Insulin and glomerular function

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With regard to the effect of insulin on glomerular filtration rate (GFR), observations in the isolated kidney, in experimental animals, and in humans have yielded contradictory results, as decreased, increased or unchanged GFRs have all been reported (reviewed in [63]). In healthy subjects under conditions of forced water diuresis - when changes in plasma volume are prevented -euglycaemic hyperinsulinaemia did not affect GFR [64]. Likewise, in a dose-response study in type I diabetic patients under fasting conditions, insulin was without significant effect on GFR [65]. Neither renal plasma flow (as measured with 131I-hippuran) nor renal vascular resistances were affected by acute insulin administration. The role of plasma glucose concentration itself in the induction and/or maintenance of hyperfiltration has been controversial. During oral glucose loading, if large fluid volumes are co-administered, plasma volume and, in turn, GFR will increase.

On the other hand, a large glucose delivery to the proximal tubule could increase hydrostatic pressure in the tubular lumen, thereby leading to decreased GFR. Collectively, it appears that hyperglycaemia may be associated with small changes in GFR in either direction depending on factors such as duration of hyperglycaemia, hydration, and urine flow. An important question is whether insulin affects glomerular permeability to albumin and other proteins. We examined the acute effect of insulin on the systemic transcapillary escape rate (as measured by the 1-labelled albumin technique) and the excretion of albumin under time-controlled, steady-state conditions of glucose concentrations, urine output, blood pressure, and creatinine clearance [57]. While producing no significant change in albumin exit from the vascular compartment, physiological hyperinsulinaemia increased urinary albumin excretion by 50% in normoalbuminuric patients with type 2 diabetes but not in healthy subjects. In these patients, this effect was accompanied by an enhanced excretion of N-acetyl-^-D-glucosaminidase and retinol-binding protein - which are released and reabsorbed in the proximal tubule, respectively -, whereas the excretion of two proteins handled by the distal tubule (Tamm-Horsfall protein and epidermal growth factor) was unaffected (Fig. 4). These findings lend support to the notion that even modest increments in the glomerular permeability of albumin decrease the reabsorptive capacity of the proximal tubules, thereby leading to leakage of other tubular proteins. Moreover, this tubular albumin overload is intrinsically toxic to the interstitium, where it leads to the overexpression of inflammatory and vasoactive molecules [66,67]. Thus, perturbation of the glomerulo-tubular feed-back, rather than solely an increase in glomerular permeability, may be the trigger for nephropathy. In this context, the interaction between insulin and byperglycaemia on glomerulo-tubu1ar function deserves further investigation as it may be an early sign of renal involvement in diabetes.

Insulin and tubular function

Specific binding of insulin is greatest in the thick ascending limb and distal convoluted tubules [68]. Insulin has been found to stimulate sodium transport in proximal tubules in the rabbit [69], and to increase chloride reabsorption by the loop segment in the rat [70]. Human studies, however, have indicated that the anti-natriuretic action of insulin takes place in the distal tubule [71,72]. Whether insulin affects sodium absorption by a direct effect on the renal tubules or through modulation of local or systemic factors that control sodium chloride reabsorption is still uncertain. Friedberg et al. [73], for example, reported that the anti-natriuretic effect of insulin could no longer be observed when insulin-induced hypokalaemia was prevented by simultaneous intravenous potassium administration. To test this hypothesis, we performed oral glucose tolerance tests with or without potassium replacement in a group of healthy subjects [74].

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Fig. 4 Haemodynamic parameters in lean (empty bars) or obese (tinted bars) non-diabetic subjects in response to euglycaemic hyperinsulinaemia.

Moreover, to determine whether the anti-natriuretic effect of insulin is preserved in patients with impaired insulin action on glucose metabolism, a group of non-diabetic patients with essential hypertension was also studied. We found that healthy individuals and hypertensive patients exhibited similar insulin anti-natriuresis whether or not exogenous potassium was given to clamp serum potassium at basal levels. Also, insulin anti-natriuresis was independent of the presence of metabolic (=glucose metabolism) insulin resistance. The discordance with the results of Friedberg et al. [73] may depend on the differences between their experimental conditions (forced water diuresis, euglycaemic insulin clamp) and ours (maintenance of basal urine output, OGTT). In fact, in vitro studies have shown glucose increases anti-natriuresis due to enhanced glucose-sodium co-transport at the level of the convoluted proximal tubule [69]. In vivo studies using lithium clearance have demostrated that proximal sodium reabsorption is stimulated by hyperglycaemia in rats [75]; in patients with type 1 diabetes, sodium excretion is lower under hyperglycaemic than euglycaemic conditions [76]. At least in part, the effect of hyperglycaemia can be ascribed to the brush-border sodium co-transport, where glucose:sodium stoichiometry is 1:2 [77]. In a series of elegant studies, Nosadini et al. [78] found that patients with type 2 diabetes and metabolic insulin resistance retained more sodium than non-diabetic subjects at similar plasma glucose concentrations and filtered glucose. Moreover, at comparable degrees of hyperglycaemia the more insulin resistant patients exhibited more sodium retention, suggesting that metabolic insulin resistance may be coupled with an intrinsic renal abnormality.

In summary, both insulin alone and hyperglycaemia restrain renal sodium excretion; the most probable sites of action are the proximal tubule for hyperglycaemia, the distal portions of the nephron for insulin (though the latter is still somewhat uncertain). These two actions are combined in the physiological response to feeding [74]. Most importantly, in individuals with insulin resistance of glucose metabolism - i.e., diabetic [78], hypertensive [79], or obese [80] patients - insulin anti-natriuresis is preserved. Thus, the compensatory hyperinsulinaemia of insulin resistant subjects imposes a chronic anti-natriuretic pressure on the kidney. This may play a role in the development or maintenance of high blood pressure.

Insulin has a major role in potassium homeostasis. In dose-response studies in humans [81], euglycaemic hyperinsulinaemia stimulated potassium uptake by both liver and peripheral tissues. Insulin-induced hypokalemia is accompanied by a reduction in urinary potassium excretion. Insulin does not appear to have a direct effect on renal potassium handling, however. Thus, in our own studies [74] the anti-kaliuretic response to oral glucose was abolished when insulin-induced hypokalaemia was prevented by exogenous potassium supplementation. Importantly, when plasma potassium concentrations were clamped at their basal levels, glucose-induced insulin secretion was significantly heightened [74]. Thus, insulin modulates renal potassium excretion and its own release by the P-cell through the same signal, i.e., hypokalaemia. This dual feedback loop, or glucose-potassium cycle [82], explains the improvement in insulin secretion, and therefore in glucose tolerance, observed with the chronic use of ACE-inhibitors [83].


Retinol-binding Protein

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Tamm-Horsfall Protein Epidermal Growth Factor

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Fig. 5 Renal excretion of tubular proteins in response to isoglycaemic hvperinsulinaemia in subjects and patients with type 2 diabetes. Bars are mean (±1 SE) changes in excretion between normoinsulinaemia and hvpennsulinaemia under steady-state conditions [redrawn from reference 57].

The glucose-potassium cycle may also account for the opposing effects of potassium-losing diuretics and ACE-inhibitors on the risk of incident diabetes [84]. Sodium and uric acid excretion parallel one another under many physiological conditions [85, 86]. During euglycaemic hyperinsulinaemia, serum uric acid levels and creatinine clearance do not change, whereas the clearance rate and fractional excretion of uric acid decrease by 30%. The change in uric acid excretion is significantly related to the concomitant fall in urinary sodium excretion [87]. In patients with essential hypertension [79] and in obese subjects, we have found that the anti-uricosuric effect of insulin is maintained, and thus is independent of metabolic insulin resistance. The finding that uric acid and sodium urinary excretion are both restrained by physiological hyperinsulinaemia provides an explanation for the clustering of hyperuricaemia with insulin resistant states such as hypertension, obesity, and diabetes mellitus [88].

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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