Jennifer M. Perkins

The renin-angiotensin-aldosterone system: a pivotal role in insulin sensitivity and glycemic control.

Purpose of reviewDiabetes mellitus is an exploding epidemic costing billions of dollars yearly. Type 2 diabetes mellitus is characterized by insulin resistance and is closely associated with arterial hypertension. Emerging literature has demonstrated that modulation of the renin–angiotensin–aldosterone system by use of angiotensin-converting enzyme inhibitors or angiotensn II receptor blockers leads to improved insulin sensitivity, glycemic control and possibly prevention of type 2 diabetes mellitus. Recent findingsSeveral major studies investigating angiotensn II receptor blocker or angiotensin-converting enzyme inhibitor use in either hypertensive or heart failure patients have found lower incidence of type 2 diabetes mellitus when compared with placebo, β-blocker, calcium-channel blocker or diuretic. None of these trials, however, studied prevention of diabetes as a primary endpoint. The Dream Trial and upcoming NAVIGATOR, ONTARGET/TRANSCEND trials specifically look at the prevention of diabetes as a primary endpoint. Several studies have evaluated possible mechanisms of how the renin–angiotensin–aldosterone system can alter insulin sensitivity and glycemic control. SummaryThis review will focus on the recent literature that demonstrates renin–angiotensin–aldosterone system modulation and its effects on diabetes prevention, glycemic control and insulin sensitivity, as well as possible mechanisms for achieving this goal.

Adjuvant radioactive iodine therapy is associated with improved survival for patients with intermediate-risk papillary thyroid cancer.

CONTEXT Papillary thyroid cancer (PTC) is the most common endocrine malignancy. The long-term prognosis is generally excellent. Due to a paucity of data, debate exists regarding the benefit of adjuvant radioactive iodine therapy (RAI) for intermediate-risk patients. OBJECTIVE The objective of the study was to examine the impact of RAI on overall survival in intermediate-risk PTC patients. DESIGN/SETTING Adult patients with intermediate-risk PTC who underwent total thyroidectomy with/without RAI in the National Cancer Database, 1998-2006, participated in the study. PATIENTS Intermediate-risk patients, as defined by American Thyroid Association risk and American Joint Commission on Cancer disease stage T3, N0, M0 or Mx, and T1-3, N1, M0, or Mx were included in the study. Patients with aggressive variants and multiple primaries were excluded. MAIN OUTCOME MEASURES Overall survival (OS) for patients treated with and without RAI using univariate and multivariate regression analyses was measured. RESULTS A total of 21 870 patients were included; 15 418 (70.5%) received RAI and 6452 (29.5%) did not. Mean follow-up was 6 years, with the longest follow-up of 14 years. In an unadjusted analysis, RAI was associated with improved OS in all patients (P < .001) as well as in a subgroup analysis among patients younger than 45 years (n = 12 612, P = .002) and 65 years old and older (median OS 140 vs 128 mo, n = 2122, P = .008). After a multivariate adjustment for demographic and clinical factors, RAI was associated with a 29% reduction in the risk of death, with a hazard risk 0.71 (95% confidence interval 0.62-0.82, P < .001). For age younger than 45 years, RAI was associated with a 36% reduction in risk of death, with a hazard risk 0.64 (95% confidence interval 0.45- 0.92, P = .016). CONCLUSION This is the first nationally representative study of intermediate-risk PTC patients and RAI therapy demonstrating an association of RAI with improved overall survival. We recommend that this patient group should be considered for RAI therapy.

Acute effects of hyperinsulinemia and hyperglycemia on vascular inflammatory biomarkers and endothelial function in overweight and obese humans

We investigated the separate and combined effects of hyperglycemia and hyperinsulinemia on markers of endothelial function, proinflammatory and proatherothrombotic responses in overweight/obese nondiabetic humans. Twenty-two individuals (13 F/9 M, BMI 30.1 ± 4.1 kg/m(2)) were studied during four randomized, single-blind protocols. The pancreatic clamp technique was combined with 4-h glucose clamps consisting of either 1) euinsulinemia-euglycemia, 2) euinsulinemia-hyperglycemia, 3) hyperinsulinemia-hyperglycemia, or 4) hyperinsulinemia-euglycemia. Insulin levels were higher (998 ± 66 vs. 194 ± 22 pmol/l) during hyperinsulinemia compared with euinsulinemia. Glucose levels were 11.1 mmol/l during hyperinsulinemia compared with 5.1 ± 0.1 mmol/l during euglycemia. VCAM, ICAM, P-selectin, E-selectin, IL-6, adiponectin, and PAI-1 responses were all increased (P < 0.01-0.0001), and endothelial function was decreased (P < 0.0005) during euinsulinemia-hyperglycemia compared with other protocols. Hyperinsulinemia in the presence of hyperglycemia prevented the increase in proinflammatory and proatherothrombotic markers while also normalizing vascular endothelial function. We conclude that 4 h of moderate hyperglycemia can result in increases of proinflammatory markers (ICAM, VCAM, IL-6, E-selectin), platelet activation (P-selectin), reduced fibrinolytic balance (increased PAI-1), and disordered endothelial function in a group of obese and overweight individuals. Hyperinsulinemia prevents the actions of moderate hyperglycemia to reduce endothelial function and increase proinflammatory and proatherothrombotic markers.

Comparative effects of acute hypoglycemia and hyperglycemia on pro-atherothrombotic biomarkers and endothelial function in non-diabetic humans

BACKGROUND The comparative effects of acute moderate hyperglycemia and hypoglycemia on in vivo endothelial function together with pro-inflammatory and pro-atherothrombotic responses in healthy individuals have not been determined. METHODS To investigate this question, 45 healthy subjects were compared during glucose clamp studies consisting of euinsulinemic hyperglycemia and hyperinsulinemic hyperglycemia (plasma glucose 11.1mmol/L, both with pancreatic clamps) and hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia (plasma glucose 5.1 and 2.9mmol/L, respectively). Two-dimensional Doppler ultrasound was used to determine brachial artery endothelial function. RESULTS Insulin levels during euinsulinemia hyperglycemia were 194±23 and (850±49-988±114) pmol/L during all hyperinsulinemic protocols. Responses of VCAM-1, ICAM-1, E-selectin, P-selectin, PAI-1, and IL-6 were increased (p<0.05-0.0001) during euinsulinemic hyperglycemia or hypoglycemia as compared to hyperinsulinemic euglycemia or hyperinsulinemic hyperglycemia. PAI-1 was increased (p<0.04) during hypoglycemia as compared to euinsulinemic hyperglycemia, and TNF-α responses were also increased during hypoglycemia as compared to hyperinsulinemic euglycemia or hyperinsulinemic hyperglycemia (p<0.05). In vivo endothelial function was similarly blunted by acute moderate hyperglycemia or hypoglycemia. CONCLUSION In summary, acute moderate hypoglycemia and euinsulinemic hyperglycemia can result in similar endothelial dysfunction and pro-atherothrombotic responses. Fibrinolytic balance was reduced by a greater extent by hypoglycemia as compared to moderate hyperglycemia. Acutely, hyperinsulinemia can prevent the acute pro-atherothrombotic and pro-inflammatory effects of moderate hyperglycemia but not hypoglycemia.

Lobectomy for treatment of differentiated thyroid cancer: can patients avoid postoperative thyroid hormone supplementation and be compliant with the American Thyroid Association guidelines?

Background. The American Thyroid Association recommended thyroid lobectomy as an alternative for low‐risk differentiated thyroid cancer. One hypothetical benefit includes avoiding lifelong thyroid hormone supplementation; however, guidelines recommend maintaining the thyroid‐stimulating hormone <2 mIU/L postoperatively in low‐risk patients. Our hypothesis is that most patients will require hormone supplementation to maintain thyroid‐stimulating hormone <2 mIU/L, minimizing this advantage of lobectomy. The goal of this study is to determine how often patients have thyroid‐stimulating hormone <2 mIU/L after lobectomy without thyroid hormone supplementation. Methods. A retrospective review of 555 consecutive patients who underwent thyroid lobectomy was performed. Thyroid hormone supplementation was documented, along with thyroid‐stimulating hormone levels preoperatively, 7 to 10 days, and 2 to 12 months postoperatively. Results. In the study, 478/555 (86%) patients did not take thyroid hormone before thyroidectomy; 394/478 (82%) had thyroid‐stimulating hormone levels available at 7 to 10 days postoperatively, and of these, 218 (55%) had thyroid‐stimulating hormone >2 mIU/L. From 2 to 12 months postoperatively, of the 225 patients who continued to remain off thyroid hormone supplementation, 132 (59%) experienced a thyroid‐stimulating hormone increase to >2 mIU/L; therefore, 350/478 (73%) patients after thyroid lobectomy had thyroid‐stimulating hormone levels >2 mIU/L within a year. Conclusion. It is important to counsel patients that to be compliant with the American Thyroid Association guidelines for differentiated thyroid cancer, the majority of patients undergoing thyroid lobectomy may require thyroid hormone supplementation to maintain a thyroid‐stimulating hormone level <2 m IU/L.

Appropriate dosing of adjuvant radioactive iodine for differentiated thyroid cancer.

Purpose of review The incidence of well differentiated thyroid cancer (WDTC) is increasing in the US population and is now a major public health concern. Although surgery is the mainstay of treatment, radioactive iodine (RAI) is routinely used for adjuvant therapy, remnant ablation, and for the treatment of metastatic disease. Despite excellent prognosis and stable mortality rates, the use of RAI is increasing in many low and intermediate risk WDTC patients without clear indication that it changes the outcome. As a result, the current treatment paradigm has shifted towards a risk-stratified approach. Recent findings Although there is widespread acceptance that RAI improves overall and recurrence-free survival in patients with metastatic disease, controversy remains regarding radioactive remnant ablation use in low and intermediate risk patients. Additional studies have shown that reduced doses of RAI can provide similar rates of remnant ablation and adjuvant therapy in low and intermediate risk patients without adversely affecting the recurrence rates and mortality. Summary Recent studies suggest potential new paradigms in radioactive remnant ablation dosing and indications for use. Risk stratification is important in determining the proper use and dosing of RAI.

Role of the endocannabinoid system in management of patients with type 2 diabetes mellitus and cardiovascular risk factors.

OBJECTIVE To review the role of the endogenous cannabinoid system (ECS) in the peripheral and central regulation of food intake, appetite, and energy storage and discuss the potential for the ECS to be an important target for lowering cardiovascular risk. METHODS Materials used for this article were identified through a MEDLINE search of the pertinent literature (1975 to present), including English-language randomized controlled, prospective, cohort, review, and observational studies. We summarize the available experimental and clinical data. RESULTS The ECS is composed of two 7-transmembrane G protein-coupled cannabinoid receptor subtypes, CB1 and CB2, endogenous cannabinoid ligands (anandamide and 2-arachidonoylglycerol), and the enzymes that synthesize and break down the ligands. Understanding the role of the ECS in central and peripheral metabolic processes related to the regulation of food intake and energy balance as well as the endocrine role of excess adipose tissue, particularly visceral adipose tissue, and its promotion of global cardiometabolic risk has led to the development of pharmacologic agents with potential for blockade of CB1 receptors. In several studies, rimonabant (20 mg daily) demonstrated a favorable effect on various risk factors for cardiovascular disease, including dyslipidemia, abdominal obesity, insulin resistance, blood pressure, and measures of inflammation. CONCLUSION The ECS has been shown to have a key role in the regulation of energy balance, and modulation of this system may affect multiple cardiometabolic risk factors. Clinical studies involving pharmacologic blockade of CB1 receptors in overweight patients with and without type 2 diabetes have demonstrated effective weight loss and improvements in several risk factors for cardiovascular disease.

Considerations in Thyrotropin-Stimulating Hormone Suppression in Individuals with Differentiated Thyroid Cancer

Differentiated thyroid cancer (DTC) is the most common endocrine cancer and has an overall excellent prognosis in most patients with an overall survival rate at 5 years of 97.9%. Most commonly, DTC is first treated primarily by surgical resection of either the total thyroid or partial thyroid. In patients who have undergone a total thyroidectomy, thyroxine replacement therapy will be required for the rest of their lives and may be required in those receiving partial thyroidectomy. Thyrotropin-stimulating hormone (TSH) suppression is often a cornerstone to therapy to prevent recurrence in most patients, particularly those at higher risk or in those with persistent or recurrent disease either locoregionally or with distant metastatic disease. It is critical for the clinician to risk stratify patients as well as weight the risks and benefits to determine their appropriate level of needed TSH suppression. Subsequently, patients need to be followed long term to look for risks of suppression including bone loss, atrial fibrillation, and quality of life detriments and consistently weigh these risks to the benefits of TSH suppression for their thyroid cancer. Newer guidelines suggest that not all patients require a high degree of suppression, and this chapter will discuss which patients’ need to be suppressed, for how long, and what are the goals. Additionally, this chapter will address the evidence behind the risks and benefits of TSH suppression.

Best Practices in Transgender Health: A Clinician’s Guide

Providing culturally competent and medically knowledgeable care to the transgender community is increasingly falling within the realms of practice for primary care providers. The purpose of this article is to provide an overview of best practices as they relate to transgender care. This article is by no means a comprehensive guide, but rather a starting point for clinicians as they provide high-quality care to their transgender patients.

Surveillance of Treated Thyroid Cancer Patients and Thyroid Hormone Replacement and Suppression

Differentiated thyroid cancer (DTC) incidence is increasing worldwide in recent decades and is the most common endocrine cancer. Fortunately, most of the increase is in low-risk tumors; however, we are seeing an increase across all sized tumors. Papillary thyroid cancer (PTC) is the most common form accounting for about 85 % of DTC, and prognosis overall is very favorable for patients with DTC. Initial therapy often consists of surgery and then radioactive iodine (RAI) ablation of thyroid remnant in those that are deemed intermediate risk or high risk by the American Thyroid Association (ATA) classification. An additional component of therapy also includes achieving low normal or suppression of thyroid-stimulating hormone (TSH) levels.