**2. Short history**

### **2.1. Early non-human studies**

The first researchers in this field, Bergman and Drury brought the first clues about the involvement of the kidney in glucose homeostasis in 1938 [5]. They used the glucose clamp technique in order to maintain euglycemia in two groups of rabbits – one functionally hepatectomized and another one functionally hepatectomized and nephrectomized. In the group of hepatectomized and nephrectomized rabbits, the amount of glucose requested in order to maintain euglycemia was very high compared to the one required by the other group

[6] (Figure 1). These data led to the conclusion that the kidneys are an important source of plasma glucose [6].

**Figure 1.** Effect of nephrectomy on glucose needs for maintaining euglycemia in hepatectomized rabbits (Adapted from [6])

A few years later, the study was reproduced by Reinecke in rats. He also determined the arteriorenal venous glucose concentrations in the hepatectomized rats. He found that the glucose levels in renal vein exceeded the arterial levels when the animals became hypogly‐ cemic proving that, under these conditions, the kidneys can release glucose into the circulation [7].

In 1950, Drury et al. injected 14C-labeled glucose into rats that had been hepatectomized or hepatectomized and nephrectomized. His experiment indicated that the kidney represents the source of the glucose produced endogenously and released into the circulation after hepatec‐ tomy [8].

In other experiments, Teng proved that the renal cortex of the animal models with diabetes released glucose at a very high rate, but treatment of these animals with insulin could reverse this effect. A few years later, in 1960, Landau was able to prove, having a similar model, that gluconeogenesis from pyruvate was increased by the diabetic kidney [6].

In several experiments, Krebs tried to characterize the substrates that the kidney uses for gluconeogenesis [9], the efficiency of the renal gluconeogenesis in several species [10], and some aspects of the regulation of renal gluconeogenesis [11]. He could also demonstrate that the kidney present a greater amount of gluconeogenic enzymes than the liver, and due to the comparable blood flows (therefore comparable provision of gluconeogenic precursors), Krebs argued that the kidney might be a gluconeogenic organ in vivo as important as the liver [11].

#### **2.2. Early human studies**

[6] (Figure 1). These data led to the conclusion that the kidneys are an important source of

**Figure 1.** Effect of nephrectomy on glucose needs for maintaining euglycemia in hepatectomized rabbits (Adapted

A few years later, the study was reproduced by Reinecke in rats. He also determined the arteriorenal venous glucose concentrations in the hepatectomized rats. He found that the glucose levels in renal vein exceeded the arterial levels when the animals became hypogly‐ cemic proving that, under these conditions, the kidneys can release glucose into the

In 1950, Drury et al. injected 14C-labeled glucose into rats that had been hepatectomized or hepatectomized and nephrectomized. His experiment indicated that the kidney represents the source of the glucose produced endogenously and released into the circulation after hepatec‐

In other experiments, Teng proved that the renal cortex of the animal models with diabetes released glucose at a very high rate, but treatment of these animals with insulin could reverse this effect. A few years later, in 1960, Landau was able to prove, having a similar model, that

In several experiments, Krebs tried to characterize the substrates that the kidney uses for gluconeogenesis [9], the efficiency of the renal gluconeogenesis in several species [10], and some aspects of the regulation of renal gluconeogenesis [11]. He could also demonstrate that the kidney present a greater amount of gluconeogenic enzymes than the liver, and due to the comparable blood flows (therefore comparable provision of gluconeogenic precursors), Krebs argued that the kidney might be a gluconeogenic organ in vivo as important as the liver [11].

gluconeogenesis from pyruvate was increased by the diabetic kidney [6].

plasma glucose [6].

4 Treatment of Type 2 Diabetes

from [6])

circulation [7].

tomy [8].

Studies about human renal glucose metabolism started in the late 1950s. They tried to measure the differences of glucose concentrations between arterial and renal venous blood. By not taking into consideration that the kidney is able to produce and consume glucose in the same time, the fact that many researchers found little or no differences between arterial and venous glucose values led to the conclusion that the kidneys are not able to release glucose [6].

In the mid 1960s, Aber et al. [12] found that kidney can release glucose in patients with pulmonary disease and the quantity of glucose is negatively correlated with arterial pH explaining why the greater the acidosis, the greater the renal glucose release. Several years after, Owen et al. [13] indicated that renal glucose release is increased in very obese patients who fasted for several weeks. These data led to the current textbook idea that the liver is the only source of glucose, in general, except after prolonged fasting or under acidosis.

On the other hand, in subjects that undergo liver transplantation, it may still be observed after removal of the liver, endogenous glucose production [14]. Shortly after the removal of the liver, the production of endogenous glucose decreased only by 50% (Joseph et al.) [14]. Recent research using isotopic measurements have indicated that the kidney can release significant quantities of glucose in postabsorptive normal volunteers.
