The color and odor, quantity, clarity & viscosity, foaminess, saltiness & sweetness of one’s urine was once ample information to determine the flaws in our personal well-being, summarized in the acronym of a modern shoe; ASICS. Anima sana in corpore sano. Both soul and body were represented in our clear-golden liquid.1 A particular disease, diagnosed spot-on through this method, is one of the oldest medical entities ever described.2 Already in 1500 AD, an Egyptian manuscript mentions an epithetical name; too great emptying of the urine. This emptying, defined in 230 AD by the Greek Apollonius of Memphis as διαβήτης (diabetes), “to pass through” (dia – through, betes – to go), was sufficient to characterize the condition for centuries.3 Only in 1675, when Thomas Willis, known for his discovery of the arterial circle in our brain, coined in his Pharmaceutice rationalis the term mellitus, “honey-like”, to differentiate between mellitus and insipidus, “tasteless”, the name diabetes mellitus emerged as a clinical condition.4 The doctor’s trick for diagnosis was simply to taste the urine.
The question is, where does this sweetness of one’s urine come from? Although small enough to pass freely through the glomerular barrier, glucose is under normal conditions almost absent in urine. Given the fact that approximately 180 L of plasma is filtered every 24 hours, and given the fact that a mean plasma glucose concentration is about 100 mg/dL (5.6 mmol/L), the amount of glucose filtered every day is more or less 180 g, though subsequently it is entirely reabsorbed and returned into the blood plasma.5 An increase in tubular glucose concentration is paralleled by an increase in glucose reabsorption up to approximately 11 mmol/L, and as such, no glucose is present in urine.6 The symporters responsible for this reabsorption are two sodium-glucose cotransporters (SGLTs), of which both are osmotic gradient dependent symporters that couple sodium to glucose reabsorption in a 1:1 (SGLT-2) or 2:1 (SGLT-1) ratio. The two are located sequentially in segments the proximal tubule; SGLT-2 is situated in the first segment (S1) and SGLT-1 in the adjacent two segments (S2/S3) (see figure 1).7 Roughly 90% of the glucose in the ultrafiltrate is reabsorbed through the high-affinity low-capacity SGLT-2, while the remaining 10% is reabsorbed through the low-affinity high-capacity SGLT-1.7 When the amount of glucose filtered exceeds the maximal reabsorption capacity, also called the renal threshold, glucosuria occurs. In diabetes mellitus, paradoxically this renal threshold is raised as a result of circa 30% increase of glucose reabsorption, probably due to a corresponding upregulation of SGLT-2, which adds to the persistence of a hyperglycemic state.8,9 Although glucosuria has become obsolete as diagnostic test due to modern day laboratory tools, it can still be used as an indication of early or inadequately controlled diabetes mellitus. For both hygienic and personal reasons, doctors today are more eye-orientated and will avoid this tasty task for science and prefer to use colorimetric alternatives such as the urine strip to measure the amount of glucose in urine.
Sodium-glucose cotransporters (SGLTs) responsible for reabsorption of glucose
Nonetheless, through the development and implementation of a new class of antihyperglycemic agents for type 2 diabetes patients, the sweetness of urine has regained clinical attention. The upregulation of SGLTs in the proximal tubule in humans with impaired glucose metabolism have led to the idea that these transporters could be a therapeutic target for glycemic control. Observations in the early 1980s indicated that phlorizin (which occurs naturally in certain parts of plants such as the root bark of an apple tree) was a potent inhibitor of both SGLT-1 and SGLT-2. Through its major affinity with SGLT-2, the substance proved to be a useful insulin-independent antihyperglycemic drug as a result of the inhibition of renal glucose reabsorption, without causing hypoglycemia. However, phlorizin turned out to be unsuitable for clinical use, because of its minor affinity with SGLT-1, present in the small intestine, where it enables absorption of glucose and galactose from food.10 Potent inhibition of SGLT-1 in the gut leads to intolerable gastrointestinal adverse effects due to reduced intestinal glucose absorption and subsequent osmotic diarrhea. For this reason, less potent SGLT-1 inhibitors have recently been developed, to exploit the antihyperglycemic benefits of inhibition of gut glucose absorption without the adverse effects.11 Likewise, specific SGLT-2 inhibitors have been developed, of which three are currently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for patients with type 2 diabetes; canagliflozin, dapagliflozin and empagliflozin, which are all acceptable second- or third-line options in antihyperglycemic treatment.12 Through their practical and also promising properties, indicated by the EMPA-REG Outcome Trial, where empagliflozin showed long-term cardiovascular and renal benefits beyond glucose control, SGLT inhibition might become one of our future doctor’s top-notch tricks in treatment of diabetes.5,13
This system is easy to use in day-to-day clinic, but has its limitations. It is not possible to take into account that there can be both a respiratory as well as a metabolic component in the acid-base balance disturbance, also details are easily overlooked.
M.J.B. van Baar
- Nicholson JK, Lindon JC. Systems biology: Metabonomics. Nature. 2008;455(7216):1054-6.
- Leutholtz BC, Ripoll I. Exercise and Disease Management. CRC Press; 2011. p. 25.
- Zajac J, Shrestha A, Patel P, Poretsky L. Principles of Diabetes Mellitus. Springer Science & Business Media; 2010. p. 3-16.
- Willis T. Pharmaceutice Rationalis, sive Diatriba de Medicamentorum Operationibus in humano Corpore 1675. Available here.
Special thanks to E. van Bommel and M.H.A. Muskiet, research physicians at Diabetes Centre of the VU University Medical Centre for their knowledge on the subject and the use of figures.