Rosiglitazone Reduces Glucose-Stimulated Insulin Secretion Rate and Increases Insulin Clearance in Nondiabetic, Insulin-Resistant Individuals

Abstract

Compensatory hyperinsulinemia permitting insulin-resistant individuals to maintain normal glucose tolerance is associated with a left shift in the glucosestimulated insulin secretion rate (GS-ISR) doseresponse curve and decrease in the insulin metabolic clearance rate (I-MCR). To see whether these changes would reverse with improvement in insulin sensitivity, 14 nondiabetic insulin-resistant subjects received rosiglitazone for 12 weeks (4 mg daily for 4 weeks and then 8 mg daily for 8 weeks). Insulin-mediated glucose uptake was quantified by measuring the steady-state plasma glucose concentration during the insulin suppression test. GS-ISR and I-MCR were determined during a 240-min graded intravenous glucose infusion. I-MCR was also calculated during the insulin suppression test. After rosiglitazone treatment, insulin sensitivity improved with significant fall in steady-state plasma glucose (means ؎ SE from 13.5 ؎ 0.62 to 9.8 ؎ 1.02 mmol/l, P < 0.001). In response, the integrated GS-ISR decreased by 21% (P < 0.001), with a right shift in the dose-response curve. Calculated I-MCR increased by 34% (P ‫؍‬ 0.008) during the insulin suppression test and by 21% (P ‫؍‬ 0.03) during the graded glucose infusion. In conclusion, enhanced insulin sensitivity in rosiglitazone-treated nondiabetic insulin-resistant individuals was associated with a shift to the right in the GS-ISR dose-response curve and an increase in I-MCR. Diabetes 54:2447-2452, 2005 I n insulin-resistant individuals, glucose homeostasis can be maintained if the defect in insulin action is adequately compensated for by an increase in insulin concentration. This is achieved by a shift to the left of the glucose-stimulated insulin secretion rate (GS-ISR) dose-response curve, as well as by a decrease in the insulin metabolic clearance rate (I-MCR) (1,2). Therefore, for any given plasma glucose concentration, there is more insulin secreted by pancreatic ␤-cells and less insulin cleared in insulin-resistant individuals when compared with their insulin-sensitive counterparts. Although the ensuing hyperinsulinemia is capable of preventing gross decompensation of glucose tolerance, it increases the likelihood that insulin-resistant/hyperinsulinemic individuals will develop a variety of clinical syndromes including cardiovascular disease, essential hypertension, polycystic ovary syndrome, nonalcoholic fatty liver disease, and certain forms of cancer (3-9).Studies in nondiabetic, insulin-resistant obese individuals have demonstrated that GS-ISR and the I-MCR can return toward normal when insulin sensitivity improves with weight loss (10 -12). However, because obesity may be independently associated with an increase in insulin secretion (13) and a decrease in insulin clearance (14), the impact of improving insulin sensitivity apart from weight loss is unknown. The current study was initiated to understand whether the changes in GS-ISR and I-MCR, already noted when weight loss occurs in overweight insulin-resistant subjects, would also occur when enhanced insulin sensi...

Mathematical investigation of diabetically impaired ultradian oscillations in the glucose–insulin regulation

“…In Section 4, we consider it as a combination of natural (for example, exercise [38]) and artificial (for example, through use of Rosiglitazone [13]) mechanisms, and as a function of α and β to investigate how it can be used to compensate for the effects of a reduced insulin secretion (α) and/or an increased insulin resistance (β) on an appropriate oscillatory regime.…”

“…Using the algorithm detailed above, we determine whether each (α,β), with I in as defined by (13) and d i = 0.06, leads to an oscillatory regime. The result is shown in Figure 8.…”

Effect of lifestyle intervention plus rosiglitazone or placebo therapy on left ventricular mass assessed with cardiovascular magnetic resonance in the metabolic syndrome

“…Results from large clinical trials indeed showed that lifestyle changes significantly reduced the incidence of diabetes [26,27]. Thiazolidinediones act as insulin sentitizers by multiple mechanisms and a previous study in non-diabetic insulin resistant individuals indeed demonstrated lower insulin and improvement of insulin resistance after rosiglitazone treatment [28]. In the current study, no additional effect of rosiglitazone on insulin and insulin resistance could be observed, stressing the highly beneficial effects of lifestyle intervention, overshadowing the possible effect of rosiglitazone on these parameters.…”

“…Clinical studies have shown that thiazolidinediones e.g. lower blood glucose levels by enhancing hepatic and peripheral glucose uptake and increase free fatty acid uptake and storage in adipose tissue (thereby decreasing free fatty acid uptake in other tissues) [5,9]. …”

Direct rosiglitazone-induced modifications in insulin secretion, action and clearance: a single-dose hyperglycaemic clamp study

“…This action can be either direct, or secondary to the improvement of insulin sensitivity. More recently, rosiglitazone was shown to increase insulin clearance in type 2 diabetic subjects after 12 weeks [2] and 16 weeks [3] of treatment. Although incompletely understood, this effect was considered to be secondary to a decreased liver fat content [3].…”