Joshua J. Neumiller

Nutrition Therapy Recommendations for the Management of Adults With Diabetes

There is no standard meal plan or eating pattern that works universally for all people with diabetes. In order to be effective, nutrition therapy should be individualized for each patient/client based on his or her individual health goals; personal and cultural preferences; health literacy and numeracy; access to healthful choices; and readiness, willingness, and ability to change. Nutrition interventions should emphasize a variety of minimally processed nutrient dense foods in appropriate portion sizes as part of a healthful eating pattern and provide the individual with diabetes with practical tools for day-to-day food plan and behavior change that can be maintained over the long term.

Diabetic Kidney Disease: A Report From an ADA Consensus Conference

The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly

Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus.

25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.

Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.

The kidney plays a major role in glucose homeostasis because of its role in gluconeogenesis and the glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. Approximately 180 g of glucose is filtered daily in the glomeruli of a normal healthy adult. Typically, all of this glucose is reabsorbed with <1% being excreted in the urine. The transport of glucose from the tubule into the tubular epithelial cells is accomplished by sodium-glucose co-transporters (SGLTs). SGLTs encompass a family of membrane proteins that are responsible for the transport of glucose, amino acids, vitamins, ions and osmolytes across the brush-border membrane of proximal renal tubules as well as the intestinal epithelium. SGLT2 is a high-capacity, low-affinity transporter expressed chiefly in the kidney. It accounts for approximately 90% of glucose reabsorption in the kidney and has thus become the focus of a great deal of interest in the field of diabetes mellitus.SGLT2 inhibitors block the reabsorption of filtered glucose leading to glucosuria. This mechanism of action holds potential promise for patients with type 2 diabetes mellitus (T2DM) in terms of improvements in glycaemic control. In addition, the glucosuria associated with SGLT2 inhibition is associated with caloric loss, thus providing a potential benefit of weight loss. Dapagliflozin is the SGLT2 inhibitor with the most clinical data available to date, with other SGLT2 inhibitors currently in the developmental pipeline. Dapagliflozin has demonstrated sustained, dose-dependent glucosuria over 24 hours with once-daily dosing in clinical trials. Although long-term safety data are lacking, studies to date have generally found dapagliflozin to be safe and well tolerated. Concerns related to SGLT2 inhibition include the fact that by their very nature they cause glucose elevation in the urine that can theoretically lead to urinary tract and genital infections, electrolyte imbalances and increased urinary frequency. Although studies to date have been promising in terms of these and other concerns, longer-term studies evaluating the usual safety and efficacy outcomes will need to be conducted. Similarly, head-to-head comparator trials are needed to determine the role of SGLT2 inhibitors in relation to the many other therapeutic options available for the treatment of T2DM. If significant reductions in haemoglobin Alc are associated with SGLT2 inhibitor therapy, and these agents are determined to be safe and well tolerated in the long term, they could become a major breakthrough in the T2DM treatment armamentarium.

Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors

Type 2 diabetes mellitus traditionally has been characterized by insulin resistance and β‐cell dysfunction, leading to hyperglycemia and eventual micro‐ and macrovascular complications. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a relatively new class of drugs available for the management of type 2 diabetes. In order to provide a comprehensive evaluation and comparison of the pharmacology, pharmacokinetics, efficacy, and safety of the DPP‐4 inhibitors—sitagliptin, vildagliptin, saxagliptin, and alogliptin—in the treatment of type 2 diabetes, we conducted a MEDLINE search (1966–July 2009) for pertinent English‐language articles. Abstracts of the annual meetings of the American Diabetes Association and European Association for the Study of Diabetes from 2005–2009 were also searched. As a drug class, the DPP‐4 inhibitors have become widely accepted in clinical practice because of their low risk of hypoglycemia, favorable adverse‐effect profile, and once‐daily dosing. They are weight neutral (do not cause weight gain or loss) and appear to decrease β‐cell apoptosis and increase β‐cell survival. Because clinical studies directly comparing agents from this class have not, to our knowledge, been conducted, making comparisons in terms of efficacy and safety will become difficult for clinicians as more agents become available. Based on information from preclinical, clinical, and postmarketing data, there does not appear to be a compelling advantage of one DPP‐4 inhibitor over another in terms of efficacy, safety, or ease of clinical use. Although theoretical advantages exist for agents with a higher specificity for DPP‐4 inhibition versus inhibition of other isoenzymes associated with toxicity comparative studies and/or increased clinical experience with this class of drug will determine the clinical advantages, if any, of one agent over another.

Pharmacologic management of the older patient with type 2 diabetes mellitus

OBJECTIVE To review the pharmacology (absorption, metabolism, distribution, elimination, and contraindications) of incretin-based agents currently available and in regulatory review for the treatment of patients with type 2 diabetes. DATA SOURCES Medline search of all relevant clinical and review articles. STUDY SELECTION English-language articles pertinent to the pharmacology, pharmacodynamics, pharmacokinetics, efficacy, and safety of glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors were reviewed for relevance. DATA EXTRACTION Data pertinent to the pharmacology, pharmacodynamics, pharmacokinetics, efficacy, and safety of GLP-1 agonists and DPP-4 inhibitors were extracted and used. DATA SYNTHESIS Incretin hormones are secreted from the gastrointestinal tract following meal ingestion, the two most important of which are glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. Patients with type 2 diabetes have an impaired response to GIP, while intravenous GLP-1 has been shown to increase insulin secretion in response to elevated glucose levels. Incretin-based agents include GLP-1 receptor agonists, which mimic endogenous GLP-1, and DPP-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, alogliptin), which inhibit the breakdown of endogenous incretin hormones. GLP-1 receptor agonists stimulate insulin secretion in a glucose-dependent manner and suppress glucagon secretion with a low risk of hypoglycemia. The GLP-1 receptor agonists are further differentiated as either human analogues (e.g., liraglutide) or synthetic exendin-based mimetics (e.g., exenatide). These agents delay gastric emptying and may beneficially affect satiety and are thus associated with weight reduction. CONCLUSION GLP-1 receptor agonists and DPP-4 inhibitors facilitate therapy intensification and achievement of established glycemic goals. They enhance postprandial and fasting glycemic control, and use may improve beta-cell function and possibly preserve beta-cell mass. GLP-1 receptor agonists may also have favorable effects on blood pressure. They may be introduced as adjuncts to ongoing therapy with conventional agents with a potential benefit of slowing the progression of type 2 diabetes.

Clinical review of treatment options for select nonmotor symptoms of Parkinson's disease

BACKGROUND Pharmacologic options for the treatment of elderly patients with type 2 diabetes mellitus (T2DM) are the same as in younger adults; however, treatment considerations differ in the elderly due to changes in renal and hepatic function, life expectancy, and various other clinical and practical considerations. OBJECTIVE This article discusses geriatric considerations in the pharmacologic management of T2DM and reviews the potential clinical advantages and disadvantages of pharmacologic agents currently available for the treatment of T2DM, including oral and injectable medications. METHODS A search of MEDLINE was conducted for articles published in English between January 1966 and September 2009 using the terms type 2 diabetes mellitus, elderly, geriatric, treatment, insulin, metformin, sulfonylurea, thiazolidinedione, alpha-glucosidase inhibitor, meglitinide, DPP-4 inhibitor, colesevelam, exenatide, and pramlintide. Meta-analyses, randomized controlled trials of pharmacologic treatment, and evidence-based reviews and/or expert opinions regarding the treatment of T2DM in the elderly were selected for review. RESULTS In overweight patients, metformin has been associated with reductions in risk for all-cause mortality and stroke compared with insulin and sulfonylureas. Older patients who are frail, anorexic, or underweight and those with congestive heart failure (CHF), renal or hepatic insufficiency, or dehydration may not be appropriate candidates for metformin therapy. The substantial risk of hypoglycemia with insulin secretagogues is increased by 36% in the elderly compared with younger adults; however, this risk is counterbalanced by the extensive clinical experience with these agents in the geriatric population. Thiazolidinediones should generally be avoided in patients with CHF and are absolutely contraindicated in patients with class II-IV heart failure. They have been associated with peripheral edema, as well as with decreases in bone mineral density in women. There is limited information on the use of dipeptidyl peptidase-4 inhibitors in the elderly, although dose adjustment is required in patients with renal compromise. In practice, substantial gastrointestinal adverse effects limit the use of alpha-glucosidase inhibitors in older patients. Colesevelam is associated with numerous drug interactions and can cause new or worsening constipation. There are limited data on the use of exenatide in the elderly. It may be beneficial in older patients with limited mobility who could benefit from weight loss, whereas it may not be a good option for frail, underweight adults. Use of exenatide is not recommended in patients with a creatinine clearance <30 mL/min. Given the increased monitoring required to avoid hypoglycemic events with pramlintide, this agent should be used with caution in older adults, particularly the frail elderly. Most patients with T2DM eventually require insulin; however, due to the risk of hypoglycemia and related morbidity, careful use of insulin is warranted in the geriatric population. CONCLUSIONS Overall, there is a scarcity of data regarding the use of pharmacologic agents in older adults with T2DM, and clinical guidance is largely based on data obtained from younger populations. The selection of appropriate drug regimens for these patients remains challenging.

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

BACKGROUND Parkinsons disease (PD) is associated with a host of nonmotor symptoms, including psychosis, cognitive impairment, depression, sleep disturbance, swallowing disorders, gastrointestinal symptoms, and autonomic dysfunction. The nonmotor symptoms of PD have the potential to be more debilitating than the motor features of the disorder. OBJECTIVE The aim of this article was to review treatment options for the nonmotor manifestations of PD, including pharmacologic and nonpharmacologic interventions. METHODS The PubMed and MEDLINE databases were searched for articles published in English between January 1966 and April 2010, using the terms Parkinsons disease, nonmotor, psychosis, hallucination, antipsychotic, cognitive impairment, dementia, depression, sleep disturbance, sleepiness, REM (rapid eye movement) sleep behavior disorder, dysphagia, swallowing disorder, sialorrhea, gastrointestinal, constipation, autonomic dysfunction, orthostatic hypotension, gastroparesis, erectile dysfunction, sexual dysfunction, and urinary dysfunction. Articles were selected for review if they were randomized controlled trials (RCTs), meta-analyses, or evidence-based reviews of treatment of patients with PD, and/or expert opinion regarding the treatment of nonmotor symptoms of PD. RESULTS A total of 148 articles, including RCTs, meta-analyses, and evidence-based reviews, were included in this review. The treatment of hallucinations or psychosis in PD should include a stepwise reduction in medications for motor symptoms, followed by the use of quetiapine or clozapine. Dementia may be treated with acetylcholinesterase inhibitors. Evidence is lacking concerning the optimal pharmacologic treatment for depression in PD, with expert opinions indicating selective serotonin reuptake inhibitors as the antidepressants of choice. However, the largest study to date found nortriptyline therapy to be efficacious compared with placebo, whereas paroxetine controlled release was not. A variety of sleep disturbances may plague a person with PD, and treatment must be individualized to the patients specific sleep disturbance pattern and contributing factors. Swallowing disorders may lead to aspiration and pneumonia, and patients with dysphagia should be referred to a speech therapist for further evaluation and treatment. Orthostasis may be treated with nonpharmacologic interventions as well as pharmacologic treatments (eg, fludrocortisone, midodrine, indomethacin). Other autonomic symptoms are managed in a manner similar to that in patients without PD, although careful attention must be aimed at avoiding dopamine-blocking therapies in the treatment of gastrointestinal dysfunction and gastroparesis. CONCLUSIONS Various pharmacologic and nonpharmacologic strategies are available for the management of the nonmotor symptoms of PD. The challenges associated with nonmotor symptoms must not be forgotten in light of the motor symptoms of PD, and treatment of nonmotor symptoms should be encouraged.

Liraglutide: A Once-Daily Incretin Mimetic for the Treatment of Type 2 Diabetes Mellitus

The response of CD8+ T cells to influenza virus is very sensitive to modulation by aryl hydrocarbon receptor (AhR) agonists; however, the mechanism underlying AhR-mediated alterations in CD8+ T cell function remains unclear. Moreover, very little is known regarding how AhR activation affects anamnestic CD8+ T cell responses. In this study, we analyzed how AhR activation by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the in vivo distribution and frequency of CD8+ T cells specific for three different influenza A virus epitopes during and after the resolution of a primary infection. We then determined the effects of TCDD on the expansion of virus-specific memory CD8+ T cells during recall challenge. Adoptive transfer of AhR-null CD8+ T cells into congenic AhR+/+ recipients, and the generation of CD45.2AhR−/−→CD45.1AhR+/+ chimeric mice demonstrate that AhR-regulated events within hemopoietic cells, but not directly within CD8+ T cells, underlie suppressed expansion of virus-specific CD8+ T cells during primary infection. Using a dual-adoptive transfer approach, we directly compared the responsiveness of virus-specific memory CD8+ T cells created in the presence or absence of TCDD, which revealed that despite profound suppression of the primary response to influenza virus, the recall response of virus-specific CD8+ T cells that form in the presence of TCDD is only mildly impaired. Thus, the delayed kinetics of the recall response in TCDD-treated mice reflects the fact that there are fewer memory cells at the time of reinfection rather than an inherent defect in the responsive capacity of virus-specific memory CD8+ cells.

Aryl Hydrocarbon Receptor Activation Reduces Dendritic Cell Function during Influenza Virus Infection

Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of liraglutide, a glucagon-like peptide 1 (GLP-1) analog for the treatment of type 2 diabetes mellitus. Data Sources: A MEDLINE search (1966–May 2009) was conducted for English-language articles using the terms glucagon-like peptide 1, incretin mimetic, NN2211, and liraglutide. Abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes annual meetings in 2006, 2007, and 2008 were also searched for relevant data. Study Selection and Data Extraction: Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of liraglutide were reviewed. Data Synthesis: Liraglutide is a GLP-1 analog with pharmacokinetic properties suitable for once-daily administration. Clinical trial data from large, controlled studies demonstrate the effectiveness of liraglutide in terms of hemoglobin A1c (A1C) reduction, reductions in body weight, and the drugs low risk for hypoglycemic events when used as monotherapy. Data also support benefits of liraglutide therapy on β-cell responsiveness to glucose, with animal and in vitro data indicating potential benefits in β-cell mass and neogenesis with liraglutide treatment. Liraglutide has been studied as monotherapy and in combination with metformin, glimepiride, and rosiglitazone for the treatment of type 2 diabetes. Additionally, comparative data with insulin glargine and exenatide therapy are available from Phase 3 trials providing practitioners valuable clinical data on which to base clinical decision making. Overall, liraglutide is well tolerated with dose-dependent nausea, vomiting, and diarrhea being the most commonly reported adverse events in clinical trials. Conclusions: Once-daily administration may provide a therapeutic advantage for liraglutide over twice-daily exenatide, with similar improvements in A1C and body weight observed when liraglutide was compared with exenatide. The glucose-dependent mechanism of insulin release with GLP-1 agonist therapy holds potential clinical significance in the management of postprandial hyperglycemic excursions, with minimal risk of hypoglycemia.