Let’s begin, as we do each month, with some headlines about diabetes that we hope will whet your appetite for more. We then go on to share abstracts about autonomic nerve testing to predict the development of complications and the activation of oxidative stress by acute glucose functions compared with sustained hyperglycemia in people with type 2 diabetes.
Two pharmaceutical companies, Pfizer Inc. and TransTech Pharma reached a licensing agreement to develop and commercialize drugs targeting a molecule called RAGE (Receptor for Advanced Glycation Endproducts), which has been linked to diabetic retinopathy, nephropathy, neuropathy and heart disease—not to mention nondiabetic conditions such as cancer and Alzheimer’s. The agreement will help fund Phase lll clinical trials to accelerate the pace of testing RAGE in chronic disease, where it appears to play a key role. By investing the funding and resources, the drug companies are signaling their belief that drugs targeting RAGE will be successful. Over the past 16 years Dr, Ann Marie Schmidt, Chief of the Division of Surgical Science at Columbia and collaborators have found that RAGE plays a central role in diabetic complications because it promoted inflammation and cell stress. A drug that inhibits this binding could prevent, stop the progression of, or even reverse these disorders. Since both type 1 and type 2 diabetics develop long-term complications, this research will benefit many millions of patients.
Darwin Prockop, M.D., PhD. from Tulane University Health Science Center has published an article reported on by the Juvenile Diabetes Research Foundation in their research frontline report. The researchers used cells from human bone marrow to repair damaged beta cells in mice. The study offers hope that these stem cells could be used to cure diabetes in people. The results are especially promising because the beneficial effect on mice was demonstrated with the use of human cells. Many approaches have shown therapeutic effects in mice using mice cells, but they were not replicable in trials in people. This, therefore, is an example of potential cell-based approaches to alleviate diabetes. It may also be possible to develop medications that work like the bone marrow cells and gain the same effects if we can understand the mechanisms through which the cells are acting on the islets.
JDRF is also reporting that a biotechnology company called Novocell, Inc. has developed a way to convert human embryonic stem cells into insulin-producing cells. Novocell advanced the field by differentiating the embryonic stem cells through discrete stages of development, and characterizing the cells at each stage. This process will help researchers better understand what is required to coax undifferentiated stem cells to develop into final cell types, liked pancreatic cells. This work, however, does not achieve the ultimate goal of creating insulin-secreting cells that function as islets. Cells that could be transplanted into humans to cure diabetes need to produce insulin in sufficient amounts and secrete the hormone in response to glucose, just as pancreatic beta cells do in people without diabetes. Still the JDRF reports that this is an important step toward producing an unlimited source of insulin-producing cells to treat diabetes.
Cardiology, Dec. 13, 2006 had an article of interest to all of us with diabetes titled Heart Transportation in Diabetes Patients, An analysis of outcomes data from the United Network of Organ Sharing. Diabetes is a strong risk factor for heart failure (HF), but heart transplantation has remained controversial as a treatment for HF in diabetes patients because of concern about excess risk for complications. To assess the validity of these concerns, researchers used the national United Network for Organ Sharing database to compare heart transplant outcomes between patients with and without diabetes. The cohort comprised 20,412 adults who underwent heart transplantation from 1995 through 2005. On average, diabetes patients were older, had higher body-mass indexes, and were likely to have ischemic conditions than their nondiabetic counterparts. Of the diabetes patients 21% had one pre-transplantation diabetes related complications (DRC)—prior stroke, peripheral vascular disease, renal dysfunction, ore severe obesity—and 3% had at least two DRC’s. There was a 0.8 year difference in survival rates for those with uncomplicated diabetes as compared with patients without diabetes. However, the survival rate for those diabetic patients with one DRC was 6.7 years as apposed to 10.1 years for nondiabetics and only 3.6 years for those diabetics with at least 2 DRC’s. The article suggests that because of the scarcity of donor organs and the risks for death and other adverse outcomes, that patients with complicated diabetes have a very careful evaluation for DRC’s when in end-stage heart failure when contemplating heart transplantation and consider alternative strategies.
One last headline you may want to explore. On Jan. 6th I noted that CNN had a video highlighting diabetic-alert dogs which can sense when people are slipping into hypoglycemia. The dogs in this piece flunked out of a school which trains service dogs for the blind but were able to sense the aroma of sweat for the three diabetic children in this family and alert adults to intervene. For those of us who have had dogs we know that they can often help us when we become hypoglycemic. My three standard poodles have been of great help. They make sure I notice something is amiss and I have been able to treat my condition. They not only note the aroma but my change in behavior. We all know that service dogs help children with epilepsy so why not have an extra 4 paws and great nose with our children with type 1?
Time for our abstracts. Autonomic Nerve Testing Predicts the Development of Complications, a 12 year follow-up study, Diabetes Care 30:77-82,2007 is written by Ann M. Maguire, MB,BOA,BCH et al from Australia. Cardiac autonomic nerve tests have predicted increased mortality in adults with diabetes, predominantly due to nephropathy, cardiac disease, and hypoglycemia. The significance of subclinical abnormalities has not been studied in adolescents in a systematic way. The researchers reassessed an adolescent cohort, whose autonomic nervous system had been tested 12 years earlier by both pupillometry and cardiovascular tests. From 1990 to 1993, adolescents with type 1 diabetes (n=335) were assessed for autonomic neuropathy (median age 14.7 years, duration of diabetes 6.3 years, and A1C 8.3%). Between 2003 and 2005, contact was made with 59% of the original group. Individual assessment 12 years later included completion of a valid hypoglycemia unawareness questionnaire and urinary albumin-to-creatinine ratio and retinal screening, as well as analysis pf reports from external doctors. At baseline, there was no difference in age, duration of diabetes, or complications between those who participated in the follow-up phase and those who did not participate. However, baseline A1C was lower in the follow-up participants (8.2 vs.8.5% for participants vs. nonparticipants). At 12 years of follow-up, 93% were aware and 7% were unaware that they had hypoglycemia; 31% had no retinopathy, but 10% required laser therapy, and 81% had no microalbuminuria. Small pupil size at baseline was independently associated with the development of microalbuminuria and retinopathy but not with the development of hypoglycemia unawareness. There was no association with baseline cardiovascular teats and the development of complications 12 years later. The researchers concluded that in their study they found an association between pupillometry tests and the presence of microalbuminuria and retinopathy at 12 years of follow-up. This suggests that pupillometry abnormalities may be early indicators of patients at high risk of future microvascular disease.
JAMA,2006;295:1681-1687 has an article titled Activation of Oxidative Stress by Acute Glucose Fluctuations Compared with Sustained Chronic Hyperglycemia in Patients with Type 2 Diabetes by Louis Monnier, M.D. et al. It is known that glycemic disorders, one if the main risk factors for cardiovascular disease, are associated with activation of oxidative stress. The objective of the study was to assess the respective contributions of sustained chronic hyperglycemia and acute glucose fluctuations to oxidative stress in type 2 diabetes. This was a case-control study of 21 patients with type 2 diabetes (2003-2005) compared with 21 age-and sex-matched control (studied in 2001) in Montpellier, France. Oxidative stress was estimated from 24-hour urinary excretion rates of free 8-iso prostaglandin F 2a. Assessment of glucose fluctuations was obtained from continuous glucose monitoring system data by calculating the mean amplitude of glycemic excursions (MAGE). Postprandial contribution to glycemic instability was assessed by determining the postprandial increment of glucose level above preprandial values. Long-term exposure to glucose was estimated from values. Long-term exposure to glucose was estimated from hemoglobin A1C from fasting glucose levels, and from mean glucose concentrations over a 24-hour period. Mean urinary 8-iso PGF 2a excretion rates were higher in the 21 patients with diabetes compared to controls. The authors concluded that glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress then chronic sustained hyperglycemia. This data suggest that interventional trials in type 2 diabetes should target hemoglobin A1C and mean glucose concentrations but also acute glucose swings.
BSP
