Muscle microvascular recruitment predicts insulin sensitivity in middle-aged patients with type 1 diabetes mellitus

Abstract

Aims/hypothesis: Insulin delivery to muscle is rate-limiting for insulin's metabolic action and is regulated by insulin's own action to increase skeletal muscle blood flow and to recruit microvasculature. Microvascular dysfunction has been observed in insulin resistant states. We investigated the relation between insulin's action to recruit microvasculature and its metabolic action in type 1 diabetes.

Methods: Near euglycaemia was obtained by an overnight insulin infusion during 17 inpatient admissions of participants with type 1 diabetes. This was followed by a 2 h 1 mU kg⁻¹ min⁻¹ euglycaemic-hyperinsulinaemic clamp. Microvascular blood volume (MBV) was assessed using contrast-enhanced ultrasound 10 min before and 30 min after starting the clamp.

Results: We observed that, after overnight modest hyperinsulinaemia (average ≈ 286 pmol/l), MBV was positively related to the steady-state insulin sensitivity measured during the subsequent clamp (r = 0.62, p = 0.008). The more marked hyperinsulinaemia during the clamp (average steady-state insulin ≈ 900 pmol/l) increased MBV in the more insulin resistant participants within 30 min but not in the insulin sensitive participants. The change in MBV during the clamp was negatively correlated to the insulin sensitivity (r = -0.55, p = 0.022). As a result, MBV after 30 min of marked hyperinsulinaemia was comparable between the insulin sensitive and resistant participants.

Conclusions/interpretation: We conclude that moderate overnight hyperinsulinaemia recruited microvasculature in the more sensitive participants, while higher levels of plasma insulin were needed for more insulin resistant participants. This suggests that microvascular responsiveness to insulin is one determinant of metabolic insulin sensitivity in type 1 diabetes.

Trial registration: ClinicalTrials.gov NCT00943787.

Figures

Fig. 1

(a) Plasma glucose concentrations and (b) Insulin infusion rate during the 6 hours prior to the clamp. Data shown as mean ± SD (n = 17).

Fig. 2

(a) Plasma glucose concentrations during the clamp. Microvascular recruitment was assessed through CEU imaging at basal plasma insulin levels (t = −10min) and at hyperphysiological insulin levels (t = 30min). (b) Plasma insulin concentrations before and during the clamp. The time intervals used to compute the insulin measures are indicated as “basal” for Ip,basal, concentration before the start of the clamp, as “priming” for Ip,priming, concentration during the insulin priming, and as “ss” for Ip,ss, concentration at steady-state of the clamp. All concentrations are shown as mean ± SD (n = 17).

Fig. 3

Relationship between MBVbasal and logSI (r = 0.62, p = 0.008)

Fig. 4

Negative relationship between ΔMBV and logSI (r = −0.55, p = 0.022)

Fig. 5

Cluster analysis based on ΔMBV and logSI. (a) Groups obtained from the cluster analysis; (b) Insulin sensitivity and (c) Relative change of MBV of the 2 groups