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In explaining rise of obesity, diabetes, look toward unanswered questions

LAS VEGAS— The epidemics of obesity and type 2 diabetes continue to grow, and several challenging questions may hold the clues to targeting the mechanisms behind the two chronic conditions, according to a presenter at ObesityWeek.

The causes behind obesity and type 2 diabetes are not as simple as overeating or a failure to compensate for insulin resistance, Barbara Corkey, PhD, Zoltan Kohn professor of medicine and vice chair for research in the department of medicine at Boston University, said during a keynote presentation. It may be timefor researchers to reexamine such hypotheses to better understand the complex variables at play behind the two diseases.

“When you have a hypothesis that has not benefited patients or led to improved outcomes, and the incidence is growing, it is time to sit back and re-look at these things,” Corkey said. “I’m not going to give you an answer. I hope to give you a challenge.”

Overeating vs. energy metabolism

Human energy output decreases during underfeeding and increases during overfeeding, Corkey said. Individuals with the greatest increases in energy output gain the least amount of weight during overfeeding, whereas those who with the largest decreases in energy output lose the least amount of weight during underfeeding. However, research often ignores an important variable — the involuntary control of energy metabolism. Hibernating mammals, for example, experience a fourfold increase in energy expenditure, whereas migrating birds experience a sevenfold increase, she said.

“Can variations in energy metabolism cause obesity? For some reason, we ignore this variable,” Corkey said. “Children and most adults prior to the 1980s managed to maintain the same weight regardless of what they ate. There are many examples where weight management is not what you might expect.”

Failure to adapt energy efficiency to nutrient supply, rather than overeating, may cause obesity, Corkey said, adding that environmental effects on neural satiety and hunger sensing also potentially regulatory.

“It makes one wonder, is failure to adapt energy efficiency to nutrient intake, rather than overeating, a cause of obesity?” Corkey said. “I’m not suggesting it is. I’m suggesting that we don’t have that answer. The topic has received very little attention. In addition to that, a variety of environmental influences have not been studied. We don’t know how these variations ffect the neural system.”

Benefit of insulin resistance

Before the development of type 2 diabetes, obesity, insulin resistance, inflammation, hyperlipidemia and hypersecretion of insulin all coexist, Corkey said. There is no evidence that one precedes the other. Each can cause the others in an experimental setting, and each is the basis for a reasonable hypothesis.

“So, why do we only choose one?” said.

Insulin resistance, Corkey said, may even be beneficial, serving as an adaptive response to maintain normoglycemia in the presence of high insulin.

“Improving insulin sensitivity may cause hypoglycemia, and ‘curing’ insulin resistance could be detrimental,” said.

The “bottom line,” Corkey said, is there is no evidence that insulin resistance precedes obesity, inflammation, hyperlipidemia or hyperinsulinemia to cause metabolic dysfunction.

“Diminishing either obesity, hyperlipidemia or hyperinsulinemia decreases insulin resistance, suggesting to me that it is a consequence, not a cause,” Corkey said. “One of the problems in this area is that tools to selectively alter insulin resistance alone, and none of these other things, are lacking, making it an untestable hypothesis.”

Role of diet

Food today is different, Corkey said. Much of it is highly processed, with 4,000 new agents, almost none of which have been evaluated as potential causes of diabetes or obesity. Fruits and vegetableshave also changed. According to a 2003 study published in Nutrition and Health that assessed mineral content of foods in 1991 vs. 1940, fruits overall now contain 27% less zinc, meats contain 41% less calcium, apples and oranges contain 67% less iron and spinach contains 96% less copper. Food animals are also different: Chickens today are about four times as heavy as they were in 1957, despite being fed the same foodsand are more efficient at turning feed into breast meat.

“Is it possible that such changes in efficiency were imposed on people?” Corkey said.

Test new hypotheses

The challenge before researchersis to test new hypotheses. Obesity, type 2 diabetes and free fatty acids correlate with both hyperinsulinemia and insulin resistance. Insulin infusion causes insulin resistance, and the inhibition of insulin secretion has improved insulin resistance and increased weight loss in a few small clinical trials. Environmental agents, too, may cause hypersecretion, said.

“We need to identify agents that alter energy efficiency, we need to inhibit excessive insulin secretion before beta-cell failure occurs, and we need to prevent excess lipid accumulation by stimulating oxidation and lowering insulin with existing drugs and combinations,” Corkey said. “We must choose animal and cell models well and use multiples of them.”

Several unanswered questions should serve as “food” for future research endeavors, Corkey said. How do people who successfully defend their weight differ when compared with those gain weight more easily? Which comes first for the person with excess weight — obesity, hyperlipidemia, hyperinsulinemia or insulin resistance? What are the common weight trajectories over a lifetime? Are there differences in insulin levels during over- and underfeeding in “easy gainers” compared with “easy losers?”

The answers, Corkey said, likely lie beyond single-cell tissue defects.

“Should we seek single-cell tissue defects to explain metabolic disease? I don’t think so,” Corkey said. “Beta cells are secreting too much insulin. The hepatocytes are producing too much glucose. The fat cells may release too much fat or not store enough fat. Muscle becomes insulin resistant and the neural cells are dysfunctional in their sensing of satiety or hunger.” – by Regina Schaffer

References:

Corkey B. Why have we failed to decrease obesity and diabetes? Presented at: ObesityWeek 2019; Nov. 3-7, 2019; Las Vegas.

Thomas D. Nutr Health. 2003;doi:10.1177/026010600301700201.

Disclosure: Corkey reports no relevant financial disclosures.

LAS VEGAS— The epidemics of obesity and type 2 diabetes continue to grow, and several challenging questions may hold the clues to targeting the mechanisms behind the two chronic conditions, according to a presenter at ObesityWeek.

The causes behind obesity and type 2 diabetes are not as simple as overeating or a failure to compensate for insulin resistance, Barbara Corkey, PhD, Zoltan Kohn professor of medicine and vice chair for research in the department of medicine at Boston University, said during a keynote presentation. It may be timefor researchers to reexamine such hypotheses to better understand the complex variables at play behind the two diseases.

“When you have a hypothesis that has not benefited patients or led to improved outcomes, and the incidence is growing, it is time to sit back and re-look at these things,” Corkey said. “I’m not going to give you an answer. I hope to give you a challenge.”

Overeating vs. energy metabolism

Human energy output decreases during underfeeding and increases during overfeeding, Corkey said. Individuals with the greatest increases in energy output gain the least amount of weight during overfeeding, whereas those who with the largest decreases in energy output lose the least amount of weight during underfeeding. However, research often ignores an important variable — the involuntary control of energy metabolism. Hibernating mammals, for example, experience a fourfold increase in energy expenditure, whereas migrating birds experience a sevenfold increase, she said.

“Can variations in energy metabolism cause obesity? For some reason, we ignore this variable,” Corkey said. “Children and most adults prior to the 1980s managed to maintain the same weight regardless of what they ate. There are many examples where weight management is not what you might expect.”

Failure to adapt energy efficiency to nutrient supply, rather than overeating, may cause obesity, Corkey said, adding that environmental effects on neural satiety and hunger sensing also potentially regulatory.

“It makes one wonder, is failure to adapt energy efficiency to nutrient intake, rather than overeating, a cause of obesity?” Corkey said. “I’m not suggesting it is. I’m suggesting that we don’t have that answer. The topic has received very little attention. In addition to that, a variety of environmental influences have not been studied. We don’t know how these variations ffect the neural system.”

Benefit of insulin resistance

Before the development of type 2 diabetes, obesity, insulin resistance, inflammation, hyperlipidemia and hypersecretion of insulin all coexist, Corkey said. There is no evidence that one precedes the other. Each can cause the others in an experimental setting, and each is the basis for a reasonable hypothesis.

PAGE BREAK

“So, why do we only choose one?” said.

Insulin resistance, Corkey said, may even be beneficial, serving as an adaptive response to maintain normoglycemia in the presence of high insulin.

“Improving insulin sensitivity may cause hypoglycemia, and ‘curing’ insulin resistance could be detrimental,” said.

The “bottom line,” Corkey said, is there is no evidence that insulin resistance precedes obesity, inflammation, hyperlipidemia or hyperinsulinemia to cause metabolic dysfunction.

“Diminishing either obesity, hyperlipidemia or hyperinsulinemia decreases insulin resistance, suggesting to me that it is a consequence, not a cause,” Corkey said. “One of the problems in this area is that tools to selectively alter insulin resistance alone, and none of these other things, are lacking, making it an untestable hypothesis.”

Role of diet

Food today is different, Corkey said. Much of it is highly processed, with 4,000 new agents, almost none of which have been evaluated as potential causes of diabetes or obesity. Fruits and vegetableshave also changed. According to a 2003 study published in Nutrition and Health that assessed mineral content of foods in 1991 vs. 1940, fruits overall now contain 27% less zinc, meats contain 41% less calcium, apples and oranges contain 67% less iron and spinach contains 96% less copper. Food animals are also different: Chickens today are about four times as heavy as they were in 1957, despite being fed the same foodsand are more efficient at turning feed into breast meat.

“Is it possible that such changes in efficiency were imposed on people?” Corkey said.

Test new hypotheses

The challenge before researchersis to test new hypotheses. Obesity, type 2 diabetes and free fatty acids correlate with both hyperinsulinemia and insulin resistance. Insulin infusion causes insulin resistance, and the inhibition of insulin secretion has improved insulin resistance and increased weight loss in a few small clinical trials. Environmental agents, too, may cause hypersecretion, said.

“We need to identify agents that alter energy efficiency, we need to inhibit excessive insulin secretion before beta-cell failure occurs, and we need to prevent excess lipid accumulation by stimulating oxidation and lowering insulin with existing drugs and combinations,” Corkey said. “We must choose animal and cell models well and use multiples of them.”

Several unanswered questions should serve as “food” for future research endeavors, Corkey said. How do people who successfully defend their weight differ when compared with those gain weight more easily? Which comes first for the person with excess weight — obesity, hyperlipidemia, hyperinsulinemia or insulin resistance? What are the common weight trajectories over a lifetime? Are there differences in insulin levels during over- and underfeeding in “easy gainers” compared with “easy losers?”

PAGE BREAK

The answers, Corkey said, likely lie beyond single-cell tissue defects.

“Should we seek single-cell tissue defects to explain metabolic disease? I don’t think so,” Corkey said. “Beta cells are secreting too much insulin. The hepatocytes are producing too much glucose. The fat cells may release too much fat or not store enough fat. Muscle becomes insulin resistant and the neural cells are dysfunctional in their sensing of satiety or hunger.” – by Regina Schaffer

References:

Corkey B. Why have we failed to decrease obesity and diabetes? Presented at: ObesityWeek 2019; Nov. 3-7, 2019; Las Vegas.

Thomas D. Nutr Health. 2003;doi:10.1177/026010600301700201.

Disclosure: Corkey reports no relevant financial disclosures.

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