The Excretory System and Diabetes
The excretory system consists of the kidneys and urinary tract, which together, filter and eliminate waste from the body. As blood circulates throughout the body, nutrients are extracted for energy. Once blood reaches the kidneys, any remaining waste products are extracted to maintain blood homeostasis. These filtered waste products are compiled into urine, which passes from the kidneys through the ureters to the bladder, from where it is eventually expelled.
Type 2 diabetes mellitus (T2DM) is a metabolic disease in which insulin resistance is a key causative factor. When carbohydrates are broken down after eating a meal, levels of glucose in the blood rise. In response to increased blood glucose, the pancreas secretes insulin, a hormone that circulates in the blood and binds to the insulin receptor (IR) on the surface of cells throughout the body. Once activated, the IR induces a signaling cascade that culminates in that cell taking up glucose, the breakdown of which generates cellular energy. Insulin resistance arises when the cells of the body do not respond well to insulin and do not take up glucose from the blood.
As a result, the pancreas releases more insulin to combat the glucose levels in the blood that continue to remain elevated. Essentially, cells begin to become non-responsive, or resistant, to insulin. In particular, blood glucose levels that are higher than normal cause a condition called hyperglycemia, which is associated with a number of complications; diabetes causes chronic hyperglycemia that is present even under fasting conditions.
Check out the Lifeline® catalog of bladder and renal cells (used in the diabetes research described below), including:
- Bladder dome epithelial cells
- Bladder apex epithelial cells
- Bladder fibroblasts
- Bladder smooth muscle cells
- Renal medullary epithelial cells
- Renal proximal tubule epithelial cells
- Renal cortical epithelial cells
- Renal mixed epithelial cells
Lifeline® Renal Cells in Diabetes Research
Patients with diabetes mellitus (DM) are at risk of a number of complications, including an increased risk of infection. Urinary tract infections (UTIs) are particularly common and often driven by multidrug-resistant bacteria. In the kidney, immune defense to combat infections is largely performed by intercalated cells, located in kidney collecting tubules. These cells secrete antimicrobial peptides, which function to kill various microbes. Uropathogenic E. coli (UPEC) is one of these microbes (one of the most common causes of UTIs) and attaches to intercalated cells during infection. In a 2018 study, Murtha et al. (opens in new window) set out to determine the mechanism by which DM increases UTI risk and the role of insulin signaling in this process.
The authors first assessed whether DM and the associated hyperglycemia increased incidence of UTI in mice. Using a mouse model of T2DM infected with UPEC, they found that sensitivity to UPEC infection was increased in mice with T2DM compared with control non-diabetic mice. Additionally, expression of the insulin receptor (IR) and phosphorylated Akt (a downstream mediator of IR signaling) was decreased in the kidney and bladder of T2DM mice. The authors observed similar results in a prediabetic mouse model of insulin resistance.
To determine how the IR and IR signaling mediate antibacterial responses in the urinary tract, the authors selectively deleted IR in the kidney of mice (termed IRKO mice). When challenged with UPEC, IRKO mice had increased bacterial burden, suggesting that IR signaling is important for UPEC clearance from the urinary tract. Using FACS to isolate intercalated cells and ammonium chloride-induced metabolic acidosis, the authors confirmed that loss of IR did not affect the number of intercalated cells or intercalated cell-mediated urine acidification.
The authors next investigated antimicrobial peptide expression in intercalated cells from IRKO mice compared with those from control mice. Of note, transcript and protein expression of both ribonuclease 4 (RNase4) and lipocalin 2 (Lcn2) were reduced in intercalated cells from IRKO mice. Furthermore, compared with mice with intact IR, UPEC survival in urine from IRKO mice was increased and was not affected by addition of RNsae4- or Lcn2-neutralizing antibodies. Using Lifeline® human renal epithelial cells and mouse outer and inner medullary renal epithelial cells treated insulin, the authors showed that RNase4 and Lcn2 expression was simulated by insulin.
Following the observation that RNase4 and Lnc2 expression was induced by PI3K/Akt signaling in vitro, the authors tested whether this was also true in vivo. As expected, mice infected with UPEC and treated with wortmannin (a PI3K/Akt inhibitor), had increased UPEC burden. Finally, the authors examined RNAse4 and Lcn2 concentrations in the urine of patients with T2DM and found that compared with urine from healthy patients, median RNase4 and Lcn2 concentrations were reduced.
Together, the results of this study demonstrate that insulin signaling through IR in the urinary tract regulates antimicrobial peptide expression and protects against UTI.
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