Cocoa Extract Exerts Sex-Specific Effects in an Aggressive Hyper-Glycemia Model: A Pilot Study

SummaryMetformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing Type 2 diabetes in people at high risk, by lowering body weight, fat mass and circulating insulin levels through mechanisms that are incompletely understood. Recent observational studies reporting the association of metformin use and circulating levels of GDF15 led us to hypothesize that GDF15, which signals through a specific receptor complex in the hindbrain to reduce body weight, might mediate these effects. We measured GDF15 in people without diabetes from a randomized placebo-controlled trial of metformin. Over 18 months, participants allocated metformin lost significant weight and levels of GDF15 were persistently elevated compared to placebo. The change in plasma GDF15 in this study correlated positively with weight loss. In wild-type mice, oral metformin increased circulating GDF15 with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to high fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL. In obese, high fat-fed mice, the effects of metformin to reduce body weight were reversed by a GFRAL antagonist antibody. Metformin had effects on both energy intake and energy expenditure that required GDF15. The insulin sensitising effects of metformin determined by insulin tolerance were abolished in mice lacking GDF15. Metformin significantly reduced fasting glucose and insulin levels in wild type but not in mice lacking GDF15. In summary, metformin increases the circulating levels of GDF15, which appears to be necessary for many of its actions as a metabolic chemopreventive agent.

Download Full-text

Evidence from studies in rodents and in isolated adipocytes that agonists of the chemerin receptor CMKLR1 may be beneficial in the treatment of type 2 diabetes

10.7287/peerj.preprints.643 ◽

2014 ◽

Author(s):

Ed T Wargent ◽

Mohamed S Zaibi ◽

Jacqueline F O'Dowd ◽

Mike A Cawthorne ◽

Steven J Y Wang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glucose Uptake ◽

Glucose Homeostasis ◽

Wild Type ◽

Male And Female ◽

Low Fat Diet ◽

Diet Induced Obesity ◽

Mrna Content ◽

Anti Inflammatory

It is unclear whether the adipokine chemerin has pro- or anti-inflammatory properties, plays any role in the aetiology of obesity or type 2 diabetes, or whether agonists or antagonists of the chemerin receptor CMKLR1 have potential in the treatment of these diseases. To address these questions, we investigatedthe metabolic phenotypes of both male and female, CMKLR1 knockout and heterozygote mice; the effects of murine chemerin and some C-terminal peptides on glucose uptake in wild-type and CMKLR1 knockout adipocytes; and plasma chemerin levels and chemerin gene mRNA content in adipose tissue in models ofobesity and diabetes, and in response to fasting or administration of the insulin sensitizing drug rosiglitazone, which also has anti-inflammatory properties. Both male and female, CMKLR1 knockout and heterozygote mice displayed a mild tendency to obesity and impaired glucose homeostasis, but only when they were fed on a high fat, rather than a standard low fat diet. Obesity and impaired glucose homeostasis did not occur concurrently, suggesting that obesity was not the sole cause of impaired glucose homeostasis. Picomolar concentrations of chemerin and its C15- and C19-terminal peptides stimulatedglucose uptake in the presence of insulin by rat and mouse wild-type epididymal adipocytes, but not by murine CMKLR1 knockout adipocytes. The insulin concentration-response curve was shifted to the left in the presence of 40 pM chemerin or its C-15 terminal peptide. The plasma chemerin level was raised in diet-induced obesity and ob/ob but not db/db mice, and reduced by fasting and, in ob/ob mice, by treatment with rosiglitazone. These findings suggest that an agonist of CMKLR1 is more likely than an antagonist to be of value in the treatment of type 2 diabetes and have associated anti-obesity andanti-inflammatory activities. One mechanism by which an agonist of CMKLR1 might improve glucose homeostasis is by increasing insulin-stimulated glucose uptake by adipocytes.

Download Full-text

Evidence from studies in rodents and in isolated adipocytes that agonists of the chemerin receptor CMKLR1 may be beneficial in the treatment of type 2 diabetes

10.7287/peerj.preprints.643v1 ◽

2014 ◽

Author(s):

Ed T Wargent ◽

Mohamed S Zaibi ◽

Jacqueline F O'Dowd ◽

Mike A Cawthorne ◽

Steven J Y Wang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glucose Uptake ◽

Glucose Homeostasis ◽

Wild Type ◽

Male And Female ◽

Low Fat Diet ◽

Diet Induced Obesity ◽

Mrna Content ◽

Anti Inflammatory

It is unclear whether the adipokine chemerin has pro- or anti-inflammatory properties, plays any role in the aetiology of obesity or type 2 diabetes, or whether agonists or antagonists of the chemerin receptor CMKLR1 have potential in the treatment of these diseases. To address these questions, we investigatedthe metabolic phenotypes of both male and female, CMKLR1 knockout and heterozygote mice; the effects of murine chemerin and some C-terminal peptides on glucose uptake in wild-type and CMKLR1 knockout adipocytes; and plasma chemerin levels and chemerin gene mRNA content in adipose tissue in models ofobesity and diabetes, and in response to fasting or administration of the insulin sensitizing drug rosiglitazone, which also has anti-inflammatory properties. Both male and female, CMKLR1 knockout and heterozygote mice displayed a mild tendency to obesity and impaired glucose homeostasis, but only when they were fed on a high fat, rather than a standard low fat diet. Obesity and impaired glucose homeostasis did not occur concurrently, suggesting that obesity was not the sole cause of impaired glucose homeostasis. Picomolar concentrations of chemerin and its C15- and C19-terminal peptides stimulatedglucose uptake in the presence of insulin by rat and mouse wild-type epididymal adipocytes, but not by murine CMKLR1 knockout adipocytes. The insulin concentration-response curve was shifted to the left in the presence of 40 pM chemerin or its C-15 terminal peptide. The plasma chemerin level was raised in diet-induced obesity and ob/ob but not db/db mice, and reduced by fasting and, in ob/ob mice, by treatment with rosiglitazone. These findings suggest that an agonist of CMKLR1 is more likely than an antagonist to be of value in the treatment of type 2 diabetes and have associated anti-obesity andanti-inflammatory activities. One mechanism by which an agonist of CMKLR1 might improve glucose homeostasis is by increasing insulin-stimulated glucose uptake by adipocytes.

Download Full-text