Type 2 diabetes alters bone and marrow blood flow and vascular control mechanisms in the ZDF rat

Abstract

Bone health and cardiovascular function are compromised in individuals with type 2 diabetes mellitus (T2DM). The purpose of this study was to determine whether skeletal vascular control mechanisms are altered during the progression of T2DM in Zucker diabetic fatty (ZDF) rats. Responses of the principal nutrient artery (PNA) of the femur from obese ZDF rats with prediabetes, short-term diabetes, and long-term diabetes to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilation and potassium chloride, norepinephrine (NE), and a myogenic vasoconstrictor were determined in vitro. Few changes in the PNA vasomotor responses occurred for the prediabetic and short-term diabetic conditions. Endothelium-dependent and -independent vasodilation were reduced, and NE and myogenic vasoconstriction were increased in obese ZDF rats with long-term diabetes relative to lean age-matched controls. Differences in endothelium-dependent vasodilation of the femoral PNA between ZDF rats and controls were abolished by the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester. The passive pressure-diameter response of the femoral PNA was also lower across a range of intraluminal pressures with long-term T2DM. Regional bone and marrow perfusion and vascular conductance, measured in vivo using radiolabeled microspheres, were lower in obese ZDF rats with long-term diabetes. These findings indicate that the profound impairment of the bone circulation may contribute to the osteopenia found to occur in long bones during chronic T2DM.

Keywords: Zucker diabetic fatty rat; bone blood flow; diabetes; endothelium; vascular conductance.

Figure 1

Effects of pre-diabetes (A), short-term diabetes (B), and long-term diabetes (C) on endothelium-dependent vasodilation of the femoral principal nutrient artery alone, in the presence of the nitric oxide synthase inhibitor L-NAME, and in the presence of L-NAME and the cyclooxygenase inhibitor indomethacin (Indo). Values are means ± SE, n = 14–15/group. *Mean is different from age-matched non-diabetic control animals (P<0.05).

Figure 2

Effects of pre-diabetes, short-term diabetes, and long-term diabetes on sodium nitroprusside-induced vasodilation of the femoral principal nutrient artery (PNA). Values are means ± SE, n = 8–10/group. *Mean PNA response from 20 wk obese ZDF rats is different from that of 20 wk lean ZDF rats (P<0.05).

Figure 3

Effects of long-term diabetes on norepinephrine-induced vasoconstriction of the femoral principal nutrient artery (PNA) with the endothelium intact (A) and with the endothelium removed (B). Values are means ± SE, n = 10–14/group. *Mean PNA response from 20 wk obese ZDF rats is different from that of 20 wk lean ZDF rats (P<0.05).

Figure 4

Effects of long-term diabetes on active myogenic vasoconstriction (A) and the passive pressure-diameter relation (B) of the femoral principal nutrient artery. Upward pointing arrow indicates where pressure began to be increased; downward arrow indicates where pressure began to be lowered. Values are means ± SE, n = 13–14/group. *Mean PNA response from 20 wk obese ZDF rats is different from that of 20 wk lean ZDF rats (P<0.05).

Figure 5

Scattergrams showing the relation between cancellous bone mineral density (BMD) in the distal femur and peak endothelium-dependent vasodilation of the femoral PNA from lean and obese ZDF rats during pre-diabetes (A), short-term diabetes (B), and long-term diabetes (C). A significant linear relation (P< 0.05) exists between cancellous BMD and peak PNA vasodilation in each condition.

Figure 6

Scattergrams showing the relation between total bone mineral density (BMD) of the distal femur (A) and cortical BMD of the femoral mid-shaft (B) with peak endothelium-dependent vasodilation of the femoral PNA from lean and obese ZDF rats with long-term diabetes. A significant linear relation (P< 0.05) exists between total and cortical BMD and peak PNA vasodilation.

Figure 7

Effects of long-term diabetes on regional femoral blood flow (A) and vascular conductance (B). Values are means ± SE, n = 12/group. *Mean is different from age-matched, non-diabetic control animals (P< 0.05).