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.

Fatty Pancreas: An Underappreciated Intersection of the Metabolic Profile and Pancreatic Adenocarcinoma.

Although the prevalence of pancreatic cancer is increasing, treatment strategies remain limited, and success is rare. A growing body of evidence links pancreatic cancer to pre-existing metabolic disorders, including, but not limited to, type 2 diabetes mellitus and obesity. An infrequently described finding, fatty pancreas, initially described in the context of obesity in the early 20th century, appears to be at the crossroads of type 2 diabetes and obesity on the one hand, and the development of pancreatic cancer on the other. Similarly, other conditions of the pancreas, such as intrapancreatic mucinous neoplasms, also seem to be related to diabetes while increasing the subsequent risk of pancreatic cancer. In this review, the author explores the diagnostic criteria for, and prevalence of, fatty pancreas and the potential link to other pancreatic conditions, including pancreatic cancer. Diagnostic limitations, and areas of controversy are also addressed, as are potential therapeutic approaches to fatty pancreas intended to reduce the subsequent risk of pancreatic cancer.

Assessing the Continuation of Glucagon-Like Peptide-1 Receptor Agonists When Weight and HBA1C Are Not Reduced.

Background: Glucagon-like peptide-1 agonists (GLP-1) reportedly lower HbA1c and promote weight reduction and improve cardiovascular outcomes. The primary objective of this study was to evaluate the use of GLP-1 agents in patients and changes in HbA1c, weight loss, blood pressure, and lipoid profiles. Methods: Patient information was extracted from a regional Veteran Affairs data mart. Patients were included if they had prescriptions for at least 90 days of a GLP-1 between April 1, 2005, and December 1, 2016, and HbA1Cs and weights at both baseline and within first 15 months of therapy. Blood pressure and lipids were also measured. Pearson's correlation and multiple regression analysis were used. Results: Three hundred twenty-two patients met inclusion criteria. Average HbA1c decreased by 0.81% and weight by 4.4 kg. At 1 year, 160 patients had both weight and HbA1c measured, and of those, 92 (58%) patients had HbA1c reduction of at least 0.5% and 94 (59%) patients had <-2 kg change in weight. Fifty-seven (36%) patients met both of those outcomes. Veterans who met both weight and HbA1c outcomes were slightly, but significantly, older than those who did not meet both. No correlation was found between weight and HbA1c change at each quarter (P > 0.05); however, weight change was correlated with systolic blood pressure change (P = 0.03). Multiple regression for meeting weight and HbA1c target outcomes, and changes at quarters 1-3, all correlated to success at 1 year (P < 0.05). Conclusions: Weight change was independent of HbA1c changes in patients receiving GLP-1s for diabetes control. Weight loss was associated with decreases in systolic BP.

The Lived Experience of Older Adults With Type 2 Diabetes Mellitus and Diabetes-Related Distress.

An older, more diverse population and longer lifespans are major contributors to the anticipated tripling of diabetes prevalence by 2050. Diabetes-related distress affects up to 40% of people with diabetes and may be a higher risk for older adults due to greater prevalence of comorbidities. The objective of the current phenomenological study was to describe how diabetes-related distress might be uniquely experienced by older adults (age ≥65) with type 2 diabetes mellitus (T2DM). Interpretive phenomenology guided the research design and analysis. Everyday life experiences of living with T2DM and elevated diabetes distress were investigated with interpretive interviews. The most prevalent lived experiences were strained relationships with health care providers, guilt, fear, loneliness, and forgetfulness. These experiences created challenges in managing diabetes and increased diabetes-related distress. Improving knowledge regarding the lived experience of older adults with diabetes-related distress may allow health care providers to tailor treatment to this population, thus improving outcomes. [Journal of Gerontological Nursing, 46(3), 37-44.].

Symptom Experience of Older Adults With Type 2 Diabetes and Diabetes-Related Distress.

BACKGROUND: An older, more diverse population and longer life spans are major contributors to the anticipated tripling of Type 2 diabetes prevalence by 2050. Diabetes-related distress affects up to 40% of people diagnosed with Type 2 diabetes and may be a greater risk for older adults due to greater prevalence of comorbidities. OBJECTIVE: The objective of this phenomenological study was to describe how diabetes-related distress in older adults (≥65 years) with Type 2 diabetes might be uniquely experienced. METHODS: Participants were recruited using convenience sampling and snowball sampling. Interpretive phenomenology guided the research design and analysis. With interpretive interviews, we investigated the everyday health, symptoms, and life experiences of living with Type 2 diabetes and elevated diabetes distress. RESULTS: Among the older adults in this study, the most prevalent symptoms were fatigue, hypoglycemia, diarrhea, pain, loss of balance, and falling. These diabetes-related symptoms led to substantial loss of independence, decreased quality of life, and constrained social lives due to restricted activities. DISCUSSION: Diabetes-related distress presents with some unique symptoms and responses in older adults. Improving knowledge regarding the symptom experience of older adults with diabetes-related distress may allow healthcare providers to tailor treatment and thus improve outcomes for older adults struggling with diabetes.

Nonglycemic Effects of GLP-1 Agonists: From a Starling to Lizards to People.

With the approval of exenatide in 2005, physicians had a new class of hypoglycemic agents available for the treatment of type 2 diabetes-the glucagon-like peptide-1 receptor agonists (or GLP-1 receptor agonists). As of this writing, there are seven drugs in this class available in the United States. In addition to demonstrating either cardiovascular risk neutrality or overt benefit, as now mandated by the United States Food and Drug Administration (FDA), many of these drugs have other, unexpected actions. It is our goal to outline these actions, some beneficial, some not. We have reviewed English-language articles in this area, not for an exhaustive study, but rather a broad search to define current understanding and perhaps generate further investigation.

The Effect of Proton Pump Inhibitors on Glycemic Control in Patients with Type 2 Diabetes.

Background: Type 2 diabetes patients have decreased pancreatic beta cell mass with a decline in beta cell function. Gastrin has increased beta cell proliferation in vitro and in animal studies. High gastric acid levels inhibit gastrin secretion. Proton pump inhibitors (PPIs) lower gastric acid, subsequently increasing gastrin levels. This may stimulate beta cell proliferation and function, and improve glycemic control. Studies with small numbers of type 2 diabetes patients have shown a slightly lower A1C in those taking PPI versus non-PPI users. Methods: This study was a retrospective multicenter electronic data analysis using data obtained from health care facilities within Veterans Integrated Service Network (VISN) 21. Patients were included if they had established care within VISN 21 and had type 2 diabetes with an A1C > 6.5%, were started on a PPI concurrently with stable doses of metformin or sulfonylurea (SFU) monotherapy, had at least two documented A1C values, and had a medication possession ratio >80% for metformin, SFU, or a PPI. Veterans were excluded if they were using insulin, combination antihyperglycemic therapy, or oral corticosteroids. A control group not using PPI was also identified. Results: There was a statistically significant decrease in A1C within each group. However, there was no statistically significant difference between the PPI and control group in the post-A1C. Conclusion: In patients with type 2 diabetes, A1C improved in both groups, but PPI addition did not affect glycemic control. Future randomized controlled trials are needed to determine the value of PPIs as a treatment option for patients with type 2 diabetes.

Adherence to and Persistence With Statin Therapy in a Veteran Population.

BACKGROUND: A relative cardiovascular risk reduction of 25% to 35% has been reported in patients starting a statin for elevated cholesterol; yet many patients fail to consistently take these medications as directed. OBJECTIVE: To evaluate factors affecting adherence and persistence with statin therapy. METHODS: This retrospective study analyzed data from a Veterans Affairs database of facilities west of the Rocky Mountains. Patient demographics, co-morbidities, and prescription information was collected for individuals newly prescribed a statin between July 1, 2007, and December 31, 2012. Adherence was determined using the medication possession ratio (MPR). Persistence was defined as the time from initiation of therapy until a refill gap of 135 days or greater occurred. RESULTS: Of 164 687 unique patients, overall adherence to statins a mean MPR of 0.843. Approximately 63% of patients were persistent with statin therapy 675 days after statin initiation. Patients prescribed pravastatin, atorvastatin, lovastatin, and rosuvastatin and those who took more than 1 different statin during the follow-up period had statistically significantly higher rates of adherence than those prescribed simvastatin. Older patients and those with a greater number of active prescriptions were found to be more adherent to statin medications. Patients with hypertension were more adherent to a statin, and those with diabetes mellitus and/or posttraumatic stress disorder (PTSD) were less adherent. Conclusion and Relevance: In veterans, overall statin adherence was excellent. Certain populations may benefit from interventions targeted at improving statin adherence, including younger veterans, those prescribed fewer medications, those taking simvastatin, and veterans with PTSD or diabetes mellitus.

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.

El metabolismo de la glucosa en pacientes con hipertensión arterial / Glucose metabolism in hypertension patients

Thiazide diuretics (TD) are recommended as first-line therapy in uncomplicated hypertension by several professional organizations. However, they also may pose a risk of glucose metabolism abnormalities in certain individuals. Early studies showed TD cause a small increase in fasting glucose. These effects may be related to exacerbation of insulin resistance as insulin blood levels increased. It could be postulated that long-term use may result in a higher risk of developing diabetes. This was not seen in the Systolic Hypertension in the Elderly study which used low doses of chlorthalidone but an increase in the odds of developing diabetes was demonstrated for chlorthalidone in comparison to lisinopril or amlodipine in the ALLHAT study. Nonetheless, in ALLHAT there was no increased risk of adverse cardiovascular outcomes. In addition, use of chlorthalidone in the ALLHAT study in patients with pre-existing diabetes maintained the same advantage in lower stroke rate versus lisinopril and lower heart failure rate versus amlodipine or lisinopril. Other factors that may play a role in thiazide-induced glucose elevation are potassium levels and weight. In a meta-analysis of 59 trials a correlation existed for lower potassium levels and higher fasting glucose. pidemiological studies suggest that elevated BMI and the level of pre-thiazide fasting glucose predict glucose elevation and new onset diabetes after thiazide therapy. Patients with a BMI over 32.3 kg/m2 had a 6.5% risk of developing diabetes. Whether co-administration of a thiazide diuretic with other classes of antihypertensives modulates the glucose alteration remains unknown. Studies suggest combination with valsartan may reduce the effect perhaps by conserving potassium. Practical implications of these observations would suggest reserving thiazide diuretics to later stages in treatment for patients who are obese, particularly if they have fasting blood glucoses in the pre-diabetic range. However, for the majority of patients thiazide diuretics remain an excellent choice given their long track record of safety and beneficial long-term cardiovascular outcomes

Los diuréticos tiazídicos (DT) se recomiendan como tratamiento de primera línea para la hipertensión no complicada, por varias organizaciones profesionales. Sin embargo, también pueden suponer un riesgo de alteraciones del metabolismo de la glucosa en ciertos individuos. Los primeros estudios mostraron que los DT causan un pequeño aumento de la glucemia en ayunas. Estos efectos pueden estar relacionados con la exacerbación de la resistencia a la insulina y los niveles de insulina plasmáticos están incrementados. Se podría postular que el uso a largo plazo puede resultar en un mayor riesgo de presentar diabetes. Esto no se observó en el estudio Systolic Hypertension in the Elderly, realizado con adultos mayores que utilizaban bajas dosis de clortalidona; sin embargo, un aumento en las probabilidades de contraer diabetes fue demostrado por el uso de clortalidona en comparación con lisinopril y amlodipina en el estudio ALLHAT. No obstante, en el ALLHAT no hubo mayor riesgo de eventos cardiovasculares adversos. Además, el uso de clortalidona en el estudio ALLHAT en pacientes con diabetes preexistente mantuvo la misma ventaja en la baja tasa de accidentes cerebrovasculares, en comparación con lisinopril, y la menor tasa de paro cardíaco, en comparación con amlodipina o lisinopril. Otros factores que pueden desempeñar un papel en la elevación de la glucosa inducida por tiazidas son los niveles de potasio y el peso del paciente. En un metanálisis de 59 ensayos se encontró una correlación entre los niveles de potasio más bajos y los niveles más elevados de glucemia en ayunas. Los estudios epidemiológicos sugieren que el índice de masa corporal (IMC) elevado y el nivel de la glucemia previo al tratamiento con tiazidas pueden predecir la elevación de la glucosa y la diabetes de nueva aparición después de la terapia con tiazidas. Los pacientes con un IMC superior a 32.3 kg/m2 tenían un riesgo de 6.5% de presentar diabetes. Se desconoce aún si la administración de un diurético tiazídico con otras clases de antihipertensivos modula la alteración de la glucosa. Los estudios sugieren que la combinación con valsartán puede reducir el efecto, quizá mediante la conservación del potasio. Las repercusiones prácticas de estas observaciones sugieren reservar los diuréticos tiazídicos para etapas posteriores del tratamiento para los pacientes que son obesos, sobre todo si han presentado glucemia en ayunas en el rango de prediabetes. Sin embargo, para la mayoría de los pacientes, los diuréticos tiazídicos siguen siendo una excelente opción dado su largo historial de seguridad y los resultados cardiovasculares beneficiosos a largo plazo

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.

Evaluating Vitamin D Repletion Regimens and Effects in Veteran Patients.

BACKGROUND: There are wide variations in recommended dosing for vitamin D repletion. The identification of specific dosing thresholds to optimize repletion of 25-hydroxyvitamin D3 (also known as 25(OH)D) may help narrow the wide spectrum of vitamin D dosing. OBJECTIVE: The primary objective of this study was to evaluate vitamin D treatment regimens and their dose response effect on vitamin D serum levels. Secondary outcomes include evaluation of the frequency of monitoring vitamin D serum levels and prescription adherence. METHODS: This was a multicenter, retrospective data extraction analysis conducted in patients who initiated monotherapy of ergocalciferol and cholecalciferol between January 1, 2005 and December 31, 2010. Following vitamin D therapy initiation, changes in laboratory values, frequency of laboratory monitoring, and prescription adherence were assessed. Ergocalciferol and cholecalciferol groups were separately organized into quartiles to identify dosing ranges that had the most impact on changes in 25(OH)D laboratory values. RESULTS: There were 2272 and 4140 monotherapy patients in the ergocalciferol and cholecalciferol groups, respectively. Cholecalciferol mean doses between 600 and 1100 IU had similar changes in 25(OH)D ranging from 8 to 9.1 ng/mL. Cholecalciferol mean doses of 2700 IU had 12.7 ng/mL 25(OH)D increase (P < 0.05). Ergocalciferol at mean doses of 11 000 IU had a 19.9 ng/mL increase of 25(OH)D (P < 0.05). At baseline 25(OH)D levels less than 15 ng/mL, 90% of subjects reached a therapeutic 25(OH)D level with a cumulative 300 000 IU cholecalciferol dose. Adherence, calculated by medication possession ratio, was greater with cholecalciferol than ergocalciferol (87% compared with 68%). CONCLUSIONS: Lower vitamin D dose ranges had a comparable effect on 25(OH)D change. Higher doses can produce higher levels, but the relationship is not linear.

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.

Comparing fracture absolute risk assessment (FARA) tools: an osteoporosis clinical informatics tool to improve identification and care of men at high risk of first fracture.

BACKGROUND: Fracture absolute risk assessment (FARA) is recommended for guiding osteoporosis treatment decisions in males. The best strategy for applying FARA in the clinic setting is not known. OBJECTIVES: We compared 2 FARA tools for use with electronic health records (EHRs) to determine which would more accurately identify patients known to be high risk for fracture. Tools evaluated were an adaptation of the World Health Organization's Fracture Risk Assessment Tool used with electronic data (eFRAX) and the Veterans Affairs (VA)-based tool, VA-FARA. METHODS: We compared accuracies of VA-FARA and eFRAX for correctly classifying male veterans who fractured and who were seen in the VA's Sierra Pacific Network in 2002-2013. We then matched those cases to nonfracture controls to compare odds of fracture in patients classified as high risk by either tool. RESULTS: Among 8740 patients, the mean (SD) age was 67.0 (11.1) years. Based on risk factors present in the EHR, VA-FARA correctly classified 40.1% of fracture patients as high risk (33.0% and 34.6% for hip and any major fracture, respectively); eFRAX classified 17.4% correctly (17.4% for hip and 0.2% for any major fracture). Compared with non-high-risk patients, those classified as high risk by VA-FARA were 35% more likely to fracture (95% CI = 23%-47%; P < 0.01) compared with 17% for eFRAX (95% CI = 5%-32%; P < 0.01). CONCLUSIONS: VA-FARA is more predictive of first fracture than eFRAX using EHR data. Decision support tools based on VA-FARA may improve early identification and care of men at risk.

Hypothalamic-Pituitary-Adrenal Suppression and Iatrogenic Cushing's Syndrome as a Complication of Epidural Steroid Injections.

Epidural steroid injections are well accepted as a treatment for radicular back pain in appropriate candidates. While overall incidence of systemic side effects has not been well established, at least five biochemically proven cases of iatrogenic Cushing's Syndrome have been reported as complications of epidural steroid treatment. We present an additional case of iatrogenic Cushing's Syndrome and adrenal suppression in a middle-aged woman who received three epidural steroid injections over a four-month period. We review this case in the context of previous cases and discuss diagnostic and management issues.