High-Altitude Residents Exhibit Lower Prevalence of Diabetes and Obesity

People who live at altitudes above 1,500 meters tend to have a lower fasting glycemia and better glucose tolerance compared to those who live closer to sea level, and understanding why that is could lead to new therapeutic options, according to a study recently published in Endocrine Reviews.

Researchers led by Orison O. Woolcott, MD, of the Diabetes and Obesity Research Institute at Cedars- Sinai Medical Center in Los Angeles, noted that about 7% of the world’s population (about 440 million people) live above 1,500 meters, but there hasn’t been much research on the long-term effects of living at that altitude. There is emerging evidence of the lower prevalence of both obesity and diabetes at higher altitudes, but, according to the authors, the mechanisms underlying improved glucose control at higher altitudes remain unclear.

The authors looked at the most current evidence on glucose homeostasis in residents living above 1,500 meters and reached a number of hypotheses. Insulin is unlikely to play a part. The liver may be involved since “studies showing higher glucagon levels in highlanders and reduced hepatic glycogen content in rodents chronically exposed to hypoxia suggest that the liver may play a role,” they write. The gut may be implicated, but that’s unclear, since most studies have focused on the short-term exposure to high altitudes.

Woolcott and colleagues hypothesized that the lower fasting glycemia in individuals living at high altitudes is determined by a lower hepatic glucose output (HGO) and a higher glucose disposal in the skeletal muscle, since “in the postabsorptive state, blood glucose supply depends primarily on the liver, whereas glucose disposal occurs primarily in the brain (~50%) and to a lesser extent in the skeletal muscle (<25%).” Thet widely accepted concept, along with the evidence of higher glucose disposal in vivo in highlanders and increased glucose uptake in the skeletal muscle induced by anoxia and hypoxia in vivo, helped the team reach that hypothesis. The authors pointed out that further experimental studies could have an important clinical impact, and understanding “the mechanisms that regulate and maintain the lower fasting glycemia in individuals who live at higher altitudes could lead to new therapeutics for impaired glucose homeostasis.”

Metformin Rarely Prescribed to Treat Pre-Diabetes

Low-cost metformin is effective at treating pre-diabetes, but the drug is rarely prescribed for it, according to a study recently published in the Annals of Internal Medicine. Metformin has been shown to prevent full-blown diabetes, but researchers found that only 3.7% of patients were prescribed metformin for their pre-diabetes over the study’s three-year window.

Researchers led by Tannaz Moin, MD, assistant professor of medicine in the Division of Endocrinology at the David Geffen School of Medicine at UCLA and VA Greater Los Angeles, analyzed a national sample of 17,352 adults aged 19 through 58 with pre-diabetes. They found:

  • Prevalence of metformin prescriptions was 7.8% for patients with a BMI of greater than 35 kg/m2.
  • Metformin prescriptions were nearly twice as high for women (4.8%) than for men (2.8%).
  • Among patients with pre-diabetes, prevalence of prescriptions for obese individuals was 6.6% vs. 3.5% for non-obese people.
  • Prescription prevalence for people with pre-diabetes and two comorbidities was 4.2% vs. 2.8% with people with no comorbidities.

The reasons for this metformin underuse are not clear, the researchers write, though lack of knowledge of the 2002 Diabetes Prevention Program (DPP) Study, which showed that both lifestyle changes and metformin use can prevent or delay progression to diabetes among those with prediabetes, or the fact that the drug does not have FDA approval for pre-diabetes, or reluctance by both patient and physician to “medicalize” pre-diabetes, may play into it.

“Metformin or lifestyle changes can be used to prevent diabetes, but getting people to make those changes is really difficult,” Moin says in a statement. “Diabetes is prevalent, but pre-diabetes is even more prevalent and we have evidence-based therapies like metformin that are very safe and work. Metformin is rarely being used for diabetes prevention among people at risk for developing it. This is something that patients and doctors need to be talking about and thinking about.”

While adopting healthier life habits can definitely curb the progression of pre-diabetes, it isn’t always easy to make those changes. For instance, setting aside time for weekly classes on healthy lifestyle changes and regular exercise can be particularly challenging for people with long work hours or other commitments that eat into their time. “Taking metformin in cases like these could be a viable alternative, so patients should be educated about the potential benefits of metformin as an option for preventive treatment since it is covered by most prescription drug plans, is inexpensive, and has been shown to be very safe in long-term studies,” Moin says.

Cellular Defect Linked to Diabetes

A cellular defect that can impair the body’s ability to handle high glucose levels and could point the way to a potential new treatment for diabetes has been identified by Columbia University Medical Center (CUMC) researchers, according to a study recently published in the Journal of Clinical Investigation. The CUMC team found that ryanodine receptor type 2 (RyR2) calcium channels in insulinproducing cells play an important and previously underappreciated role in glucose balance.

RyR2 channels control intracellular calcium release. When leaky, they were found to reduce insulin release from the pancreas, resulting in high blood sugar levels in a test that measures the ability to regulate glucose. The researchers also demonstrated, in a mouse model of diabetes, that these leaks can be stopped and glucose levels normalized with an experimental drug called Rycal.

“We’ve known that calcium in the pancreatic beta cells plays a signifi- cant role in regulating insulin secretion, but calcium levels were thought to be controlled largely by the entry of calcium into the cell,” says senior author Andrew R. Marks, MD, professor and chair of Physiology and Cellular Biophysics at CUMC. “It turns out that there’s another mechanism in pancreatic beta cells that also controls calcium. This mechanism involves RyR2 channels, and leaks in these channels can lead to impaired glucose tolerance. These findings open up a whole new area of research into the molecular underpinnings of prediabetes and diabetes and point to potential therapeutic targets.”

The CUMC researchers were initially studying a rare form of exerciseinduced arrhythmia called catecholaminergic polymorphic ventricular tachycardia (CPVT), which can be caused by mutations in the RyR2 gene.

“When we generated murine models of CPVT that harbor mutations in the RyR2 channels that make them leaky, we observed that they weren’t secreting enough insulin in response to glucose,” says lead author Gaetano Santulli, MD, PhD, a cardiologist at CUMC. “Since RyR2 channels are also expressed in pancreatic cells, we wondered whether they were mechanistically contributing to the glucose imbalance.”

The investigators performed glucose tolerance tests on 27 CPVT patients with known mutations that make the RyR2 channels leaky. Many of these individuals exhibited reduced serum insulin levels and higher-than-normal blood sugar following a glucose challenge — a novel finding in this type of patient. “This was completely unexpected, and it suggested we were on to something important in terms of understanding diabetes,” says Marks.

The researchers then turned back to the mouse models of CPVT, in an effort to determine what role, if any, RyR2s might play in impaired glucose tolerance. “Pancreatic beta cells were found to have leaky RyR2s, which were disrupting the function of mitochondria that provide cells with energy required for insulin release. The dysfunction was consistent with mitochondrial alterations that have been described in pancreatic beta cells from patients with type 2 diabetes,” says Santulli.

Finally, the scientists tested the effects of Rycal (an experimental drug that Marks’ team has shown can stop RyR2 leak) on CPVT mice with RyR2 mutations and on type 2 diabetic mice. The drug improved insulin secretion and glucose tolerance in both mouse models. “The advantage of Rycal is that many drugs now used to treat type 2 diabetes increase the risk for low blood sugar and for heart disease,” says Marks. “Based on the mechanism of action of Rycal, we would not expect this drug to cause either of these. Also, Rycals are currently being tested in patients with heart disease and muscle disorders and have a good safety record so far.”

EDCS, Along With Obesity, Increase CVD Risk in Younger Women

Pesticide exposure has been implicated along with obesity in increased cardiovascular disease risk and inflammation in premenopausal women, according to a new study in the Journal of Clinical Endocrinology & Metabolism.

Researchers looked at the effects of exposure to polychlorinated pesticides such as DDT. “After the body breaks down DDT along with similar pesticides, chemical remnants called metabolites accumulate in women’s fat tissue,” says one of the study’s authors, Diana Teixeira, a PhD student at the University of Porto in Porto, Portugal. “When higher amounts of these environmental estrogens collect in the fat tissue, it can compromise the protective effect the body’s natural estrogen has on a premenopausal woman’s heart health. This leaves women at increased risk of developing cardiovascular disease and inflammation.”

Investigators analyzed the amount of endocrine-disrupting chemicals in fat tissue and blood samples from 121 obese women who underwent bariatric surgery at S. João Hospital in Porto. Among the participants, 73 were classified as premenopausal and 48 were postmenopausal. The researchers tested the participants’ fasting blood glucose and cholesterol. Using the Framingham risk score, the researchers assessed the women’s 10-year risk of developing cardiovascular disease.

They found that among premenopausal women, women with higher concentrations of environmental estrogens in their visceral fat tissue from the belly were more likely to have higher average blood sugar levels. Among premenopausal women, those with higher levels of environmental estrogens in their blood tended to have more inThammation and faced a greater risk of cardiovascular disease on the Framingham scale. “Our findings show that endocrine-disrupting chemicals tend to aggravate complications of obesity, including inThammation and cardiovascular disease risk, in premenopausal women,” Teixeira says. “Measuring environmental estrogen levels may help physicians identify women who are at risk of developing cardiovascular and metabolic disease so they can take preventative action.”

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