Glucose and insulin exert additive ocular and renal vasodilator effects on healthy humans

Abstract

The pathogenesis of diabetic vascular complications in the eye and kidney of humans is still not clear. There is evidence that glomerular filtration rate and renal plasma flow increase during poor metabolic control in patients with Type I (insulin-dependent) diabetes mellitus [1±3]. Several authors have also observed increased retinal and choroidal blood flow in patients with early diabetes [4±8], although there is some evidence of decreased ocular perfusion [9±10]. It has been suggested that this hyperperfusion in the kidney and the eye could predispose patients to develop vascular complications in these organs [11±14].Insulin treatment in patients with Type I diabetes induces peripheral blood hyperinsulinaemia in order to suppress interprandial hepatic glucose release. Patients treated for Type I diabetes are therefore exposed to high plasma concentrations of glucose and insulin. It has been known for a long time that a rapid increase in glucose plasma concentrations could cause vasodilation in the renal and ocular vasculature [15±16]. More recently it has been reported that insu- Diabetologia (2001) Abstract Aims/hypothesis. There is evidence that insulin and glucose cause renal and ocular vasodilation. There is, however, currently no data on the effect of combined hyperglycaemia and hyperinsulinaemia on the renal and ocular blood flow seen in diabetic patients on insulin therapy. Methods. We carried out two different 3-way crossover studies in healthy subjects (each, n = 9). In study one, hyperglycaemic clamps (5.6 mmol/l, 11.1 mmol/ l, 16.7 mmol/l) were carried out during placebo or insulin (dose 1: 1 mU/kg/min; dose 2: 2 mU/kg/min) infusion. The second study was identical but endogenous insulin secretion was blocked with somatostatin. The renal plasma flow, glomerular filtration rate and pulsatile choroidal blood flow were measured using the paraaminohippurate method, the inulin method and a laser interferometric measurement of fundus pulsation amplitude, respectively.Results. Insulin increased renal plasma flow and fundus pulsation amplitude but not the glomerular filtration rate. Hyperglycaemia increased all the renal and ocular parameters studied. Haemodynamic effects of glucose and insulin were additive when somatostatin was co-administered but not under basal conditions. Conclusions/interpretation. Glucose and insulin can exert additive vasodilator properties on renal and ocular circulation. To find out whether this observation is related to the increased regional perfusion in diabetes longitudinal studies on patients with Type I (insulin-dependent) diabetes mellitus are needed. [Diabetologia (2001) 44: 95±103]

Renal and Metabolic Effects of Insulin Lispro in Type 2 Diabetic Subjects With Overt Nephropathy

“…These findings provide support to our working hypothesis that lispro may inhibit IGF-1-dependent renal vasodilation (26,27), possibly through antagonism for the IGF-1 receptors located on mesangial cell surface. This effect is specific for lispro, since previous studies found that human insulin may have opposite effects on renal hemodynamics, thereby resulting in a trend to increase GFR and RPF (39) and to synergize the vasodilator effects of blood glucose (40). Regardless of the involved mechanisms, in the present study, modulating renal hemodynamics most likely limited the increase in albuminuria sustained by postprandial hyperperfusion and hyperfiltration.…”

Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney

“…Table 5 summarises all human data on the effects of somatostatin or octreotide on kidney function. Somatostatin and octreotide have been described in healthy subjects and patients with diabetes mellitus and acromegaly to decrease renal plasma flow (RPF) and concomitantly decrease glomerular filtration rate (GFR) with an unchanged filtration fraction [25][26][27][28][29][30][31][32]. However, it should be noted that some of these studies administered supraphysiological doses of somatostatin [100-420 μg/h intravenously (IV) or 600 μg/day subcutaneously (SC)].…”

“…This, taken together with the reduced kidney uptake caused by both octreotide and LAR-octreotide, might provide a basis in the future for continuation of LAR-octreotide treatment during PRRT as it causes little reduction in tumour uptake but sustained kidney uptake reduction, enlarging the therapeutic window of PRRT. Larger studies that apply smaller intervals [26] Healthy (n=3) 6 μg/kg/h somatostatin IV, for 3 h Inulin clearance 131→124 ml/min Schmidt et al [27] Healthy (n=9) 6 μg/kg/h somatostatin IV, for 3 h Inulin clearance 138→119 ml/min Tulassay et al [28] Healthy (n=7) 250 μg somatostatin/h IV, for 2 h Inulin clearance 131→62 ml/min Vora et al [29] Healthy (n=6) and diabetics (n=9) Tc-DTPA clearance 79→72 ml/min Castellino et al [33] Healthy (n=18) 480 μg/h somatostatin IV, for 3 h No effect of somatostatin on inulin clearance Tulassay et al [34] Healthy (n=8) 100 μg octreotide SC, once Creatinine clearance 124→66 ml/min Krempf et al [35] Diabetics (n=5) 480 μg octreotide IV/h, for 10 h 99m Tc-DTPA clearance unchanged Malesci et al [36] Cirrhotics (n=11) T.i. Cr-EDTA clearance 120→114 ml/min (NS) Pomier-Layrargues et al [42] Hepatorenal syndrome (n=14) 50 μg/h IV, for 2 days Creatinine clearance unchanged between the scans are needed before such a strategy can be implemented in PRRT protocols, however.…”

Ocular hyperperfusion following onset of intensified insulin therapy is inversely correlated with plasma endothelin-1 in Type I diabetes

“…The reason for this reduced ET-1 release, which could in turn influence ocular perfusion, is not known. It has, however, been shown that insulin and glucose exert ocular haemodynamic effects [7,8,9,10,41], which are additive [12]. Moreover, both, insulin and glucose could alter the expression of ET-1 in ocular tissues.…”

“…On the one hand alterations in concentrations of plasma insulin and plasma glucose could affect ocular vascular tone, because insulin and glucose induce vasodilation at the level of the ocular vasculature [7,8,9,10,11,12]. Alternatively the institution of strict metabolic control could exert effects The Diabetes Control and Complications Trial (DCCT) demonstrated a reduction in the development and progression of the long-term complications of Type I diabetes with intensive insulin therapy…”