1. |
- Andersen, Birgitte, et al.
(author)
-
Fibroblast growth factor 21 prevents glycemic deterioration in insulin deficient mouse models of diabetes.
- 2015
-
In: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 764, s. 189-194
-
Journal article (peer-reviewed)abstract
- In type 1 diabetes, there is a rapid loss of glycemic control immediately after onset of the disease. We aimed to determine if the deterioration of glycemic control that occurs early after the onset of insulin-deficient diabetes could be blunted by treatment with recombinant fibroblast growth factor 21 (FGF21). Normal C57BL/6J mice made diabetic by a single high dose injection of streptozotocin (STZ) were randomized to receive twice daily subcutaneous injection of vehicle or recombinant human FGF21 at doses of 0.3 and 1.0mg/kg for 10 days. Body weight was recorded daily and 5h fasted glucose, insulin, glucagon, free fatty acids and ketones were determined at 6 and 10 days post-randomization. The increase in fasting plasma glucose induced by STZ in untreated mice was prevented with FGF21 at 0.3mg/kg BID. In contrast, at 1.0mg/kg BID, FGF21 did not prevent the rise in plasma glucose after STZ. At the end of the study, plasma glucagon was significantly higher in the diabetic group treated with FGF21 1.0mg/kg BID than in the untreated group. This was not seen for the group treated with FGF21 0.3mg/kg BID. There were significant dose dependent reductions in plasma free fatty acids with FGF21 treatment but no significant change in plasma ketones (β-hydroxybutyrate). FGF21 treatment did not have significant effects on body weight in lean insulin deficient mice. In conclusion, FGF21 prevents increases in glycaemia and has lipid lowering properties in mouse models of insulin deficient diabetes, although by increasing the dose increased glucagon levels are seen and hyperglycemia persists.
|
|
2. |
- Kjaergaard, Marina, et al.
(author)
-
Hypothalamic Oxidative stress and inflammation, and peripheral glucose homeostasis in Sprague-Dawley rat offspring exposed to maternal and postnatal chocolate and soft drink
- 2018
-
In: Nutrition & Diabetes. - : NATURE PUBLISHING GROUP. - 2044-4052. ; 8
-
Journal article (peer-reviewed)abstract
- Background: Predisposition to obesity and type 2 diabetes can arise during foetal development and in early postnatal life caused by imbalances in maternal nutritional overload. We aimed to investigate the effects of maternal and postnatal intake of chocolate and soft drink on hypothalamic anti-oxidative stress markers, inflammation and peripheral glucose homeostasis. Methods: Pregnant Sprague-Dawley rats were fed ad libitum chow diet only (C) or with chocolate and high sucrose soft drink supplements (S). At birth, litter size was adjusted into 10 male offspring per dam. After weaning at 3 weeks of age, offspring from both dietary groups were assigned to either S or C diet, giving four groups until the end of the experiment at 26 weeks of age. Results: Offspring exposed to maternal S had up-regulated hypothalamic anti-oxidative markers such as SOD2 and catalase at 3 weeks of age as an indication of oxidative stress. However, at 12 weeks of age these anti-oxidative markers tended to decrease while pro-inflammatory markers such as TNF and IL-1 beta became up-regulated of all offspring exposed to S diet during some point of their life. Thus, despite an increase in anti-oxidative stress response, offspring exposed to maternal S had a reduced ability to counteract hypothalamic inflammation. At the same time point, postnatal S resulted in increased adiposity, reduced glucose tolerance and insulin sensitivity with no effect on body weight. However, at 25 weeks of age, the impaired glucose tolerance was reversible to the response of the control regardless of increased adiposity and body weight pointing towards a compensatory response of the insulin sensitivity or insulin secretion. Conclusion: Indications of hypothalamic oxidative stress was observed prior to the inflammatory response in offspring exposed to maternal S. Both maternal and postnatal S induced hypothalamic inflammation prior to increased weight gain and thus contributing to obese phenotype.
|
|
3. |
- Omar, Bilal, et al.
(author)
-
Fibroblast Growth Factor 21 (FGF21) and Glucagon Like-Peptide 1 Contribute to Diabetes Resistance in Glucagon Receptor Deficient Mice.
- 2014
-
In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:1, s. 101-110
-
Journal article (peer-reviewed)abstract
- Mice genetically deficient in the glucagon receptor (Gcgr(-/-)) show improved glucose tolerance, insulin sensitivity and α-cell hyperplasia. In addition, Gcgr(-/-) mice do not develop diabetes after chemical destruction of β-cells. Since fibroblast growth factor 21 (FGF21) has insulin independent glucose lowering properties we investigated whether FGF21 was contributing to diabetes resistance in insulin deficient Gcgr(-/-) mice. Plasma FGF21 was 25 fold higher in Gcgr(-/-) mice than in wild type mice. FGF21 was found to be expressed in pancreatic β- and α-cells, with high expression in the hyperplastic α-cells of Gcgr(-/-) mice. FGF21 expression was also significantly increased in liver and adipose tissue of Gcgr(-/-) mice. To investigate the potential anti-diabetic actions of FGF21 in insulin deficient Gcgr(-/-) mice, an FGF21 neutralizing antibody was administered prior to oral glucose tolerance tests (OGTT). FGF21 neutralization caused a decline in glucose tolerance in insulin deficient Gcgr(-/-) mice during the OGTT. Despite this decline, insulin deficient Gcgr(-/-) mice did not develop hyperglycemia. Glucagon-like peptide (GLP-1) also has insulin independent glucose lowering properties and elevated circulating GLP-1 is a known characteristic of Gcgr(-/-) mice. Neutralization of FGF21 while concurrently blocking the GLP-1 receptor with the antagonist Exendin9-39 resulted in significant hyperglycemia in insulin deficient Gcgr(-/-) mice, while Exendin9-39 alone did not. In conclusion, FGF21 acts additively with GLP-1 to prevent insulinopenic diabetes in mice lacking glucagon action.
|
|
4. |
- Zouhar, Petr, et al.
(author)
-
UCP1-independent glucose-lowering effect of leptin in type 1 diabetes : only in conditions of hypoleptinemia
- 2020
-
In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 318:1, s. E72-E86
-
Journal article (peer-reviewed)abstract
- The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity- and thus also leptin level-sin the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.
|
|