Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease

Abstract

In uremic patients resistance to the action of insulin has been documented, but it is not known at what stage of renal disease it appears. We therefore examined 29 patients with IgA glomerulonephritis (IgAGN) and 21 patients with adult polycystic kidney disease (ADPKD) in different stages of renal failure, and in addition, healthy age-matched subjects. Insulin sensitivity and other variables of glucose metabolism were assessed using a frequent sampling intravenous glucose tolerance test (minimal-model technique). Glomerular filtration rate (GFR) was assessed in renal patients using the inulin-clearance technique. Mean insulin sensitivity index (SI), that is, insulin sensitivity, was significantly lower (P < 0.001) in all patients combined than in matched healthy subjects (N = 16; 14 males, mean age 42 +/- 3 years; mean SI 8.6 +/- 0.8 min-1 uU/ml). The mean SI was not significantly different in patients with renal disease of immune (IgAGN) or non-immune (ADPKD) origin, and it was not correlated with GFR (r = 0.01, P < 0.52), intact PTH (r = -0.23, P < 0.11) or calcitriol concentration (r = -0.03, P < 0.82). Consequently, the mean SI was similar in renal patients with GFR within the normal range (N = 19; 17 males, mean age 41 +/- 2 years; mean GFR 119 +/- 5 ml/min/1.73 m2; 5.1 +/- 0.7 min-1 uU/ml), in patients with mild to moderate renal failure (N = 16; 15 males, 46 +/- 3 years; 67 +/- 4 ml/min/1.73 m2; 5.1 +/- 0.7 min-1 microU/ml) and in patients with advanced renal failure (N = 15; 13 males, 46 +/- 3 years; 25 +/- 2 ml/min/1.73 m2; 4.7 +/- 0.6 min-1 uU/ml). Mean fasted plasma insulin concentration, the area under the curve for plasma insulin concentration (AUC) and total insulin delivery (TID) during the glucose tolerance test were significantly higher in patients than in healthy subjects, reflecting hyperinsulinemia in renal patients. Further, fasted plasma insulin concentration (r = -0.32, P < 0.009), AUC (r = -0.62, P < 0.0001) and TID (r = -0.34, P < 0.004) in patients were significantly correlated with insulin sensitivity (SI). The present data document that insulin resistance and concomitant hyperinsulinemia are present early in the course of renal disease, that is, even in patients with GFR within the normal range, irrespective of the type of renal disease. This observation may have potential implications with respect to the high cardiovascular morbidity and mortality in patients with renal disease.

Regulation of Muscle Protein Degradation

“…Besides suppressing protein synthesis, our findings show that a reduced PI3K activity contributes to muscle atrophy via coordinated regulation of apoptotic and Ub-P'some systems, ultimately leading to protein degradation. It is tempting to speculate that the identified pathways account for the excessive muscle protein loss that occurs in conditions associated with insulin resistance, including metabolic acidosis, uremia, and conditions that increase glucocorticoids (11,16,27,(35)(36)(37)(38)(39).…”

Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: The significance of transthyretin

“…Furthermore, stress and glucocorticoids associated with increased insulin resistance are also known to induce TTR expression in liver and choroids plexus (33,34). Interestingly, renal failure associated with increase in plasma RBP4 levels was also reported to be linked with insulin resistance (35).…”

Insulin Resistance in CKD

“…It was actually shown in a CKD population comprising patients with autosomal dominant polycystic kidney disease and IgA-GN that a syndrome of insulin resistance is already present in the earliest stages of kidney disease (i.e., even before the true GFR determined by inulin clearance is decreased). No difference in insulin resistance was observed between patients with autosomal dominant polycystic kidney disease and IgA-GN, suggesting that the impairment of kidney function itself, rather than the etiology of a specific kidney disease, causes insulin resistance (12). Furthermore, the finding of insulin resistance in patients with CKD even before detection of reduced GFR renders uremia and secondary complications of CKD, such as anemia, hyperparathyroidism, vitamin D insufficiency, or metabolic acidosis, unlikely as the underlying mechanisms of insulin resistance.…”