Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Betatrophine, Letpin and PPAR-gamma

Reporter: Stuart Cantor, PhD

 

 

Leptin:

Leptin is termed the “satiety hormone” and decreases appetite. It is made by adipose cells and other cells and regulates energy balance. It works opposite to the hormone ghrelin, known as the “hunger hormone.” Obese patients have elevated blood levels of leptin and have reduced leptin sensitivity. Thus, obese patients can be unable to feel satiety despite having high energy stores.  Leptin levels are decreased by exercise and increased by insulin. Fasting or a very low calorie diet will also decrease levels of leptin.

 

A 2010 study by Wang M-Y et al. showed that in non-obese uncontrolled diabetic mice with Type 1 diabetes, recombinant leptin therapy alone or combined with low dose insulin reversed the catabolic state by suppressing elevated glucagon levels in the blood (and without increasing body fat). Leptin can normalize hemoglobin A1c with far less glucose variability. Results showed that leptin may have multiple short- and long-term advantages over insulin monotherapy for Type 1 diabetes. However – they also stated that well-controlled diabetic patients with normal or increased levels of adipocytes MAY be LESS responsive to leptin therapy.

 

In 2014, FDA approved Myalept (metreleptin for injection) to treat leptin deficiency (affects ~ 200 patients) & lipodystrophy (can be caused by repeated insulin injections in the same place on the body). The drug is marketed now by Astra Zeneca. FDA is requiring 7 post-marketing studies, including the assessment for immunogenicity (antibody formation), which is a potential serious risk. In clinical trials (48 patients), a common side effect observed was hypoglycemia.

Betatrophin:

Wang L, et al.   Circulating Levels of Betatrophin and Irisin Are Not Associated with Pancreatic β-Cell Function in Previously Diagnosed Type 2 Diabetes Mellitus Patients. J Diabetes Res. 2016;2016:2616539. doi: 10.1155/2016/2616539. Epub 2015 Nov 16.

Wang et al. concludes that betatrophin and irisin were not associated with β-cell function in previously diagnosed T2DM patients.

 

Betatrophin is also called Angiopoietin-like protein 8 (ANGPTL8).   Harvard stem cell researcher Doug Melton published a paper on the supposed ability of betatrophin to increase the production of beta cells. His work has been cited 59 times, according to Thomson Scientific’s Web of Knowledge, however, the results have been called into question by research from an independent group, as well as follow-up work from the original team.

http://retractionwatch.com/2014/11/10/i-kind-of-like-that-about-science-harvard-diabetes-breakthrough-muddied-by-two-new-papers

Gusarova et al paper says that no, ANGPTL8 does not have an effect on beta-cell replication and Melton agrees with them. Melton and co-authors say “the conclusion from Yi et al. must be corrected and modified with respect to the magnitude of the effect [..] some mice respond strongly to ANGPTL8/betatrophin expression but many do not. When all mice are taken into account the results show a modest average increase in beta cell replication.

 

PPAR-gamma:

PPARG regulates fatty acid storage and glucose metabolism. This article mentions the use of pomegranate flower having dual alpha/gamma PPAR activating properties.

http://onlinelibrary.wiley.com/doi/10.1111/j.1463-1326.2007.00708.x/abstract;jsessionid=E269728CDCE2B26DB92BAC6E1CD4E001.f03t03

 

Medagama AB^. . The glycaemic outcomes of Cinnamon, a review of the experimental evidence and clinical trials. Nutr J. 2015 Oct 16;14(1):108. doi: 10.1186/s12937-015-0098-9.

This work was done in Sri Lanka. There already is a marketed water-soluble cinnamon extract product developed in 2006 sold under the name Cinnulin PF (IN ingredients).

Cinnamon is currently marketed as a remedy for obesity, glucose intolerance, diabetes mellitus and dyslipidaemia. Integrative medicine is a new concept that combines conventional treatment with evidence-based complementary therapies.

The aim of this review is to critically evaluate the experimental evidence available for cinnamon in improving glycaemic targets in animal models and humans.

Insulin receptor auto-phosphorlylation and de-phosphorylation, glucose transporter 4 (GLUT-4 ) receptor synthesis and translocation, modulation of hepatic glucose metabolism through changes in Pyruvate kinase (PK) and Phosphenol Pyruvate Carboxikinase (PEPCK), altering the expression of PPAR (γ) and inhibition of intestinal glucosidases are some of the mechanisms responsible for improving glycaemic control with cinnamon therapy. We reviewed 8 clinical trials that used Cinnamomum cassia in aqueous or powder form in doses ranging from 500 mg to 6 g per day for a duration lasting from 40 days to 4 months as well as 2 clinical trials that used cinnamon on treatment naïve patients with pre-diabetes. An improvement in glycaemic control was seen in patients who received Cinnamon as the sole therapy for diabetes, those with pre-diabetes (IFG or IGT) and in those with high pre-treatment HbA1c. In animal models, cinnamon reduced fasting and postprandial plasma glucose and HbA1c.

Cinnamon has the potential to be a useful add-on therapy in the discipline of integrative medicine in managing type 2 diabetes. At present the evidence is inconclusive and long-term trials aiming to establish the efficacy and safety of cinnamon is needed. However, high coumarin content of Cinnamomum cassia is a concern, but Cinnamomum zeylanicum with its low coumarin content would be a safer alternate.

 

Han, JM. Effects of Lonicera japonica Thunb. on Type 2 Diabetes via PPAR-γ Activation in Rats. Phytother Res. 2015 Oct;29(10):1616-21. doi: 10.1002/ptr.5413. Epub 2015 Jul 14.

 

Lonicera japonica Thunb. (Caprifoliaceae) is a traditional herbal medicine and has been used to treat diabetic symptoms. Notwithstanding its use, the scientific basis on anti-diabetic properties of L. japonica is not yet established. This study is designed to investigate anti-diabetic effects of L. japonica in type 2 diabetic rats. L. japonica was orally administered at the dose of 100 mg/kg in high-fat diet-fed and low-dose streptozotocin-induced rats. After the treatment of 4 weeks, L. japonica reduced high blood glucose level and homeostatic model assessment of insulin resistance in diabetic rats. In addition, body weight

 

and food intake were restored by the L. japonica treatment. In the histopathologic examination, the amelioration of damaged β-islet in pancreas was observed in L. japonica-treated diabetic rats. The administration of L. japonica elevated peroxisome proliferator-activated receptor gamma and insulin receptor subunit-1 protein expressions. The results demonstrated that L. japonica had anti-diabetic effects in type 2 diabetic rats via the peroxisome proliferator-activated receptor gamma regulatory action of L. japonica as a potential mechanism.

 

Gu C, et al. Astragalus polysaccharides affect insulin resistance by regulating the hepatic SIRT1-PGC-1α/PPARα-FGF21 signaling pathway in male Sprague Dawley rats undergoing catch-up growth. Mol Med Rep. 2015 Nov;12(5):6451-60. doi: 10.3892/mmr.2015.4245. Epub 2015 Aug 25.

The present study investigated the effects of Astragalus polysaccharides (APS) on insulin resistance by modulation of hepatic sirtuin 1 (SIRT1)‑peroxisome proliferator‑activated receptor (PPAR)‑γ coactivator (PGC)‑1α/PPARα‑fibroblast growth factor (FGF)21, and glucose and lipid metabolism. Thirty male Sprague Dawley rats were divided into three groups: A normal control group, a catch‑up growth group and an APS‑treated (APS-G) group. The latter two groups underwent food restriction for 4 weeks, prior to being provided with a high fat diet, which was available ad libitum. The APS‑G group was orally treated with APS for 8 weeks, whereas the other groups were administered saline. Body weight was measured and an oral glucose tolerance test (OGTT) was conducted after 8 weeks. The plasma glucose and insulin levels obtained from the OGTT were assayed, and hepatic morphology was observed by light and transmission electron microscopy. In addition, the mRNA expression levels of PGC‑1α/PPARα, and the protein expression levels of SIRT1, FGF21 and nuclear factor‑κB were quantified in the liver and serum. APS treatment suppressed abnormal glycolipid metabolism and insulin resistance following 8 weeks of catch‑up growth by improving hepatic SIRT1‑PPARα‑FGF21 intracellular signaling and reducing chronic inflammation, and by partially attenuating hepatic steatosis. The suppressive effects of APS on liver acetylation and glycolipid metabolism‑associated molecules contributed to the observed suppression of insulin resistance. However, the mechanism underlying the effects of APS on insulin resistance requires further research in order to be elucidated. Rapid and long‑term treatment with APS may provide a novel, safe and effective therapeutic strategy for type 2 diabetes.