Shivani Misra

A single injection of kisspeptin-54 temporarily increases luteinizing hormone pulsatility in healthy women.

Kisspeptin is a novel hypothalamic peptide which stimulates endogenous gonadotrophin releasing hormone (GnRH) secretion. A single subcutaneous bolus injection of kisspeptin‐54 increases circulating luteinizing hormone (LH) levels in women, but its acute effects on LH pulsatility are not known.

Utility of ketone measurement in the prevention, diagnosis and management of diabetic ketoacidosis

Ketone measurement is advocated for the diagnosis of diabetic ketoacidosis and assessment of its severity. Assessing the evidence base for ketone measurement in clinical practice is challenging because multiple methods are available but there is a lack of consensus about which is preferable. Evaluating the utility of ketone measurement is additionally problematic because of variability in the biochemical definition of ketoacidosis internationally and in the proposed thresholds for ketone measures. This has led to conflicting guidance from expert bodies on how ketone measurement should be used in the management of ketoacidosis. The development of point‐of‐care devices that can reliably measure the capillary blood ketone β‐hydroxybutyrate (BOHB) has widened the spectrum of applications of ketone measurement, but whether the evidence base supporting these applications is robust enough to warrant their incorporation into routine clinical practice remains unclear. The imprecision of capillary blood ketone measures at higher values, the lack of availability of routine laboratory‐based assays for BOHB and the continued cost‐effectiveness of urine ketone assessment prompt further discussion on the role of capillary blood ketone assessment in ketoacidosis. In the present article, we review the various existing methods of ketone measurement, the precision of capillary blood ketone as compared with other measures, its diagnostic accuracy in predicting ketoacidosis and other clinical applications including prevention, assessment of severity and resolution of ketoacidosis.

Elevated Lactate Levels in Patients With Poorly Regulated Type 1 Diabetes and Glycogenic Hepatopathy: A New Feature of Mauriac Syndrome

Glycogenic hepatopathy is a rare but probably underdiagnosed feature of poorly controlled diabetes, in particular type 1 diabetes. It is characterized by excessive hepatic glycogen storage as first described in 1930 by Mauriac as a part of a syndrome comprising growth retardation, delayed puberty, and Cushingoid features in young patients with type 1 diabetes (1). Recent case reports have demonstrated that glycogenic hepatopathy can be the sole presenting feature of Mauriac syndrome (reviewed in ref. 2). Here, we describe four strikingly similar cases of young adults with poorly controlled type 1 diabetes who presented with excess hepatic glycogen storage and increased plasma lactate levels. The combination of these metabolic abnormalities led to the initial presumption …

Combination of Peptide YY3–36 with GLP-17–36 amide Causes an Increase in First-Phase Insulin Secretion after IV Glucose

Context: The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY3–36 and GLP-17–36 amide, on glucose homeostasis are unknown. Objective: This study sought to investigate the acute effects of PYY3–36 and GLP-17–36 amide, individually and in combination, on insulin secretion and sensitivity. Setting and Design: Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY3–36 alone, GLP-17–36 amide alone, and a combination of PYY3–36 and GLP-17–36 amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility. Results: PYY3–36 alone caused a small but nonsignificant increase in AIRg. GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide did increase AIRg significantly. No significant differences in SI were observed with any intervention. Conclusions: PYY3–36 lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY3–36 and GLP-17–36 amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI.

Diabetic ketoacidosis in adults

#### What you should know Diabetic ketoacidosis (DKA) is an extreme metabolic state caused by insulin deficiency. The breakdown of fatty acids (lipolysis) produces ketone bodies (ketogenesis), which are acidic. Acidosis occurs when ketone levels exceed the body’s buffering capacity (figure⇓).1 2 Diabetic ketoacidosis may follow absolute insulin deficiency or relative insulin deficiency. Relative insulin deficiency may occur in the presence of increased levels of counter-regulatory hormones such as glucagon, cortisol, and catecholamines. Insulin deficiency results in lipolysis and ketogenesis. Ketone bodies are acidic and may initially be buffered, but when levels are high enough, will result in acidosis Data from the UK National Diabetes audit shows a crude one year incidence of 3.6% among people with type 1 diabetes.3 In the UK nearly 4% of people with type 1 diabetes experience DKA …

Diabetic ketoacidosis: not always due to type 1 diabetes

This article discusses how to diagnose and manage patients with ketosis prone type 2 diabetes

How good is the evidence base for test selection in clinical guidelines

Clinical guidelines are ubiquitous, manifold and form an integral component of evidence-based clinical practice. Guidelines on test selection are often considered a useful adjunct to aid clinical decision-making, as test selection is a complex process that is influenced by many patient, clinician and laboratory factors. However, it is important to carefully evaluate several aspects of these guidelines, which include the context of the test in the guideline, the quality of the studies underpinning recommendations, the extent of the evaluation of effectiveness (or performance) of the specific test and in the clinical pathway, its applicability and ease of implementation. A robust evaluation of a diagnostic test should incorporate several stages including evaluation in healthy, symptomatic but unaffected and affected populations, and importantly a measurement of impact on patient outcomes. Few diagnostic studies meet these criteria, and therefore crucial aspects of test evaluation are overlooked prior to incorporation into clinical guidelines. Whilst efforts are made to standardise reporting of studies, strength of evidence and quality of guidelines, further work is required to improve the quality of the diagnostic studies that formulate these guidelines. It is important that clinicians using guidelines for test selection appreciate the limitations of the diagnostic test, and the guidelines themselves.

Gestational diabetes mellitus: primum non nocere.

Maturity-onset diabetes of the young (MODY) encompasses a collection of distinct forms of diabetes, which are inherited in an autosomal-dominant mode from the maternal or paternal side of the family or occasionally occur as a de novo mutation. All the genes involved affect either β-cell sensing or insulin secretion (1). The clinical presentations of MODY are heterogeneous, reflecting the different gene mutations involved, and the glucose dysregulation observed ranges from a relatively innocent rise in the fasting glucose to frank diabetes with neurological involvement (2,3). An exact MODY prevalence within the general diabetes population has proven difficult to assess because of underrecognition and lack of routinely available and affordable diagnostic tools. A further confounder is that the reported regional prevalence of specific MODY mutations varies considerably (4). Conservative estimates suggest that between 0.14–1.8% of all cases of diabetes could be attributable to MODY (4). It is to be expected that among women screened for gestational diabetes mellitus (GDM) the prevalence of MODY will be higher, reflecting both the proportionately lower prevalence of type 2 diabetes in women of this age group and the probability that those with undiagnosed MODY will screen positive (5). From the few population studies reported, mutations in the hepatocyte nuclear factor 1 α ( HNF1a ) gene (MODY 3) and glucokinase ( GCK ) gene (MODY 2) account for the majority of cases (6). MODY 2 is characterized by its high penetrance, early onset, and lifelong fasting hyperglycemia. It is due to mutations in the pancreatic GCK gene, which acts as the β-cell glucose sensor, setting the glucose threshold at which amplification of insulin …

Why are clinical practice guidelines not followed

Abstract Clinical practice guidelines (CPG) are written with the aim of collating the most up to date information into a single document that will aid clinicians in providing the best practice for their patients. There is evidence to suggest that those clinicians who adhere to CPG deliver better outcomes for their patients. Why, therefore, are clinicians so poor at adhering to CPG? The main barriers include awareness, familiarity and agreement with the contents. Secondly, clinicians must feel that they have the skills and are therefore able to deliver on the CPG. Clinicians also need to be able to overcome the inertia of “normal practice” and understand the need for change. Thirdly, the goals of clinicians and patients are not always the same as each other (or the guidelines). Finally, there are a multitude of external barriers including equipment, space, educational materials, time, staff, and financial resource. In view of the considerable energy that has been placed on guidelines, there has been extensive research into their uptake. Laboratory medicine specialists are not immune from these barriers. Most CPG that include laboratory tests do not have sufficient detail for laboratories to provide any added value. However, where appropriate recommendations are made, then it appears that laboratory specialist express the same difficulties in compliance as front-line clinicians.

Guidelines are written, but are they followed?

Clinical practice guidelines are statements that include recommendations intended to optimize patient care, which are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options. Guidelines are widely published, increasing in number and aim to standardize practice based on best available evidence. They should assist decision-making by clinicians and patients about appropriate healthcare for specific clinical situations and are written for a variety of reasons, including: clarification of areas of confusion or controversy, increasing efficiency and streamlining pathways. However, the real purpose of guidelines is to improve patient care and outcome though in reality it is very difficult to measure this specific effect. Inappropriate requests for tumour markers, perhaps in contrast to many other analytes, have a very tangible impact on patient care both when they are used for diagnosis or case-finding and disease monitoring. It is easy to appreciate the patient anxiety surrounding an unknown diagnosis or whether a malignant disease is responding to treatment. Moreover, the impact of false-positive tests, inappropriate requests and the downstream consequences of these have only undergone limited study, which may explain why tumour marker requests are still widely available and seldom vetted. It is therefore of no surprise that guidelines on tumour marker requesting are extensively written, and a PubMed search of ‘tumour markers’ filtered for guidelines reveals 200 hits. In addition multiple articles in mainstream medical journals have tried to address the issue. The article by Schulenburg-Brand et al. in this issue investigated the impact of local guidance on tumour marker requesting within a single surgical department. They found a significant rate of inappropriate requesting, underpinned by an apparent lack of test knowledge (for example, CA-125 in men and multiple tumour marker panel requests). There was a significant improvement following guideline implementation, though a degree of inappropriate requesting persisted on re-audit. This, like so many other audits of adherence to guidelines raises important questions.