Age is a determinant of acute hemodynamic responses to hyperglycemia and angiotensin II in humans with uncomplicated type 1 diabetes mellitus

Abstract

-Hyperglycemia is associated with hemodynamic changes in type 1 diabetes (DM), acting in part through renin-angiotensin system activation. Since aging is associated with vascular dysfunction in DM, we hypothesized that acute hemodynamic responses to clamped hyperglycemia and infused ANG II would be exaggerated in older adults compared with a group of adolescent/young adults with type 1 DM. Renal hemodynamic function, blood pressure, and arterial stiffness were assessed in adolescent/young adults (n ϭ 34; mean age: 18 Ϯ 3 yr) and older adults (n ϭ 32; mean age: 45 Ϯ 9 yr). Studies were performed during clamped euglycemia (4 -6 mmol/l) and hyperglycemia (9 -11 mmol/ l). Renal and systemic hemodynamic responses to ANG II were measured during clamped euglycemia in diabetic subjects. ANG II responses were also assessed in a cohort of non-DM subjects (n ϭ 97; mean age: 26; age range: 18 -40 yr). Older DM adults exhibited higher baseline blood pressure, arterial stiffness, and renal vascular resistance, and lower glomerular filtration rate (GFR) and effective renal plasma flow, compared with adolescent/young DM adults (P Ͻ 0.05). Clamped hyperglycemia was associated with exaggerated peripheral and renal hemodynamic responses uniquely in older DM adults; only GFR increased in adolescent/young DM adults. ANG II infusion also produced exaggerated vasoconstrictive responses in older DM adults vs. adolescent/young DM adults (P Ͻ 0.05). The independent effect of age on hemodynamic responses to hyperglycemia and ANG II was confirmed using multivariate regression analysis in DM subjects (P Ͻ 0.05), and results were still significant when participants were matched for DM duration. Age-related alterations in hemodynamic function and ANG II response were not observed in healthy non-DM control subjects. Acute hemodynamic responses to clamped hyperglycemia and ANG II were exaggerated in older subjects with type 1 DM, highlighting an important interaction between age and factors that contribute to the pathogenesis of acute vascular dysfunction in DM. renal hemodynamic function; systemic blood pressure; arterial stiffness HYPERGLYCEMIA PLAYS A CRITICAL role in the pathogenesis of renal and systemic vascular complications in type 1 diabetes mellitus (DM), in part by promoting many of the early, permissive hemodynamic changes characteristic of DM (1). In early type 1 DM, hyperglycemia is associated with reduced renal vascular resistance (RVR) and renal hyperfiltration, which may promote susceptibility to kidney injury mediated by intraglomerular hypertension (2). Hyperglycemia-mediated renin-angiotensin system (RAS) activation is also associated with renal hyperfiltration through arterial vasoconstriction (3). In older subjects with DM and clinical evidence of nephropathy, RVR is increased, which has also been associated with vascular injury and adverse renal outcomes (4, 5).In early, uncomplicated type 1 DM, vascular resistance in the systemic circulation is also low, resulting in systemic hyperperfusion; this vasodilated systemic phe...

Non-invasive investigation of kidney disease in type 1 diabetes by magnetic resonance imaging

“…Previous studies of renal haemodynamics in diabetes have typically reported renal plasma flow rather than renal blood flow, measured by clearance studies using radioisotopes or other tracers, and a good correlation between MR and tracer studies has been reported [27]. The MRI-derived values for renal blood flow in our control participants are of the same order of magnitude as previously reported using MRI [27] and clearance methods [8]. Clearance studies have suggested increased [28] or normal [26,29] effective renal plasma flow in younger normoalbuminuric type 1 patients with relatively short disease duration.…”

“…The pattern of flow through the renal arteries was similar in our diabetic and control groups, suggesting that the reduction in flow was not due to haemodynamically significant narrowing of the renal artery, but attributable to increased intrarenal vascular resistance. RVR, calculated from clearance of para-aminohippurate, is reduced in young type 1 diabetic patients without complications, and increases with age, independent of diabetes duration [8]. In contrast, in control participants, there is no or a very weak effect of age on RVR [8].…”

“…RVR, calculated from clearance of para-aminohippurate, is reduced in young type 1 diabetic patients without complications, and increases with age, independent of diabetes duration [8]. In contrast, in control participants, there is no or a very weak effect of age on RVR [8]. Increasing systemic arterial stiffness accompanies the increase in RVR in diabetes [8], suggesting that in our older, long duration normoalbuminuric diabetic patients, RVR may be secondary to stiffening in the intralobular arteries and arterioles.…”

“…RVR increases with age in type 1 diabetic patients without complications, to a much greater extent than in non-diabetic participants [8], but it is not known whether there is a further increase in type 1 diabetic patients with early nephropathy, independent of age.…”

“…The three study volunteer groups were of similar age to obviate age-related changes in RVR [8]. Type 1 diabetic volunteers were recruited from the Newcastle Diabetes Centre.…”