Could resetting our internal clocks help control diabetes?
January 31, 2020
Science Daily/Université de Genève
The circadian clock system allows the organisms to adjust to periodical changes of geophysical time. Today, increasing evidence show that disturbances in our internal clocks stemming from frequent time zone changes, irregular working schedules or ageing, have a significant impact on the development of metabolic diseases including type-2 diabetes. Using a molecule extracted from lemon peel, researchers have succeeded in 'repairing' the disrupted cellular clocks.
The circadian clock system (from Latin "circa diem," about a day) allows the organisms to anticipate periodical changes of geophysical time, and to adjust to these changes. Nearly all the cells in our body comprise molecular clocks that regulate and synchronize metabolic functions to a 24-hour cycle of day-night changes. Today, increasing evidence show that disturbances in our internal clocks stemming from frequent time zone changes, irregular working schedules or ageing, have a significant impact on the development of metabolic diseases in human beings, including type-2 diabetes. Such disturbances seem to prevent the proper functioning of the cells in the pancreatic islet that secrete insulin and glucagon, the hormones that regulate blood sugar levels. By comparing the pancreatic cells of type 2 diabetic human donors with those of healthy people, researchers at the University of Geneva (UNIGE) and at the University Hospitals of Geneva (HUG), Switzerland, were able to demonstrate, for the first time, that the pancreatic islet cells derived from the Type 2 Diabetic human donors bear compromised circadian oscillators. The disruption of the circadian clocks was concomitant with the perturbation of hormone secretion. Moreover, using clock modulator molecule dubbed Nobiletin, extracted from lemon peel, the researchers succeeded in "repairing" the disrupted cellular clocks and in partial restoring of the islet cell function. These results, published in the Proceedings of the National Academy of Sciences of the United States, provide a first insight into innovative approach for diabetes care.
Two years ago, the team led by Charna Dibner, Principle Investigator in the Departments of Medicine and of Cell Physiology and Metabolism, and Diabetes Centre at UNIGE Faculty of Medicine, and at HUG, has already shown that in rodents the perturbation of pancreatic cellular clocks led to disrupted insulin and glucagon secretion, thus promoting the onset of diabetes. But what is the situation in human beings? "We had also previously observed that if the clocks of human pancreatic cells were artificially disrupted in the cellular culture in vitro, secretion of the key islet hormones -- insulin and glucagon -- was compromised," says Volodymyr Petrenko, a researcher in Dr. Dibner's lab and the first author of these publications. Hence our next step, that we report here, was to unravel whether the circadian rhythms were perturbed in human pancreatic islets in type 2 diabetes, and, if so, how would this perturbation affect the islet function."
Using combined bioluminescence-fluorescence time-lapse microscopy, a technology that allows tracking the molecular clock activity in living cells very precisely over time, the scientists compared the behaviour of pancreatic cell of type-2 diabetic donors and those of healthy subjects throughout the day. "The verdict is indisputable," says Charna Dibner. The biological rhythms of the islet cells in type-2 diabetes exhibit both reduced amplitudes of circadian oscillations and poor synchronization capacity. "As a result, hormone secretion is no longer coordinated. Moreover, the defects in temporal coordination of insulin and glucagon secretion observed in patients with type-2 diabetes were comparable to those measured in healthy islet cells with artificially-disrupted circadian clock."
It's all in the timing!
Circadian clocks represent the daily cycles governing the various cellular functions. There are several interlocking levels of synchronization of these clocks, the main one being light, which in particular regulates the central clock located in the cerebral hypothalamus. Like a conductor in the orchestra, it regulates peripheral clocks present in organs and cells. The latter are therefore partly centrally regulated, but function differently in each organ, and even in each cell, depending on their functions. "Pancreatic cells are also subject to the rhythm of fasting and food intake, and to a tight hormonal regulation," says Charna Dibner. "Coordinating all levels of regulation therefore allows the optimization of metabolic functions. Clocks deregulation in pancreatic islet leads to a compromised function: they are not anymore anticipating food-derived signals. Indeed, if you eat the same food but at night rather than during the day, you may gain weight much faster, due to a suboptimal response of your metabolism."
Setting the right time again
Step two of their research: the Geneva scientists used Nobiletin, a small clock modulator molecule -- a natural ingredient of lemon peel whose impact on circadian clocks has been recently discovered -- in order to resynchronize the clocks. "By acting on one of the core-clock components, it resets efficiently the amplitude of the oscillations in the human islets" says Volodymyr Petrenko. "And as soon as we got the clocks back in sync, we also observed an improvement in insulin secretion."
"This is the first proof of principle that repairing compromised circadian clocks may help improving the function of the pancreatic islet hormone secretion," says Charna Dibner. "We will continue by exploring this repair mechanism in vivo, first in animal models. Our society experiences epidemic growth in metabolic diseases, concomitant with shifted working and eating schedules, and lack of sleep. By re-synchronizing the perturbed molecular clocks, either by personalized eating and exercise schedules or with the help of clock modulator molecules, we hope to ultimately be able to provide an innovative solution to an epidemical metabolic problem affecting an ever-increasing proportion of the world's population."
https://www.sciencedaily.com/releases/2020/01/200131074205.htm
Low-carb diets cause people to burn more calories
All calories are not alike, finds largest, longest macronutrient feeding trial to date
November 14, 2018
Science Daily/Boston Children's Hospital
Most people regain the weight they lose from dieting within one or two years, in part because the body adapts by slowing metabolism and burning fewer calories. A meticulous study now finds that eating fewer carbohydrates increases the number of calories burned. The findings suggest that low-carb diets can help people maintain weight loss, making obesity treatment more effective.
The study, known as the Framingham State Food Study, or (FS)2, tightly controlled what people ate by providing them with fully prepared food-service meals for a 20-week period. Researchers carefully tracked participants' weight and measured insulin secretion, metabolic hormones and total energy expenditure (calories burned).
"This is the largest and longest feeding study to test the 'Carbohydrate-Insulin Model,' which provides a new way to think about and treat obesity," says David Ludwig, MD, PhD, who is co-principal investigator with Cara Ebbeling, PhD. (Ludwig and Ebbeling are co-directors of the New Balance Foundation Obesity Prevention Center in Boston Children's Division of Endocrinology.) "According to this model, the processed carbohydrates that flooded our diets during the low-fat era have raised insulin levels, driving fat cells to store excessive calories. With fewer calories available to the rest of the body, hunger increases and metabolism slows -- a recipe for weight gain."
Comparing carb levels head to head
After careful telephone screening of 1,685 potential participants, Ebbeling, Ludwig and colleagues enrolled 234 overweight adults (age 18 to 65, body mass index of 25 or higher) to an initial weight-loss diet for about 10 weeks. Of these, 164 achieved the goal of losing 10 to 14 percent of body weight and went on to the study's maintenance phase.
These participants were then randomized to follow high-, moderate- or low-carbohydrate diets for an additional 20 weeks -- with carbs comprising 60, 40 and 20 percent of total calories, respectively. Carbs provided to all three groups were of high quality, conforming to guidelines for minimizing sugar and using whole rather than highly processed grains.
In all three groups, total calorie intake was adjusted to maintain weight loss, so participants' weight did not change notably. During this phase, the goal was to compare energy expenditure -- how the different groups burned calories at the same weight. Energy expenditure was measured by a gold-standard method using doubly labeled water.
Over the 20 weeks, total energy expenditure was significantly greater on the low-carbohydrate diet versus the high-carbohydrate diet. At the same average body weight, participants who consumed the low-carb diet burned about 250 kilocalories a day more than those on the high-carb diet.
"If this difference persists -- and we saw no drop-off during the 20 weeks of our study -- the effect would translate into about a 20-pound weight loss after three years, with no change in calorie intake," says Ebbeling.
In people with the highest insulin secretion at baseline, the difference in calorie expenditure between the low- and high-carb diets was even greater, about 400 kilocalories per day, consistent with what the Carbohydrate-Insulin Model would predict. Ghrelin, a hormone thought to reduce calorie burning, was significantly lower on the low- versus high-carb diet.
"Our observations challenge the belief that all calories are the same to the body," says Ebbeling. "Our study did not measure hunger and satiety, but other studies suggest that low-carb diets also decrease hunger, which could help with weight loss in the long term."
Ludwig and Ebbeling recently launched another clinical trial called FB4, in which 125 adults with obesity live in a residential center for 13 weeks. Participants are being randomized to one of three diets: very-low-carb, high carb/low sugar or high carb/high sugar diets, with their calorie intakes individually matched to their energy expenditure. Results are expected in 2021.
https://www.sciencedaily.com/releases/2018/11/181114120302.htm