Clinical significance of glucose toxicity
Type 1 diabetes
After diagnosis of type 1 diabetes, initiation of insulin therapy induces partial clinical remission in ∼30% of the patients during the first year . This honeymoon period is characterized by normoglycemia, recovery of endogenous insulin secretion, and by improved insulin sensitivity . Although correction of several alterations secondary to insulin deficiency, such as increased counterregulatory hormone secretion , hyperosmolarity , acidosis , electrolyte changes  and high free fatty acids  could contribute to normalization of insulin secretion and sensitivity, reversal of glucose toxicity may also be of importance for the occurrence of remission. In the DCCT, 855 patients had had type 1 diabetes for 1 to 5 years at baseline and of these 303 were considered C-peptide responders (C-peptide level, 0.20 to 0.50 pmolmL−1 after ingestion of a standardized, mixed meal). Responders receiving intensive therapy maintained a higher stimulated C-peptide level and a lower likelihood of becoming nonresponders than did responders receiving conventional therapy (relative risk reduction, 57%) .
As discussed earlier, in type 1 patients with long-standing disease, chronic hyperglycemia can be regarded as the key factor responsible for insulin resistance. Therefore and in contrast to the results obtained in patients with type 2 diabetes (see later), insulin sensitivity can be markedly improved and even normalized in type 1 patients by optimizing insulin therapy . The enhanced insulin sensitivity explains why glycemic control can be improved without necessarily having to increase the daily dose [115,116]. Thus, although the loss of insulin secretion is irreversible in type 1 diabetes, insulin sensitivity is amenable to marked modification by alterations in glycemic control.
Type 2 diabetes
Data from both several cross-sectional and prospective studies have documented that hyperinsulinemia and insulin resistance both precede and predict the subsequent development of type 2 diabetes. The etiology of insulin resistance is multifactorial and involves familiar/genetic and acquired components. Consequently, one would not expect normalization of insulin sensitivity by improved glycemic control. In keeping with this, insulin resistance has been a uniform finding in patients with type 2 diabetes and has only been partially reversed by, for example, aggressive insulin therapy [7,24,117–119]. Both weight loss [23,120–123], sulfonylureas , and insulin therapy [24,25,123–126] improve insulin secretion. Since neither insulin therapy nor weight loss have any direct stimulatory effects on insulin secretion, their effects could be mediated indirectly via diminution of glucose toxicity on β-cell secretion. Indeed, the “extrapancreatic effect” (improved insulin sensitivity) of sulfonylureas has been entirely attributed to amelioration of insulin resistance via lowering of the plasma glucose concentration . In terms of practical clinical care, the fact that the core defects that contribute to hyperglycemia in type 2 diabetes, including excess hepatic glucose production, impaired insulin secretion, and insulin resistance, all improve with control of glycemia means that control of type 2 diabetes should be easier to maintain after a relatively short period of near-normoglycemia. In the largest of such studies 382 Chinese patients were randomly assigned to therapy with insulin or oral hypoglycemic agents . Treatment was stopped after normoglycemia was maintained for 2 weeks after an initial treatment period of ∼10 days. Patients were then followed for 1 year on diet and exercise alone. Better glycemic control was achieved with insulin therapy than with oral agents and the remission rates were higher at 1 year in those treated initially with insulin as compared to oral hypoglycemic agents. The acute insulin response was significantly improved by intensive glucose control with insulin. This increase was sustained at 1 year in the insulin groups but significantly declined in patients treated with oral hypoglycemic agents . This study as well as many smaller studies (reviewed in ) suggest that short-term intensive insulin therapy early in the course of may offer favorable long-term effects on β-cell function.
Supported by grants from the National Institutes of Health (DK 43526 and RR025764,DAM),Veterans Administration Research Service (DAM), and Finnish Academy of Science (HY-J).