1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
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7<br />
kindreds (but not similar obese control subjects) exhibit impairment in beta-cell<br />
compensation for obesity-related insulin resistance. Furthermore, the heritability of insulin<br />
secretion is 67% (16).<br />
The demonstration of beta-cell dysfunction before the onset of DM2, as well as the<br />
recognition of the confounding effect of obesity on insulin sensitivity, cast doubt on the<br />
theory that insulin resistance is the primary cause of DM2 (15). Several studies of the<br />
insulin-secretory capacity of glucose-tolerant individuals with a predisposing ethnicity or a<br />
family history of DM2, have indicated that beta-cell dysfunction, like insulin resistance,<br />
occurs in genetically predisposed individuals with normal glucose tolerance - well before<br />
the emergence of overt diabetes (ref. cit in 15). Of note in these studies is the fact that there<br />
were no significant differences with respect to insulin sensitivity between the predisposed<br />
subjects and the control groups (glucose-tolerant subjects with no family history of DM2),<br />
suggesting that alterations in insulin secretion precede insulin resistance in patients at risk<br />
for developing DM2.<br />
Considering that the vast majority (85-90%) of DM2 are obese, and intraabdominal<br />
obesity, being the major determinant of insulin resistance (not only in obese individuals but<br />
also in apparently nonobese individuals who have evidence of increased abdominal fat)<br />
represents a significant genetic component (18) then insulin resistance occurring as a result<br />
of this could be considered genetic. Nevertheless, most obese individuals who are insulin-<br />
resistant are not diabetic and what distinguishes them from those who are diabetic is, as<br />
indicated previously, the ability of their pancreatic beta-cells to compensate for insulin<br />
resistance. Although insulin resistance may be critical for the development of diabetes,<br />
irreversibly impaired insulin secretion plays, as expected, an essential role in diabetes<br />
persistence after weight loss and restoration to normal or near normal insulin sensitivity<br />
(19).<br />
Regarding the 10-15% of patients with DM2 who are not obese, whether they<br />
become diabetic depends on the balance between the severity of insulin resistance and the<br />
ability of the beta-cell to compensate for the insulin resistance, as in the case of obese<br />
individuals. A spectrum could exist: at one extreme, the non-obese individual may be<br />
insulin resistant before or after the development of diabetes. High-fat diet, decreased<br />
physical fitness, increase in visceral fat, smoking, pregnancy, certain medications and