Dysfunction of the circadian clock in the renal tubule leads to enhanced renal gluconeogenesis and exacerbated hyperglycemia in diabetes

In diabetes, the kidney contributes to the development of diabetic hyperglycemia by increasing glucose reabsorption from the primary urine and by upregulating gluconeogenesis in the proximal tubule. However, these two processes are also controlled by the circadian clock, a mechanism that synchronizes a large number of specific renal functions with environmental daily cycles. Here, we investigated the (patho)physiological role of intrinsic renal tubule circadian clocks in the diabetic kidney. We demonstrate that diabetic mice devoid of the circadian transcriptional regulator BMAL1 in the renal tubule exhibit additional enhancement of renal gluconeogenesis, exacerbated hyperglycemia, increased glucosuria, polyuria and renal hypertrophy. Collectively, our results suggest that diabetic hyperglycemia can be worsened by dysfunction or misalignment of intrinsic renal circadian clocks. Overall design: We induced type I diabetes with the drug streptozotocin (STZ) in mice devoid of the circadian transcriptional regulator BMAL1 in the renal tubule (cKOt mice). We had four experimental groups (STZ-control, STZ-cKOt, PBS-control, PBS-cKOt) and nine animals per group.