Physicians Bust Myths About Insulin

People diagnosed with type 2 diabetes often resist taking insulin because they fear gaining weight, developing low blood sugar and seeing their quality of life decline.A study recently completed at UT Southwestern Medical Center suggests that those fears are largely unfounded and that patients and physicians should consider insulin as a front-line defense, as opposed to a treatment of last resort for non-insulin-dependent diabetes.

"We found that those patients who received insulin initially did just as well, if not better, than those who didn't receive insulin," said Dr. Ildiko Lingvay, assistant professor of internal medicine at UT Southwestern and lead author of the study appearing online and in a future issue of Diabetes Care. "This reinforces the idea that insulin treatment is a viable and safe option for patients, even in the very initial stages of their diagnoses.

"There is a myth out in the community, especially among certain ethnicities, that insulin is the last resort, and that somebody started on insulin is going to die," Dr. Lingvay added. "We as physicians are responsible for teaching the patient that that's not the case."

More than 20 million Americans have type 2 diabetes. Obesity, age and lack of exercise all increase the risk for the disease, which is characterized by a progressive loss of insulin-producing beta cells. Diabetes is the single greatest independent risk factor for heart disease, as well as a contributor to a number of other medical problems, including blindness and kidney disease.

The standard initial treatment for type 2 diabetes is a single drug, often metformin, followed by the addition of more oral hypoglycemic agents as needed.

For this study, researchers evaluated the effectiveness of offering insulin-based therapy as an initial treatment option to newly diagnosed type 2 diabetes patients. They compared rates of compliance, satisfaction, effectiveness, safety and quality of life among the patients, who were randomized to receive either the standard triple oral therapy or insulin plus metformin, an oral drug that helps regulate blood sugar levels.

The patients, ranging in age from 21 to 70 years old, had been diagnosed with type 2 diabetes within the past two months. Researchers recruited study participants from Parkland Memorial Hospital or by self-referral to the Clinical Diabetes Research Clinic at UT Southwestern between November 2003 and June 2005.

After enrollment, every participant followed an insulin and metformin regimen for three months. The patients were then randomized to continue taking insulin and metformin or begin the triple oral therapy regimen. All participants were checked monthly for the first four months, at six months after randomization, and every three months thereafter for three years. Of the 58 patients randomized, 24 of the insulin-treated group and 21 of the triple oral therapy group completed the study.

The researchers found that the patients taking insulin plus metformin had fewer low-blood-sugar, or hypoglycemic, events, gained less weight and reported high satisfaction with the insulin.

Dr. Lingvay said she hopes physicians use these findings as the rationale to offer insulin-metformin as the first, rather than last, line of defense.

"Modern medicine uses insulin as a very effective and safe treatment tool," she said. "With the new devices that we're using, giving yourself an insulin shot is not much harder than taking pills."

The data represent the first three years of a six-year study still under way at UT Southwestern. The next step, Dr. Lingvay said, is to begin analyzing how the insulin plus metformin and oral triple therapy regimens affect insulin production in beta cells.

Other UT Southwestern researchers involved in the study included Jaime Legendre, recipient of a Clinical Research Fellowship from the Doris Duke Charitable Foundation; Dr. Polina Kaloyanova, former fellow in endocrinology; Dr. Song Zhang, assistant professor of clinical sciences; and Beverley Adams Huet, assistant professor of clinical sciences.

The study was supported by Novo Nordisk Inc., the National Institutes of Health and the Doris Duke Charitable Foundation.

African Tea Offers Promising Treatment For Type-2 Diabetes

Researchers are attempting, with the help of a special African tea, to develop a new treatment for type-2 diabetics. The tea is used as a treatment in traditional Nigerian medicine and is produced from the extract of Rauvolfia Vomitoria leaves and the fruit of Citrus aurantium. The scientists have recently tested the tea on patients with type-2 diabetes and the results are promising.The researchers have harvested the ingredients for the tea in Africa, totalling approximately fifty kilos of leaves and three hundred kilos of fruit from the wild nature of Nigeria. Afterwards the tea has been produced exactly as local healers would do so. The recipe is quite simple: boil the leaves, young stalks and fruit and filter the liquid.

First mice, then humans

Associate professor Per Mølgaard and postdoc Joan Campbell-Tofte from the Department of Medicinal Chemistry have previously tested the tea on genetically diabetic mice. The results of the tests showed that after six weeks of daily treatment with the African tea, combined with a low-fat diet, resulted in changes in the combination and amount of fat in the animals' eyes and protection of the fragile pancreas of the mice.

The researchers have recently completed a four month long clinical test on 23 patients with type-2 diabetes and are more than satisfied with the result.

"The research subjects drank 750ml of tea each day. The [tea] appears to differentiate itself from other current type-2 diabetes treatments because the tea does not initially affect the sugar content of the blood. But after four months of treatment with tea we can, however, see a significant increase in glucose tolerance," said postdoc Joan Campbell-Tofte from the University of Copenhagen.

Changes in fatty acid composition

The clinical tests show another pattern in the changes in fatty acid composition with the patients treated in comparison with the placebo group.

"In the patient group who drank the tea, the number of polyunsaturated fatty acids increased. That is good for the body's cells because the polyunsaturated fat causes the cell membranes to be more permeable, which results in the cells absorbing glucose better from the blood," said Joan Campbell-Tofte.

The researchers hope that new clinical tests and scientific experiments in the future will result in a new treatment for type-2 diabetics.

'Obesity Gene' Involved In Weight Gain Response To High-fat Diet Identified

Scientists have determined that a specific gene plays a role in the weight-gain response to a high-fat diet.The finding in an animal study suggests that blocking this gene could one day be a therapeutic strategy to reduce diet-related obesity and associated disorders, such as diabetes and liver damage, in humans.

The researchers found that a diet rich in fat induced production of this gene, called protein kinase C beta (PKC beta), in the fat cells of mice. These mice rapidly gained weight while eating a high-fat diet for 12 weeks.

On the other hand, mice genetically engineered to lack PKC beta gained relatively little weight and showed minimal health effects after eating the same high-fat diet.

In comparing the effects of the high-fat diet and a regular diet, the scientists found that mice fed the high-fat diet produced more PKC beta in their fat tissue than did mice eating a regular diet.

“So we now know this gene is induced by a high-fat diet in fat cells, and a deficiency of this gene leads to resistance to fat-induced obesity and related insulin resistance and liver damage,” said Kamal Mehta, senior author of the study and a professor of molecular and cellular biochemistry in Ohio State University’s College of Medicine.

“It could be that the high-fat diet is a signal to the body to store more fat. And when that gene is not there, then the fat storage cannot occur.”

Though the complete mechanism remains unknown, the research to date suggests that rather than storing fat, mice lacking the gene burn fat more rapidly than they would if the PKC beta were present, Mehta said.

The research is available online in the journal Hepatology and is scheduled for later print publication.

Mehta and colleagues previously had created the hybrid mouse model by cross-breeding mice deficient in PKC beta with the C57 black mouse, a common animal used in research for studying diabetes and obesity. Despite the propensity for obesity from their original genes, the new mice lost weight while eating up to 30 percent more food than other mice.

In the earlier study, the mice ate a regular diet. In this new study, the researchers fed PKC beta-deficient and normal mice either a diet in which 60 percent of calories were derived from fat – the high-fat diet – or a standard diet in which 15 percent of calories came from fat. In the typical American diet, about 40 percent of calories are derived from fat.

The normal mice on the high-fat diet showed weight gain within three weeks, a trend that continued throughout the 12-week study. The PKC beta-deficient mice on the same diet gained less weight even while appearing to be extra hungry and eating more calories than the normal mice – meaning their lower body weight was not the result of eating less.

Of animals eating the high-fat diet, the fat tissue and livers in the normal mice were larger than those in the PKC beta-deficient mice, as well. The livers of the normal mice were on average about 50 percent larger than the livers in mice lacking the gene. And the white fat tissue – the tissue in which PKC beta was expressed as a result of the high-fat diet – was almost three times as heavy in the normal mice as in the PKC beta-deficient mice.

The protein-deficient mice were able to clear insulin to regulate blood sugar more rapidly than normal mice after eating the high-fat diet, meaning avoiding obesity also allowed them to avoid development of insulin resistance associated with diabetes, said Mehta, also an investigator in Ohio State’s Davis Heart and Lung Research Institute.

“Obesity leads to liver damage and to diabetes. So if we can take care of obesity associated with a high-fat diet, we can also take care of most of the related disorders,” Mehta said.

A separate component of the current study further showed that mice engineered to be obese also had about 500 percent more of the gene in their fat cells than did normal mice. Mehta and colleagues have assembled a team that includes an endocrinologist, bariatric surgeon and molecular biologist to examine human fat tissue from obese and lean patients to see if levels of PKC beta are elevated in obese humans, as well.

“It is very likely that this gene may be involved in a predisposition to obesity,” he said.

Knowing the gene is responsive in the fat cells is important to figuring out how to suppress its action. Future research will involve deleting the gene from fat cells in mice to see if these new mice have the same lean body type as mice that are completely deficient of PKC beta throughout their entire genome.

“We are generating more mouse models to vary expression of this gene and study the consequences of that on obesity and related disorders,” Mehta said.

So far, mouse models lacking the protein have not shown any damaging side effects related to the suppression of the gene, Mehta said. He speculates that PKC beta could be a so-called “thrifty” gene left over from humans’ days as hunter-gatherers, when the body needed to retain fat for survival.

This work is supported by the National Institutes of Health.

Co-authors on the paper were Wei Huang and Rishipal Bansode of the Department of Molecular and Cellular Biochemistry, and Madhu Mehta of the Department of Internal Medicine, all at Ohio State.

Molecule That Suppresses Immune Response Under Study In Type 1 Diabetes

he idea is to teach the immune system of children at high risk for type 1 diabetes not to attack the insulin-producing cells of the pancreas."We want to create a no-go zone," said Dr. Andrew Mellor, immunologist who directs the Medical College of Georgia Immunotherapy Center. Type 1 diabetes is classified as an autoimmune disease because the immune system targets healthy islet cells for destruction, leaving young patients unable to use glucose, a major fuel source for the body.

MCG researchers think they may be able to delay or even prevent that destruction by boosting the body's levels of an enzyme fetuses uses to escape the mother's immune response or by packaging islet cell antigens, which get the immune system's attention, with this suppressor. T-cells are immune cells that decide whether to attack or ignore an antigen. Dr. Mellor believes they'll ignore insulin-producing cells if they see them for the first time with indoleomine 2,3-dioxegenase, or IDO, a powerful immune system inhibitor.

"We are going to be in a situation, in the not too distant future where you can identify an individual at risk, such as a 5-year-old child who has a 90 percent chance of becoming a type 1 diabetic within 10 years," he said. "Once you know that information the onus is on medicine to do something about reducing that risk."

A three-year, $646,000 grant from the Juvenile Diabetes Research Foundation International will enable studies in a classic model of type 1 diabetes: a normal-weight mouse that develops diabetes. Eighty percent of the female mice get diabetes by age 12 to 15 weeks. MCG researchers suspect it's because they have a transient defect in their dendritic cells that hurts IDO expression. Dendritic cells, which can express IDO, show antigens to the T-cells.

A Journal of Immunology paper last year reported that when dendritic cells and IDO are depleted in the mouse, the disease gets worse. Dr. Mellor's research partner Dr. David Munn collaborated with Dr. Jonathan Katz, who directs the Diabetes Research Center at the Cincinnati Children's Hospital Medical Center, on the study. "That was formal evidence that the dendritic cells with IDO were putting the brakes on the disease," said Dr. Mellor, Georgia Research Alliance Eminent Scholar in Molecular Immunogenetics. "It leads to the hypothesis that by reinforcing the IDO mechanism in these mice, you can slow or even prevent the disease." He'll further explore IDO's role in type 1 diabetes by using several different methods to get rid of IDO and observe what happens. He'll also enhance IDO expression in the females by giving a drug commonly used to treat rheumatoid arthritis that the MCG team has learned can boost IDO expression. "The mouse has an endogenous mechanism; it's just defective," said Dr. Mellor. "If you have the IDO come on earlier and stronger, maybe you can slow or halt disease progression or maybe even prevent it."

They'll also deliver a two-step treatment: prompting inflammation, which causes dendritic cells to express IDO, at the same time they give antigens to the insulin-producing cells. "The presence of the antigen excites the T cells if you will, but the presence of IDO tells it to stop getting excited," said Dr. Mellor. The approach has its risks. "The opposite would be disastrous: you would accelerate the disease," said Dr. Mellor. However novel strategies are needed, not just to treat the disease, but to try to prevent it, he said.

Dr. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and Georgia Research Alliance Eminent Scholar in Genomic Medicine, is leading efforts to identify these children. He's a principal investigator on an international effort looking at thousands of babies with genes that put them at high risk for diabetes then following them for years to see how genetics and environment work together to cause the disease. His laboratory studies include identifying additional high-risk genes as well as biomarkers for children at risk.

A different kind of vaccine – one that teaches the immune system to avoid something rather than attack it – may be the best option for these high-risk children, Dr. Mellor said. So he's also using disabled viral vectors, which are good at infecting cells, to deliver IDO as an off switch for the immune system. "We've been thinking IDO for a long time on this one," said Dr. Mellor.

A team of MCG scientists led by Drs. Mellor and Munn showed in research published in Science in 1998 that the fetus expresses IDO to help avoid rejection by the mother’s immune system. They also are exploring its therapeutic potential in transplantation and cancer.

Getting Diabetes Before 65 More Than Doubles Risk For Alzheimer's Disease

Diabetics have a significantly greater risk of dementia, both Alzheimer's disease — the most common form of dementia — and other dementia, reveals important new data from an ongoing study of twins. The risk of dementia is especially strong if the onset of diabetes occurs in middle age, according to the study.
"Our results . . . highlighted the need to maintain a healthy lifestyle during adulthood in order to reduce the risk of dementia late in life," explained Dr. Margaret Gatz, who directs the Study of Dementia in Swedish Twins.

In a study published in the journal Diabetes, Gatz and researchers from Sweden show that getting diabetes before the age of 65 corresponds to a 125 percent increased risk for Alzheimer's disease. Nearly 21 million people in the United States have diabetes, according to the American Diabetes Association, which publishes the journal.

This risk of Alzheimer's disease or other dementia was significant for mid-life diabetics — as opposed to those who develop diabetes after 65 — even when controlling for family factors. In other studies, genetic factors and childhood poverty have been shown to independently contribute to the risk of both diabetes and dementia.

"Twins provide naturally matched pairs, in which confounding factors such as genetics and childhood environment may be removed when comparisons are made between twins," explained Gatz, professor of psychology, gerontology and preventive medicine at the University of Southern California and foreign adjunct professor of medical epidemiology and biostatistics at the Karolinska Institute in Sweden.

Indeed, the chances of a diabetic developing Alzheimer's disease may be even greater in real life than in the study, the researchers write. They identify several factors that might have led them to underestimate the risk of dementia and Alzheimer's among those who develop diabetes before the age of 65.

Diabetes usually appears at a younger age than dementia does, the researchers note. Diabetes is also associated with a higher mortality rate, which may reduce the size of the sample of older adults. In addition, approximately 30 percent of older adults with diabetes have not been diagnosed.

The results of the study implicate adult choices such as exercise, diet and smoking, as well as glycemic control in patients with diabetes, in affecting risk for Alzheimer's disease and diabetes, according to the researchers.

The sample for the study was 13,693 Swedish twins aged 65 or older in 1998, the year tracking for dementia began. Information about diabetes came from prior surveys of twins and linkage to hospital discharge registry data beginning in the 1960s.

Weili Xu of the Karolinska Institute was the lead author of the study, which was a part of her dissertation research.

The research was supported by grants from the National Institute on Aging, the Alzheimer's Association (U.S.A.), the Swedish Research Council in Medicine, and Swedish Brain Power.

New Hope For Diabetes Patients?

Researchers have identified a signal pathway that could be involved in the occurrence of Type 2 diabetes. If it is deactivated, it may be possible to delay the illness by many years.

Diabetes, a metabolic disease, affects about 246 million people throughout the world, about a quarter of a million of them in Switzerland. Obesity and lack of exercise often play a decisive role in the illness. During his thesis work in collaboration with researchers from Oxford and the University of Lausanne, Jens Zehetner, a doctoral student with Wilhelm Krek, Professor at the Institute of Cell Biology of ETH Zurich, has identified one of the mechanisms that may play a part in diabetes. The study reveals that the signal pathway for the secretion of insulin is controlled by the pVHL and HIF1a genes, which are familiar from cancer research and are known to play an important role in growth and in the cell’s energy supply. Not only do the results help understand the origin of diabetes, the knowledge could also be used to combat the illness.

Signal pathway for insulin production

Wilhelm Krek explains that, “Cells need energy in the form of adenosine triphosphate (ATP), the cell’s energy currency, to enable them to maintain their functions. In a healthy person, the b-cells of the pancreas, which are responsible for insulin production, recognise when food is ingested. Sugar is burnt in the mitochondria of the b-cells by what is known as oxidative phosphorylation, producing ATP which, in turn, initiates insulin secretion in the b-cells. This stimulates the muscle cells, among others, to absorb sugar, thus regulating and normalising the level of sugar in the blood. Krek says that some diabetics may have an abnormality in this signal pathway. The plan now is to investigate this in a follow-up study.

Changeover to glycolysis

In their study of the pVHL and HIF1a genes, the scientists began by modifying mice genetically to end up with four kinds of mice with different gene combinations: those in which both genes were intact and those in which one, or the other, or both had been deactivated.

Under normal conditions with an adequate oxygen supply, HIF1a is constantly suppressed and destroyed by pVHL. However, if there is a shortage of oxygen, ATP cannot be formed in the mitochondria, which in turn activates HIF1a to enable the cells to produce the necessary ATP via glycolysis – independently of the mitochondria. The researchers now studied what happens in the b-cells if HIF1a is activated in mice.

Zehetner says, “Even when the amount of ATP produced was equal to that in “normal” mice, the insulin secretion profile in the animals without pVHL changed dramatically.” The secretion of insulin is increased at basal glucose levels but is less efficiently upon glucose stimulation. He says that this shows that the ATP production taking place in the mitochondria activates yet more factors – at present unknown – that are important in regulating the secretion of insulin. ATP production on its own is not enough.

Oxygen deficiency as the cause

In obese mice, the mass of the b-cells increases. This causes newly formed b-cells to have a worse blood supply at first, due to a lack of oxygen. Krek explains that, “Our hypothesis states that this oxygen deficiency is exactly what leads to activation of the suppressed HIF1a gene to keep the oxygen-starved cells alive.” The result is a changeover from a regulated, effective secretion of insulin to a physically increased but less efficient glucose-stimulated insulin secretion – the possible start of Type 2 diabetes. The illness becomes apparent when all the b-cells gradually die off through permanent overloading.

Gene deactivation as a therapy

Krek explains that “The study enabled us to show that pVHL and HIF1a play an important part in insulin secretion and that they are decisive in the strategy of ATP production.” One of the next steps will now be to utilise this knowledge in the form of a treatment for diabetes, although this has yet to be developed. If one were to be able to inactivate the HIF1a signal pathway in the b-cells of diabetes patients, it might be possible to delay the outbreak of the illness perhaps for many years. This is because experiments in mice whose HIF1a was inactivated showed that their insulin secretion was stimulated by the ATP formed in the mitochondria and functioned with no problems.

Breakthrough In Understanding Development Of Type 1 Diabetes

Finnish scientists have reported a breakthrough in understanding the development of type 1 diabetes. They discovered disturbances in lipid and amino acid metabolism in children who later progressed to type 1 diabetes, also known as juvenile diabetes. The alterations preceded the autoimmune response by months to years. The study may prompt new approaches for prediction and prevention of type 1 diabetes in pre-autoimmune phase of the disease.

The results of the Finnish research team, which consists of scientists from VTT Technical Research Centre of Finland and the Universities of Turku, Oulu and Tampere, have been published on 15 December 2008, in the Journal of Experimental Medicine.

Type 1 diabetes is an autoimmune disease in which the immune system attacks the insulin producing pancreatic beta cells. The gradual loss of beta cells results in life-long dependence on exogenous insulin.

At the moment, the earliest identifiable process in the pathogenesis of type 1 diabetes has been the development of autoimmunity to pancreatic beta cells in the measurable form of islet autoantibodies. Although the autoimmunity usually precedes the clinical disease by months to years, its occurrence may already be too late for therapeutic approaches aimed at preventing progression to overt diabetes. The initiators of the autoimmune response have remained unknown and the mechanisms supporting progression towards beta cell failure have been poorly understood, making discovery of effective prevention a challenge. The results of the SYSDIPP project, which was supported by the Tekes FinnWell Program, bring significant new information for combating the disease.

The SYSDIPP project has made use of metabolomics. Metabolomics systematically studies the chemical fingerprints in cells, tissues and biofluids in a given physiological and environmental context. The metabolic phenotype is sensitive to subtle factors such as age, lifestyle, nutrition and the microbe environment of the intestines. Changes in the concentrations of metabolites may thus reflect both genetic and environmental factors influencing later susceptibility to chronic diseases.

In 1994, an ongoing birth cohort study (DIPP, the Type 1 Diabetes Prediction and Prevention study) was launched in Finland, supported by the Juvenile Diabetes Research Foundation International. Over a period of 14 years, more than 130,000 newborn infants have been screened for genetic risk and over 8000 at-risk children are being regularly followed.

The research team was led by Prof. Matej Orešič from VTT Technical Research Centre of Finland and Prof. Olli Simell from University of Turku. Also Professors Mikael Knip, Jorma Ilonen, and Riitta Lahesmaa together with Dr. Riitta Veijola and Dr.Tuula Simell took part in the study, which investigated metabolic profiles of DIPP children prospectively from birth. The research team has published the results in The Journal of Experimental Medicine on 15 December 2008. The article reports the discovery of metabolic disturbances that precede the autoimmune response in children who later progress to type 1 diabetes.

The investigators found that the individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow-up and increased levels of proinflammatory lysophosphatidylcholines several months prior to autoimmunity to pancreatic beta cells. The metabolic profile was partially normalized following the autoimmune response, suggesting autoimmunity may be a relatively late physiological response to the early metabolic disturbances. The observed lipid changes were not attributable to HLA-associated genetic risk.

Metabolic profiling at early age may therefore aid in determining the risk of type 1 diabetes. The reported findings imply that metabolic or immunomodulatory interventions during the pre-autoimmune period may be used as a new potential strategy for prevention of type 1 diabetes.

The incidence of type 1 diabetes among children and adolescents has increased markedly in the Western countries during recent decades. The incidence has reached record levels in Finland, where currently 1 child out of 120 develops type 1 diabetes before the age of 15 years. The annual incidence is increasing at accelerated rate, with the number of new cases expected to double in the next 15 years.