Dexamethasone-induced Insulin Resistance Research Articles

Amylin-insulin relationships in insulin resistance with and without diabetic hyperglycemia.

To determine if increased secretion of amylin can be implicated in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) in vitro and in vivo, we studied its relationships to insulin in insulin-resistant rats with and without NIDDM. In obesity-associated and dexamethasone-induced insulin resistance without diabetes, basal and stimulated secretion of amylin and insulin by isolated pancreata were proportionately elevated, leaving the amylin-to-insulin ratio (A/I) unchanged. By contrast, whenever diabetes occurred in dexamethasone-treated rats or in spontaneously diabetic obese insulin-resistant ZDF-drt male rats, a doubling of A/I was invariably observed due to an increase in amylin without a proportional increase in insulin secretion. Correction of dexamethasone-induced hyperglycemia with the glucocorticord receptor antagonist RU-486 was accompanied by a decline in A/I. Longitudinal in vivo studies demonstrated in both spontaneous and dexamethasone-induced models of NIDDM an increase in plasma A/I at the onset of hyperglycemia. In dexamethasone-induced diabetes, the increased A/I was associated with a high proamylin mRNA relative to proinsulin mRNA. We conclude that amylin and insulin expression and secretion rise in concert in compensated insulin-resistant states, but when hyperglycemia is present the increase in amylin exceeds that of insulin. Although a role of an increased A/I in the pathogenesis of NIDDM has not been established directly, these studies indicate that such a role could be possible.

Evolution of dexamethasone-induced insulin resistance in rats

Glucocorticoids are known to cause insulin resistance and glucose intolerance. Although there have been many studies investigating the mechanism of this effect, several aspects remain to be clarified. The aim of this study was to investigate the evolution and sites of insulin resistance in dexamethasone-treated rats. To achieve this, chronically catheterized nonstressed rats had glucose kinetics measured during an oral glucose tolerance test by means of a double isotope technique. Studies were performed after 6, 48, or 96 h of dexamethasone administration (10 micrograms.rat-1.day-1) and were compared with control rats not treated with the steroid. Total hepatic glucose production (HGP) was increased in the 6-h (166 +/- 8.3, P less than 0.05) and 48-h (198 +/- 21, P less than 0.03) treated groups but not in the 96-h treated rats (140 +/- 8, P = 0.99) compared with the controls (141 +/- 8 mg/55 min). This increased HGP was despite the presence of higher insulin levels in the steroid-treated rats (1,220 +/- 115, P less than 0.09; 1,732 +/- 197, P less than 0.005; 1,567 +/- 107, P less than 0.001 in 6-, 48-, and 96-h treated rats, respectively, compared with 937 +/- 99 mU.l-1 x 55 min-1 in control rats). The metabolic clearance rate of glucose was higher in the dexamethasone-treated rats (200 +/- 14, P less than 0.07; 227 +/- 18, P less than 0.01; 227 +/- 17, P less than 0.01 in 6-, 48-, and 96-h groups, respectively, compared with 165 +/- 10 ml/55 min in control rats).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dexamethasone on glucose-induced insulin and proinsulin release in low and high insulin responders

We compared the effects of dexamethasone-induced insulin resistance on B-cell secretory performance in 12 low insulin responders (LIR) and in eight high insulin responders (HIR). A hyperglycemic clamp (120 minutes) was performed before and after the subjects had ingested dexamethasone 3 mg × 2 for 2 1 2 days. Fasting levels of blood glucose increased from 4.60 ± 0.13 to 5.74 ± 0.23 mmol/L after dexamethasone in LIR and from 4.37 ± 0.18 to 5.26 ± 0.13 mmol/L in HIR. Dexamethasone treatment increased fasting levels of total immunoreactive insulin (IRI), C-peptide, and proinsulin, as well as the proinsulin to IRI ratio to a similar degree in LIR and HIR. The amount of glucose infused to uphold hyperglycemia during the clamp decreased by 54% after dexamethasone in LIR and by 46% in HIR. Mean level of stimulated IRI during the clamp increased after dexamethasone by 43% in LIR and by 53% in HIR. Mean level of stimulated C-peptide increased by 11% (not significant) in LIR and by 24% in HIR. Mean level of stimulated proinsulin increased by 86% in LIR and by 93% in HIR. The effects of dexamethasone on insulin secretion varied among individuals, since steroid treatment failed to affect IRI responses to glucose in two LIR and two HIR. The magnitude of dexamethasone effects on secretion was not correlated to pre-dexamethasone insulin sensitivity as assessed by a somatostatin-insulin-glucose infusion test (SIGIT) or by M I (glucose infused/insulin level) ratios of the control clamp. The results indicate that enhancement of B-cell response after 60 hours of insulin resistance is party proportional to preexisting capacity and partly to other factors. The failure of dexamethasone to increase glucose-induced insulin secretion in some LIR may indicate genetically determined propensity for diabetes in such subjects.

The effect of dexamethasone on B cell mass and function in partial pancreatctomized rats.

We have now examined islet mass and B-cell secretory function 19 days following a 40–50% pancreatectomy (Px). Plasma glucose and insulin values in Px were equal to those of sham-operated control rats both in the fed state and following an in traperitoneal glucose tolerance test. Glucose potentiation of arginine-induced insulin secretion remained fully preserved when assessed with the invitro perfused pancreas. On the other hand, 5 days of dexamethasone caused mild hyperglycemia in Px, but not in the control group. Moreover, in vitro insulin secretion from the dexamethasone-treated Px rats tended to be modestly lower than the dexamethasone-treated controls.Islet mass returned to a value not significantly lower than that of shams, with a further 30% increase noted in both dexamethasone-treated groups. In contrast, pancreatic insulin content in both Px groups was only about 40% of comparable controls.These data show almost complete islet regeneration within 3 weeks of the 40–50% pancreatectomy. Islet function, on the other hands, was characterized by limited reserve capacity which coexisted with and may have contributed to the development of mild hyperglycemia in the presence of dexamethasone-induced insulin resistance.

Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance.

In this study, we found that the ratio of proinsulin to total immunoreactive insulin was much higher in 22 patients with Type 2 (non-insulin-dependent) diabetes mellitus than in 28 non-diabetic control subjects of similar age and adiposity (32 +/- 3 vs 15 +/- 1%, p less than 0.001). In addition, the arginine-induced acute proinsulin response to total immunoreactive insulin response ratio was greater in diabetic patients (n = 10) than in control subjects (n = 9) (8 +/- 2 vs 2 +/- 0.5%, p = 0.009), suggesting that increased islet secretion per se accounted for the increased ratio of proinsulin to immunoreactive insulin. One explanation for these findings is that increased demand for insulin in the presence of islet dysfunction leads to a greater proportion of proinsulin secreted from the B cell. We tested this hypothesis by comparing proinsulin secretion before and during dexamethasone-induced insulin resistance in diabetic patients and control subjects. Dexamethasone treatment (6 mg/day for 3 days) raised the proinsulin to immunoreactive insulin ratio in control subjects from 13 +/- 2 to 21 +/- 2% (p less than 0.0001) and in diabetic patients from 29 +/- 5 to 52 +/- 7% (p less than 0.001). Dexamethasone also raised the ratio of the acute proinsulin response to the acute immunoreactive insulin response in control subjects from 2 +/- 0.5 to 5 +/- 2% (p = 0.01) and in diabetic patients from 8 +/- 2 to 14 +/- 4% (p = NS), suggesting that the dexamethasone-induced increment in the basal ratio of proinsulin to immunoreactive insulin was also due to increased secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Dexamethasone-induced insulin resistance enhances B cell responsiveness to glucose level in normal men.

To determine whether islet adaptation during insulin resistance involves increased responsiveness to the level of plasma glucose, insulin resistance was induced in nine normal men by giving dexamethasone (Dex) (3 mg twice daily for 2 days). Plasma insulin and acute insulin responses (AIR) to isoproterenol were measured at three different glucose levels under control and Dex conditions. During Dex there were elevations above control levels of basal glucose (104 +/- 2 vs. 94 +/- 3 mg/dl) and insulin (21 +/- 3 vs. 13 +/- 2 microU/ml, both P less than 0.03). When glucose levels were raised stepwise by matching amounts using glucose clamps, AIR to isoproterenol rose as a linear function of glucose level under both conditions but rose more steeply during Dex. That is, the potentiating effect of glucose (delta AIR/delta glucose) was greater during Dex: 1.3 +/- 0.2 vs. 0.8 +/- 0.2 (P less than 0.01). Similarly, matched increments in glucose level produced greater increments in prestimulus insulin level during Dex (P less than 0.03). We conclude that 48 h of Dex raises the "gain" of the potentiating effect of glucose. Because the direct effect of glucocorticoids on B cell function has been reported to be inhibitory, the observed stimulation is likely to be a result of the insulin resistance caused by Dex.