pasireotide and Insulin-Resistance

This review focuses on the pathophysiological and clinical aspects of diabetes mellitus occurring in patients with Cushing disease (CD).. Insulin resistance and impairment in insulin secretion are both involved in the pathogenesis of glucocorticoid-induced diabetes. Correction of glucocorticoid excess does not always resolve abnormalities of glucose homeostasis, and correction of hyperglycaemia is specifically required. In fact, insulin resistance may persist even after correction of glucocorticoid excess and diabetes needs to be treated for long term. On the other hand, emerging drugs used in the treatment of CD, such as the novel somatostatin analog pasireotide, may have direct effects on glucose homeostasis regardless of control of cortisol excess. Diabetes mellitus is a frequent and early complication of CD with important diagnostic, prognostic and therapeutic implications. Specifically, diagnosis of CD in patients with diabetes may be difficult due to potential misinterpretation of markers of cortisol hypersecretion. Moreover, diabetes mellitus is often difficult to be controlled in CD requiring a careful and dedicated therapeutic approach. Finally, the coexistence of diabetes may influence the therapeutic decision making in CD, since drugs used in this setting may variably influence glucose homeostasis regardless of control of hypercortisolism.

Topics: Adrenocorticotropic Hormone; Diabetes Mellitus; Humans; Insulin Resistance; Pituitary ACTH Hypersecretion; Somatostatin

Acromegaly is associated with insulin resistance and an increased incidence of cardiovascular disease. However, it remains unclear to what extent the effects of growth hormone (GH) excess on cardiovascular morbidity and mortality are mediated through insulin resistance versus through other direct or indirect effects of GH. Adequate control of GH excess by surgery or pharmacologic interventions is associated with decreased insulin resistance, reflected in decreased plasma insulin levels and fasting glucose levels or improved glucose tolerance. Despite divergent effects of both somatostatin and somatostatin analogs on GH, insulin and glucagon secretion, and glucose absorption, treatment with the somatostatin analogs octreotide and lanreotide has only limited effects on glucose metabolism. However, glucose sensitivity has only been formally examined using a hyperinsulinemic euglycemic clamp in a minority of these studies. Treatment with the GH-receptor antagonist pegvisomant ameliorates insulin sensitivity, reflected in decreased fasting plasma insulin levels and fasting glucose levels. Nonetheless, the effect of pegvisomant on glucose sensitivity has not been formally tested by hyperinsulinemic clamp conditions. In acromegaly, preliminary observations on new octreotide analogs with greater specificity for somatostatin-receptor subtypes indicate that these compounds achieve better control of GH hypersecretion than octreotide, but may also negatively influence insulin release. Assessment of insulin secretion and glucose levels in acromegalic patients during administration of these compounds is thus mandatory.

Topics: Acromegaly; Animals; Blood Glucose; Glucose Intolerance; Growth Hormone; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Like Growth Factor I; Octreotide; Peptides, Cyclic; Receptors, Somatostatin; Receptors, Somatotropin; Somatostatin

To evaluate the effect of pasireotide on β-cell and adipose function in patients with Cushing's disease (CD).. 12 months of treatment with pasireotide in CD is associated with an impairment of insulin secretion and an improvement of adipose function without any interference in insulin sensitivity.

Topics: Adipokines; Adult; Blood Glucose; Body Weight; Cohort Studies; Female; Hormones; Humans; Injections, Subcutaneous; Insulin; Insulin Resistance; Male; Middle Aged; Pituitary ACTH Hypersecretion; Somatostatin; Treatment Outcome; Young Adult

Cushing’s disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM−) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 µg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM− (p < 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Insulin; Insulin Resistance; Meals; Pituitary ACTH Hypersecretion; Somatostatin

Long-term medical management of hypersomatotropism (HS) in cats has proved unrewarding. Pasireotide, a novel somatostatin analogue, decreases serum insulin-like growth factor 1 (IGF-1) and improves insulin sensitivity in cats with HS when administered as a short-acting preparation.. Assess once-monthly administration of long-acting pasireotide (pasireotide LAR) for treatment of cats with HS.. Fourteen cats with HS, diagnosed based on diabetes mellitus, pituitary enlargement, and serum IGF-1 > 1000 ng/mL.. Uncontrolled, prospective cohort study. Cats received pasireotide LAR (6-8 mg/kg SC) once monthly for 6 months. Fructosamine and IGF-1 concentrations, and 12-hour blood glucose curves (BGCs) were assessed at baseline and then monthly. Product of fructosamine concentration and insulin dose was calculated as an indicator of insulin resistance (Insulin Resistance Index). Linear mixed-effects modeling assessed for significant change in fructosamine, IGF-1, mean blood glucose (MBG) of BGCs, insulin dose (U/kg) and Insulin Resistance Index.. Eight cats completed the trial. Three cats entered diabetic remission. Median IGF-1 (baseline: 1962 ng/mL [range 1051-2000 ng/mL]; month 6: 1253 ng/mL [524-1987 ng/mL]; P < .001) and median Insulin Resistance Index (baseline: 812 μmolU/L kg [173-3565 μmolU/L kg]; month 6: 135 μmolU/L kg [0-443 μmolU/L kg]; P = .001) decreased significantly. No significant change was found in mean fructosamine (baseline: 494 ± 127 μmol/L; month 6: 319 ± 113.3 μmol/L; P = .07) or MBG (baseline: 347.7 ± 111.0 mg/dL; month 6: 319.5 ± 113.3 mg/dL; P = .11), despite a significant decrease in median insulin dose (baseline: 1.5 [0.4-5.2] U/kg; 6 months: 0.3 [0.0-1.4] U/kg; P < .001). Adverse events included diarrhea (n = 11), hypoglycemia (n = 5), and worsening polyphagia (n = 2).. Pasireotide LAR is the first drug to show potential as a long-term management option for cats with HS.

Topics: Acromegaly; Animals; Blood Glucose; Cat Diseases; Cats; Cohort Studies; Delayed-Action Preparations; Diabetes Mellitus; Female; Fructosamine; Hormones; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Male; Prospective Studies; Somatostatin