© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Reply to Letter to the Editor
aEndocrinology Unit, University of Edinburgh, Edinburgh, UK
bDepartment of Vascular Medicine & Diabetes Research, University of Exeter, Exeter, UK
* Corresponding author B.Walker{at}ed.ac.uk
Received 2 April 2002; accepted 2 April 2002
To the editor
In our recent article [1], we observed close associations between higher blood pressure, higher fasting plasma glucose, and insulin resistance (as measured by fasting plasma insulin and the fasting insulin/glucose relationship (HOMA)). Indices of microvascular structure in the skin were associated with blood pressure and fasting plasma glucose, but not with hyperinsulinaemia. We concluded that altered microvascular structure may be an important mediator of variations in blood pressure and fasting plasma glucose, but is unlikely to explain their link with insulin resistance.
Erik Serne and colleagues contrast these findings with their own important body of work. They comment that our measurement of insulin resistance using fasting plasma insulin reflects hepatic, rather than peripheral insulin sensitivity, and is less reproducible than the euglycaemic hyperinsulinaemic clamp technique. It is implied that, had we performed such clamps in our subjects, we would have detected relationships between insulin resistance and microvascular structure. Clearly, we cannot exclude this possibility. However, given the lack of trends for correlations between fasting plasma insulin and microvascular structure in our data, this would require remarkable disparity between measurements of fasting hyperinsulinaemia and peripheral glucose disposal. Although the agreement between these techniques is, as Serne et al. point out, not complete, it is over-simplistic to suggest that they measure exclusively hepatic and peripheral insulin sensitivity, respectively. Apparently ‘selective’ peripheral insulin resistance (e.g. in lipodystrophies and transgenic animal models) is manifest by fasting hyperinsulinaemia [2]; while conversely, failure of suppression of hepatic glucose production can affect ‘M values’ during hyperinsulinaemic euglycaemic clamps, particularly if the clamps are not prolonged [3]. Indeed, there is emerging evidence of the links between peripheral and hepatic insulin resistance (mediated for example by resistin, adiponectin, free fatty acids etc) which makes it unlikely that these two are ever truly dissociated in human disease.
So, while we certainly accept that differences in techniques of measuring insulin sensitivity might attenuate relationships with microvascular structure, the question remains of why we did not see any relationship at all while Serne et al. have reported very strong correlations. One issue is the characteristics of the participants. Our 105 participants did have a wide variation in blood pressure and insulin sensitivity (note the range of fasting insulin concentrations of 1.1–29.6 mU/l, as stated in the manuscript), but were homogeneous in other respects (all male, age 23–33 y). Serne et al. studied a group of 18 men and women with a wide age range (20–64 y). Although they corrected for age and gender in their analysis, the validity of these corrections in such a small sample must be uncertain. Our study identified a further potential confounder, since higher fasting plasma glucose was strongly associated with fewer dermal capillaries and higher blood pressure. Fasting glucose was not described in Serne et al.'s previous paper, but it is known that higher fasting glucose levels at the beginning of a euglycaemic hyperinsulinaemic clamp will decrease apparent insulin sensitivity measured by ‘M value’ [4]. It would be important to know if this was a confounding variable in their analysis.
Finally, these studies differ in the site and method of measurement of dermal microvascular structure; we counted all capillaries (whether continuously or intermittently perfused) on the dorsum of the middle phalanx, while Serne et al. measured continuously perfused capillaries immediately proximal to the nail fold. Both techniques measure differences which reliably predict blood pressure, but they do differ; in the nail fold fewer capillaries are usually visible in the resting state but more can be recruited following stimulation. The variable which Serne and colleagues have repeatedly associated with insulin resistance is not the absolute number of capillaries, but the incremental increase (or ‘recruitment’) of capillaries following ischaemia. This index may reflect both structural and functional components of the microvasculature. Importantly, we cannot know whether either site represents capillaries in tissues responsible for substantial glucose uptake such as skeletal muscle and adipose.
In summary, there are important differences between our study and those performed by Serne et al. For this reason, neither should be interpreted as ‘disproving’ the other. The disparity between them, however, makes it important that careful further work is done to test a highly attractive, but as yet unproven, hypothesis.
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- Irving R.J., Walker B.R., Noon J.P., Watt G.C.M., Webb D.J., Shore A.C. Microvascular correlates of blood pressure, plasma glucose, and insulin resistance in health. Cardiovasc Res (2002) 53:271–276.
[Abstract/Free Full Text] - Zabolotny J.M., Kim Y.-B., Peroni O.D., Kim J.K., Pani M.A., Boss O., Klaman L.D., Kamatkar S., Shulman G.I., Kahn B.B., Neel B.G. Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance. Proc Nat Acad Sci USA (2001) 98:5187–5192.
[Abstract/Free Full Text] - Soop M., Nygren J., Brismar K., Thorell A., Ljungovist O. The hyperinsulinaemic-euglycaemic glucose clamp: reproducibility and metabolic effects of prolonged insulin infusion in healthy subjects. Clinical Science (2000) 98:367–374.[CrossRef][Web of Science][Medline]
- Neilsen M.F., Basu R., Wise S., Caumo A., Cobelli C., Rizza R. Normal glucose-induced suppression of glucose production but impaired stimulation of glucose disposal in type 2 diabetes. Diabetes (1998) 47:1735–1747.[Abstract]
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