Building on mounting evidence that implicates infection-fighting cells found in obese fat tissue in the growing problem of insulin resistance and Type 2 diabetes, researchers at the University of California, San Diego, School of Medicine have identified a particular subset of cells that are linked to obesity -associated insulin resistance, and that offer a promising new target for the treatment of diabetes. They showed that depletion of these cells, called CD11c-positive, in obese mice resulted in a reversal of obesity-associated insulin resistance.

Obesity-Related Insulin Resistance, Type 2 Diabetes Study

The study, led by Jaap Neels, Ph.D., formerly of UC San Diego School of Medicine and now at the Université de Nice-Sophia Antipolis, and Jerrold Olefsky, M.D., Distinguished Professor of Medicine and Associate Dean for Scientific Affairs at UC San Diego, will be published in the October 8 issue of Cell Metabolism.

Obese adipose, or fat, tissue is characterized by the presence of macrophages, specialized cells that usually fight infection. Adipose tissue macrophages (ATMs) accumulate in fat tissue as body weight increases. Growing evidence shows that ATMs are a significant contributor to inflammation in obesity – inflammation that leads to insulin resistance, resulting in Type 2 diabetes.

“Recent studies showed that a decrease in ATMs is associated with a decrease in adipose tissue inflammation and a reduction in insulin resistance, while an increase in ATMs is associated with a further deterioration of insulin sensitivity,” said Olefsky.

The research team looked at a particular subset of ATMs, bone marrow-derived, pro-inflammatory cells called CD11c+. Research by Olefsky’s group and others has shown that high levels of CD11c+ cells are present in obese adipose and muscle tissue, suggesting that these are a specific sub-population of macrophages recruited to these tissues as a result of a high-fat diet.

The scientists tested whether removing CD11c+ cells would suppress inflammation in obese, transgenic mouse models with insulin resistance and diabetes. According to Olefsky, they used a “genetic trick” to specifically remove these CD11c+ cells. They took advantage of an already existing genetic mouse model in which CD11c+ cells have been made sensitive to diphtheria toxin. Treatment of these genetically modified mice with the toxin specifically kills off all their CD11c+ cells.

These mice were fed a high-fat diet and once they were obese and insulin resistant, they were treated with the diphtheria toxin, which led to a rapid removal of their CD11c+ cells. Measuring the insulin sensitivity in these mice, the researchers discovered that by removing the CD11c+ cells, their insulin resistance and diabetes rapidly disappeared.

“The CD11c+ macrophages appear to cause insulin resistance and diabetes,” said Neels. “If the results of our work with mice translate into humans, suppressing this macrophage subset could offer a very promising target for Type II diabetes treatments.”

Additional contributors to the study include co-first authors David Patsouris, Ph.D. and Ping-Ping Li, and co-authors Divya Thapar from UCSD’s Division of Endocrinology and Metabolism, and Justin Chapman from Pfizer Inc., San Diego.

Support from the study was provided by the National Institutes of Health, the UC Discovery program, the American Heart Association, and an Inserm Junior Researchers Temporary contract to J.G.N.

About Obesity

Obesity is a condition in which the natural energy reserve, stored in the fatty tissue of humans and other mammals, exceeds healthy limits. It is commonly defined as a body mass index (BMI) (weight divided by height squared) of 30 kg/m² or higher.

Mortality is increased in obesity, with a BMI of over 32 being associated with a doubled risk of death.  Central obesity (male-type or waist-predominant obesity, characterized by a high waist-hip ratio), is an important risk factor for the metabolic syndrome, the clustering of a number of diseases and risk factors that heavily predispose for cardiovascular disease. These are diabetes mellitus, Type 2 diabetes mellitus, high blood pressure, high blood cholesterol, and triglyceride levels (combined hyperlipidemia).

• Cardiovascular: congestive heart failure, stroke, enlarged heart and its associated arrhythmias and dizziness, varicose veins, and pulmonary embolism
• Endocrine: type 2 diabetes mellitus, insulin resistance, polycystic ovarian syndrome (PCOS), menstrual disorders, and infertility
• Gastrointestinal: gastroesophageal reflux disease (GERD), fatty liver disease, cholelithiasishernia, and colorectal cancer
• Renal and genitourinary: erectile dysfunction, urinary incontinence, chronic renal failure, hypogonadism (male), breast cancer (female), uterine cancer (female), stillbirth
• Integument (skin and appendages): stretch marks, acanthosis nigricans, lymphedema, cellulitis, carbuncles, intertrigo
• Musculoskeletal: hyperuricemia (which predisposes to gout), immobility, joint pain, osteoarthritis, low back pain
• Neurologic: stroke, meralgia paresthetica, headache, carpal tunnel syndrome, dementia, idiopathic intracranial hypertension
• Respiratory: obstructive sleep apnea, obesity hypoventilation syndrome, asthma
• Psychological: depression, low self esteem, body dysmorphic disorder, social stigmatization
• Erectile Dysfunction 

About Insulin Resistance

Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin resistance in fat cells reduces the effects of insulin and results in elevated hydrolysis of stored triglycerides in the absence of measures which either increase insulin sensitivity or which provide additional insulin. Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma.

Insulin resistance in muscle cells reduces glucose uptake (and so local storage of glucose as (glycogen), whereas insulin resistance in liver cells reduces storage of glycogen, making it unavailable for release into the blood when blood insulin levels fall (normally only when blood glucose levels are at low storage. Both cause elevated blood glucose levels. High plasma levels of insulin and glucose due to insulin resistance often lead to metabolic syndrome and type 2 diabetes, including its complications.

About Diabetes

Type 2 diabetes is also referred to as non-insulin dependent diabetes mellitus (NIDDM), or adult onset diabetes mellitus (AODM). Type 2 diabetes affects nearly 21 million in the United States and nearly 200 million people worldwide.

Type 2 diabetes is characterized by high levels of blood sugar, caused by the body's inability to utilize insulin to move blood sugar into the cells for energy. In type 2 diabetes, patients can still produce insulin, but do so relatively inadequately for their body's needs, particularly in the face of insulin resistance as discussed above. In many cases this actually means the pancreas produces larger than normal quantities of insulin.

Diabetes is a major cause of heart disease and stroke, as well as the most common cause of blindness, kidney failure and amputations in U.S. adults.