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Clinical significance of glucose toxicity
Diabetes type 1
After the diagnosis of type 1 diabetes, the introduction of insulin therapy induces partial clinical remission in approximately 30% of patients in the first year. [96]. This honeymoon period is characterized by normoglycemia, recovery of endogenous insulin secretion and improved insulin sensitivity. [109]. Although correction of several alterations resulting from insulin deficiency, such as an increase in the secretion of counter-regulating hormones [110], hyperosmolarity [111]acidosis [112], electrolyte changes [113] and high free fatty acids [114] could contribute to the normalization of secretion and sensitivity of insulin, the reversal of glucose toxicity could also be important for the occurrence of remission. In DCCT, 855 patients had type 1 diabetes for 1 to 5 years and 303 of them were considered to respond to peptide C (peptide level C, 0.20 to 0.50 pmolm-1 after Ingestion of a standardized mixed meal). Respondents receiving intensive treatment maintained a higher stimulated C peptide level and a lower probability of becoming non-responder than those receiving conventional treatment (relative risk reduction, 57%) [1].
As previously reported, in type 1 patients with long-standing disease, chronic hyperglycemia may be considered the key factor responsible for insulin resistance. Therefore and contrary to the results obtained in patients with type 2 diabetes (see below), insulin sensitivity can be significantly improved and even normalized in type 1 patients by optimizing insulin therapy. . [20]. Increased sensitivity to insulin explains why it is possible to improve glycemic control without necessarily increasing the daily dose. [115,116]. Thus, although loss of insulin secretion is irreversible in type 1 diabetes, insulin sensitivity may be markedly altered by alterations in glycemic control.
Type 2 diabetes
Data from several cross-sectional and prospective studies have shown that hyperinsulinemia and insulin resistance precede and predict the further development of type 2 diabetes. The etiology of resistance to Insulin is multifactorial and involves familiar / genetic and acquired components. Therefore, one does not expect a normalization of insulin sensitivity through improved glycemic control. In this regard, insulin resistance has been consistently observed in patients with type 2 diabetes and has only been partially reversed, for example, by aggressive insulin therapy. [7,24,117–119]. Weightloss [23,120–123], sulfonylureas [123]and insulin therapy [24,25,123–126] improve the secretion of insulin. Since neither insulin therapy nor weight loss has a direct stimulating effect on insulin secretion, their effects could be mediated indirectly by a decrease in glucose toxicity on the secretion of β cells. Indeed, the "extrapancreatic effect" (improvement in insulin sensitivity) of sulfonylureas was entirely attributed to the improvement of insulin resistance via lowering plasma glucose concentration. [127]. In terms of practical clinical care, the fact that the main defects contributing to hyperglycemia in type 2 diabetes include excessive production of hepatic glucose, impaired insulin secretion and resistance to hypertension. insulin, all attenuate with the control of blood glucose. be easier to maintain after a relatively short period of near normal blood glucose. In the largest of these studies, 382 Chinese patients were randomly assigned to treatment with insulin or oral hypoglycemic agents. [128]. Treatment was discontinued after maintenance of normal blood glucose for 2 weeks after an initial treatment period of approximately 10 days. The patients were then followed for 1 year on their diet and exercises alone. Better glycemic control was obtained with insulin therapy compared to oral agents and remission rates were higher at 1 year in those initially treated with insulin compared with oral hypoglycemic agents. The acute insulin response was significantly improved by intensive control of insulin glucose. This increase was maintained at 1 year in insulin groups, but significantly decreased in patients treated with oral hypoglycemic agents. [128]. This study as well as many small studies (reviewed in [129]) suggest that intensive short-term insulin therapy at the beginning of exercise could have long-term favorable effects on β cell function.
Thanks
Supported by grants from the National Institutes of Health (DK 43526 and RR025764, DAM), the Veterans Research Service (DAM) and the Academy of Sciences of Finland (HY-J).
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