Diabetes treatments
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page232-233
2025-12-01
84
Improved glycaemic levels can relieve glucotoxicity and restore, to some extent, β- cell function. However, there is discussion on the potential direct effects that currently available glucose- lowering therapies may exert on the preservation of β cells. Potential protective effects have been claimed with the use of DPP- 4 inhibitors , GLP- 1 receptor agonists, and pioglitazone. GLP- 1 receptor agonists protect β cells from lipotoxicity by increasing cell defences, reducing inflammatory response, and preventing autophagy inhibition. Glitazones can reduce oxidative stress, inflammation, and endoplasmic reticulum stress associated with lipotoxicity. Incubation of pancreatic islets of individuals with type 2 diabetes in the presence of therapeutic concentrations of metformin increases insulin content and the number and density of mature insulin gran ules, improves glucose- induced insulin release, and reduces apoptosis along with normalization of several markers of oxidative stress. Weight reduction and physical activity may exert a favourable effect on β- cell function of people with type 2 diabetes. Fat accumulation has been found in intrapancreatic adipocytes of these individuals and its reduction with a very low- calorie diet is associated with a recovery of first- phase insulin secretion. Exercise can also elicit a decrease of pancreatic fat, but can also enhance IL- 6. Administration of IL- 6 or elevated IL- 6 concentrations in response to exercise stimulate GLP- 1 secretion from intestinal L cells and pancreatic α cells, improving insulin secretion and glycaemia in experimental animals.
In ex vivo studies, concern has been expressed with respect to the effects of sulfonylureas on the β cell. In vitro experiments have shown increased β- cell apoptosis, although some difference may exist among different sulfonylureas. In isolated human pancreatic islets, glibenclamide but not repaglinide activates β- cell apoptosis. Other observations have indicated a reduced insulin content in pancreatic islets incubated in the presence of glimepiride, glibenclamide, and chlorpropamide, although no change in insulin release in response to glucose was observed with glimepiride. In cultured β- cell lines, no activation of apoptosis was found with gliclazide treatment along with some antioxidant effect noted in human pancreatic islets.
The real impact of these findings is still unclear. In the clinical setting, the durability of the glucose- lowering efficacy of sulfonylureas is claimed to be poorer than with other anti- diabetes agents. These findings are in keeping with animal studies showing that chronic glibenclamide treatment causes loss of insulin- secretory capacity due to β- cell hyperexcitability. However, the same studies also revealed rapid reversibility of this secretory failure, arguing against β- cell apoptosis or other cell death induced by sulfonylureas. In contrast, these findings support earlier observations showing in vivo restoration of β- cell response to sulfonylureas, once sustained sulfonylurea therapy was discontinued.
In summary, on the development of overt hyperglycaemia, several factors, including chronic hyperglycaemia, obesity, increased free fatty acid availability, persistent stimulation of β cells, and, potentially, the use of specific drugs, may contribute to the acceleration of the decline in insulin- secretory capacity of individuals with type 2 diabetes and progression of the disease. These accelerating factors promote common damage mechanisms, including oxidative stress, endoplasmic reticulum stress, inflammation, and immune system activation (Figure 1). Because of these mechanisms, a vicious cycle develops by which the ability of the β cells to cope with hyperglycaemia and insulin resistance becomes weaker and the impact of the accelerating factors becomes greater. These factors impair both the function and the survival of the β cells, although the relative contribution of the two remains to be established.
Fig1. Mechanisms of β- cell damage in type 2 diabetes. Environmental factors and genetic backgrounds interact to activate stress processes that contribute to functional abnormalities and also progressive loss/dedifferentiation of β cells. ER, endoplasmic reticulum. Source: Adapted from Halban et al. 2014.
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