Diabetes and Heart Failure: A Marriage of Inconvenience.

Type 2 diabetes and congestive heart failure are growing public health problems and are expected to worsen in the next decade. There is an inarguable link between diabetes and heart failure but only recently has there been an effort to elucidate the underlying pathophysiologic connection resulting in diabetic cardiomyopathy. Traditionally, diabetes and heart failure have been treated as 2 distinct disease entities, but recent advances in individual therapies have shown remarkable concomitant improvements in both diabetes and cardiovascular outcomes. This article aims to review the key connections in the epidemiology and etiopathophysiology of type 2 diabetes and heart failure.

Spontaneous Hypoglycemia After Islet Autotransplantation for Chronic Pancreatitis.

CONTEXT: Spontaneous hypoglycemia has been reported in patients after total pancreatectomy (TP) and islet autotransplantation (IAT) with maintained insulin independence. Details surrounding these events have not been well described. OBJECTIVE: The objective of the study was to determine the frequency and characteristics of spontaneous hypoglycemia in patients undergoing TP-IAT and/or to ascertain predictive or protective factors of its development. DESIGN: This was an observational cohort study in 40 patients who underwent TP-IAT from August 2008 to May 2014, with a median follow-up of 34 months. SETTING: The study was conducted at a single institution (Cleveland Clinic). PATIENTS: Patients included recipients of TP-IAT. INTERVENTION: The intervention included small, frequent meals in those patients who developed spontaneous hypoglycemia. MAIN OUTCOME MEASURES: Incidence of spontaneous hypoglycemia development, characteristics of the patients developing hypoglycemia, and their response to small, frequent meals were measured. RESULTS: Six of 12 patients, who maintained insulin independence, developed spontaneous hypoglycemia. The episodes could be fasting, postprandial, and/or exercise associated, with the frequency ranging from two to three times daily to once every 1-2 weeks. All patients experienced at least one episode that required external assistance, glucagon administration, and/or emergent medical attention. Patients who developed hypoglycemia had a lower median age and tended to have a lower median islet equivalent/kg body weight but a higher median total islet equivalent, body mass index, and homeostatic model assessment for insulin resistance score. All patients who received small, frequent meal intervention had improvement in severity and/or frequency of the hypoglycemic episodes. CONCLUSIONS: Spontaneous hypoglycemia is prevalent after TP-IAT. Although the underlying pathophysiology responsible for these hypoglycemia events remains to be elucidated, small, frequent meal intervention is helpful in ameliorating this condition.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF TESTOSTERONE AND CARDIOVASCULAR RISK.

This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

PITUITARY MRI FINDINGS IN PATIENTS WITH PITUITARY AND ECTOPIC ACTH-DEPENDENT CUSHING SYNDROME: DOES A 6-MM PITUITARY TUMOR SIZE CUT-OFF VALUE EXCLUDE ECTOPIC ACTH SYNDROME?

OBJECTIVE: Expert opinion and a consensus statement on Cushing syndrome (CS) indicate that in a patient with a clinical presentation and biochemical studies consistent with a pituitary etiology, the presence of a pituitary tumor ≥6 mm is highly suggestive of Cushing disease (CD). The purpose of the present study was to determine the optimal pituitary tumor size that can differentiate between patients with CD and ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) and obviate the need for inferior petrosal sinus sampling (IPSS). METHODS: We performed a retrospective study of 130 patients seen between 2000 and 2012 including 104 patients with CD and 26 patients with EAS. RESULTS: A pituitary lesion was reported in 6/26 (23%) patients with EAS and 71/104 (68.3%) patients with CD, with median (range) sizes of 5 mm (3-14) and 8 mm (2-31), respectively. All tumors in the EAS group measured ≤6 mm except for 1 that measured 14 mm. The presence of a pituitary tumor >6 mm in size had 40% sensitivity and 96% specificity for the diagnosis of CD. ACTH levels >209 pg/mL and serum potassium <2.7 mmol/L were found in patients with EAS. All patients with EAS had a 24-hour urine free cortisol (UFC) >3.4 times the upper limit of normal (×ULN) Conclusion: Pituitary incidentalomas as large as 14 mm in size can be seen in patients with EAS. However, the 6-mm tumor size cut-off value provided 96% specificity and may be a reasonable threshold to proceed with surgery without the need for IPSS when the biochemical data support a pituitary etiology.

Factors associated with islet yield and insulin independence after total pancreatectomy and islet cell autotransplantation in patients with chronic pancreatitis utilizing off-site islet isolation: Cleveland Clinic experience.

CONTEXT: Total pancreatectomy (TP) with islet cell autotransplantation (IAT) can reduce or prevent diabetes by preserving beta cell function and is normally performed with on-site isolation laboratory facilities. OBJECTIVE: We examined factors associated with islet yield and metabolic outcomes in patients with chronic pancreatitis undergoing TP-IAT. We report our experience of TP-IAT with an off-site islet isolation laboratory. PATIENTS AND METHODS: Data (August 2008 to February 2014) were obtained from a TP-IAT database which included information from medical records, clinic visits, questionnaires, and follow-up telephone calls. Each patient was assessed with pre- and postoperative 5-hour mixed-meal tolerance tests for metabolic measurements and with serial glycosylated hemoglobin (HbA1c) determinations. RESULTS: Thirty-six patients with a mean age of 38 years (range, 16-72 y) underwent TP-IAT for different etiologies. At a median follow-up time of 28 months (range, 3-66 mo), 12 patients were insulin independent and 24 patients were on at least one insulin injection a day. Postoperatively, C-peptide levels ≥0.3 ng/mL were present in 23/33 (70%) of the patients, with a median fasting C-peptide value of 0.8 ng/mL (range, <0.2-1.5 ng/mL). Those who were insulin independent were more likely to be female (P = .012), have normal morphology on pre-operative pancreatic imaging (P = .011), and have significantly higher median islet yield (6845 islet equivalent numbers [IEQ]/kg, n = 12 vs 3333 IEQ/kg, n = 24; P < .001). CONCLUSIONS: IAT after TP performed in our facility with an off-site islet isolation laboratory shows islet yield and rates of insulin independence that are comparable to other large centers with on-site laboratories.

The clinical utility of free thyroxine in oral levothyroxine absorption testing.

OBJECTIVE: Original absorption studies for levothyroxine (LT4) were validated using total thyroxine (TT4) measurements. Free thyroxine (FT4) has largely supplanted TT4 in clinical practice. The objective of our study was to assess the clinical utility of FT4 in oral LT4 absorption testing. METHODS: In this retrospective electronic health record analysis, we recorded data of patients who underwent LT4 oral absorption testing between November 2010 and January 2012 because of persistent hypothyroidism despite a greater than anticipated weight-based dose of LT4. Patients included had primary hypothyroidism and an absorption test with assessment of both TT4 and FT4 measured at times 0, 30, 60, 90, 120, 180, 240, 300, and 360 minutes. The test was conducted with 1 mg (five 200-µg tablets) of Synthroid® after an overnight fast by a standard nonisotopic method. RESULTS: A total of 10 patients (3 men/7 women) underwent absorption testing. Prior to testing, the median daily LT4 dose was 250 µg (range, 150 to 350 µg). Three patients were also on liothyronine (10, 20, or 50 µg daily). Based on the calculated amount absorbed, 1 patient demonstrated subnormal absorption, and 9 patients were normal. Median body mass index was 33 kg/m2 (range, 21 to 50 kg/m2). Median calculated absorption was 105% (range, 3.7 to 195.6%). The correlation comparing FT4 and TT4 was 0.88 (95% confidence interval, 0.56 to 0.97; P<.001), a significant correlation. CONCLUSION: FT4 and TT4 correlated highly, even in patients who were severely hypothyroid; FT4 may be used interchangeably with TT4 as a qualitative assessment of suspected malabsorption using an oral LT4 absorption test.

Testicular "hyperstimulation" syndrome: a case of functional gonadotropinoma.

Gonadotropins secreting pituitary tumors tend to present as sellar mass with hypogonadism. Biologically active LH secretion by these tumors resulting in elevated testosterone is extremely rare. We report a case of a 48-year-old male patient who presented with giant pituitary tumor, elevated testosterone, and elevated levels of gonadotropins. Surgical resection of the tumor resulted in normalization of gonadotropins and fall in serum testosterone to subnormal levels in the postoperative period confirming that the tumor was secreting bioactive luteinizing hormone (LH).

Biochemical and radiological relationships in patients with pheochromocytoma: lessons from a case control study.

BACKGROUND: An elevation of fractionated plasma or urinary metanephrine (MN) or nor-metanephrine (NMN), collectively called metanephrines (MN and NMN), >4-fold above the upper limit of normal (ULN) is usually considered to be diagnostic for pheochromocytoma (PHEO). There are a greater number of false positive results when the elevations are more modest. AIM: To identify biochemical and radiological features in PHEOs with modest elevations (<4-fold above ULN) of metanephrines. METHODOLOGY: We retrospectively reviewed the charts of 112 patients with PHEO (10% extra-adrenal) and 208 patients with a non-PHEO adrenal mass operated from 1997-2011, who had metanephrines measured pre-operatively. We divided PHEO into group 1 (n = 90) with metanephrines ≥4-fold ULN and group 2 (n = 22) with metanephrines <4-fold ULN. The non-PHEO group was designated as group 3. RESULTS: The median (range) tumour size in group 1 and group 2 was 4·8 cm (1·7-22) and 3·0 cm (1·7-5) respectively (P < 0·001). All patients with PHEO in group 2 had a tumour <5 cm in size. The MN fraction was elevated in about 65% of groups 1 and 2; only 2 (1%) patients in group 3 had an elevated urinary MN fraction, and none were associated with an elevated plasma MN fraction. All PHEOs had a pre-contrast attenuation ≥17 Hounsfield Units (HU). CONCLUSIONS: Modest elevations (<4-fold ULN) of the NMN fraction in an adrenal mass >5 cm are almost always falsely positive. Elevations in plasma and urinary MN fraction are less likely to be false positive. The CT pre-contrast attenuation of PHEOs is >10 HU.

Is a stable or decreasing prolactin level in a patient with prolactinoma a surrogate marker for lack of tumor growth?

The optimal interval for follow-up imaging of patients with prolactinomas is unclear. We wish to determine the likelihood of tumor enlargement in patients with prolactinomas who have a stable or reduced prolactin (PRL) level over time, whether or not they are treated with a dopamine agonist (DA). We identified 80 patients with prolactinomas (34 men, 46 women) who had at least two paired sets of serum PRL levels and pituitary MRIs, 3 or more months apart. Patients with hyperprolactinemia due to drug or stalk effects were excluded. The median (range) age was 45 (25-77) years. Sixty-three patients (78.8%) were treated with DA. PRL levels (ng/mL) at the initial and latest sets were 114 (0.3-15,732) and 16 (0.3-1,204), respectively. In patients with identifiable tumors, the maximum tumor diameters (mm) at the initial and latest MRI studies were 12.5 (2-60) and 12.5 (2-39) respectively, with an interval of 2.9 (0.3-9.7) years. Sixty percent of patients (n = 48) had a macroadenoma. Forty-two (52.5%) patients had either disappearance of the tumor (n = 22) or reduction (n = 20) in tumor size. In the remainder, tumor size was stable in 35 but increased in 3 patients. One of these patients, observed off therapy had a concomitant rise in PRL level. The other 2 had evidence of pituitary hemorrhage with no PRL increase. Tumor growth in prolactinoma patients with a stable or decreasing PRL level, regardless of size, is a rare event. Repetitive pituitary imaging in these patients may not be warranted.

Mody-3: novel HNF1A mutation and the utility of glucagon-like peptide (GLP)-1 receptor agonist therapy.

OBJECTIVE: An estimated 1 to 2% of cases of diabetes mellitus have a monogenic basis; however, delayed diagnosis and misdiagnosis as type 1 and 2 diabetes are common. Correctly identifying the molecular basis of an individual's diabetes may significantly alter the management approach to both the patient and his or her relatives. We describe a case of mature onset diabetes of the young (MODY) with sufficient evidence to support the classification of a novel HNF1A (hepatocyte nuclear factor-1-α) mutation as a cause of MODY-3. METHODS: A 21-year-old Caucasian female presented to our office with a diagnosis of noninsulin-dependent diabetes mellitus (NIDDM) at age 10; glycemia was initially managed with oral antidiabetic (OAD) agents and insulin detemir. The patient reported a strong family history of early-onset NIDDM in both her mother and maternal grandmother, both of whom eventually required insulin therapy to control glycemia. The patient's medical and family history were highly suggestive of maturity-onset diabetes of the young (MODY), and genetic testing was performed. RESULTS: Genetic screening detected a mutation p. Arg200Trp in the HNF1A gene in the patient, her mother, and maternal grandmother, suggesting a diagnosis of MODY-3. This finding resulted in a change of antidiabetic therapy in all 3 patients, including the addition of once-daily liraglutide therapy, which helped improve their glycemic control. CONCLUSION: Our case report supports the classification of the p. Arg200Trp mutation as a cause of MODY-3. The findings also suggest that glucagon-like peptide-1 (GLP-1) receptor agonist therapy may be of value in managing glycemia in patients with MODY-3.

Liraglutide effective in the severely insulin-resistant patient with type 2 diabetes requiring U-500 insulin: a case report.

BACKGROUND/OBJECTIVE: We describe the effectiveness of liraglutide therapy in a severely insulin-resistant patient with type 2 diabetes mellitus (DM-2) requiring U-500 insulin. SUBJECT AND METHODS: A 65-year-old morbidly obese man (body mass index, 67.3 kg/m(2); weight, 156.2 kg) presented with a 20-year history of DM-2; the glycemic control deteriorated to U-500 insulin requirement. He was inadequately controlled (hemoglobin A1c [HbA1c], 9.1%) on metformin plus U-500 insulin titrated to 575 units daily. Liraglutide was added and titrated to 1.8 mg once daily over 3 weeks. RESULTS: Insulin requirements decreased markedly (>50%) to 250 units daily after 5 months of added liraglutide, with a concurrent improvement in HbA1c from 9.1% to 6.9% and weight loss of 22.6 kg. CONCLUSIONS: The addition of once-daily liraglutide to the regimen of patients with uncontrolled DM-2 requiring U-500 insulin should be considered as it may help to reduce insulin requirements, improve glycemic control, and assist with weight management.

Male hypogonadism: more than just a low testosterone.

Confronted with a low serum testosterone level, physicians should not jump to the diagnosis of hypogonadism, as confirmation and thorough evaluation are warranted before making the diagnosis or starting therapy. This review discusses how to approach the finding of a low testosterone value, stressing the need to confirm the finding, the underlying pathophysiologic processes, drugs that can be responsible, and the importance of determining whether the cause is primary (testicular) or secondary (hypothalamic-pituitary).

Serum IGF-1 in the diagnosis of acromegaly and the profile of patients with elevated IGF-1 but normal glucose-suppressed growth hormone.

OBJECTIVE: To report the utility of insulin-like growth factor-1 (IGF-1) as a single biomarker for establishing the diagnosis of acromegaly and to examine the clinical and biochemical profile of patients with an elevated IGF-1 in whom a diagnosis of acromegaly could not be confirmed by means of the oral glucose tolerance test (OGTT). METHODS: Between the years 1999 and 2010, we identified 101 patients who underwent pituitary surgery and had histologically proven somatotroph adenomas (Group 1, Gr 1). We selected 149 patients with non-growth hormone (GH) secreting pituitary macroadenomas (Gr 2, n = 97) and microadenomas (Gr 3, n = 52) to serve as control subjects. In addition, we identified 34 patients with elevated IGF-1values in whom acromegaly could not subsequently be proven by the OGTT (Gr 4). RESULTS: IGF-1 was elevated in all patients with acromegaly prior to therapy with a median (range) standard deviation score (SDS) of +9.52 (+2.34 to +9.2), compared to SDS -1.46 (-2.91 to +2.17) and -1.22 (-2.8 to +1.58) in Gr 2 and 3, respectively (P<0.001). IGF-1 SDS values were +3.28 (+2.05 to +6.1), and IGF-1 was less than twice the upper limit of normal in all patients in Gr 4. OGTT was performed in 51 of the 101 acromegalic patients. The nadir GH in these patients was 4.01 (0.2 to 46.7) in comparison with 0.2 (<0.05 to 0.6) in Gr 4 (P<0.001). CONCLUSION: Elevated IGF-1 levels, alone, are sufficient to establish a diagnosis of acromegaly in the majority of clinically suspected cases. The OGTT may be useful to obtain corroborative evidence when there is modest elevation of IGF-1 with absent or equivocal clinical features.

Prolactin measurement during inferior petrosal sinus sampling improves the localization of pituitary adenomas in Cushing's disease.

OBJECTIVE: Inferior petrosal sinus sampling (IPSS) distinguishes pituitary-dependent Cushing's disease (CD) from ectopic ACTH syndrome with a high degree of certainty, but has not been reliable in predicting the location of an adenoma within the pituitary gland. We investigated whether prolactin measurements during IPSS would improve pituitary tumour localization. METHODS: Fifty-four patients with suspected ACTH-dependent Cushing's syndrome who underwent IPSS between 1997 and 2009 were studied retrospectively. Twenty-eight patients who had an identifiable tumour that stained for ACTH on histopathology are the subject of this study. Intersinus ACTH gradients before and after adjustment for prolactin were compared with surgical findings and pathology. RESULTS: Magnetic resonance imaging localized a pituitary adenoma in 17/28 (61%) patients. Using a maximum intersinus ACTH gradient of ≥1·4 before or after CRH stimulation, we could diagnose the tumour location correctly in 15/28 (54%) patients. By comparison, tumour lateralization by means of a dominant (≥1·4) prolactin-adjusted ACTH intersinus gradient was correct in 21/28 (75%) patients (P = 0·041). Tumour localization was correct in 23/28 (82%) patients when MRI and prolactin-adjusted ratio data were combined. Fourteen patients with proper bilateral IPS venous sampling (as determined by concurrent IPS to peripheral prolactin ratio ≥1·8) either had correct localization of the tumour (n = 12) or had a central lesion (n = 2). In none of these 14 patients was the dominant prolactin-adjusted ACTH ratio associated with a tumour on the opposite side of the gland. CONCLUSION: Prolactin measurement, during IPSS, improves our ability to correctly localize the pituitary adenoma site in CD.

Pregnancy and acromegaly: a review.

To review the literature regarding the diagnosis and management of acromegaly during pregnancy. A systematic literature search was performed using MEDLINE including hand-searching reference lists from original articles. The diagnosis of acromegaly during pregnancy is made difficult due to the physiologic changes in pituitary GH secretion and IGF-1 production resulting from placental GH secretion and the inability of commercial assays to discriminate between pituitary and placental GH. Most patients with acromegaly during pregnancy do not have an increase in tumor size, metabolic complications are uncommon, and neonatal outcome is largely unaffected. IGF-1 levels tend to be stable in such patients possibly due to the high estrogen levels causing GH resistance. Dopamine agonists, somatostatin analogues, and a GH receptor antagonist have been reported to be safe during pregnancy. Patients with visual field defects should be considered for surgery, but in most cases this can be safely postponed until after delivery. Overall, pregnancy in acromegaly is uneventful and newborns unaffected. Dopamine agonists and somatostatin analogues have not been associated with major adverse effects to the fetus; however, more data are needed to validate their safety.

Insulin glargine use during pregnancy.

OBJECTIVE: To review the literature regarding the use of insulin glargine during pregnancy, specifically addressing the issues and concerns surrounding mitogenicity, placental transfer, and maternal and fetal safety. METHODS: We performed a systematic literature search using MEDLINE and BIOSIS Previews up to March 2011. Additional studies were identified by hand-searching reference lists from original articles. Inclusion was limited to studies and abstracts in the English language. RESULTS: A total of 23 reports with 1001 pregnancies managed with insulin glargine contained relevant information regarding the maternal and fetal safety of its use during pregnancy. Insulin glargine does not appear to have enhanced mitogenic activity when compared with the mitogenic activity of native human insulin. The transplacental transfer of insulin glargine appears to be negligible, although it is possible that antibody-bound insulin glargine may gain access to the fetal compartment. The available data suggest that there are no identifiable, consistent adverse maternal or fetal outcomes with the use of insulin glargine during pregnancy, including during the first trimester. CONCLUSIONS: Use of insulin glargine during pregnancy should be seriously considered in uncontrolled diabetes during pregnancy and in those patients taking insulin glargine before conception, because the benefits from improved glycemic control would be expected to outweigh any, as yet, unproven risks of insulin glargine exposure.

Hyperandrogenism in a postmenopausal woman: diagnostic and therapeutic challenges.

OBJECTIVE: To describe a postmenopausal woman with severe hyperandrogenism who responded dramatically to a gonadotropin-releasing hormone (GnRH) agonist. METHODS: Detailed clinical and laboratory findings are presented, and the pertinent literature is reviewed. RESULTS: A 53-year-old postmenopausal woman with end-stage renal disease, who had undergone kidney transplantation, was referred because of high serum testosterone levels. She presented with worsening acne and hirsutism for the previous 2 years. Her medications included prednisone (7.5 mg every other day). On examination, mild facial acne and hirsutism but no virilizing features were noted. Laboratory results showed generous postmenopausal gonadotropin levels and markedly elevated total and free testosterone levels, which failed to suppress with a 2-day low-dose dexamethasone test. Transvaginal ultrasonography and a computed tomographic scan failed to identify an ovarian or adrenal abnormality. Administration of a GnRH agonist (Depo-Lupron) resulted in a dramatic decline in follicle-stimulating hormone, luteinizing hormone, and testosterone levels after 1 month, which persisted during the course of 11 months of therapy. The source of marked hyperandrogenism in postmenopausal women represents a diagnostic challenge. The absence of a tumor on diagnostic imaging and the inability to perform catheterization studies confound the problem. Androgen levels did not suppress with glucocorticoids. We reasoned that a clear response to a GnRH agonist would indicate a nontumorous ovarian source of hyperandrogenism. Regrettably, the literature has described cases of ovarian tumors and, rarely, adrenal adenomas that are responsive to gonadotropins. CONCLUSION: The striking improvement in a postmenopausal woman with severe hyperandrogenism by means of GnRH agonist therapy demonstrates its potential use in poor surgical candidates without necessarily delineating the source of androgen excess.

Reduction of false-negative results in inferior petrosal sinus sampling with simultaneous prolactin and corticotropin measurement.

OBJECTIVE: To investigate the value of prolactin as an independent marker of catheter placement to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) in patients with corticotropin-dependent Cushing syndrome. METHODS: In this retrospective cohort study, we reviewed hospital records of patients who underwent IPSS procedures at the Cleveland Clinic between 1997 and 2009. Serum prolactin and plasma corticotropin levels were measured prospectively in peripheral and inferior petrosal sinus (IPS) samples. RESULTS: Forty-one patients underwent 42 IPSS procedures at our institution during the study period. Among 35 patients with Cushing disease, 1 patient had erroneous IPSS results: all pre-corticotropin-releasing hormone (CRH) and post-CRH IPS to peripheral (IPS:P) ACTH ratios were less than 2 and less than 3, respectively. Despite radiologic evidence of appropriate IPS catheter placement, concurrent IPS:P prolactin ratios indicated that successful IPS venous sampling was not achieved. A second case with equivocal IPSS results could also be explained by corresponding IPS:P prolactin ratios. During IPSS, all patients with an identifiable ACTH-staining adenoma localizing to 1 side of the pituitary gland (n = 22) who demonstrated absent IPS:P ACTH gradients (<2 before or <3 after CRH administration) on the ipsilateral side of the corticotroph adenoma had corresponding IPS:P prolactin ratios less than 1.3. CONCLUSIONS: Measurement of prolactin during IPSS testing may reduce false-negative results in patients with Cushing disease who do not demonstrate an appropriate central-to-peripheral ACTH gradient. In our series, all false-negative IPS:P ACTH ratios had a corresponding IPS:P prolactin ratio less than 1.3.