diabetes and risk

Indo-American leads possible treatment for diabetes

In a significant discovery, a team of researchers led by an Indian-American has found that a single gene dysfunction in mice results in developing fasting hypoglycemia, one of the major symptoms of Type 2 diabetes.

The discovery by researchers, led by Prof. Bellur S Prabhakar, focused on a gene MADD for the study and may enable a new potential treatment for diabetes patients.
If MADD is not functioning properly, insulin is not released into the bloodstream to regulate blood sugar levels, said Prabhakar, professor and head of microbiology and immunology at University of Illinois at Chicago.

In previous work, Prabhakar isolated several genes from human beta cells, including MADD, which is also involved in certain cancers. Small genetic variations found among thousands of human subjects revealed that a mutation in MADD was strongly associated with Type 2 diabetes in Europeans and Han Chinese.

People with this mutation had high blood glucose and problems of insulin secretion – the “hallmarks of type 2 diabetes”, Prabhakar said.

But it was unclear how the mutation was causing the symptoms, or whether it caused them on its own or in concert with other genes associated with Type 2 diabetes.

To study the role of MADD in diabetes, Prabhakar and his colleagues developed a mouse model in which the MADD gene was deleted from the insulin-producing beta cells. All such mice had elevated blood glucose levels, which the researchers found was due to insufficient release of insulin.

“We didn’t see any insulin resistance in their cells, but it was clear that the beta cells were not functioning properly,” Prabhakar said.

Examination of the beta cells revealed that they were packed with insulin. “The cells were producing plenty of insulin, they just weren’t secreting it,” he said.

Prabhakar said that the work shows that Type 2 diabetes can be directly caused by the loss of a properly functioning MADD gene alone.

“Without the gene, insulin can’t leave the beta cells, and Blood sugar levels are chronically high,” he said.

In the future, the researchers plan to look into effects of a drug that allows for the secretion of insulin in MADD-deficient beta cells.

“If this drug works to reverse the deficits associated with a defective MADD gene in the beta cells of our model mice, it may have potential for treating people with this mutation who have an insulin-secretion defect and/or type 2 diabetes,” he said.

Type 2 diabetes affects roughly 8 per cent of Americans and over 366 million people worldwide. It can cause serious complications, including cardiovascular disease, kidney failure, loss of limbs and blindness.

Source: The Sen Times

Link Between Diabetes and Osteoporosis

What is the link between diabetes (both type 1 and type 2) and bone mineral density/osteoporosis in postmenopausal women?

Ashraf Kardousha, MD

Adult women with type 1 diabetes have relatively decreased bone mass, increased fracture risk, and delayed fracture healing compared with healthy women without diabetes. In addition, researchers have show that the biomechanical integrity of diabetic bone may be impaired. However, patients with type 2 diabetes usually do not have a decreased bone mass and, in fact, may be relatively protected from osteoporosis.

Early onset of diabetes, in particular, is associated with reduced bone density, and patients with type 1 diabetes show evidence of low bone mass following adolescence. This finding may explain the higher incidence of hip fracture reported for postmenopausal women with type 1 diabetes. The osteopenia associated with diabetes appears to be associated with a decreased bone turnover associated with impaired osteoblastic maturation and function. This is reflected in a decrease in serum markers of bone formation, such as osteocalcin. Bone resorption and formation are usually tightly coupled, but this has not been well studied in patients with diabetes. The few available studies suggest that the rate of bone resorption in diabetes is normal and therefore elevated relative to the decreased rate of bone formation. Evidence that there are significant alterations in serum parathyroid hormone levels or function is lacking. Boullion and colleagues[3] showed reduced serum levels of insulin-like growth factor 1 (IGF-1), osteocalcin, and bone-specific alkaline phosphatase in adolescents with type 1 diabetes, but not all markers were reduced in adults. Studies in diabetic animals show that there is enhanced apoptosis of osteoblastic cells and, although there is sufficient production of immature mesenchymal tissue, there is failure to adequately express genes that regulate osteoblast differentiation.

In contrast to findings in type 1 diabetes, patients with type 2 diabetes do not have low bone mass and may be relatively protected from osteoporosis. It is not known whether adolescents with type 2 diabetes will demonstrate a low bone mass. However, it is hypothesized that this is unlikely since most of these children are also obese. Our own studies in type 2 diabetes show that, while bone turnover is suppressed in patients in poor glycemic control, bone metabolism returns to normal with normalization of glycemia. Recent studies suggest that a negative correlation may exist between levels of osteocalcin and glycemic control. It is not clear if hyperglycemia per se is responsible or if the associated absolute or relative insulin deficiency might be involved. Bone cells have receptors for both insulin and IGF-1, and in vitro insulin has been shown to increase proliferation and function of osteoblasts. In animals, insulin deficiency suppresses osteoblastic activity. Levels of IGF-1 tend to be low in patients with poorly controlled diabetes mellitus and improve with improving glycemic control. A correlation between IGF-1 and osteocalcin levels has been shown for both type 1 and type 2 patients, and IGF-1 has been shown to stimulate osteoblastic differentiation, maturation, and function.

The difference in bone loss between the 2 forms of diabetes is often attributed to the degree of adiposity. Increased body weight has been associated with an increased bone mass in both normal and diabetic individuals, and may account for the relative protection seen in patients with type 2 disease. In addition to the mechanical effects of increased weight bearing, many women who are obese and relatively insulin-resistant have elevated levels of androgens, which may contribute to bone maintenance. In addition, it is not clear whether bone cells are insulin-resistant, similar to other tissues in type 2 diabetes. If not, then high circulating insulin levels could be expected to increase osteoblast function and have a beneficial effect on bone mass. It has been suggested that hyperinsulinemia may be partially responsible for the association of both diabetes and obesity with a higher BMD in women. It should be noted that there is some evidence of higher fracture risk in type 2 patients despite normal bone mass. Other factors, such as neuropathy and impaired vision, may contribute to the increased fracture risk.

Type 1 diabetes does appear to be a significant risk factor for osteoporosis. Currently, we recommend that patients with type 1 diabetes be monitored more carefully than persons without diabetes or those with type 2 disease, and should be encouraged to consume a diet high in both calcium (at least 1200 mg/day) and vitamin D (400-600 IU/day). It appears that intensive insulin therapy and a stable body weight in patients with type 1 diabetes is important in preventing bone loss. Patients with diabetes and osteopenia or osteoporosis have successfully been treated with bisphosphonates, with similar bone density results as patients without diabetes. Due to impaired osteoblast function, patients with diabetes might be expected to benefit more from bone anabolic (rather than anti-resorptive) medications, but this has yet to be demonstrated in a clinical trial.

For patients with type 2 diabetes who are in good metabolic control, prevention and treatment of osteoporosis can be approached in a manner similar to patients without diabetes as outlined in the National Osteoporosis Foundation (NOF 2003) physician guidelines.

Source: Med Scape