CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2015 EXECUTIVE SUMMARY.

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.

Lipid-induced insulin resistance is associated with increased monocyte expression of scavenger receptor CD36 and internalization of oxidized LDL.

Elevated free fatty acids (FFAs) contribute to the development of insulin resistance, type 2 diabetes mellitus (T2DM), and may be atherogenic. We tested the relationship among lipid-induced insulin resistance, endothelial dysfunction, and monocyte capacity to form foam cells through scavenger receptor A (SRA) and CD36. Ten healthy subjects underwent 24-h infusion of Intralipid/heparin and saline (0.5 ml/min) on two separate occasions followed by brachial artery reactivity testing and a euglycemic hyperinsulinemic (80 mU/(kg.min)) clamp study to determine insulin sensitivity. Isolation of blood monocytes was performed 24 h after infusion. Surface expression and function of CD36 and SRA to take up oxidized low-density lipoprotein (oxLDL) was determined by flow cytometry and quantitative confocal imaging. Lipid infusion resulted in a twofold increase in serum FFA levels, reduced whole-body glucose disposal by approximately 20% (P < 0.05), and possibly impaired endothelial-dependent vasodilation (P = 0.1). Blood monocytes obtained during lipid infusion demonstrated a approximately 25% increase in cell surface expression of CD36 (P < 0.05) but no change in SRA expression. Enhanced CD36 expression was associated with a 50% increase in internalization of oxLDL (P < 0.05). The increase in CD36 surface expression during lipid infusion correlated inversely with glucose disposal (P < 0.05) and not with FFA levels or brachial artery dilation. These data support a role for FFAs in induction of insulin resistance and provide a link to atherogenic mechanisms mediated by expression of scavenger receptor CD36.

Effect of spironolactone therapy on albuminuria in patients with type 2 diabetes treated with angiotensin-converting enzyme inhibitors.

OBJECTIVE: To investigate whether the addition of spironolactone to angiotensin-converting enzyme (ACE) inhibitors further decreases albuminuria in patients with type 2 diabetes mellitus (DM). METHODS: We conducted a prospective open-label trial in patients recruited at the Cleveland Clinic between February 2004 and November 2006. Patients with type 2 DM were eligible if they were older than 18 years of age, had been treated with any ACE inhibitor for longer than 1 month, and had a random urinary albumin to creatinine ratio (ACR) greater than 100 mg/g within 1 month of study entry. Based on screening ACR, patients were assigned to a microalbuminuria group (ACR 100-300 mg/g) or a macroalbuminuria group (ACR >300 mg/g). Patients were followed up for 12 weeks, with 4 clinic visits, 4 weeks apart. At visit 2, spironolactone, 25 mg once daily, was initiated and continued for 4 weeks. At visit 3, spironolactone was discontinued. Clinical information was obtained at each visit as were serum chemistries and 24-hour urinary albumin excretion. RESULTS: Twenty-four patients with type 2 DM and albuminuria completed the study. Eleven patients had microalbuminuria and 13 had macroalbuminuria. Following treatment with spironolactone, urinary albumin excretion dropped from a mean +/- SD of 404.6 +/- 60.9 mg/d to 302.7 +/- 52.7 mg/d (25.7% decrease, P<.001). In the microalbuminuria and macroalbuminuria groups, the urinary albumin excretion dropped 27.2% (P = .05) and 24.3% (P = .02), respectively. Despite a significant decrease in systolic blood pressure between visits 2 and 3 (141.2 +/- 3.5 to 132.5 +/- 3.6 mm Hg; P = .002), this change did not correlate to the change in albuminuria (r(2) = 0.02; P = .23). There were no withdrawals due to hyperkalemia. CONCLUSION: Spironolactone is effective in further decreasing albuminuria in patients with type 2 DM who are already treated with ACE inhibitors.

Impaired diurnal blood pressure variation and all-cause mortality.

BACKGROUND: Most healthy people exhibit a decrease in systolic blood pressure (SBP) at night. A drop of <10% from mean daytime values, "non-dipping," is associated with kidney disease and cardiovascular events. We hypothesized that non-dipping would predict all-cause mortality. METHODS: Consecutive patients referred for ambulatory blood pressure (BP) monitoring at the Cleveland Clinic between 1994 and 2004 were included. Mean daytime (6 AM-11 PM) and nighttime (11 PM-6 AM) SBP values were calculated. We examined diurnal BP variation as a continuous variable, ((Mean daytime SBP - Mean nighttime SBP)/(Mean daytime SBP)) x 100%, and also as a categorical variable, defining "non-dipping" as a nocturnal SBP drop of <10%; subjects who exhibited non-dipping were defined as "non-dippers" and the others as "dippers." All-cause mortality was ascertained from the Social Security Death Index. RESULTS: Of the 621 patients included in the study, 261 were dippers and 360 were non-dippers. Non-dippers were older (P < 0.0001), more likely to be non-white (P < 0.05), and had higher rates of smoking, diabetes, hypertension, coronary artery disease, congestive heart failure, and renal insufficiency (P < 0.01 for all). Over a mean follow-up of 6.3 years, 61 patients died, including 10 dippers (3.8%) and 51 non-dippers (14.2%). The unadjusted hazard ratio for death based upon a decrement in the dipping percentage from the 75th to 25th percentile was 2.22 (95% confidence interval 1.64-2.95; P < 0.0001). This was attenuated after adjustment for comorbid conditions, including mean 24-h SBP and renal function: adjusted hazard ratio 1.62 (1.14-2.24; P < 0.005). CONCLUSIONS: Blunted diurnal BP variation is a strong predictor of death, but this may be accounted for, in large part, by its association with other cardiovascular risk factors.

Inhaled human insulin: an inspiration for patients with diabetes mellitus?

Inhaled insulin offers a novel option for controlling blood glucose levels in type 1 and type 2 diabetes, obviating the need for multiple daily injections. The first of several delivery systems, insulin Exubera, was recently approved by the US Food and Drug Administration (FDA). However, questions remain regarding its efficacy, cost-effectiveness, and possible deleterious effects on pulmonary function. This review will discuss the pharmacology, efficacy, important clinical trials, and practical aspects of inhaled insulin, and potential concerns associated with its use.

Association of impaired diurnal blood pressure variation with a subsequent decline in glomerular filtration rate.

BACKGROUND: Most healthy people exhibit a decrease in systolic blood pressure (SBP) at night. A drop of less than 10% from mean daytime values (nondipping) is associated with chronic kidney disease, insulin resistance, and cardiovascular events. Whether nondipping precedes a decline in renal function remains unclear. We hypothesized that nondipping would predict a decline in the glomerular filtration rate (GFR) over time. METHODS: Consecutive patients referred for ambulatory blood pressure monitoring were included in our retrospective cohort if they had a serum creatinine level noted at the time of their ambulatory blood pressure recording and a follow-up creatinine level recorded at least 1 year later. Mean day and night SBPs were compared (nighttime SBP-daytime [corrected] SBP ratio). We defined nondipping as a nighttime [corrected] SBP-daytime [corrected] SBP ratio higher than 0.90. The GFR was calculated using the Modification of Diet in Renal Disease 4-variable equation. RESULTS: Of 322 patients included, 137 were dippers and 185 were nondippers; their mean baseline GFRs were 80.5 mL/min per 1.73 m(2) and 76.4 mL/min per 1.73 m(2), respectively. During a median follow-up of 3.2 years, the GFRs remained stable among dippers (mean change, 1.3%) but declined among nondippers (mean change, -15.9%) (P<.001). The creatinine levels increased by more than 50% in 2 dippers (1.5%) and in 32 nondippers (17.3%) (P<.001). These findings persisted after adjustment for other predictors of GFR decline. CONCLUSION: Blunted diurnal blood pressure variation is associated with a subsequent deterioration in renal function that is independent of SBP load and other risk factors for renal impairment.

Relation of diurnal blood pressure variation and triglyceride-to-high-density lipoprotein cholesterol ratio in patients without diabetes mellitus.

A night-time decrease in systolic blood pressure that differs <10% from mean daytime values ("nondipping") is associated with increased rates of cardiovascular morbidity and mortality. We hypothesized that insulin resistance would be associated with nondipping in patients who did not have frank diabetes mellitus or hypertension. We included 106 consecutive outpatients who had been referred for 24-hour ambulatory monitoring of blood pressure. Our data suggest that insulin resistance, defined as a high ratio of triglyceride to high-density lipoprotein, is associated with blunted diurnal blood pressure variation (odds ratio 6.3, 95% confidence interval 2.6 to 16.4, p <0.0001) before the development of abnormal levels of fasting blood glucose.

Diabetic cardiomyocyte dysfunction and myocyte insulin resistance: role of glucose-induced PKC activity.

Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of a number of diabetic complications, and high concentrations of glucose have been shown to increase PKC activity. The present study was designed to examine the role of PKC in diabetes-induced (and glucose-induced) cardiomyocyte dysfunction and insulin resistance (measured by glucose uptake). Adult rat ventricular myocytes were isolated from nondiabetic and type 1 diabetic animals (4-5 days post-streptozotocin treatment), and maintained overnight, with/without the nonspecific PKC inhibitor chelerythrine (CHEL = 1 microM). Myocyte mechanical properties were evaluated using a video edge-detection system. Basal and insulin-stimulated glucose uptake was measured with [3H]-2-deoxyglucose. Blunted insulin-stimulated glucose uptake was apparent in diabetic myocytes, and both mechanical dysfunctions (e.g., slowed shortening/relengthening) and insulin resistance were maintained in culture, and normalized by CHEL. Cardiomyocytes isolated from nondiabetic animals were cultured in a high concentration of glucose (HG = 25.5 mM) medium, with/without CHEL. HG myocytes exhibited slowed shortening/relengthening and impaired insulin-stimulated glucose uptake compared to myocytes cultured in normal glucose (5.5 mM), and both impairments were prevented by culturing cells in CHEL. Our data support the view that PKC activation contributes to both diabetes-induced abnormal cardiomyocyte mechanics and insulin resistance, and that elevated glucose is sufficient to induce these effects.

Evaluation of hyponatremia: a little physiology goes a long way.

Hyponatremia is common in hospitalized patients. By taking a careful and logical approach, one can promptly recognize the causative factor or factors in nearly all cases. Most cases of hyponatremia are due to impaired renal water excretion, and recognizing the cause and pathophysiologic process makes it possible to provide focused individualized care and avoid mistreatment.

Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments.

We recently identified cardiomyocyte dysfunction in the early stage of type 2 diabetes (i.e., diet-induced insulin resistance). The present investigation was designed to determine whether a variety of clinically relevant interventions are sufficient to prevent and reverse cardiomyocyte dysfunction in sucrose (SU)-fed insulin-resistant rats. Subsets of animals were allowed to exercise (free access to wheel attached to cage) or were treated with bezafibrate in drinking water to determine whether these interventions would prevent the adverse effects of SU feeding on cardiomyocyte function. After 6-8 wk on diet and treatment, animals were surgically prepared to assess whole body insulin sensitivity (intravenous glucose tolerance test), and isolated ventricular myocyte mechanics were evaluated (video edge recording). SU feeding produced hyperinsulinemia and hypertriglyceridemia, with euglycemia, and induced characteristic whole body insulin resistance. Both exercise and bezafibrate treatment prevented these metabolic abnormalities. Ventricular myocyte shortening and relengthening were slower in SU-fed rats (42-63%) compared with starch (ST)-fed controls, and exercise or bezafibrate completely prevented cardiomyocyte dysfunction in SU-fed rats. In separate cohorts of animals, after 5 wk of SU feeding, animals were either switched back to an ST diet or given menhaden oil for an additional 7-9 wk to determine whether the cardiomyocyte dysfunction was reversible. Both interventions have previously been shown to have favorable metabolic effects, and both improved myocyte mechanics, but only the ST diet reversed all indications of cardiomyocyte dysfunction induced by SU feeding. Thus phenotypic changes in cardiomyocyte mechanics associated with early stages of type 2 diabetes were found to be both preventable and reversible with clinically relevant treatments, suggesting that the cellular processes contributing to this dysfunction are modifiable.

Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome.

Tumor lysis syndrome is an oncologic emergency that is characterized by severe electrolyte abnormalities and, frequently, by acute renal failure. The syndrome typically occurs in patients with lymphoproliferative malignancies, most often after initiation of treatment. The pathophysiology involves massive tumor cell lysis resulting in the release of large amounts of potassium, phosphate, and uric acid. Deposition of uric acid and calcium phosphate crystals in the renal tubules may lead to acute renal failure, which is often exacerbated by concomitant intravascular volume depletion. The kidney normally excretes these products, and consequently preexisting renal failure exacerbates the metabolic derangements of tumor lysis syndrome. Standard treatment aims to clear high plasma levels of potassium, uric acid, and phosphorus; correct acidosis; and prevent acute renal failure by way of aggressive intravenous hydration; lowering serum potassium levels; use of allopurinol; urinary alkalinization; or renal replacement therapy (if necessary). Allopurinol is the standard of care for treating hyperuricemia of malignancy, but is associated with drawbacks. Recombinant urate oxidase (rasburicase), which recently became available in the United States, provides a safe and effective alternative to allopurinol for lowering uric acid levels and preventing uric acid nephropathy.