Intermittent hyperinsulinaemia and arterial glycosaminoglycans in dogs

Abstract

Summary. The effect of insulin on the glycosaminoglycan content of the arterial ground substance was compared in age-matched alloxan-diabetic dogs, hypophysectomized dogs and normal controls. Hyaluronic acid and the three sulphated components, heparan, dermatan and isomeric chondroitin sulphates were quantitatively determined in the arch, thoracic and abdominal aorta, and in the carotid, coronary, iliac, renal and mesenteric arteries. Diabetic animals were either well or poorly controlled. Six well controlled dogs with a fasting mean plasma glucose level of 8.5 mmol/1 were given around 30 units of porcine insulin/day and showed fluctuations in plasma insulin concentrations between 24 and 175 mU/1. Four poorly controlled dogs with a mean fasting plasma glucose level of 18.5 mmol/1 received an average of 14 units of insulin/day, and the fluctuations ranged from 8 to 113 mU/1. Eight normal, untreated controls showed mean fluctuations between 15 and 22 mU/1. Within 14 weeks of insulin treatment, well controlled animals displayed glycosaminoglycan alterations in five arterial segments, usually involving more than one glycosaminoglycan constituent. In poorly controlled animals the number of segments that showed glycosaminoglycan alterations was the same, but abnormalities were limited to one of the sulphated components only. The coronary arteries displayed identical glycosaminoglycan alterations in the two groups of diabetic dogs, namely a significant rise in dermatan sulphate content (p < 0.01, mean _+ SEM) from the normal value of 1.12 _+ 0.03 mg/g dry defatted tissue to 1.31 + 0.03 mg/g in well controlled animals and to 1.37 _ 0.08 mg/g in poorly controlled animals. In order to ascertain that the abnormalities in the glycosaminoglycan chemistry were related to hyperinsulinaemia rather than hyperglycaemia, six hypophysectomized dogs were treated with 1.5 U/day of porcine protamine zinc insulin, for 3 weeks. Average plasma glucose levels were in the order of 4.3 mmol/1 and plasma insulin levels fluctuated between 9 and 27 mU/1; the latter represented twice the peak value seen in five untreated hypophysectomized dogs. The resulting chemical changes in the glycosaminoglycan content were in line with those encountered in diabetic animals, including the rise in dermatan sulphate content of the coronary arteries. These results indicate that: (1) hyperinsulinaemia produced by injections of insulin causes alterations of the arterial glycosaminoglycan content; (2) not all segments of the arterial tree are equally responsive to insulin and (3) the coronary arteries have a particularly insulin-sensitive dermatan sulphate metabolism.Key words: Diabetic and hypophysectomized dogs, insulin, arterial glycosaminoglycans.There appears to be a concensus of opinion that good management of diabetes requires more than normalization of blood glucose levels if coronary heart disease and late vascular complications in general are to be prevented [1,2]. The artificial B cell has focused attention on physiological 24 h plasma insulin profile...

Glycosaminoglycans in the human aorta in diabetes mellitus: a study of tunica media from areas with and without atherosclerotic plaque

“…Morphological studies of diabetic arteries have shown decreased Alcian blue staining suggesting either a decreased GAG content or altered sulphation of the macromolecules [3]. Data from some studies of experimental diabetes have pointed to an increased hyaluronic acid content in rodent aorta [11,12], others have given less clear results [13], however, there is no information available about the distribution of GAG in tunica media of the human aorta in diabetes. GAG/proteoglycans are considered to be involved in some of the key events which lead to the formation of atherosclerotic lesions [14], e. g. binding of lipoproteins [15,16], platelet aggregation [17], and growth inhibition of smooth muscle cells [18].…”

Association of hyaluronan with rat vascular endothelial and smooth muscle cells.

“…On the basis principally of biochemical evidence, both normal and especially pathologically altered arterial walls appear to be relatively rich in hyaluronan (25,36,53). A number of attempts have also been made to identlfy this non-sulfated glycosaminoglycan histochemically within vascular tissues.…”