**4. The kidney in diabetes mellitus**

All the metabolic pathways regarding the involvement of the kidney in glucose homeostasis are modified in subjects with diabetes mellitus. Subjects with type 2 diabetes mellitus (T2DM) have an increased renal release of glucose into the circulation in the fasting state [34]. Although one can think that the liver determines increased glucose release into the circulation in diabetes, the liver and the kidneys have comparable increase in renal glucose release (2.60 and 2.21 µmol ⁄ (kg min). The kidney can increase its glucose production with 300% compared with the liver that can increase gluconeogenesis only by 30%. Gluconeogenesis, in the kidney, could explain this glucose increase, in the fasting state [34].

In postprandial state, renal glucose release is greater increased in subjects with T2DM than in people without glucose metabolism abnormalities [35]. Meyer et al. studied systemic glucose appearance in subjects with T2DM and individuals with normal glucose tolerance over several hours following ingestion of 75 g glucose. They found that it was significantly greater in diabetic patients than in normal subjects (100.0 ± 6.3 vs. 70.0 ± 3.3 g; p < 0.001). The result was determined by a higher endogenous glucose release because the general appearance of ingested glucose was only 7 g greater in the subjects with DM. Almost 40% of the increased endogenous glucose release was caused by increased renal glucose release [35]. This fact was determined mainly by impaired suppression of endogenous glucose release and secondary by reduced initial splanchnic sequestration of ingested glucose. This effect is expected in diabetic patients that have decreased postprandial insulin release and insulin resistance, taking into account that renal glucose release is regulated by insulin [4].

Both renal glucose uptake and glucose production are increased in both the postprandial and post-absorptive states in diabetic patients [35].

Direct *in vivo* experiments of Vallon et al. on gene targeted mice lacking *Sglt2* gene, demon‐ strated that the SGLT2 protein is responsible for all glucose reabsorption in the proximal tubule and for the bulk of glucose reabsorption in the kidney overall [29]. According to this study, in wild-type mice, 99.7 ± 0.1% of fractional glucose is reabsorbed and in Sglt2−/− mice (not expressing SGLT2), only 36 ± 8% is reabsorbed. It was also found that in Sglt2−/− mice, even if SGLT1 glucose reabsorption is increased (SGLT1 transporters reach their transport maximum), up regulation of SGLT1 expression does not occur (both SGLT1 mRNA and protein expression are reduced by ~40%) when the amount of glucose in proximal tubule is increased. The results of the study of Gorboulev et al. [30] are in correspondence with those of Vallon et al., indicating that wild-type mice do not use the maximal transport capacity of SGLT1 at normoglycemic conditions but when glucose load to the SGLT1 is increased (for instance, diabetes and SGLT2

**Figure 3.** Glucose filtration and reabsorption in the proximal tubule of the kidney (adapted from [28])

Molecular structure of SGLTs has been studied thoroughly on SGLT1, which is the first described member of SGLTs family [31]. SGLT2 is 59% identical to SGLT1 and has almost the same architecture. Its secondary structure consists of 14-transmembrane helices (TM1–TM13) with both the NH2 and COOH termini facing the extracellular side of the plasma membrane [32]. The first kinetic model of Na+/glucose co-transporters was proposed by Parent et al. [33].

All the metabolic pathways regarding the involvement of the kidney in glucose homeostasis are modified in subjects with diabetes mellitus. Subjects with type 2 diabetes mellitus (T2DM)

inhibition), SGLT1 may operate at full transport capacity [30].

**4. The kidney in diabetes mellitus**

10 Treatment of Type 2 Diabetes

It is well known that glucosuria in diabetic patients occurs at different plasma glucose levels compared with the levels where glucosuria can occur in non-diabetic individuals [36]. This is determined by the increased glucose reabsorbtion in subjects with diabetes mellitus. Therefore, the Tm for glucose is increased and glucosuria may occur at higher than normal blood glucose levels. Several studies indicated that the Tm increased from near 350 mg ⁄ min in subjects with normal glucose tolerance to approximately 420 mg⁄min in subjects with diabetes mellitus [36].

As an evolutionary process, the kidney was able to develop a system in order to reabsorb all of the filtered glucose in order to conserve energy especially at a time when energy intake was reduced. Therefore, this may be considered as an adaptive response as the SGLT2 transport increases in response to hyperglycaemia. But, in subjects with diabetes this adaptive response is considered maladaptive, and glycosuria occurs only at very high plasma glucose levels. Thus, instead of allowing the kidneys to excrete excess of glucose, SGLT2 transporters help maintain a higher plasma glucose concentrations [1].

Human and animal studies of renal cells have demonstrated enhanced expression of SGLT2 transporters [37]. Factors like hyperglycaemia, albumin and angiotensin II have been reported to increase the expression of SGLT2 in T2DM [37].

It has also been demonstrated that acidosis increases renal gluconeogenesis and impairs hepatic gluconeogenesis [38]. Therefore one can speculate that the kidney represents an important factor that accelerates gluconeogenesis in diabetic ketoacidosis. Moreover, the exaggerated increase in renal glucose release can be the result of the insufficient suppression of endogenous glucose release postprandial in diabetic patients [39]. These processes can explain the quantity of glycogen stored in diabetic kidneys. A major part of the high renal glucose release found in subjects with diabetes may be determined by increased renal glyco‐ genolysis [6].
