1,038 ± 185 vs. 860 ± 171 µg/dL/180 min, P = 0.46) and peaked at the same time (90 min) (Fig. 4G and H). The counterregulatory hormone levels returned to baseline during the recovery period.

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