In This Issue of Diabetes

The key to treating diabetic nephropathy and the associated massive proteinuria may lie in how podocytes, a type of blood-filtering cell in the kidney, deal with lysosomes (a sort of intracellular trash bag) via a process called autophagy. This is according to Tagawa et al. (p. 755), who report this month on a series of experiments in rodents and human tissue samples designed to investigate the underlying pathogenesis of proteinuria in diabetic nephropathy. The approach used by the authors initially found that there was insufficient podocyte autophagy in patients and rats with both diabetes and massive levels of proteinuria and that this was accompanied by podocyte injury and loss. This was not the case where there was no proteinuria or minimal proteinuria was present. Next, in controlled experiments, the authors investigated diabetic mice that were bred specifically with a disabled podocyte autophagy system. They found again that massive proteinuria developed and that podocytes became injured. At the same time they found that huge damaged lysosomes developed in both the podocytes of diabetic rats with massive proteinuria and the mice with the disabled podocyte autophagy system. Confirming their observations, Tagawa et al. then found that cultured podocytes stimulated with sera from either rats or humans with diabetes and massive proteinuria resulted in impaired autophagy and, consequently, damaged lysosomes and apoptosis. According to the authors, this may well point to a mechanism of action involving as yet unknown serum factors that impair podocyte autophagy. They suggest that additional studies into these factors and associated molecular pathways could be key in terms of developing a therapy for the treatment of refractory diabetic nephropathy. Currently few effective treatments are available—meaning that patients with diabetes and massive proteinuria often experience rapid renal failure. Taken together with their previous research, Tagawa et al. suggest that autophagy activation might well represent a target for therapy since its impairment in podocytes, at least according to this study, appears to lead to the massive proteinuria seen in diabetic nephropathy.

Tagawa et al. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 2016;65:755–767

An investigation into the inflammation of pancreatic islet cells (insulitis) in the early development phases of type 1 diabetes suggests that insulitis and β-cells may still be present several years after diagnosis. Together with other evidence, the authors of the study, Campbell-Thompson et al. (p. 719), suggest that there may be “a potentially long window of therapeutic opportunity” for type 1 diabetes prevention and reversal. It was significant that the study directly assessed transplantation-grade pancreata from organ donors, which meant that many of the difficulties associated with studying islets and β-cells from autopsy cases could be circumvented. Consisting of donors with and without type 1 diabetes and then either with or without islet autoantibodies, the study reveals a number of associations between insulitis frequency, β-cells, leukocyte phenotype, and duration of diabetes. For example, insulitis frequency was inversely correlated with diabetes duration but not with age at disease onset. Meanwhile, residual β-cells were observed in all type 1 diabetes patients who had insulitis in comparison to those without insulitis. According to the authors, insulitis appeared to affect islets that could produce insulin much more than those that did not. Infiltrating lymphocytes meanwhile increased in parallel to insulitis frequency. Commenting more widely on the study, author Martha Campbell-Thompson said: “This study is important because it shows that children and young adults with diabetes for several years have ongoing immune cell attacks of remaining β-cells while other β-cells appear unscathed. The use of contemporary cases, many who die from causes other than their diabetes, was also important as the incidence of type 1 diabetes is increasing worldwide. Along with other studies showing that β-cells can persist for decades after disease onset, a wider window of opportunity exists than previously thought available wherein strategies based at restoring functional β-cell mass can be employed.”

Campbell-Thompson et al. Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes 2016;65:719–731

Another insulin-independent therapeutic target for diabetes may exist. It is called the ArcPOMC-SNS-rGLUT2 axis, and authors Chhabra et al. (p. 660) claim it should represent an alternative target for diabetes control even in the presence of insulin resistance and obesity. The research is focused on the brain and, in particular, POMC (proopiomelanocortin) neurons that likely sense and regulate glucose in the blood in a manner that appears to be independent of food intake and insulin levels. To test whether POMC actually has a role in glucose homeostasis, the authors generated mice that were deficient in hypothalamic arcuate nucleus (Arc)-derived POMC polypeptide. The resultant mice developed severe obesity and insulin resistance but unexpectedly had improved glucose tolerance and did not develop fasting hyperglycemia. The subsequent experiments then looked to explain this paradoxical effect. Focusing first on glycosuria, Chhabra et al. established that the mutated mice achieved enhanced rates of urinary glucose excretion in comparison to controls that had equivalent blood glucose levels. To then investigate why this occurred, the authors employed the classic agonist/antagonist approach to reverse or enhance glucose tolerance in the different mouse types. According to the authors, decreased levels of renal GLUT2 (a glucose transporter) resulted in increased urinary excretion of glucose in the mutated mice. Epinephrine then abolished the differences between the two types of mice, suggesting that a reduced renal sympathetic nervous system response (SNS) is likely to be the mechanism behind the effects they observed. According to author Malcolm J. Low: “This newly discovered axis raises the possibility of a feedback mechanism from the kidneys that signals the brain about elevated glycosuria. The brain, in turn, activates autonomic systems such as the SNS that are responsible for conserving glucose (energy) in the body. The feedback mechanism could also explain some of the adverse effects, such as elevated ketogenesis and hepatic gluconeogenesis, of SGLT2 inhibitors. Given that the latest approach of controlling diabetes is elevating glycosuria, it would be interesting to see in the near future how the brain responds to this novel therapy.”

Chhabra et al. Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing glycosuria. Diabetes 2016;65:660–672

The findings of Lund et al. (p. 585) that glucagon may have an extrapancreatic origin and likely be gut-derived suggest there may be additional avenues of treatment for hyperglycemia in diabetes. While insulin deficiency or defects in its production rule diabetes progression, elevated levels of glucagon can also contribute to hyperglycemia and, up until now, the hormone has been thought to originate in the pancreas. This small controlled study measured the circulating glucagon levels in insulin-treated patients with diabetes or control subjects who underwent oral glucose tolerance tests and a corresponding isoglycemic intravenous glucose infusion. The crucial difference between the two experimental groups was that the test group had all undergone a total pancreatectomy (i.e., they had no pancreas). The control subjects were healthy and intact in terms of a pancreas. The authors then applied novel sandwich ELISA and proteomics techniques to accurately quantify the picomolar levels of glucagon in the blood of the volunteers before, during, and after the two sequential tests for glucose levels in the blood. According to the authors, the results show that “glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients.” Commenting more widely on the outcomes of the study, author Filip K. Knop stated: “These findings stress that the pancreas is not the only source of glucagon and clearly indicate that the classical conception of glucagon as a pancreas-specific hormone in man needs redefinition. Also, our results may constitute the basis for a novel explanation of the postprandial hyperglucagonemia observed in patients with other forms of diabetes where similar glucagon secretory patterns after oral and intravenous glucose have been observed. Thus, we now face an enormous and exciting challenge in describing the completely uncharted implications of extrapancreatic glucagon and its role in diabetic pathophysiology. I hope that our findings will give renewed fuel to the scientific and clinical interest in the neglected hormone of diabetes, glucagon.”

Lund et al. Evidence of extrapancreatic glucagon secretion in man. Diabetes 2016;65:585–597