Insulin Resistance In Acromegaly Research Articles

Fetuin A and retinol-binding protein 4 are associated with insulin resistance in acromegaly.

Fetuin A and retinol-binding protein 4 are associated with insulin resistance in acromegaly.

OR06-05 Inadequate High Mitochondrial ATP-Synthesis Explains “Non-Fatty-Liver” in Patients with Acromegaly

BackgroundPatients with active acromegaly exhibit low hepatocellular lipid content (HCL) despite pronounced insulin resistance. This contrasts the strong association of insulin resistance with non-alcoholic fatty liver disease in the general population. Acromegaly may therefore help to elucidate antisteatotic pathways. Since low HCL in acromegaly might be caused by changes in oxidative substrate metabolism and interorgan crosstalk we investigated mitochondrial activity and plasma metabolomics as well as lipidomics in active acromegaly.Approach & ResultsPatients In this cross-sectional study, 15 patients with active acromegaly (ACRO) and 17 healthy controls (CON) matched for age, BMI, gender and body composition were included. All participants were invited to undergo 31P/1H-7T-MR-spectroscopy of the liver and skeletal muscle, as well as plasma metabolomic profiling and an oral glucose tolerance test.In comparison to CON, ACRO were insulin resistant, and showed significant lower HCL but their hepatic ATP-synthesis rate adjusted to HCL was significantly increased (h_kATP:0.19[0.14;0.24]vs0.28[0.22;0.34]s-1);p=0.024). Furthermore, the HCL-adjusted ratio of unsaturated to saturated intracellular fatty acids was decreased in ACRO (8.4%vs25.5% of HCL,p<0.04). In skeletal muscle, intramyocellular lipids and ATP-synthesis rate were significantly decreased in ACRO. Plasma lipids and lipidomics did not differ between ACRO and CON, but decreased levels of carnitine species were observed in ACRO.ConclusionsThe dissociation of hepatic lipid content and peripheral insulin resistance in acromegaly is associated with high mitochondrial activity as indicated by liver specific upregulation of the ATP-synthesis rate. This is paralleled by a decreased ratio of unsaturated-to-saturated lipids in hepatocytes and by a change in circulating carnitine species, also reflecting an increased mitochondrial activity. Our findings hint at potential direct effects of growth hormone excess on hepatic lipid and energy metabolism.

Inflammatory adipokines contribute to insulin resistance in active acromegaly and respond differently to different treatment modalities

Active acromegaly is associated with insulin resistance, but it is uncertain whether inflammation in adipose tissue is a contributing factor. To test if GH/IGF1 promotes inflammation in adipocytes, and if this is relevant for systemic insulin resistance in acromegaly. Furthermore, to investigate the effect of treatment modalities (transsphenoidal surgery (TS), somatostatin analogs (SAs), and pegvisomant (PGV)) on glucose metabolism and inflammatory biomarkers in acromegaly. The in vitro effects of GH/IGF1 on gene expression of adipokines in human adipocytes were investigated. Body composition, glucose metabolism, and circulating adipokines (adiponectin (AD), high-molecular weight AD (HMWAD), leptin, vascular endothelial growth factor-A (VEGF-A), monocyte chemotactic protein 1 (MCP1), and thioredoxin (TRX)) were measured in 37 patients with active acromegaly before and after treatment. In vitro GH, but not IGF1, increased VEGF and MCP1 in human adipocytes. In all treatment groups, body fat increased and IGF1 decreased to the same extent. Fasting glucose decreased in the TS (P=0.016) and PGV (P=0.042) groups, but tended to increase in the SA group (P=0.078). Insulin and HOMA-IR decreased in both TS and SA groups, while the PGV group showed no changes. Serum VEGF and MCP1 decreased significantly in the TS group only (P=0.010, P=0.002), while HMWAD increased with PGV treatment only (P=0.018). A multivariate analysis model identified the changes in GH and VEGF as predictors of improvement in HOMA-IR after treatment (R²=0.39, P=0.002). i) GH directly promotes inflammation of human adipocytes by increasing VEGF and MCP1 levels; ii) glucose metabolism and inflammation (VEGF and MCP1) improve to some extent after treatment, despite an increase in adipose tissue mass; and iii) the decrease in insulin resistance after therapy in acromegaly depends, to some extent, on treatment modalities.

The impact of transsphenoidal surgery on glucose homeostasis and insulin resistance in acromegaly

Background and purposeImpaired glucose tolerance and overt diabetes mellitus are frequently associated with acromegaly. The aim of this study was to find out whether these alterations could be reversed after transsphenoidal surgery. Material and methodsTwo hundred and thirty-nine acromegalic patients were studied before and 6–12 months after transsphenoidal surgery. Diagnosis of active acromegaly was established on the basis of widely recognized criteria. In each patient, glucose and insulin concentrations were assessed during the 75 g oral glucose tolerance test (OGTT). To estimate insulin resistance, we used homeostasis model assessment (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). ResultsAt the moment of diagnosis, diabetes mellitus was present in 25% of the acromegalic patients. After surgery, the prevalence of diabetes mellitus normalized to the level present in the general Polish population. We found a statistically significant reduction after surgery in plasma glucose levels both fasting (89.45 ± 13.92 mg/dL vs. 99.12 ± 17.33 mg/dL, p < 0.001) and during OGTT. Similarly, a prominent reduction in insulin secretion was found after surgery compared to the moment of diagnosis (15.44 ± 8.80 mIU/mL vs. 23.40 ± 10.24 mIU/mL, p < 0.001). After transsphenoidal surgery, there was a significant reduction in HOMA-IR (3.08 vs. 6.76, p < 0.0001) and a significant increase in QUICKI (0.32 vs. 0.29, p < 0.001). There were no statistically significant differences after surgery in fasting glucose and insulin levels between patients with controlled and inadequately controlled disease. ConclusionsWe conclude that in acromegalic patients glucose homeostasis alterations and insulin sensitivity can be normalized after transsphenoidal surgery, even if strict biochemical cure criteria are not fulfilled.

Effects of the long-acting somatostatin analogue Lanreotide Autogel on glucose tolerance and insulin resistance in acromegaly

Treatment with somatostatin analogues (SA) not only inhibits GH secretion but may also impair insulin secretion. In order to evaluate the influence of SA on glucose metabolism, we investigated insulin resistance (IR) and beta-cell function, using the recommended combination of homeostatic model assessment of IR (HOMA-IR) and beta-cell function (HOMA-beta). This is a prospective, cross-sectional study. We measured fasting insulin, blood glucose and IGF-I. Insulin and blood glucose measurements were taken 120 min after an oral glucose tolerance test with 75 g glucose. We studied 51 patients (27 female/24 male, age 54 years (20-75)). Eighteen patients were on Lanreotide Autogel (LA) treatment, 33 had no medical treatment. GH-levels of more than 2.5 ng/ml was reached by 59% of the patients, 74.5% had normal IGF-I levels. We found no significant influence of disease activity on HOMA-IR and HOMA-beta. In the 33 of 51 subjects without any drug treatment, median HOMA-beta was 170.4% (36.0-624.0%). In contrast, in the 18 patients on LA treatment, median HOMA-beta was found to be significantly lower (84.2% (36.5-346.2%); P = 0.001). Despite this, there was no difference in HOMA-IR in both groups (2.4 (0.7-8.4) vs 2.3 (0.7-6.1); P < 0.001) despite similar insulin values. In conclusion, we found that LA decreases beta-cell function significantly without affecting IR. Therefore, we think that insulin secretagogues are probably more effective in the treatment of diabetes mellitus in acromegalic patients on LA therapy than insulin sensitizers.

Effects of long acting somatostatin analogues on glucose tolerance and insulin resistance in acromegaly

Patients with active acromegaly often develop diabetes mellitus (DM) or impaired glucose tolerance (IGT). Treatment with somatostatin analogues (SA) does not only inhibit GH secretion but may also impair insulin secretion. In order to evaluate the influence of SA on glucose metabolism we investigated insulin resistance (IR) and β-cell function (HOMA-β), using the recommended combination of HOMA-R and HOMA-β model.

Insulin action on protein metabolism in acromegalic patients.

Insulin resistance in acromegaly causes glucose intolerance and diabetes, but it is unknown whether it involves protein metabolism, since both insulin and growth hormone promote protein accretion. The effects of acromegaly and of its surgical cure on the insulin sensitivity of glucose and amino acid/protein metabolism were evaluated by infusing [6,6-(2)H(2)]glucose, [1-(13)C]leucine, and [2-(15)N]glutamine during a euglycemic insulin (1 mU x kg(-1) x min(-1)) clamp in 12 acromegalic patients, six studied again 6 mo after successful adenomectomy, and eight healthy controls. Acromegalic patients, compared with postsurgical and control subjects, had higher postabsorptive glucose concentration (5.5 +/- 0.3 vs. 4.9 +/- 0.2 micromol/l, P < 0.05, and 5.1 +/- 0.1 micromol/l) and flux (2.7 +/- 0.1 vs. 2.0 +/- 0.2 micromol x kg(-1) x min(-1), P < 0.01, and 2.2 +/- 0.1 micromol x kg(-1) x min(-1), P < 0.05) and reduced insulin-stimulated glucose disposal (+15 +/- 9 vs. +151 +/- 18%, P < 0.01, and 219 +/- 58%, P < 0.001 from basal). Postabsorptive leucine metabolism was similar among groups. In acromegalic and postsurgical subjects, insulin suppressed less than in controls the endogenous leucine flux (-9 +/- 1 and -12 +/- 2 vs. -18 +/- 2%, P < 0.001 and P < 0.05), the nonoxidative leucine disposal (-4 +/- 3 and -1 +/- 3 vs. -18 +/- 2%, P < 0.01 and P < 0.05), respectively, indexes of proteolysis and protein synthesis, and leucine oxidation (-17 +/- 6% in postsurgical patients vs. -26 +/- 6% in controls, P < 0.05). Within 6 mo, surgery reverses insulin resistance for glucose but not for protein metabolism. After adenomectomy, more leucine is oxidized during hyperinsulinemia.

Roles of insulin-like growth factor-I and growth hormone in mediating insulin resistance in acromegaly.

Most patients with acromegaly have some degree of insulin resistance. The principal mediator of insulin resistance in acromegaly is hypersecretion of growth hormone. Growth hormone acts at several levels to block insulin actions including inhibiting phosphorylation of the insulin receptor and one of its principal signaling molecules IRS-1 in response to insulin administration. This leads to reduced sensitivity to insulin in the periphery in stimulating peripheral glucose uptake and to increased resistance to insulin's ability to suppress gluconeogenesis. Furthermore growth hormone excess leads to mobilization of free fatty acids which inhibit insulin stimulated glucose oxidation by acting as a competitive energy source thus leading to further worsening of insulin resistance. These abnormalities can be overcome by administering agents which either lower growth hormone secretion or block growth hormone action. The role of elevated IGF-I in acromegaly in mediating insulin resistance is more difficult to analyze. Indirect inferences from the data that are available suggest that IGF-I is acting to enhance insulin sensitivity and partially counteracting the insulin antagonistic effects of growth hormone. In a recent study administration of IGF-I to acromegalics was shown to improve insulin sensitivity over and above the level that could be achieved by simply blocking growth hormone action. Therefore it appears that the net effect of IGF-I is to counterbalance some of the effects of growth hormone hypersecretion on insulin resistance.

Influence of growth hormone on glucose-glucose 6-phosphate cycle and insulin action in normal humans.

Increased activity of the hepatic glucose-glucose 6-phosphate (G/G-6-P) cycle is associated with hepatic and peripheral insulin resistance in acromegaly. To determine whether a similar association occurs after short-term growth hormone (GH) elevation within the physiological range, two-step euglycemic hyperinsulinemic clamps were performed in normal human males after 12-h GH (2.2 ng.kg-1 x h-1) and control infusions. G/G-6-P cycle activity and endogenous glucose production (EGP) were determined by [2-3H]- and [6-3H]-glucose using labeled exogenous glucose infusions and selective enzymatic detritiation. GH increased levels of circulating lipid intermediates despite a twofold increase in basal insulin (P < 0.005), but plasma glucose, EGP, and G/G-6-P cycle activity were unchanged. GH impaired insulin suppression of EGP and lipid intermediates and impaired insulin stimulation of glucose disposal, but G/G-6-P cycle activity was unchanged. We conclude that increased activity of the G/G-6-P cycle does not contribute to the hepatic insulin resistance induced by GH under these conditions but that changes in fatty acid metabolism may be partly responsible for the impairment in hepatic and peripheral insulin action.

Relationship between Glucose Intolerance and Insulin Resistance in Acromegaly

Relationship between Glucose Intolerance and Insulin Resistance in Acromegaly

Insulin resistance in acromegaly: evaluation by studies of insulin binding to erythrocytes.

Insulin binding to erythrocytes (RBC) was evaluated in 10 acromegalic patients (6 females and 4 males) in comparison to 22 normal subjects (12 females and 10 males) in an attempt to study the insulin resistance of acromegaly. Basal glucose from all acromegalic patients were within the normal range but incremental glucose and insulin curves, respectively, on oGTT were significantly increased in the acromegalic patients suggesting an insulin resistant state. Basal growth hormone concentrations were elevated in all acromegalic patients, but no correlation was observed between insulin and GH levels. The insulin binding studies in the acromegalic patients showed a decreased binding due to a reduction in the receptor number per cell but with no alterations in the affinity state. Correction of data for creatine, as a procedure of normalization of binding data for a standardized RBC cell age, enhanced the reduction of insulin binding of the acromegalic patients in comparison to controls in consequence to the younger population of acromegalic RBC as indicated by their increased creatine concentrations. In conclusion, the insulin resistant state in acromegalics observed in our study is accompanied by a decrease in the insulin binding to the RBC receptor due to a reduction of the receptor concentration as mediated by the compensatory hyperinsulinemia.

Insulin action in human adipose tissue in acromegaly.

The mechanisms underlying insulin resistance in acromegaly were investigated. Adipose tissue was obtained from nine patients with acromegaly who had in vivo insulin resistance and from 14 matched healthy control subjects. Receptor binding and the antilipolytic effect of insulin were determined in isolated fat cells. Insulin-induced glucose oxidation at a physiological hexose concentration was investigated in fat segments. In fat cells obtained from acromegaly patients after an overnight fast, insulin binding at low hormone concentrations was significantly reduced by 20-30%, insulin-induced antilipolysis was unchanged, but glucose oxidation was unresponsive to insulin. Since it has recently been observed that glucose feeding may rapidly modify insulin action in human adipocytes, fat cells were also obtained 60 min after an 100-g oral glucose load. In this situation, insulin binding at low hormone concentrations was further reduced to one-half of that in the control group, and the sensitivity of insulin-induced antilipolysis was markedly decreased in acromegaly. It is concluded that, in the fasting state, the action of insulin on glucose utilization but not on lipolysis is impaired in adipose tissue of acromegalic patients because of a postreceptor defect. After glucose ingestion, the resistance to insulin in acromegaly is further enhanced and antilipolysis is also impaired. Altered coupling between receptor and effector alone or in combination with an additional decrease in receptor binding may explain the enhancement of insulin resistance. These mechanisms may be essential factors in the pathogenesis of insulin resistance in acromegaly.