StemCell Therapy

VA research on Diabetes Introduction

Diabetes is a chronic disease in which the body cannot produce or properly use insulin. Normally, insulin brings sugar out of the bloodstream and into cells. If the body cannot make insulin or does not respond to it, the sugar stays in the bloodstream. As a result of high blood sugar levels, damage eventually occurs to blood vessels and organs.

More than 29 million Americans have diabetes, according to the Centers for Disease Control and Prevention, and 86 million more Americans are at risk to develop the disease. Many Veterans have the disease, including some who developed it as a result of being exposed to herbicides while serving in Vietnam.

Symptoms of diabetes include blurry vision, excessive thirst, fatigue, frequent urination, hunger, and weight loss. Persons with diabetes need to have their hemoglobin A1C levels checked every three to six months.

A1c is a measure of average blood glucose during the previous two to three months. It is one of the markers, along with blood pressure and cholesterol control, of good diabetes care.

There are three major types of diabetes. Type 1 diabetes is usually diagnosed in childhood. In this type of diabetes the body makes little or no insulin, so daily injections of insulin are needed.

Type 2 diabetes usually occurs in adults. In this type of diabetes, the pancreas does not make enough insulin to keep blood glucose levels normal, often because the body does not respond well to insulin. More than 90 percent of adults with diabetes have type 2 diabetes. More are at risk due to overweight or obesity.

The third type of diabetes is gestational diabetes, high blood glucose that develops during pregnancy in a woman who does not have diabetes.

Diabetes affects nearly 25 percent of VA's patient population. The disease is also the leading cause of blindness, end-stage renal disease, and amputation for VA patients.

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VA researchers are studying innovative strategies and technologies, including group visits, telemedicine, peer counseling, and Internet-based education and case management, to enhance access to diabetes care and to improve outcomes for patients.

In addition, VA researchers are working to develop better ways to prevent or treat diabetes, especially in special populations such as the elderly, amputees, minorities, spinal cord injured patients, and those with kidney or heart disease.

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Two of VA's three Nobel laureates have done important work to benefit Veterans with diabetes. The late Dr. Rosalyn S. Yalow received the Nobel Prize for Physiology or Medicine in 1977 for her work in discovering the radioimmunoassay, an extremely sensitive way to measure insulin and other hormones in the blood. The technique made possible major advances in diabetes research and in diagnosing and treating hormonal problems related to growth, thyroid function, and fertility.

Dr. Andrew V. Schally also received the Nobel Prize in Physiology or Medicine in 1977 for his discovery that the hypothalamus links the nervous system to the endocrine system via the pituitary gland, is currently doing research, along with teams of national and international researchers, on growth hormone-releasing hormone (GHRH). Among other possibilities opened up by Schally's work with GHRH is the possibility of reducing or eliminating the need for diabetics to regularly inject insulin.

In 2013, an international research including Schally devised a way to transplant healthy cells into the body without the usual risk of rejection. The study involved a middle-aged man with diabetes, but it may be relevant to a range of other diseases as well. The researchers developed what amounts to an artificial pancreas (the place where the body makes insulin), which the patient tolerated well without taking drugs to suppress the immune system.

A 2015 study by Schally and his team evaluated newly developed GHRH agonists' ability to promote the growth and function of pancreatic islet cells, and found that these new agonists may provide an improved approach to treating diabetes. Agonists are substances that act like other substances and therefore stimulate an action in the body. Islet cells, also called Islets of Langerhans, sense blood sugar levels and release insulin to maintain normal levels.

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For seven and a half years, researchers involved in a VA cooperative study(CSP 465) looked at nearly 1,800 patients with diabetes. The researchers examined cardiovascular disease, the cause of death in nearly two-thirds of patients with diabetes.

Researchers attempted to determine whether intensive glucose control (using medication and other methods to reduce the level of sugar in the blood in diabetic patients to levels that would be normal in patients without diabetes) reduced heart attacks, strokes, and death from cardiovascular disease.

It had been previously shown that improvements in blood pressure and cholesterol levels can reduce cardiovascular disease in patients with diabetes, but no previous study had shown the beneficial effects of glucose control on cardiovascular disease.

VADT researchers showed that intensive glucose control in patients whose type 2 diabetes had previously been poorly controlled had no significant effect on the rates of major cardiovascular events such as coronary artery disease and stroke, compared to those who were using standard glucose control measures.

The research team also found that the two groups of patients had similar death rates, and that both groups had similar levels of complications such as diabetic neuropathy and retinopathy, except that patients using standard glucose control measures had higher levels of albumin in their urine. (Albumin in the urine is a possible indicator of kidney disease.)

Trial researchers concluded that both very high and very low blood sugar levels can be dangerous, and that big swings between high and low levels are also potentially harmful.

As a follow up to VADT, VA researchers looked at whether the improvements in glucose control made by one of the groups in the trial led to long-term improved consequences. They collected information on the VADT cohort for more than nine years of additional study, using VA's electronic records system.

The team found in 2015 that patients who had been in the intensive-control group had a lower incidence of cardiovascular events after the trial was over, but their survival rates were no better than those of the other group.

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Sleep apnea and poor sleep qualityA 2013 study conducted by researchers at the VA Puget Sound Health Care System that was part of the joint VA-Department of Defense Millennium Cohort Study on the health of service members and Veterans, found that sleep apnea and poor sleep quality predicted diabetes, independent of other diabetes risk factors or mental health status.

Sleep apnea increased the risk of diabetes by 78 percent, and simply having trouble sleeping increased the risk of diabetes by 21 percent. The study included more than 47,000 service members and Veterans who were an average age of about 49.

Statin useResearchers at the VA North Texas Health System and their colleagues examined the health records of tens of thousands of Tricare beneficiaries for a nearly 10-year period. Their study, published in 2015, found that the use of statins to lower cholesterol is associated with a significantly higher risk of new-onset diabeteseven in a very healthy population.

They also found that statin use is associated with a very high risk of diabetes complications in this healthy population, and with a higher risk of obesity. High-intensity statin therapy was associated with greater risks for all outcomes.

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Implantation of insulin-producing cellsInsulin-producing cells that respond to glucose and correct blood-sugar levels in diabetic mice have been created by researchers at the Iowa City VA Health Care System and correct blood-sugar levels in diabetic mice.

The researchers took human skin cells and reprogrammed them to create induced pluripotent stem (IPS) cells, which were then coaxed into forming insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near normal-levels.

The study raises the possibility that patients with diabetes could be treated with their own cells, which will accelerate treatment.

GRADE trialVA researchers are participating in a five-year National Institutes of Health study to compare the long-term benefits and risks of four diabetes drugs in combination with metformin. The study, called the Glycemic Reduction Approaches in Diabetes (GRADE) trial, is expected to include some 5,000 participants nationwide.

Metformin is the first medication doctors typically use when treating type 2 diabetes. If metformin does not control the disease, doctors may add one of several other drugs, all of which have been shown to lower blood sugar levels in studies. However, no previous long-term study has focused on which drug combination works best and has the least side effects.

The four drugs being studied are sulfonylurea, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 agonist, and long-acting insulin.

Drug combination causes adverse effectsIn 2013, VA researchers stopped a large multicenter study, part of the Veterans Affairs Nephropathy in Diabetes Study (NEPHRON-D), before its scheduled conclusion. They found that the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin-receptor blocker (ARB) increases the risk for serious adverse effects in patients with diabetic nephropathy, the leading cause of chronic kidney disease in the United States.

The significant increase in risk caused by taking the combination of drugs overshadowed any benefits taking the drugs may have in reducing the progression of kidney disease.

Diabetic kidney diseaseIn 2015, researchers participating in the NEPHRON-D study found that in patients with proteinuric diabetic kidney disease, a mean systolic blood pressure greater than 140 and a mean diastolic blood pressure greater than 80 were associated with a higher risk of kidney failure and death.

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The Veterans Affairs Implantable Insulin Pump Study; effect on cardiovascular risk factors. Duckworth WC, Saudek CD, Giobbie-Hurder A, Henderson WG, Henry RR, Kelley DE, Edelman SV, Zieve FJ, Adler RA, Anderson RJ, Hamilton BP, Donner TW, Kirkman MS, Morgan NA. Implantable insulin pump therapy in insulin-requiring patients with type 2 diabetes has advantages over multiple-dose insulin therapy in decreasing the requirement for antihypertensive therapy and for decreasing total and free insulin and insulin antibodies. Diabetes Care, 1998 Oct;21(10):1596-602.

Glucose control and vascular complications in veterans with type 2 diabetes. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD, VADT investigators. Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications with the exception of progression of albuminuria. N Engl J Med. 2009 Jan 8;360(2):129-39.

Agonist of growth hormone-releasing hormone as a potential effector for survival and proliferation of pancreatic islets . Ludwig B, Ziegler CG, Schally AV, Richter C, Steffen A, Jabs N, Funk RH, Brendel MD, Block NL, Ehrhart-Bornstein M, Bornstein SR. Evidence that agonists of GHRH represent a promising pharmacological therapy aimed at promoting islet graft growth and proliferation in diabetic patients. Proc Natl Acad Sci USA, 2010 Jul 13;107(28);12623-8.

Sleep characteristics, mental health, and diabetes risk: a prospective study of U.S. military service members in the Millennium Cohort Study. Boyko EJ, Seelig AD, Jacobson IG, Hooper TI, Smith B, Smith TC, Crum-Cianflone NF; Millennium Cohort Study Team. Trouble sleeping and sleep apnea predict diabetes risk independent of mental health conditions and other diabetes risk factors. Diabetes Care. 2013 Oct;36(10):3154-61.

Combined angiotensin inhibition for the treatment of diabetic nephropathy. Fried LF, Emanuele N, Zhang JH, Brophy M, Connor TA, Duckworth W, Leehey DJ, McCullogh PA, O'Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P; VA NEPHRON-D investigators. Combination therapy with an angiotensin-converting-enzyme (ACE) inhibitor and an angiotensin-receptor-blocker (ARB) was associated with an increased risk of adverse events among patients with diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20); 1892-903.

Human iPS cell-derived insulin producing cells form vascularized organoids under the kidney capsules of diabetic mice. A pancreatic organ can be created in vivo, providing evidence that human iPS cells might be a novel option for the treatment of type 1 diabetes. PLoS One, 2015 Jan 28;10(1):e0116582.

Enriching the diet with menhaden oil improves peripheral neuropathy in streptozotocin-induced type 1 diabetic rats. Coppey LJ, Davidson EP, Obrosov A, Yorek MA. Enriching the diet with n-3 fatty acids may be a good treatment strategy for diabetic neuropathy. J Neurophysiol. 2015 Feb 1;113(3):701-8.

Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, Duckworth WC, Emanuele NV, VADT Investigators. After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival. N Engl J Med. 2015 Jun 4; 372(23):2197-206.

Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function.Aroor AR, Habibi J, Ford DA, Nistala R, Lastra G, Manrique C, Dunham MM, Ford KD, Thyfault JP, Parks EJ, Sowers JR, Rector RS. Mice fed a diet that includes a DPP-4 inhibitor were found to have less insulin resistance than those not given the inhibitor. Diabetes. 2015 Jun;64(6):1988-2001.

BP and Renal Outcomes in Diabetic Kidney Disease: The Veterans Affairs Nephropathy in Diabetes Trial. Leehey DJ, Zhang JH, Emanuele NV, Whaley-Connell A, Palevsky PM, Reilly RF, Guarino P, Fried LF; VA NEPHRON-D Study Group. In patients with proteinuric diabetic kidney disease, mean systolic blood pressure greater than or equal to 140 mmHg and mean diastolic blood pressure greater than or equal to 80 mmHg were associated with worse renal outcomes. Clin J Am Soc Nephrol. 2015 Oct 19. pii: CJN.02850315. [Epub ahead of print]

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice. Zhang, X, Cui T,He J, Wang H, Cai R, Popovics P, Vidaurre I, Sha W, Schmid J, Ludwig B, Block NL, Bornstein SR, Schally AV. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus. Proc Natl Acad SCi USA, 2015 Nov 3; 112(44):13651-6.

Practical telemedicine for Veterans with persistently poor diabetes control: a randomized pilot trial. Crowley MJ, Edelman D, McAndrew AT, Kistler S, Danus S, Webb JA, Zanga J, Sanders LL, Coffman CJ, Jackson Gl, Bosworth HB. A comprehensive telemedicine intervention improved outcomes among Veterans with persistently poor diabetes control despite clinic-based care. Telemed J E Health. 2015 Nov 5. (Epub ahead of print.)

Statins and New-- Mellitus and Diabetic Complications: A Retrospective Cohort Study of US Healthy Adults. Mansi I, Frei CR, Wang CP, Mortensen EM. Diabetes, diabetic complications, and overweight/obesity were more commonly diagnosed among statin users than similar nonusers in a healthy cohort of adults. J Gen Intern Med. 2015 Nov;30(11):1599-610.

Rates of deintensification of blood pressure and glycemic medication treatment based on levels of control and life expectancy in older patients with diabetes mellitus. Sussman JB, Kerr EA, Saini SD, Holleman RG, Klamerus ML, Min LC, Vijan S, Hofer TP. Physicians are not likely to cut back on blood pressure and glycemic medication treatments in older patients with diabetes after they reach low BP or hemoglobin A1c levels. JAMA Intern Med. 2015;175(12):1942-1949.

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Diabetes - research.va.gov

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