Discussion
weight gain, weight loss, T2DM, beta-cell dysfunction
REGRESSION, INSULIN RESISTANCE, INSULIN SENSITIVITY, GESTATIONAL DIABETES
In this study, we show that 55 of 99 patients with T2DM achieved sustained stabilization of beta-cell function over 2-years in response to induction IIT followed by metformin maintenance. These individuals had poorer beta-cell function than their peers at baseline but experienced greater recovery thereof in response to 3-weeks of induction IIT. Over the subsequent 2-years, they had greater stability of weight/adiposity, hepatic insulin sensitivity and ALT compared to their peers, and ultimately exhibited better beta-cell function and glycemic control. Logistic regression analyses revealed 3 independent predictors of the sustained stabilization of beta-cell function: the change in ISSI-2 during induction IIT and the changes in HOMA-IR and ALT during maintenance. It thus emerges that the initial reversibility of beta-cell dysfunction during induction and the subsequent preservation of hepatic insulin sensitivity during maintenance are underlying determinants of sustained stabilization of beta-cell function in response to short-term IIT and metformin.Two elements of these data point to the role of reversible beta-cell dysfunction. First, it is notable that those who ultimately achieved stabilization 2-years later had poorer (not better) beta-cell function than their peers at baseline. Second, in response to induction IIT, they experienced a greater improvement in beta-cell function than did their peers. Importantly, when both of these variables were included in the optimal model (Model V in Table After addressing reversible beta-cell dysfunction with induction therapy, the next challenge is maintaining this beneficial effect. In this regard, current thinking holds that improving insulin sensitivity (e.g. through weight loss) can off-load the secretory demands placed on the beta-cells and thereby reduce their functional deterioration in T2DM. Conversely, weight gain may increase insulin resistance and hasten beta-cell demise. In this context, it is notable that, during maintenance from 3-weeks to 2-years, there were differential changes over time in BMI between the stabilization and non-stabilization groups, with evidence of a decrease in the stabilization group (Fig. This emerging role of hepatic insulin sensitivity is supported by earlier observations. First, in women with recent gestational diabetes, worsening hepatic insulin resistance in the 1It is notable that, while the change in HOMA-IR from 3-weeks to 2-years superseded the changes in Matsuda, BMI and waist, consideration of the concomitant change in ALT yielded the optimal model of sustained stabilization of beta-cell function (Model V in Table An additional limitation is the relatively modest sample size (In conclusion, treatment with 3-weeks of induction IIT followed by metformin maintenance achieved stabilization of beta-cell function over 2-years in 55 of 99 participants. These individuals had poorer beta-cell function than their peers at baseline but experienced greater functional recovery thereof in response to induction IIT, suggestive of reversibility of beta-cell dysfunction. Their subsequent changes in HOMA-IR and ALT during the ensuing 2 years emerged as significant predictors of sustained stabilization of beta-cell function, coupled with the initial beta-cell response to induction IIT. Thus, the initial reversibility of beta-cell dysfunction during induction and the subsequent preservation of hepatic insulin sensitivity during maintenance are physiologic changes associated with the sustained stabilization of beta-cell function in response to short-term IIT and metformin.