Stephen D. Luzio

Bio: Stephen D. Luzio is an academic researcher from Swansea University. The author has contributed to research in topics: Insulin & Diabetes mellitus. The author has an hindex of 35, co-authored 160 publications receiving 4461 citations. Previous affiliations of Stephen D. Luzio include University Hospital of Wales & Queen Elizabeth Hospital Birmingham.

Sensitive and specific two-site immunoradiometric assays for human insulin, proinsulin, 65-66 split and 32-33 split proinsulins

Abstract: Monoclonal antibody-based two-site immunoradiometric assays are described for human insulin, proinsulin, 65-66 split and 32-33 split proinsulin. The detection limits of the assays lie in the range 0.8-2.5 pM. The assays for 65-66 and 32-33 split proinsulins do not distinguish between these substances and their respective C-terminal di-desamino derivatives. The assay of 65-66 split proinsulin does not cross-react with insulin, proinsulin or 32-33 split proinsulin. This material was undetectable (less than 1.0 pM) in plasma taken after an overnight fast in eight normal male subjects and the maximum individual concentration reached in plasma taken during an oral glucose tolerance test of these subjects was 3.8 pM. The proinsulin assay cross-reacted 66% with 65-66 split proinsulin but not with insulin or 32-33 split proinsulin. The 32-33 split proinsulin assay cross-reacted 84 and 60% with proinsulin and 65-66 split proinsulin respectively. The insulin assay cross-reacted 5.3, 62 and 5.0% with intact proinsulin, 65-66 split proinsulin and 32-33 split proinsulin respectively. The very low concentration of 65-66 split proinsulin meant that this derivative did not interfere significantly with the specificity of the assays of proinsulin and insulin. The concentration of 32-33 split proinsulin could be calculated by subtracting the cross-reactivity of the measured proinsulin. The mean concentrations of insulin, proinsulin and 32-33 split proinsulin in eight young male subjects in the fasting state were (pM +/- S.E.M.) 20 +/- 0.3, 2.3 +/- 0.3 and 2.1 +/- 0.7 and at the maximum reached during an oral glucose tolerance test, 150 +/- 26, 9.9 +/- 1.4 and 19.7 +/- 6.0 respectively.

Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study.

Abstract: OBJECTIVE—To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 ± 10 years, BMI 22.4 ± 1.6 kg/m2, and A1C 7.2 ± 0.7%) were studied after a 2-week treatment with either glargine or detemir once daily (randomized, double-blind, crossover study). RESEARCH DESIGN AND METHODS—Plasma glucose was clamped at 100 mg/dl for 24 h after subcutaneous injection of 0.35 unit/kg. The primary end point was end of action (time at which plasma glucose was >150 mg/dl). RESULTS—With glargine, plasma glucose remained at 103 ± 3.6 mg/dl up to 24 h, and all subjects completed the study. Plasma glucose increased progressively after 16 h with detemir, and only eight subjects (33%) completed the study with plasma glucose <180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P < 0.001). Estimated total insulin activity (GIR area under the curve [AUC]0–end of GIR) was 1,412 ± 662 and 915 ± 225 mg/kg (glargine vs. detemir, P < 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P < 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids0–24 h 11 ± 1.7 vs. 8 ± 2.8 mmol/l, respectively, P < 0.001). CONCLUSIONS—Detemir has effects similar to those of glargine during the initial 12 h after administration, but effects are lower during 12–24 h. Abbreviations: AUC, area under the curve • FFA, free fatty acid • GIR, glucose infusion rate • IIR, intravenous insulin infusion rate • IV, intravenous • SC, subcutaneous

Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites.

Abstract: Objective To determine the subcutaneous absorption rates and the appearance in plasma of 3 formulations of the long-acting human insulin analog insulin glargine (HOE 901) differing only in zinc content (15, 30, and 80 microg/ml). Research design and methods We conducted 2 studies. Study 1 compared the subcutaneous abdominal injection of 0.15 U/kg of 125I-labeled insulin glargine[15], insulin glargine[80], NPH insulin, and placebo. In study 2, 0.2 U/kg of insulin glargine[30] was injected into the arm, leg, and abdominal regions. Both studies had a randomized crossover design; each enrolled 12 healthy men, aged 18-50 years. Results In study 1, the time in hours for 25% of the administered radioactivity to disappear after bolus subcutaneous injection (T75%) for NPH insulin indicated a significantly faster absorption rate compared with the 2 insulin glargine formulations (3.2 vs. 8.8 and 11.0 h, respectively P Conclusions Subcutaneous absorption of insulin glargine is delayed compared with NPH insulin. There is little or no difference in the absorption rate of insulin glargine between the main subcutaneous injection sites.

Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes

Abstract: Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen–DR4(DRB1*0401)–restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group’s daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell–specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.

Prevalence of diabetic retinopathy within a national diabetic retinopathy screening service

Abstract: Aims Determine the prevalence and severity of diabetic retinopathy (DR) and risk factors in a large community based screening programme, in order to accurately estimate the future burden of this specific and debilitating complication of diabetes. Methods A cross-sectional analysis of 91 393 persons with diabetes, 5003 type 1 diabetes and 86 390 type 2 diabetes, at their first screening by the community based National Diabetic Retinopathy Screening Service for Wales from 2005 to 2009. Image capture used 2×45° digital images per eye following mydriasis, classified by qualified retinal graders with final grading based on the worst eye. Results The prevalence of any DR and sightthreatening DR in those with type 1 diabetes was 56.0% and 11.2%, respectively, and in type 2 diabetes was 30.3% and 2.9%, respectively. The presence of DR, non-sight-threatening and sight-threatening, was strongly associated with increasing duration of diabetes for either type 1 or type 2 diabetes and also associated with insulin therapy in those with type 2 diabetes. Conclusions Prevalence of DR within the largest reported community-based, quality assured, DR screening programme, was higher in persons with type 1 diabetes; however, the major burden is represented by type 2 diabetes which is 94% of the screened population.

Standards of Medical Care in Diabetes

Abstract: XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Abstract: Erratum to: DiabetologiaDOI 10.1007/s00125-012-2534-0In the text box ‘Properties of currently available glucose-lowering agents that may guide treatment choice in individualpatients with type 2 diabetes mellitus ’ vildagliptin was incor-rectly assigned footnote ‘a’ (Limited use in the USA/Europe)instead of footnote ‘b’ (Not licensed in the USA).

Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.

Abstract: Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The “gold standard” glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 non-obese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SIClamp) and minimal model analysis (SIMM) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I0) and glucose (G0)] contain critical informa...

Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.

Abstract: In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin dependent) diabetes mellitus. The concept underlying our hypothesis is that poor foetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.

Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach: Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Abstract: Glycemic management in type 2 diabetes mellitus has become increasingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available (1–5), mounting concerns about their potential adverse effects and new uncertainties regarding the benefits of intensive glycemic control on macrovascular complications (6–9). Many clinicians are therefore perplexed as to the optimal strategies for their patients. As a consequence, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a joint task force to examine the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant adults with type 2 diabetes. Several guideline documents have been developed by members of these two organizations (10) and by other societies and federations (2,11–15). However, an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes (16,17), the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care (18,19). This statement has been written incorporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowledged below). The document refers to glycemic control; yet this clearly needs to be pursued within a multifactorial risk reduction framework. This stems from the fact that patients with type 2 diabetes are at increased risk of cardiovascular morbidity and mortality; the aggressive management of cardiovascular …