Cardiovascular Disease in Acromegaly.

In patients with acromegaly, chronic excess of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) leads to the development of acromegalic cardiomyopathy. Its main features are biventricular hypertrophy, diastolic dysfunction, and in later stages, systolic dysfunction and congestive heart failure. Surgical and/or pharmacological treatment of acromegaly and control of cardiovascular risk factors help reverse some of these pathophysiologic changes and decrease the high risk of cardiovascular complications.

Hyperthyroidism and the Heart.

Thyroid hormones have a significant impact on cardiac function and structure. Excess thyroid hormone affects cardiovascular hemodynamics, leading to high-output heart failure and, in late stages, dilated cardiomyopathy. In this review, we discuss how hyperthyroidism affects cardiovascular pathophysiology and molecular mechanisms and examine the complications caused by excess thyroid hormone, such as heart failure and atrial fibrillation.

Detecting subtle fingertip sensory and motor dysfunction in adults with type II diabetes.

Although evidence has emerged regarding functional neural impairment of all four limbs with a diagnosis of type II diabetes (T2D), there is conflicting evidence regarding impairment in manual function with the disease. The purpose of the current study was to evaluate hand/fingertip function in T2D as compared to healthy age- and gender-matched controls. Ten adults with T2D and ten healthy age- and gender-matched control subjects underwent a battery of clinically validated and laboratory-based evaluations of sensory function, motor function, and quality of life evaluation. The T2D group exhibited sensory dysfunction and altered kinetic output and inconsistent differences in clinically-validated timed performance tasks as compared to age-matched controls. No difference in quality of life was found between the two groups. Sensory dysfunction and some timed evaluations correlated with disease severity. Linear kinetic features did not covary with diminished sensation; however, nonlinear measures did covary with sensation changes. None of the recorded measures were related to clinical diagnosis of peripheral neuropathy. The relationship among exhibited behavioral changes is discussed in terms of small fiber neuropathy, micro-vascular adaptations, and endothelial dysfunction co-occurring with T2D.

Type 2 diabetes and cardiovascular risk factors.

Diabetes is associated with higher cardiovascular morbidity and mortality. Hypertension, hyperlipidemia and diabetes are independently associated with increased risk of cardiovascular (CV) disease. Subjects with type 2 diabetes are at two- to four-fold increased risk of CV disease compared to those without diabetes. Long-term hyperglycemia is much more closely associated with microvascular complications than macrovascular complications. There is a lack of adequate evidence that improvement in glycemic control decreases CV risk.

Role of saxagliptin as monotherapy or adjunct therapy in the treatment of type 2 diabetes.

Type 2 diabetes is associated with decreased incretin hormone response to an oral glucose load, and a progressive decline in postprandial glucagon-like peptide-1 (GLP-1) secretion. Incretin-based therapies offer a new option for treatment of type 2 diabetes. Saxagliptin, a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor specifically designed for extended inhibition of the DPP-4 enzyme, causes increased endogenous GLP-1 concentration. In a phase 3 clinical trials program of 24 weeks duration, saxagliptin was studied in 6 multicenter, multinational, randomized, controlled studies and in combination with 3 of the most commonly administered oral antidiabetic drugs: metformin, glyburide and a thiozolidinedione (TZD). Saxagliptin provided significant reductions in hemoglobin HbA(1c) when given with metformin, glyburide, a TZD, or as monotherapy. Saxagliptin also reduced fasting plasma glucose and 2-hour post-prandial glucose in each of these studies, and was weight and lipid neutral. Saxagliptin was well tolerated and had a low risk of hypoglycemia when used as monotherapy.

What is the best treatment for prediabetes?

Worldwide, along with the increasing prevalence of obesity, the number of people with prediabetes is increasing. The diagnostic criteria for prediabetes include impaired fasting glucose, impaired glucose tolerance, and metabolic syndrome. The presence of two or more of these three criteria renders a person at high risk for future diabetes. The treatment goal of prediabetes is to prevent future development of type 2 diabetes and diabetes-related cardiovascular complications. The treatment approach is twofold: glycemic control and control of cardiovascular risk factors, mainly hypertension and hyperlipidemia. Intensive lifestyle modification is the mainstay of treatment in low-risk patients. When lifestyle modification fails and in high-risk patients, medications such as metformin and/or acarbose are recommended. For high-risk patients and those who progress despite intensive lifestyle modification, thiazolidinediones are also recommended. The goals for cardiovascular risk factor control are similar to those for patients with diabetes.

Role of insulin signaling in maintaining energy homeostasis.

OBJECTIVE: To examine the role that insulin signaling plays in modulating metabolic functions involving both peripheral and hypothalamic systems. METHODS: We review the literature regarding insulin signaling as it relates to energy homeostasis. RESULTS: Insulin signaling in the periphery is known to affect hepatic glucose production and glucose uptake in muscle and adipose tissue. In the brain, insulin is involved in a variety of signaling pathways that control positive and negative aspects of food intake and energy metabolism. Disruption of insulin signaling can affect key cellular pathways that serve to maintain energy balance and glucose homeostasis, which can then lead to insulin resistance and progression toward various metabolic disorders, including cardiovascular disease, obesity, and type 2 diabetes. The use of exogenous insulin as therapy for patients with type 2 diabetes is traditionally associated with increases in weight. CONCLUSION: An enhanced understanding of how these insulin signaling pathways function may provide answers about how to control weight gain associated with exogenous insulin use. Pharmacologic agents, such as the long-acting insulin analogues and particularly insulin detemir, that may reduce these weight effects hold considerable advantage.

Update: vildagliptin for the treatment of Type 2 diabetes.

Vildagliptin is a selective inhibitor of dipeptidyl peptidase-4, and prevents the rapid degradation of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Vildagliptin has been evaluated in > 4800 patients in nine Phase III studies in the range of 24 - 52 weeks in duration: four placebo- or active-controlled monotherapy trials that enrolled drug-naive patients; four add-on studies in which vildagliptin was added to a stable regimen of either metformin, a sulfonylurea, a thiazolidinedione or insulin; and a study in which an initial combination of vildagliptin plus pioglitazone in drug-naive patients was evaluated. Across studies, vildagliptin was effective in reducing HbA(1c), had a low risk of hypoglycemia and was weight-neutral and well tolerated.

Recurrent hypercalcemia due to ectopic production of parathyroid hormone-related protein and intact parathyroid hormone in a single patient with multiple malignancies.

OBJECTIVE: To report a case of recurrent hypercalcemia due to ectopic production of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTH-rP) from transitional cell carcinoma of the urinary bladder. METHODS: We present clinical, laboratory, and pathologic findings in a 73-year-old man with recurrent hypercalcemia. Results of serum calcium, PTH, PTH-rP and immunostaining of tumors for PTH and PTH-rP over 9 years are presented. RESULTS: In 1990 this patient was diagnosed with primary hyperparathyroidism, which was cured by resection of a parathyroid adenoma in the neck. Hypercalcemia recurred in 1992, and he was found to have squamous cell carcinoma of the right lung. PTH-rP levels were not measured, but the resected tumor immunostained positive for the presence of PTH-rP. The patient subsequently remained normocalcemic until 1996, when the plasma calcium and PTH levels increased again. Surgical exploration of the neck revealed no parathyroid adenoma. Elevated plasma levels of calcium and PTH persisted after surgery. In 1998 the patient was diagnosed with stage IV invasive transitional cell carcinoma (TCC) of the urinary bladder and underwent radical cystectomy. The tumor tissue was not immunoreactive to PTH-rP. A year later, plasma levels of PTH and PTH-rP increased, but surgical re-exploration of the neck again revealed no parathyroid adenoma. CT scanning identified a large retroperitoneal mass, and a CT-guided biopsy of the mass showed metastatic, poorly differentiated TCC immunopositive for PTH and PTH-rP. CONCLUSION: This is the first report of ectopic production of PTH from metastatic TCC of the urinary bladder coexisting with PTH-rP mediated hypercalcemia.

Short- and long-term effects of growth hormone (GH) replacement on protein metabolism in GH-deficient adults.

Reduced fat-free mass (FFM) in GH-deficient (GHD) adults is improved by GH replacement, but the protein metabolic changes are unclear. Using iv [(2)H(3)]leucine and oral l-[(13)C(1)]leucine infusions and dual emission x-ray absorptiometry, we compared leucine kinetics and body composition in eight GHD adults and eight healthy controls in the fasted and fed states, before and after 2 wk and 6 months of GH replacement. Leucine kinetics were not different between pretreatment GHD subjects and controls. After 2 wk of GH treatment, leucine oxidation decreased in the GHD subjects compared with baseline values [fasted, 41 +/- 6 vs. 30 +/- 5 micromol/kg FFM.h (P < 0.01); fed, 49 +/- 3 vs. 41 +/- 3.6 micromol/kg FFM.h (P < 0.05)], leucine balance improved [fasted, -14 +/- 4 vs. -3.5 +/- 3 micromol/kg FFM.h (P < 0.01); fed, 65 +/- 10 vs. 72 +/- 7 micromol/kg FFM.h (P = 0.07)], and protein synthesis increased [fasted, 116 +/- 5 vs. 131 +/- 6 micromol/kg FFM.h (P < 0.05); fed, 103 +/- 6 vs. 116 +/- 6 micromol/kg FFM.h (P < 0.05)]. After 6 months of GH treatment, these changes were not maintained in the fed state. The five GHD subjects with decreased FFM at baseline showed a significant increase after 6 months of GH treatment (P < 0.05). GH replacement in GHD acutely improves protein balance by stimulating synthesis and inhibiting catabolism. After 6 months, protein kinetics reached a new homeostasis to maintain the net gain in FFM.