Glucose Trajectory: More than Changing Glucose Tolerance with Age?

While glucose tolerance is widely known to deteriorate with age, there are individuals whose borderline elevated glucose does not presage development of diabetes, but there are people who do develop overt diabetes. In addition, elevated glucose may also presage other morbidities, particularly for those who show progressive deterioration in glucose control over time. This concept of the glucose trajectory has taken on recent significance with sophisticated mathematical modeling that can identify several different arcs, primarily based on longitudinal changes in fasting plasma glucose. Other trajectories, calculated on changes in glycated hemoglobin, or integrated responses to oral glucose tolerance tests, are less well characterized. The author has reviewed the literature in an attempt to clarify these different themes of age-related deterioration in glucose control, highlight conflicting definitions of glucose trajectory, and potentially identify avenues of further investigation. Genetic contributions to the risk of development of type 2 diabetes, artificial intelligence and mathematical models of diabetes risk, and the discrepancy between fasting glucose and postprandial measures, including glycated hemoglobin, in risk prediction are also considered.

Peyronie Disease as a Marker of Inflammation-Is There Hope on the Horizon?

Although the description of Peyronie disease, a connective tissue disorder involving the growth of fibrous plaques in the soft tissue of the penis, is attributed to François de la Peyronie, surgeon to Louis XV of France, there are reports previous to that time. Over the intervening 450 years, a variety of empiric treatments, varying in barbarity, have been proposed. The frequency of this condition and the etiology of the fibrosis are unknown. Quality of life for affected men and their partners is adversely impacted. In this review, the authors summarize the history of the discovery of this condition, review contemporary management approaches, and address the pathophysiology leading to the underlying disordered fibrosis. The potential immunomodulatory role of testosterone as well as inflammatory conditions and environmental stimuli that may provoke fibrosis are also considered. Peyronie disease may be part of a spectrum of fibrotic conditions, including Dupuytren contracture. Treatment strategies to date have focused on reversing fibrosis; work is needed to prevent fibrosis and to accurately document disease prevalence.

Detection of inadequate anastomotic perfusion with handheld vital microscopy in two patients during colorectal surgery.

INTRODUCTION: Anastomotic leakage is one of the most feared complications after gastrointestinal surgery. Assessment of anastomotic viability during surgery remains challenging. Sufficient bowel tissue perfusion is a requisite for anastomotic healing. Handheld vital microscopy (HVM) is a non-invasive technique that can directly visualize the intestinal microcirculation during surgery. PRESENTATION OF TWO CASES: Two patients underwent elective laparoscopic colorectal surgery. During surgery HVM was used to assess bowel perfusion prior to creation of a primary anastomosis. Although the bowel macroscopically appeared to be well perfused, HVM showed a severely compromised microcirculation. The colon was re-internalized and during the following minutes cyanosis of the bowel occurred which was visually determined by the surgeon. After dissection towards cranially, a new site for the primary anastomosis was chosen. The postoperative period was uncomplicated. DISCUSSION: Sufficient bowel tissue perfusion is often mentioned as key in the pathophysiology of anastomotic leakage. HVM is a technique that could potentially aid surgeons in the assessment of microcirculatory perfusion of the bowel during surgery. CONCLUSION: We report two cases undergoing colorectal surgery in which HVM showed merit in detecting compromised bowel perfusion before creation of a primary anastomosis.

Intestinal Mucosal and Serosal Microcirculation at the Planned Anastomosis during Abdominal Surgery.

INTRODUCTION: Intestinal blood flow is often named as a key factor in the pathophysiology of anastomotic leakage. The distribution between mucosal and serosal microperfusion during surgery remains to be elucidated. OBJECTIVE: The aim of this study was to assess if the mucosal microcirculation of the intestine is more vulnerable to a surgical hit than the serosal microcirculation during surgery. METHODS: In an observational cohort study (n = 9 patients), the microcirculation of the bowel serosa and mucosa was visualized with incident dark-field imaging during surgery. At the planned anastomosis, the following microcirculatory parameters were determined: microvascular flow index (MFI), percentage of perfused vessels (PPV), perfused vessel density (PVD), and total vessel density (TVD). Data are presented as median (interquartile range [IQR]). RESULTS: Perfusion parameters and vessel density were significantly higher for the mucosa than the serosal microcirculation at the planned site for anastomosis or stoma. Mucosal MFI was 3.00 (IQR 3.00-3.00) compared to a serosal MFI of 2.75 (IQR 2.21-2.94), p = 0.03. The PPV was 99% (IQR 98-100) versus 92% (IQR 66-94), p = 0.01. The TVD was 16.77 mm/mm2 (IQR 13.04-18.01) versus 10.42 mm/mm2 (IQR 9.36-11.81), p = 0.01, and the PVD was 15.44 mm/mm2 (IQR 13.04-17.78) versus 9.02 mm/mm2 (IQR 6.43-9.43), p = 0.01. CONCLUSIONS: The mucosal microcirculation was preserved, while lower perfusion of the serosa was found at the planned anastomosis or stoma during surgery. Further research is needed to link our observations to the clinically relevant endpoint of anastomotic leakage.

Prevalence of Suspicious Ultrasound Features in Hot Thyroid Nodules.

Ultrasound for patients with hyperthyroidism and thyroid hot nodules is of limited value, given the high prevalence of suspicious findings, but may be useful for patients with high-risk factors.

A Perspective on Reagent Diversity and Non-covalent Binding of Reactive Carbonyl Species (RCS) and Effector Reagents in Non-enzymatic Glycation (NEG): Mechanistic Considerations and Implications for Future Research.

This perspective focuses on illustrating the underappreciated connections between reactive carbonyl species (RCS), initial binding in the nonenzymatic glycation (NEG) process, and nonenzymatic covalent protein modification (here termed NECPM). While glucose is the central species involved in NEG, recent studies indicate that the initially-bound glucose species in the NEG of human hemoglobin (HbA) and human serum albumin (HSA) are non-RCS ring-closed isomers. The ring-opened glucose, an RCS structure that reacts in the NEG process, is most likely generated from previously-bound ring-closed isomers undergoing concerted acid/base reactions while bound to protein. The generation of the glucose RCS can involve concomitantly-bound physiological species (e.g., inorganic phosphate, water, etc.); here termed effector reagents. Extant NEG schemes do not account for these recent findings. In addition, effector reagent reactions with glucose in the serum and erythrocyte cytosol can generate RCS (e.g., glyoxal, glyceraldehyde, etc.). Recent research has shown that these RCS covalently modify proteins in vivo via NECPM mechanisms. A general scheme that reflects both the reagent and mechanistic diversity that can lead to NEG and NECPM is presented here. A perspective that accounts for the relationships between RCS, NEG, and NECPM can facilitate the understanding of site selectivity, may help explain overall glycation rates, and may have implications for the clinical assessment/control of diabetes mellitus. In view of this perspective, concentrations of ribose, fructose, Pi, bicarbonate, counter ions, and the resulting RCS generated within intracellular and extracellular compartments may be of importance and of clinical relevance. Future research is also proposed.

Diabetes Management and Cardiovascular Risk: Are SGLT-2 Inhibitors the Safest?

For five millennia, diabetes management has focused on controlling blood sugar and efforts to minimize the complications of this disease have depended on normalizing glucose. Since the 1970's, however, a growing awareness of the adverse effect of hypoglycemic agents on cardiac health has led to an increasing focus on the effect of diabetes management on cardiac risk. This was brought into focus in the early years of this century with issues around rosiglitazone and resulted in the United States Food and Drug Administration, mandating that new drug applications for diabetes include documentation of no adverse effect on cardiac health. We have recently reported on the potential benefit of SGLT-2 inhibitors in terms of glucose control; recent data suggesting a specific cardiac benefit of this class of agent have obligated us to update our understanding of this class of drugs. This review focuses, in general, on the increasing awareness of the effects of diabetes medications on cardiac health and, more specifically, on newer agents, including incretin-based therapies and SGLT-2 inhibitors.

The Novel Role of the Kidney in Diabetes Management: Sodium-Glucose Co-Transporter 2 Inhibitors.

The global epidemic of diabetes continues to progress, despite efforts of public health agencies and health care systems to identify and treat impacted patients. Although lifestyle is the cornerstone of treatment, there is an array of pharmacologic agents now available, many in classes that did not exist a few years ago. In addition to insulin and its secretogogues, such as sulfonylureas, there are agents that improve insulin action, reduce gastric emptying, reduce glucagon concentrations, and sympathetic nervous system activity. A novel class recently entering the fray includes drugs that interfere with renal glucose reabsorption. These drugs, collectively called sodium-glucose co-transporter 2 (SGLT2) inhibitors, are available both as single agents and in various combinations. They work by promoting glycosuria and may have benefits that extend beyond lowering glycemia, such as weight loss and blood pressure reduction. This review focuses on several of these new agents and considers their efficacy and potential side effects. We address drugs approved for use in the United States at the time of this writing (March, 2015), but do not address recently approved combination agents.

Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer.

The phosphatidylinositol-3-kinase pathway plays an important role in proliferation, migration and survival in breast cancer and may play a role in resistance to endocrine therapy. Pathway activation occurs as a result of mutations in PIK3CA or loss of functional PTEN. Matched primary and recurrent samples from 120 breast cancer patients treated with endocrine therapy were profiled with a qPCR-based mutation assay covering eight mutational hotspots in PIK3CA. PTEN was assayed by immunohistochemistry. Samples were well characterized with respect to anatomic location of recurrence (metastatic nodal or local recurrence as opposed to contralateral or ipsilateral new primary cancers). In total, 43 % of patients had at least one PIK3CA mutation at diagnosis, and 41 % had a mutation at the time of recurrence. Only 8 % of patients with local recurrence, metastatic disease or progression on primary endocrine treatment changed their PIK3CA mutation status (four gains, two losses, total 76). The most common changes in PIK3CA mutation status were seen in patients who developed a new cancer either in the treated or contralateral breast (64 %, three gains, four losses, total 11). PIK3CA mutation status does not change in the majority of patients with breast cancer and the acquisition of mutations in PIK3CA is not responsible for the development of endocrine resistance. PTEN loss at diagnosis is associated with a significantly shorter time to progression compared with tumours in which PTEN was retained. These are the most comprehensive data currently available correlating PIK3CA status, site of recurrence and endocrine resistance.

Pharmacotherapy for the metabolic syndrome.

The Metabolic Syndrome (MetS) confers a greater risk for both diabetes and cardiovascular diseases. Both insulin resistance and low grade inflammation appear to be pivotal in the pathogenesis of this disorder. The cornerstone of treatment presently is therapeutic lifestyle change with the emphasis on weight loss by diet and exercise. It appears that the evidence base will support statins as first line therapy for the dyslipidemia. Also, there is a limited role for both bile acid sequestrants and fibrates in certain subgroup of patients. It would appear that the Angiotensin converting enzyme inhibitors (ACEs) and angiotensin II receptor blockers (ARBs) are the preferred therapies for hypertension but invariably a combination therapy with additional drugs is required keeping in mind that certain drugs can exacerbate the dyslipidemia and or glycemia of MetS. Whilst metformin appears to be the drug of choice for the dysglycemia, thiazolidinediones (TZDs) like pioglitazone can also be beneficial but recent concern about bladder cancer has resulted in its discontinuation in certain countries in Europe. Metformin therapy has been shown to prevent new onset MetS. Modulating the incretin axis can prove very fruitful. A drug targeting all 3 disorders would be ideal but to date does not exist.

Long-term maintenance of glucose control in veterans with type 2 diabetes mellitus using oral agents.

PURPOSE OF STUDY: The aim of this study was to evaluate long-term glycemic control in individuals with type 2 diabetes mellitus on oral hypoglycemic agents. METHODS: We identified the cohort of veterans prescribed hypoglycemic agents every year from July, 1992, through June, 2007 (n=191). Glycosylated hemoglobin (HbA1c) was used to assess glycemic control. Data are expressed as mean±standard deviation (SD); statistics are expressed by t-test and chi-squared. P<0.05 was considered significant. RESULTS: In the first year, 96 of the select group of 191 veterans identified above received oral agents only (OAO), 74 insulin only, and 21 both insulin and oral agents. Fifteen years later, 59 were OAO, 78 insulin only, and 54 both. Six patients receiving insulin in 1992-1993 were OAO-treated in 2006-2007. In the subgroup on OAO both at baseline and at the end (n=53), HbA1c decreased from 7.89±1.21 to 7.09±1.13 (P<0.001). These veterans were older at baseline (62.4±6.2) and leaner at the 15-year follow-up [body mass index (BMI) 28.1±4.9] than those who received insulin in 2006-2007 (n=43; age=57.9±9.6; BMI=32.3±7.9; P<0.05 and 0.005, respectively). Patients in the stable OAO group (n=53) were 74.0% Caucasian, compared to 51.2% in former-OAO [n=43; P<0.05 (chi-squared)]. CONCLUSIONS: Over half (n=53; 55%) of patients originally in the OAO group remained so 15 years later. These stable patients were in better glycemic control, both at baseline and follow-up, less obese, older, and more likely to be Caucasian, than those who eventually received insulin. Currently used oral agents often maintain, or even improve, glucose control, over 2 decades after diagnosis of diabetes mellitus.

Resistant hypertension and undiagnosed primary hyperaldosteronism detected by use of a computerized database.

A pharmacy database was used to identify patients with resistant hypertension who could then be tested for the presence of primary hyperaldosteronism. Inclusion criteria were: (1) resistant hypertension defined as uncontrolled hypertension and use of 3 antihypertensive medication classes or ≥ 4 antihypertensive classes regardless of blood pressure; (2) low or normal potassium levels (≤ 4.9 mEq/L); and (3) continuous health care from October 1, 2008, to February 28, 2009. Exclusion criteria were: (1) past or current use of an aldosterone antagonist, or (2) a medication possession ratio (adherence) <80% for any antihypertensive drug. Hyperaldosteronism was classified as an aldosterone/renin ratio (ARR) ≥ 30. Using the computer, 746 patients were identified who met criteria. After manual chart review to verify inclusion and exclusion criteria, 333 patients remained. Of 184 individuals in whom an ARR was obtained, 39 (21.2%) had a ratio of ≥ 30. A computer database is useful to identify patients with resistant hypertension and those who may have primary aldosteronism.

The ACCORD Study: the devil is in the details.

Abstract The Action to Control Cardiovascular Risks in Diabetes Study (ACCORD) was a well-designed trial of 10,251 patients with type 2 diabetes mellitus that studied the effects of tight control of blood sugar, hypertension, and lipids. Disappointingly, as compared with standard treatment, the use of intensive therapy to target normal glycosylated hemoglobin (HbA1c) levels, tight lipid control by adding fenofibrate to a statin and aggressive blood pressure treatment with a systolic blood pressure goal of 120 mmHg did not significantly reduce major cardiovascular events. The authors compare these results to other studies of the same issues and speculate about reasons for the lack of benefit in ACCORD.

Hypertensive treatment in patients with metabolic syndrome.

The prevalence of obesity, hypertension, and type 2 diabetes mellitus-in other words, the metabolic syndrome-is increasing in the United States. In this setting, it is important to understand the effects of antihypertensives on parameters of the metabolic syndrome in addition to glucose metabolism. Here the authors review pertinent clinical studies.

The effect of body mass index on fasting blood glucose and development of diabetes mellitus after initiation of extended-release niacin.

BACKGROUND: Niacin increases blood glucose, but whether the degree of increase is associated with increasing body mass index (BMI) is unknown. We evaluated the effect of extended-release niacin initiation on fasting plasma glucose (FPG) and the development of new-onset diabetes mellitus (DM) in relation to body mass index (kg/m(2)) in nondiabetic patients. METHODS: This retrospective observational study used data from six facilities within a geographical region of the Department of Veterans Affairs (VA). Patients included were 18 years of age or older and on a stable extended-release niacin dose (minimum 100 days) of at least 250 mg/day between January, 2001, and April, 2007. Patients were excluded if they were new to the VA, on corticosteroids or insulin, if medication adherence was <80%, or if they met criteria for DM. RESULTS: A total of 811 nondiabetic patients taking extended-release niacin initiation were studied. FPG after niacin initiation was stastically significantly correlated with increasing BMI (P < 0.001, R = 0.144 Pearson correlation coefficient). Factors independently associated with change in FPG using multiple linear regression were BMI (P = 0.043), baseline average glucose (P < 0.001), and baseline average triglycerides (P = 0.037). Of all patients started on niacin, 220 (27.1%) patients developed DM after niacin initiation. BMI, (P = 0.002) and baseline average glucose (P < 0.001) were independent predictors of the development of new-onset DM (logistic regression analysis). CONCLUSIONS: We found an association between increasing BMI and increasing FPG and diagnosis of new-onset DM after initiation of extended-release niacin initiation. This suggests that extended-release niacin may increase FPG into the diabetic range, especially for obese patients.

Computer-based screening of veterans for metabolic syndrome.

BACKGROUND: The worldwide obesity epidemic has focused attention on the prevalence of the metabolic syndrome, which is greater than previously believed. However, estimates of its overall prevalence vary widely. We wished to ascertain the prevalence of metabolic syndrome in the Veteran Affairs Northern California Health Care System (VANCHCS). METHODS: We used the VA computerized clinical database and modified Adult Treatment Panel III (ATP III) criteria of fasting blood glucose (FBG) >or=110 mg/dL, blood pressure >or=130/>or=85, triglyceride >or=150 mg/dL, high-density lipoprotein cholesterol (HDL-C) <40 mg/dL (men) or <50 mg/dL (women), but body mass index (BMI) >or=30 in lieu of waist circumference >102 cm (40 inches) for men and 88 cm (35 inches) for women. We also accepted current pharmacotherapy for diabetes as qualifying for elevated fasting blood sugar (FBS); current therapy with niacin, gemfibrozil, or fenofibrate for elevated triglyceride concentrations; and recent use of multiple International Classification of Diseases, 9(th) Revision (ICD-9) codes for hypertension for elevated blood pressure. RESULTS: We examined all clinical records for veterans registered in VANCHCS who filled any prescription between July 1, 2004, and June 30, 2005 (n = 51,026). Their average age was 63 years; 93% were male. In all 25% (n = 13,010) were diagnosed as having metabolic syndrome by meeting at least 3 of the above 5 criteria. Because only 60% (n = 30,727) of the population had data for 3 or more criteria, the actual percent with metabolic syndrome is probably substantially higher. CONCLUSIONS: Over one quarter of veterans in the VANCHCS may have metabolic syndrome based on our modified ATP III criteria. We urge screening more veterans with fasting laboratory testing. Computerized screening of a large clinical database can provide an effective strategy to aid clinicians in identifying more patients at risk for cardiovascular disease.

Smokeless nicotine exposure has no lasting effect on fasting or postglucose circulation leptin in young rats.

BACKGROUND: Nicotine exposure has been associated with weight loss and reduced weight gain. Previously, we have reported that nicotine exposure in rats is associated with reduced weight gain, unless diets are rigidly controlled. Leptin, a hormone released by adipose tissue, is believed to have appetite suppressant effects. We used a smokeless tobacco model to study leptin responses to nicotine or placebo treatment. METHODS: We studied 6-week-old male and female Sprague-Dawley rats, and implanted 50 mg of nicotine or placebo pellets. Weight gain was controlled by chow restriction in all four groups of rats. Systolic blood pressure was measured noninvasively, and glucose, insulin, free fatty acid, and leptin responses to an oral glucose load were determined at 8.5 weeks of age. RESULTS: Males were generally heavier than females, both before and after nicotine or placebo placement; there was no difference in weight between nicotine and placebo groups for each sex. Blood pressure was slightly, but not significantly, increased by nicotine treatment. Glucose, insulin, free fatty acid, and leptin responses to glucose were essentially unaffected by nicotine treatment. CONCLUSIONS: In summary, smokeless nicotine at this dose has no significant effect on fasting or postglucose leptin values in sexually immature male and female rats.