Top Diabetes Items from the 13th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists

By Claresa Levetan, MD

1. Diabetes Agents of the Future—The Role of the Gut
   Incretins, or gut peptides, play a role in insulin secretion, reducing postprandial glucagons and delaying gastric emptying, and may reduce food intake.
2. Controlling Diabetes in the Hospital—A Matter of Life and Death
   New inpatient consensus on glycemic targets that all major scientific organizations have developed.
3. The ABCs of Diabetes Treatment
   Less than 7.3% of Americans with diabetes have met their A1C, Blood Pressure and Cholesterol goals.
4. Islet Cell Transplants—Past and Present
   Does the future still hold promise or can the  β-cell be resurrected?
5. Where We are With PPARs
   PPARs and their role in cardiovascular risk reduction

The role of the gut

Two satellite symposia at the AACE meeting were dedicated to hormones secreted by or acting on the gut and the promise, in particular for amylin and glucagon-like peptide-1 (GLP-1), as novel treatments for Type 2 diabetes in the near future. 

Incretins are a new class of gut-derived growth factors that stimulate insulin secretion following meals.  The two principal incretins identified to date have been GLP-1 and gastric inhibitory peptide (GIP). The gut is just beginning to be viewed as an important endocrine organ that is affected by many newly described peptides including amylin, bombesin, ghrelin, motilin, Neuropeptide Y, secretin, somatostatin, vasoactive intestinal peptide and many others which may play a role in gastric emptying, glucagon secretion and the reduction of food intake.

GLP-1 is primarily synthesized in the ileum and colon.  It has been demonstrated to increase release in response to glucose, increase synthesis and secretion of insulin, inhibit postprandial glucagon (which is dysregulated in diabetes), delay gastric emptying, and reduce food intake. GIP is synthesized primarily in the duodenum and plays a role in the first phase of insulin secretion, but its actions are less defined than GLP-1. 

Dipeptidyl peptidase IV (DP4)is a membrane-associated peptidase of 766 amino acids that is widely distributed in numerous tissues providing a critical molecule for inactivation of GLP-1. They are currently being evaluated for possible treatment in Type 2 diabetes.  Additionally, pramlintide, a synthetic form of the hormone amylin, which was discovered in 1987, is co-secreted in equimolar concentrations with insulin, and has been used in clinical trials. It delays gastric emptying as well as plays a role in restraining postprandial glucagons in patients with Type 1 and 2 diabetes.

Controlling diabetes in the hospital: a matter of life and death

The importance of glycemic control in the hospital both for patients with a history of diabetes and for those with no prior history of diabetes was addressed.  The data from the DIGAMI study demonstrated that among patients with acute myocardial infarction who had glucose levels of  >198 mg/dL on admission, and were treated with intravenous insulin followed by multiple dosages of insulin during the day, had significant reductions in both acute and long-term mortality, as compared with patients who received conventional diabetes care.  A pivotal trial by Van Den Berghe[1] of 1548 patients enrolled showed that intensive insulin therapy reduced mortality by 42.5% and 47.5% among patients who remained in the intensive care unit for more than five days. Intensive insulin therapy also reduced sepsis by 46%, acute renal failure by 41%, and the median number of transfusions. 

Based on these studies and many more in the field of stroke and bypass surgery, the American College of Endocrinology in conjunction with the American Association of Clinical Endocrinologists, American College of Cardiology, American Diabetes Association, American Heart Association, American Society of Anesthesiologists, The Endocrine Society, Society of Critical Care Medicine, The Society of Hospital Medicine and Society of Thoracic Surgeons have agreed upon new upper limits for glycemic targets in the hospital.  The upper limit target in the intensive care unit is 110 mg/dL, and on noncritical hospital units the pre-prandial glycemic goal is 110 mg/dL, with a maximal glucose target of 180 mg/dL. These aggressive targets are designed to achieve the optimal outcomes for hospitalized patients with hyperglycemia, regardless of prior diabetes status.

The ABCs of diabetes treatment

Despite the known increased cardiovascular risk profiles of patients with diabetes, the goals for the ABCs of diabetes are not achieved among patients with diabetes.[2] Some experts contend that the current recommendations, including an A1C of less than 6.5% (ACE/AACE and EASD), Blood pressure goals of less than 130/80, and a total Cholesterol of less than 100. 

The United Kingdom Prospective Diabetes Trial found that by lowering BP from 154/87 to 144/82 mm Hg, there was a significant reduction in diabetes-related deaths (32%), stroke (44%), visual loss (35%), and heart failure (56%). The guidelines by the ADA call for angiotensin receptor blockers (ARBs) as the first-line antihypertensive agents among patients with diabetes.  The initiation of either ACE inhibitors or ARBs for the treatment of early nephropathy to delay the progression of microalbuminuria to macroalbuminuria and overt nephropathy among those without hypertension is also recommended.  

A 2004 JAMA article entitled “Poor Control of Risk Factors for Vascular Disease Among Adults With Previously Diagnosed Diabetes”underscores the lack of aggressive care provided to patients with diabetes.Saydah and colleagues[3] reported that between 1999 and 2000 only 7.3% of adults with diabetes attained recommended goals of A1C levels (less than 7% but higher than the AACE/ACE guidelines of 6.5%), blood pressure less than 130/80 mm Hg, and total cholesterol level less than 200 mg/dL. 

Islet cell transplants—past and present

Dr. Gordon Weir, Head of the Islet Transplantation and Cell Biology Division of Joslin Diabetes Center, gave a comprehensive overview of pancreas and islet cell transplantation.  Unfortunately, although hailed as a possible cure when the first pancreas transplants were conducted in 1966, there have been only12,000 pancreas transplants to date, most of which have been done in the United States.  Most patients today who undergo pancreas transplants are also receiving a kidney or have had previous kidney transplants.  Most of these patients have had long-standing diabetes complications prior to transplant, but quality of life and the ability to live without insulin is a major benefit.  The most difficult issue has been in procuring enough organs for transplant.

By the early 1980s, human islet cell allografts utilizing immunosuppressive therapy among recipients were underway.  Up until 1995, only 10% of the allograph islet recipients were insulin free for more than a week.  The Edmonton group began its trials using a nonsteroid approach with rapamycin and found this to be much less toxic to the islet cells.  Ultimately, a combination of immunosuppressive therapies was used, and the islets were introduced through the portal vein via transhepatic angiography with much greater success than had been seen earlier.  Unfortunately, normal glucose levels were not achieved until the second or third transplant. Over the past two years, Dr. Weir reported that, following islet cell transplants utilizing the Edmonton protocol, most patients slip back to mild diabetes, but their control is much better, and they report significantly fewer episodes of hypoglycemia.  

Based upon other presentations at the AACE meeting, with data presented by Daniel Drucker and Susan Bonner-Weir, there is potential to resurrect β-cell function, even after years of diabetes.  In both animal and more recent studies in man, there can be a significant compensatory growth of β cell mass.  Studies are currently underway with a host of new compounds including islet neogenesis associated peptide (INGAP), glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase inhibitors (inhibit the degradation of GLP-1), which may hold promise for islet neogenesis both in Type 1 and Type 2 diabetes.

Where We are With the PPARs

Cardiovascular disease remains the leading cause of morbidity and mortality for patients with diabetes.  The thiazolidinediones, which are activators of the Peroxisome Proliferator-Activated Receptor (PPAR) gamma receptor, with limited α activity, may be useful for decreasing cardiovascular risk among people with diabetes. Results of three new studies presented at the meeting demonstrated that pioglitazone decreased triglycerides and increased high-density lipoprotein (HDL) cholesterol.  Consistent with similar findings within this class, there was a significant increase in the size and buoyancy of HDL particles.

Other data presented at the meeting discussed the anti-inflammatory characteristics of glucose-lowering agents. Data were presented supporting the role of insulin in suppressing free fatty acids, enhancing endothelial nitrous oxide, reducing cytokines and suppressing inflammatory growth factors. Additionally, there may be a significant anti-inflammatory effect of PPAR agonists.  Pioglitazone has been demonstrated to reduce plasminogen activator inhibitor, Type 1 (PAI-1). Recent research shows that elevated PAI-1 in persons with Type 2 diabetes and insulin resistance increases the risk of acute cardiac events by inhibiting fibrinolysis. Decreasing PAI-1 levels may reduce cardiovascular risk. 

Other studies with rosiglitazone and pioglitazone have found a reduction in protein marker, matrix metalloproteinase-9 (MMP-9), which is involved in the modification of atherosclerotic plaque, making it more vulnerable to rupture, thereby increasing the risk of heart attack. C-reactive protein (CRP) and tumor necrosis factor alpha, both associated with inflammation, also appear to be reduced when PPAR activators are utilized.

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