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Effects of GIP and GLP-1 on Glucagon Response in Type 1 Diabetes

Glucose-dependent insulinotropic polypeptide and glucagon- like peptide-1 have glucose-dependent effects on glucagon secretion but differ in their effects on type 1 and type 2 diabetes patients…

From various studies we know that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have glucose-dependent effects on glucagon secretion. GIP causes increased glucagon levels when fasting and when blood glucose becomes suboptimal. GLP-1 lowers glucagon while fasting or when blood glucose becomes elevated. In most type 1 diabetic patients, this counter regulatory effect on hypoglycemia that is insulin induced is absent, so the effect of incretin hormones in this case is not well known.

This study is a double-blinded, randomized, crossover study comparing the effects of GIP, GLP-1, and placebo (saline) on the glucagon response to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus. There were only 10 male participants (C-peptide neg, mean; age 26, BMI 24, A1c 7.3%) with T1DM.

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Each patient randomly underwent three separate study days with intervals of at least one week. Subjects were instructed to maintain a regular diet, avoid alcohol and demanding physical activity for 3 days prior to each study day. Subjects were asked to wear a Guardian REAL-time continuous glucose monitor for 2–4 days before each study day to monitor glycemic variability and help make therapeutic decisions in relation to food intake and insulin delivery.

Two hours before study start an infusion of stable isotopes was initiated (D2-glucose and D5- glycerol) and at the same time basal insulin intravenous infusion was initiated. At time 0 min, a 60-min. infusion of human insulin was initiated to lower plasma glucose. Also, at time 0 minutes, similar appearing infusions of GIP, GLP-1, or placebo (saline) were initiated and continued for the remainder of the study that day. Plasma glucose was measured bedside every 5 minutes.

Bedside glucose concentrations were measured by glucose oxidase method, and concentrations of intact GIP, total GLP-1, and glucagon were measured by specific immunoassays. Results were compared with healthy volunteers concentrations.

Area under the curve (AUC) and incremental AUC (iAUC) were calculated using the trapezoidal rule for detection of a real difference in glucagon responses. To test for differences in concentration time courses, a two-way repeated-measures ANOVA followed by Holm-S’dák corrected posttests was done. A two-sided P value <0.05 was used to indicate statistically significant differences.

Baseline plasma levels of glucagon were similar on all study days (P = 0.29). Glucagon responses expressed as AUC differed between study days (P <0.001). During the first hour, the glucagon iAUCs amounted to -88 ± 38 (GIP) vs. -166 ± 28 (GLP-1) vs. -49 ± 20 (saline) min · pmol/L (P <0.006), and during the second hour, the glucagon iAUCs amounted to 164 ± 50 (GIP) vs. 23 ± 25 (GLP-1) vs. 17 ± 46 (saline) min · pmol/L (P < 0.036). Therefore, during the insulin infusion during the first hour, glucagon iAUC was significantly lower on the GLP-1 days (P < 0.01 vs. saline), whereas during the “recovery period” (after termination of insulin infusion), there was a higher glucagon response on the GIP days (P < 0.02 vs. saline).

In T1DM without residual beta-cell function, GIP was shown to increase glucagon responses to experimental hypoglycemia and reduced the need for exogenous glucose administration to prevent severe hypoglycemia. This would be if accompanied by a high rate of endogenous glucose production, compared with placebo. They also reported that the GLP-1 infusion slightly suppressed plasma glucagon during induction of hypoglycemia, with no additional need for exogenous glucose administration during the time of the study.

Practice Pearls:

  • The mechanism of these effects could be the direct action of the incretin hormones on the alpha cell of the pancreas (demonstrated in rat pancreas studies).
  • There is not enough power to support this study due to such a small sample size, and there were large abrupt glucose infusions leading to analytical and modeling limitations so further studies and investigation may be needed.
  • The doses of GIP and GLP-1 that were used resulted in supra-physiological plasma levels in the subjects studied.

Mikkel Christensen, Salvatore Calanna, Alexander H. Sparre-Ulrich, et al. “Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes”. Diabetes Volume 64;72-78. January 2015