Intrinsic Gluconeogenesis Is Enhanced in Renal Proximal Tubules of Zucker Diabetic Fatty Rats

Abstract

Recent studies indicate that renal gluconeogenesis is substantially stimulated in patients with type 2 diabetes, but the mechanism that is responsible for such stimulation remains unknown. Therefore, this study tested the hypothesis that renal gluconeogenesis is intrinsically elevated in the Zucker diabetic fatty rat, which is considered to be an excellent model of type 2 diabetes. For this, isolated renal proximal tubules from diabetic rats and from their lean nondiabetic littermates were incubated in the presence of physiologic gluconeogenic precursors. Although there was no increase in substrate removal and despite a reduced cellular ATP level, a marked stimulation of gluconeogenesis was observed in diabetic relative to nondiabetic rats, with near-physiologic concentrations of lactate (38%), glutamine (51%) and glycerol (66%). This stimulation was caused by a change in the fate of the substrate carbon skeletons resulting from an increase in the activities and mRNA levels of the key gluconeogenic enzymes that are common to lactate, glutamine, and glycerol metabolism, i.e., mainly of phosphoenolpyruvate carboxykinase and, to a lesser extent, of glucose-6-phosphatase and fructose-1,6-bisphosphatase. Experimental evidence suggests that glucocorticoids and cAMP were two factors that were responsible for the long-term stimulation of renal gluconeogenesis observed in the diabetic rats. These data provide the first demonstration in an animal model that renal gluconeogenesis is upregulated by a long-term mechanism during type 2 diabetes. Together with the increased renal mass (38%) observed, they lend support to the view so far based only on in vivo studies performed in humans that renal gluconeogenesis may be stimulated by and crucially contribute to the hyperglycemia of type 2 diabetes.

Deletion of the Insulin Receptor in the Proximal Tubule Promotes Hyperglycemia

“…In contrast, we show decreased renal expression of IR protein and phosphorylated IR, the first step in insulin signaling, in alternative rat models of insulin resistance, 6 such as the obese Zucker rats, 6 which have been demonstrated by other investigators 18 to have elevated renal gluconeogenesis. Some of the differences may be due to model/strain differences.…”

“…16,17 Our results concur with the finding of enhanced gluconeogenesis in renal proximal tubules of insulin-resistant Zucker rats. 18 In this regard, we have shown reduced IR in the proximal tubule of insulin-resistant Zucker rats. 6 These data also suggest that transcriptional regulation may be the major mechanism of G6Pase modulators that account for variations observed in G6Pase activity.…”

Contributions of Hepatic Gluconeogenesis Suppression and Compensative Glycogenolysis on the Glucose-Lowering Effect of CS-917, a Fructose 1,6-Bisphosphatase Inhibitor, in Non-obese Type 2 Diabetes Goto-Kakizaki Rats

“…Recent ex vivo studies showed that renal gluconeogenesis was augmented 38% -66% more in Zucker diabetic fatty rats than in the non-diabetic rats (23) and that CS-917 suppressed gluconeogenesis from lactate in a normal rat perifusion study (6). However, the present study showed that glucose was taken up by the kidney in the overnightfasted diabetic GK rats, and that CS-917 did not decrease glucose release from the kidney in the overnight-fasted state, as described in Figs.…”

Urinary Fructose-1,6-Bisphosphatase (FBP-1,6) and N-Acetyl-β-Hexosaminidase (HEX) in Monitoring Kidney Transplantation - Literature Review

“…The above data is supported by analysis of gene expression profiles of renal transplants, which revealed reduced FBP-1,6 mRNA level in graft with IF/TA (Scherer et al, 2003). Determination of urinary FBP-1,6 activity was not only used for evaluation of transplanted kidneys, but also to estimate the degree of damage to renal tubules of diabetic patients (Eid et al, 2006), in idiopatic nephrotic syndrome (Kępka et al, 2008) acute pyelonephritis (ZochZwierz et al, 2004), heavy metal (e.g.HgCl 2 ) or, maleic acid intoxication (Kotanko et al, 1984), after trichloroethylene (TCE) administration (Khan et al, 2009). The urinary FBP-1,6 activity significantly increases after nephrotoxic drugs (ifosfamide, cisplatinum) (Pfaller et al, 1994) prednisolone, and azathioprine (Kotanko et al, 1986), cyclosporine, sirolimus and tacrolimus (Klawitter et al,2010).…”