Animal studies show that naturally occurring peptide catestatin has potential as anti-obesity and type 2 diabetes treatment

Research by team from University of California San Diego School of Medicine shows that treating obese mice with catestatin (CST), a peptide naturally occurring in the body, showed significant improvement in glucose and insulin tolerance and reduced body weight.

In a study published in journal Diabetes, researchers identified catestatins’s role in the recruitment and function of macrophages in the liver as well as regulation of obesity-induced liver inflammation and insulin resistance.

“We have shown that an endogenous peptide, catestatin, can directly suppress glucose production from hepatocytes and can indirectly suppress lipid accumulation in liver as well as macrophage-mediated inflammation in obese mice,” said Sushil K. Mahata, PhD, professor of medicine at UC San Diego School of Medicine. “The net results are improved glucose tolerance and insulin sensitivity. Therefore, this peptide has immense potential for an anti-obesity reagent as well as a novel drug to treat type 2 diabetes.”

Treating obese mice with catestatin inhibited the recruitment of monocyte-derived macrophages to the liver and decreased inflammation, suggesting catestatin is an anti-inflammatory peptide. Catestatin treatment also lowered blood sugar and insulin levels to normal, and reduced fatty liver. Administering catestatin had no effect on insulin or glucose tolerance in control lean mice, showing that the effect of catestatin is restricted to obese animals. This difference may be explained by the reduced levels of normal catestatin in obese mice compared to the lean control animals. To confirm the importance of naturally occurring catestatin, the authors studied mice that lacked catestatin. These mice ate more and were heavier but lost weight when treated with catestatin. The researchers theorize that naturally occurring catestatin may help maintain body weight by suppressing hunger and enhancing glucose tolerance.

“The improved glucose and insulin sensitivity with catestatin treatment may be partly explained by the anti-inflammatory effects of catestatin on the liver,” said Mahata. “We have identified a novel pathway for suppression of liver glucose production that could be used to compensate for the loss of naturally occurring catestatin or to bolster its impact. But further studies are needed to uncover how catestatin suppresses liver inflammation to improve metabolism.”

Citation: Ying, Wei, Sumana Mahata, Gautam K. Bandyopadhyay, Zhenqi Zhou, Joshua Wollam, Jessica Vu, Rafael Mayoral, Nai-Wen Chi, Nicholas J.g. Webster, Angelo Corti, and Sushil K. Mahata. “Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production Leading to Improved Insulin Sensitivity.” Diabetes, 2018. doi: 10.2337/db17-0788.

Funding:  Department of Veterans Affairs, American Heart Association, National Natural Science Foundation of China, Noland Scholarship.

Adapted from press release by University of California San Diego School of Medicine.

Brain changes in diabetic patients

A new study published in Diabetologia reveals that overweight and obese individuals with early stage type 2 diabetes (T2D) had more severe and progressive abnormalities in brain structure and cognition compared to normal-weight study participants.

The research conducted by Dr Sunjung Yoon and Dr In Kyoon Lyoo (Ewha Brain Institute, Ewha Womens University, Seoul, South Korea), Hanbyul Cho (The Brain Institute, University of Utah, Salt Lake City, UT, USA), and colleagues in Korea and the USA looked into the effects of being overweight or obese on the brains and cognitive functions of people with early stage type 2 diabetes.

The study found that grey matter was significantly thinner in clusters in the temporal, prefrontoparietal, motor and occipital cortices of the brains of diabetic study participants when compared to the non-diabetic control group. Further thinning of the temporal and motor cortices was also observed in the overweight/obese diabetic group, compared to normal-weight diabetics. The team also discovered region-specific changes which suggested that the temporal lobe has a particular vulnerability to the combined effects of having type 2 diabetes and being overweight or obese.

Citation: Yoon, Sujung, Hanbyul Cho, Jungyoon Kim, Do-Wan Lee, Geon Ha Kim, Young Sun Hong, Sohyeon Moon, Shinwon Park, Sunho Lee, Suji Lee, Sujin Bae, Donald C. Simonson, and In Kyoon Lyoo. “Brain changes in overweight/obese and normal-weight adults with type 2 diabetes mellitus.” Diabetologia, 2017.
doi:10.1007/s00125-017-4266-7.
Adapted from press release by Diabetologia.

Medical device that activates heat shock response found helpful in Diabetic patients

Although effective for the treatment of diabetes, exercise is sometimes difficult for overweight or elderly people. A new wearable medical device developed by Kumamoto University has been found to effect visceral fat loss and improve blood glucose (sugar). The current study reports clinical trial results for optimal use frequency.

Type 2 diabetes is a disease of systemic organ failure due to chronic hyperglycemia and inflammation from the accumulation of excess visceral fat. Metabolic disorders such as hyperglycemia attenuate stress resistance in the human body and exacerbate insulin resistance. The ability of insulin to lower blood sugar levels is reduced and insulin secretion is decreased.

The heat shock response (HSR) is activated as a response to stress in the human body, but its function decreased in those with type 2 diabetes. A research team from Kumamoto University, Japan has found that by restoring the function of HSP72, the main protein of  heat shock response HSR, improved glucose-related abnormalities. The team found that a suitable combination of mild electrical stimulation (MES) with heat shock (HS) activated HSP72 more efficiently.

The researchers developed a belt-type medical device that uses a special type of rubber to transmit MES and HS at the same time. They then performed a clinical trial of MES + HS on 40 obese men suffering from type 2 diabetes. Results showed a decrease fasting glucose levels, a loss of visceral fat, improve insulin resistance, and a significant (-0.43%) improvement in glycated hemoglobin (HbA1c) values. About half of all subjects (52.5%) achieved less than 7.0% HbA1c, which is a treatment goal for diabetes. The first trial showed that activation of the HSR produced a large therapeutic effect. This research was posted online in the nature.com journal Scientific Reports.

In the researcher’s next clinical trial, 60 obese patients with type 2 diabetes from both genders were given a 12-week treatment with the belt-shaped MES+HS medical device. Trial subjects received treatments for 60 minutes each time, and were separated into three groups of 2, 4, and 7 treatments per week. This determined the most effective treatment frequency.

The reduction in the visceral fat area was 5.37 sq. cm in the 2 treatment per week group, 14.24 sq. cm in the 4 per week group and 16.45 sq. cm in the 7 per week group. Declines in HbA1c were 0.10%, 0.36%, and 0.65% in the 2, 4, and 7 treatment-per-week groups respectively. Improvements in chronic inflammation, fatty liver markers, renal function and lipid profile were also shown. Furthermore, adding the MES+HS treatment to a DPP-4 inhibitor, which is the most often used therapeutic drug for diabetes in Japan, showed an even stronger blood glucose improvement.

“This device is very easy to use since it simply attaches to the abdomen, and it has a low-impact on the patient. One can expect the effects to be similar to exercise therapy,” said Dr. Tatsuya Kondo, who lead the research. “Even in patients who have difficulty exercising, such as those who are overweight, elderly, or have some form of disability, this device can be expected to provide acceptable treatment in addition to conventional diabetic medical care.”

Citation: Kondo, Tatsuya, Rieko Goto, Kaoru Ono, Sayaka Kitano, Mary Ann Suico, Miki Sato, Motoyuki Igata et al. “Activation of heat shock response to treat obese subjects with type 2 diabetes: a prospective, frequency-escalating, randomized, open-label, triple-arm trial.” Scientific Reports 6 (2016).
DOI: http://dx.doi.org/10.1038/srep35690
Research funding: Japan Agency for Medical Research and Development, Grants-in-Aid for Scientific Research
Adapted from press release by Kumamoto University.

Sleep loss and change in gut microbiota

Results from a new clinical study conducted at Uppsala University suggest that curtailing sleep alters the abundance of bacterial gut species that have previously been linked to compromised human metabolic health. The new article is published in the journal Molecular Metabolism.

Changes in the composition and diversity of the gut microbiota have been associated with diseases such as obesity and type-2 diabetes in humans. These diseases have also been linked with chronic sleep loss. However, it is not known whether sleep loss alters the gut microbiota in humans. With this in mind, Christian Benedict, associate professor of neuroscience, and Jonathan Cedernaes, M.D., Ph.D, both from Uppsala University, collaborated with researchers from the German Institute of Human Nutrition Potsdam-Rehbruecke. In their study, the researchers sought to investigate in nine healthy normal-weight male participants whether restricting sleep to about four hours per night for two consecutive days as compared with conditions of normal sleep (about 8 hours of sleep opportunity) may alter the gut microbiota in humans.

“Overall we did not find evidence that suggests that the diversity of the gut microbiota was altered by sleep restriction. This was somewhat expected given the short-term nature of the intervention and the relatively small sample size. In more specific analyses of groups of bacteria, we did however observe microbiota changes that parallel some of the microbiota changes observed when for instance obese subjects have been compared with normal-weight subjects in other studies, such as an increased ratio of Firmicutes to Bacteroidetes. Longer and larger clinical sleep interventions will be needed to investigate to what extent alterations of the gut microbiota may mediate negative health consequences attributed to sleep loss, such as weight gain and insulin resistance,” says senior author Jonathan Cedernaes.

“We also found that participants were over 20 percent less sensitive to the effects of the hormone insulin following sleep loss. Insulin is a pancreatic hormone needed to bring down blood glucose levels. This decreased insulin sensitivity was however unrelated to alterations in gut microbiota following sleep loss. This suggests that changes in microbiota may not, at least in the short-term, represent a central mechanism through which one or several nights of curtailed sleep reduce insulin sensitivity in humans,” says first author Christian Benedict.

Citation: Gut Microbiota and Glucometabolic Alterations in Response to Recurrent Partial Sleep Deprivation in Normal-weight Young Individuals.
Authors: Christian Benedict, et., al.
DOI: http://dx.doi.org/10.1016/j.molmet.2016.10.003
Journal: Molecular Metabolism
Adapted from press release by Uppsala University