Insulin Centennial: Milestones influencing the development of insulin preparations since 1922.

During 1921 to 1922, a team effort by Banting, Macleod, Collip and Best isolated and purified insulin and demonstrated its life-giving properties, giving rise to the birth of insulin therapy. In the early years (1922-1950), priorities revolved around the manufacture of insulin to meet demand, improving purity to avoid allergic reactions, establishing insulin standards and increasing its duration of action to avoid multiple daily injections. Shortly after the emergence of insulin, Joslin and Allen advocated the need to achieve and maintain good glycaemic control to realize its full potential. Although this view was opposed by some during a dark period in the history of insulin, it was subsequently endorsed some 60 years later endorsed by the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study. Major scientific advances by the Nobel Laureates Sanger, Hodgkin, Yalow and Gilbert and also by Steiner have revolutionized the understanding of diabetes and facilitated major advances in insulin therapy. The more recent advent of recombinant technology over the last 40 years has provided the potential for unlimited source of insulin, and the ability to generate various insulin 'analogues', in an attempt to better replicate normal insulin secretory patterns. The emerging biosimilars now provide the opportunity to improve availability at a lower cost.

Systemic Approaches for Emission Reduction in Industrial Plants Based on Physical Accounting: Example for an Aluminum Smelter.

Greenhouse gas (GHG) accounting in industrial plants usually has multiple purposes, including mandatory reporting, shareholder and stakeholder communication, developing key performance indicators (KPIs), or informing cost-effective mitigation options. Current carbon accounting systems, such as the one required by the European Union Emission Trading Scheme (EU ETS), ignore the system context in which emissions occur. This hampers the identification and evaluation of comprehensive mitigation strategies considering linkages between materials, energy, and emissions. Here, we propose a carbon accounting method based on multilevel material flow analysis (MFA), which aims at addressing this gap. Using a Norwegian primary aluminum production plant as an example, we analyzed the material stocks and flows within this plant for total mass flows of goods as well as substances such as aluminum and carbon. The results show that the MFA-based accounting (i) is more robust than conventional tools due to mass balance consistency and higher granularity, (ii) allows monitoring the performance of the company and defines meaningful KPIs, (iii) can be used as a basis for the EU ETS reporting and linked to internal reporting, (iv) enables the identification and evaluation of systemic solutions and resource efficiency strategies for reducing emissions, and (v) has the potential to save costs.

A review of glucagon-like peptide-1 receptor agonists and their effects on lowering postprandial plasma glucose and cardiovascular outcomes in the treatment of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular (CV) comorbidities, with CV disease being the most common cause of death in adults with T2DM. Although glucocentric therapies may improve glycaemic control (as determined by glycated haemoglobin levels), evidence suggests that this approach alone has limited beneficial effects on CV outcomes relative to improvements in lipid and blood pressure control. This may be explained in part by the fact that current antidiabetic treatment regimens primarily address overall glycaemia and/or fasting plasma glucose, but not the postprandial plasma glucose (PPG) excursions that have a fundamental causative role in increasing CV risk. This literature review evaluates the relationship between PPG and the risk of CV disease, discusses the treatment of T2DM with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and examines the associated CV outcomes. The literature analysis suggests that exaggerated PPG excursions are a risk factor for CV disease because of their adverse pathophysiologic effects on the vasculature, resulting in increased all-cause and CV-related mortality. Although GLP-1 RAs are well established in the current T2DM treatment paradigm, a subgroup of these compounds has a particularly pronounced, persistent and short-lived effect on gastric emptying and, hence, lower PPG substantially. However, current long-term data on CV outcomes with GLP-1 RAs are contradictory, with both beneficial and adverse effects having been reported. This review explores the opportunity to direct treatment towards controlling PPG excursions, thereby improving not only overall glycaemic control but also CV outcomes.

Future challenges and therapeutic opportunities in type 2 diabetes: Changing the paradigm of current therapy.

Most algorithms for type 2 diabetes mellitus (T2DM) do not recommend treatment escalation until glycated haemoglobin (HbA1c) fails to reach the recommended target of 7% (53 mmol/mol) within approximately 3 months on any treatment regimen ("treat to failure"). Clinical inertia and/or poor adherence to therapy contribute to patients not reaching glycaemic targets when managed according to this paradigm. Clinical inertia exists across the entire spectrum of anti-diabetes therapies, although it is most pronounced when initiating and optimizing insulin therapy. Possible reasons include needle aversion, fear of hypoglycaemia, excessive weight gain and/or the need for increased self-monitoring of blood glucose. Studies have suggested, however, that early intensive insulin therapy in newly diagnosed, symptomatic patients with T2DM with HbA1c >9% (75 mmol/mol) can preserve beta-cell function, thereby modulating the disease process. Furthermore, postprandial plasma glucose is a key component of residual dysglycaemia, evident especially when HbA1c remains above target despite fasting normoglycaemia. Therefore, to achieve near normoglycaemia, additional treatment with prandial insulin or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) is often required. Long- or short-acting GLP-1 RAs offer effective alternatives to basal or prandial insulin in patients inadequately controlled with other therapies or basal insulin alone, respectively. This review highlights the limitations of current algorithms, and proposes an alternative based on the early introduction of insulin therapy and the rationale for the sequential or fixed combination of GLP-1 RAs with insulin ("treat-to-success" paradigm).

Basal insulin analogues in the management of diabetes mellitus: What progress have we made?

Insulin remains the most effective and consistent means of controlling blood glucose levels in diabetes. Since 1946, neutral protamine Hagedorn (NPH) has been the predominant basal insulin in clinical use. However, absorption is variable due to the need for resuspension and the time-action profile (peak activity 4-6 h after subcutaneous administration) confers an increased propensity for between-meal and nocturnal hypoglycaemia. In the 1980s, recombinant DNA technology enabled modifications to the insulin molecule resulting in the soluble long-acting insulin analogues, glargine and detemir. Both exhibit a lower risk of hypoglycaemia compared with neutral protamine Hagedorn due to improved time-action profiles and reduced day-to-day glucose variability. Glargine is indicated for administration once daily and detemir once or twice daily. Degludec is the latest prolonged-acting insulin which forms long subcutaneous multi-hexamers that delay absorption. Recent phase III trials in type 1 and type 2 diabetes show that degludec was non-inferior to comparators (predominantly glargine) with a minimal although inconsistent reduction in overall hypoglycaemia and a small absolute difference in nocturnal hypoglycaemia. Newer developmental agents include LY2605541 and glargine U300. LY2605541 comprises insulin lispro combined with polyethylene glycol, thereby increasing its hydrodynamic size and retarding absorption from the subcutaneous tissue. Glargine U300 is a new formulation of glargine resulting in a flatter and more prolonged time-action profile than its predecessor. This article reviews recent advances in basal insulin analogues, including a critical appraisal of the degludec trials.

Key indices of glycaemic variability for application in diabetes clinical practice.

Near normal glycaemic control in diabetes consists to target daily glucose fluctuations and quarterly HbA1c oscillations in addition to overall glucose exposure. Consequently, the prerequisite is to define simple, and mathematically undisputable key metrics for the short- and long-term variability in glucose homeostasis. As the standard deviations (SD) of either glucose or HbA1c are dependent on their means, the coefficient of variation (CV = SD/mean) should be applied instead as it that avoids the correlation between the SD and mean values. A CV glucose of 36% is the most appropriate threshold between those with stable versus labile glucose homeostasis. However, when near normal mean glucose concentrations are achieved a lower CV threshold of <27 % is necessary for reducing the risk for hypoglycaemia to a minimal rate. For the long-term variability in glucose homeostasis, a CVHbA1c < 5 % seems to be a relevant recommendation for preventing adverse clinical outcomes.

Insulin therapy has a complex relationship with measure of oxidative stress in type 2 diabetes: a case for further study.

BACKGROUND: Because pharmacotherapies in type 2 diabetes exert complex effects, we examined the different anti-diabetic strategies, especially the influence of insulin doses, on the activation of oxidative stress, a key player in atherosclerosis, ageing and the risk of cancer. METHODS: This observational study included 122 persons with type 2 diabetes, 61 treated with oral hypoglycaemic agents alone (group I), 61 treated with a combination of oral hypoglycaemic agents and insulin at either a low dose (<0.40 unit/kg/day, group IIa, n = 30) or high dose (≥0.40 unit/kg/day, group IIb, n = 31) of insulin. Oxidative stress was estimated from 24-h urinary excretion rates of 8-iso-prostaglandin F2α. Haemoglobin A(1c) (%) was also measured to assess overall diabetic control. RESULTS: The 24-h excretion rates of 8-iso-prostaglandin F2α [median (range) pmol/mmol of creatinine] were much lower in group IIa [68 (32-220)] than in either group I [120 (26-329) p < 0.001] or group IIb [101 (30-289) p = 0.026]. Considering groups IIa and IIb as a whole, a significant and positive relationship (p = 0.021) was observed between insulin dose and 8-iso-prostaglandin F2α. Haemoglobin A(1c) was comparable in the three groups. CONCLUSIONS: The main benefit of insulin therapy is the restoration and maintenance of near normal glycaemia. However insulin at elevated doses can promote oxidative stress which is thought to be an important mediator of some of the deleterious effects of insulin. Our study shows that the link between insulin action and oxidative stress in type 2 diabetes is complex and warrants further study.

Glucose variability and diabetes complications: Risk factor or biomarker? Can we disentangle the "Gordian Knot"?

« Variability in glucose homoeostasis ¼ is a better description than « glycaemic variability ¼ as it encompasses two categories of dysglycaemic disorders: i) the short-term daily glucose fluctuations and ii) long-term weekly, monthly or quarterly changes in either HbA1c, fasting or postprandial plasma glucose. Presently, the relationship between the "variability in glucose homoeostasis" and diabetes complications has never been fully clarified because studies are either observational or limited to retrospective analysis of trials not primarily designed to address this issue. Despite the absence of definitive evidence from randomized controlled trials (RCTs), it is most likely that acute and long-term glucose homoeostasis "cycling", akin to weight and blood pressure "cycling" in obese and hypertensive individuals, are additional risk factors for diabetes complications in the presence of sustained ambient hyperglycaemia. As hypoglycaemic events are strongly associated with short- and long-term glucose variability, two relevant messages can be formulated. Firstly, due consideration should be given to avoid within-day glucose fluctuations in excess of 36% (coefficient of variation) at least for minimizing the inconvenience and dangers associated with hypoglycaemia. Secondly, it seems appropriate to consider that variability in glucose homoeostasis is not only associated with cardiovascular events but is also a causative risk factor via hypoglycaemic episodes as intermediary step. Untangling the" Gordian Knot", to provide confirmation about the impact of variability in glucose homoeostasis and diabetes complications remains a daunting prospect.

The obesity treatment dilemma: Why dieting is both the answer and the problem? A mechanistic overview.

Restricted-calorie diets are the most worldwide used treatments for obesity. Although such strategies are based on the first law of thermodynamics, the real life clinical practice demonstrates that the observed weight losses are divergent from those theoretically predicted. Loosely adherence to recommendations is one of the main causes for the limited efficacy of dieting, but many additional factors can be involved in the hurdles to weight loss. According to the second law of thermodynamics any restriction in dietary energy intake results in energy sparing with a diminution in the basal metabolic rate and a concomitant loss in the lean body mass. This "thrifty" energetic adaptation is associated with a progressive reduction in the difference between levels of energy intake and expenditure, thus resulting in a drastic fall in weight loss rates on the medium and long-term regardless of the dietary carbohydrate/fat ratio. This loss of efficacy is aggravated by the misadaptation of the production and action of anti-obesity hormones such as leptin. During the latest past decades the discovery of changes in the gut microbiota of obese people referred to as "obese dysbiosis" has raised the question as to whether these alterations can participate to diet-resistance. Combined with the behavioral and psychological barriers to low-calorie diets, there is a broad physiologic spectrum of evidence indicating that weight loss is a hard challenge. Consequently, the answer would be primarily to prevent the development of obesity and at worst to avoid its ominous progression from metabolically healthy to unhealthy stages.

The A1C and ABCD of glycaemia management in type 2 diabetes: a physician's personalized approach.

Recent intervention trials (Veterans Affairs Diabetes Trial, Action to Control Cardiovascular Risk in Diabetes, Action in Diabetes and Vascular Disease) have underscored problems surrounding the risk-benefit balance of most therapeutic strategies in type 2 diabetes given, especially the limited cardiovascular advantage of tight glycaemic control when set against the co-incident risk of severe hypoglycaemia and weight gain. Consequently, therapy should to tailored to the individual. While attractive, such an approach remains highly empiric and to some extent difficult to implement without practical guidance, in particular for the inexperienced physician. To provide a user-friendly guide for a personalized therapeutic approach to type 2 diabetes, we performed a systematic review of the literature and elaborated a simple rule that was debated at a large independent University Symposium on the occasion of the European Association for the Study of Diabetes held in Vienna 2009. As a result of that process, we now propose an A1C and ABCD of glycaemia management in type 2 diabetes to determine appropriate glycaemic targets based on Age, Body weight, Complications and Disease Duration. 'A1C and ABCD' aims to guide clinicians in the use of therapeutic agents more effectively, efficiently and safely. While no regulatory-approved drug can be excluded, given its proven efficacy, there is a need to better phenotype patients, paying particular attention to ABCD. Based on these parameters, physicians can select the therapeutic strategy with minimum risk and maximum benefit for each individual.

Respective Contributions of Glycemic Variability and Mean Daily Glucose as Predictors of Hypoglycemia in Type 1 Diabetes: Are They Equivalent?

OBJECTIVE: To evaluate the respective contributions of short-term glycemic variability and mean daily glucose (MDG) concentration to the risk of hypoglycemia in type 1 diabetes. RESEARCH DESIGN AND METHODS: People with type 1 diabetes (n = 100) investigated at the University Hospital of Montpellier (France) underwent continuous glucose monitoring (CGM) on two consecutive days, providing a total of 200 24-h glycemic profiles. The following parameters were computed: MDG concentration, within-day glycemic variability (coefficient of variation for glucose [%CV]), and risk of hypoglycemia (presented as the percentage of time spent below three glycemic thresholds: 3.9, 3.45, and 3.0 mmol/L). RESULTS: MDG was significantly higher, and %CV significantly lower (both P < 0.001), when comparing the 24-h glycemic profiles according to whether no time or a certain duration of time was spent below the thresholds. Univariate regression analyses showed that MDG and %CV were the two explanatory variables that entered the model with the outcome variable (time spent below the thresholds). The classification and regression tree procedure indicated that the predominant predictor for hypoglycemia was %CV when the threshold was 3.0 mmol/L. In people with mean glucose ≤7.8 mmol/L, the time spent below 3.0 mmol/L was shortest (P < 0.001) when %CV was below 34%. CONCLUSIONS: In type 1 diabetes, short-term glycemic variability relative to mean glucose (i.e., %CV) explains more hypoglycemia than does mean glucose alone when the glucose threshold is 3.0 mmol/L. Minimizing the risk of hypoglycemia requires a %CV below 34%.

Review of methods for detecting glycemic disorders.

Prediabetes (intermediate hyperglycemia) consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) detected by a standardized 75-gram oral glucose tolerance test (OGTT). Individuals with isolated IGT or combined IFG and IGT have increased risk for developing type 2 diabetes (T2D) and cardiovascular disease (CVD). Diagnosing prediabetes early and accurately is critical in order to refer high-risk individuals for intensive lifestyle modification. However, there is currently no international consensus for diagnosing prediabetes with HbA1c or glucose measurements based upon American Diabetes Association (ADA) and the World Health Organization (WHO) criteria that identify different populations at risk for progressing to diabetes. Various caveats affecting the accuracy of interpreting the HbA1c including genetics complicate this further. This review describes established methods for detecting glucose disorders based upon glucose and HbA1c parameters as well as novel approaches including the 1-hour plasma glucose (1-h PG), glucose challenge test (GCT), shape of the glucose curve, genetics, continuous glucose monitoring (CGM), measures of insulin secretion and sensitivity, metabolomics, and ancillary tools such as fructosamine, glycated albumin (GA), 1,5- anhydroglucitol (1,5-AG). Of the approaches considered, the 1-h PG has considerable potential as a biomarker for detecting glucose disorders if confirmed by additional data including health economic analysis. Whether the 1-h OGTT is superior to genetics and omics in providing greater precision for individualized treatment requires further investigation. These methods will need to demonstrate substantially superiority to simpler tools for detecting glucose disorders to justify their cost and complexity.

Integrating glycaemic variability in the glycaemic disorders of type 2 diabetes: a move towards a unified glucose tetrad concept.

The high incidence of atherosclerosis and cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes. Evidence is accumulating that postprandial hyperglycaemia is an independent risk factor for diabetes-associated complications and mortality, and that worsening diabetes control is characterized by postprandial glucose (PPG) deterioration preceding an impairment in fasting glucose levels. Postprandial and general glucose fluctuations play a major role in activating oxidative stress, leading to the endothelial dysfunction, one of the mechanisms responsible for vascular complications. Therefore, the management of PPG is key for any strategy used in the monitoring and treatment of diabetes. We recommend that any strategy aimed at controlling the glycaemic disorders associated with type 2 diabetes, and limiting the risk of complications, should target the 'glucose tetrad', which comprises the following components: HbA(1c), fasting and postprandial plasma glucose, and markers of glycaemic variability, such as the mean amplitude of glycaemic excursions (MAGE) index. This brings together, in a simple, unified concept, the conventional markers (HbA(1c) and fasting glucose) and the more recently recognized markers of glycaemic control (PPG excursions and acute glycaemic variability).

Glycaemic variability in diabetes: clinical and therapeutic implications.

Glycaemic variability is an integral component of glucose homoeostasis. Although it has not yet been definitively confirmed as an independent risk factor for diabetes complications, glycaemic variability can represent the presence of excess glycaemic excursions and, consequently, the risk of hyperglycaemia or hypoglycaemia. Glycaemic variability is currently defined by a large and increasing number of metrics, representing either short-term (within-day and between-day variability) or long-term glycaemic variability, which is usually based on serial measurements of HbA1c or other measures of glycaemia over a longer period of time. In this Review, we discuss recent evidence examining the association between glycaemic variability and diabetes-related complications, as well as non-pharmacological and pharmacological strategies currently available to address this challenging aspect of diabetes management.

Targeting prandial hyperglycemia: how important is it and how best to do this?

The contribution of postprandial glucose (PPG) excursions to the overall hyperglycemia of patients with type 2 diabetes depends on the degree of diabetic control. PPG is a major contributor in patients with hemoglobin A(1c) (HbA(1c)) levels below 7.3%, whereas the contribution of fasting plasma glucose (FPG) is preponderant in poorly controlled patients. In addition, the loss of postprandial glycemic control precedes stepwise degradation of fasting with worsening diabetes. As a consequence, monitoring after meals is particularly important in patients with HbA(1c) levels ranging from 6.5% to 8%. In such patients, targeting PPG below 140 mg/dL should be one of the main objectives to achieve HbA(1c) less than 6.5%. The new hypoglycemic agents, such as the glucagon-like peptide-1 analogues and the dipeptidyl peptidase-4 inhibitors which have a gluco-dependent insulinotropic effect, should normally reinforce our therapeutic armamentarium for achieving the glycemic targets that should include the three components of the glucose triad: HbA(1c), FPG, and PPG.

Modulation of CD36 protein expression by AGEs and insulin in aortic VSMCs from diabetic and non-diabetic rats.

BACKGROUND AND AIM: In type 2 diabetes, the interplay between cells and inflammatory mediators up-regulates CD36 expression in macrophages. The aim of this work was to investigate advanced glycation end products (AGE)-induced CD36 expression and its regulation by insulin in aortic vascular smooth muscle cells (VSMCs) from Goto-Kakisaki (GK) rats, a non-obese insulin model of both insulin resistance and type 2 diabetes. The context of overexpression of CD36 in aortas was also evaluated. METHODS AND RESULTS: VSMCs were isolated and cultured from the aortas of GK rats and non-diabetic rats. The expression of proteins was evaluated by Western blot. The aortic production of superoxide anion (O(2)(.-)) was measured by luminescence on isolated tissue. AGEs and advanced oxidation protein products (AOPPs) were determined in plasma by fluorescence spectroscopy and spectrophotometry, respectively. AGE receptor (RAGE), NF-kappaB, and CD36 protein expression as well as O(2)(.-) production were higher in GK aortas than in control aortas, and AGEs and AOPPs were higher in GK plasma. In VSMCs from non-diabetic rats, insulin was able to reduce (10 nM) or suppress (100 nM) the protein overexpression of CD36 induced by AGEs-BSA. In contrast, in VSMCs from GK rats, insulin was unable to reduce AGEs-BSA-induced CD36 overexpression. CONCLUSIONS: The results suggest an overexpression of CD36 in VSMCs from GK rats and impaired control by insulin. In the context of increased plasma AGEs, aortic RAGE overexpression and increased oxidative stress markers, the data are compatible with an AGEs induced CD36 overexpression in diabetes.

The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes.

OBJECTIVE: The aim of the study was to determine whether the loss of fasting and postprandial glycemic control occurs in parallel or sequentially in the evolution of type 2 diabetes. RESEARCH DESIGN AND METHODS: In 130 type 2 diabetic patients, 24-h glucose profiles were obtained using a continuous glucose monitoring system. The individuals with type 2 diabetes were divided into five groups according to A1C levels: 1 (<6.5%, n = 30), 2 (6.5-6.9%, n = 17), 3 (7-7.9%, n = 32), 4 (8-8.9%, n = 25), and 5 (> or =9%, n = 26). The glucose profiles between the groups were compared. The overall glucose concentrations for the diurnal, nocturnal, and morning periods, which represent the postprandial, fasting, and the dawn phenomenon states, respectively, were also compared. RESULTS: Glucose concentrations increased steadily from group 1 to 5 in a stepwise manner. The initial differences in mean glucose concentrations reaching statistical significance occurred 1) between groups 1 and 2 (6.4 vs. 7.7 mmol/l, P = 0.0004) for daytime postprandial periods, followed by differences; 2) between groups 2 and 3 (7.5 vs. 9.3 mmol/l, P = 0.0003) for the morning periods (dawn phenomenon); and finally 3) between groups 3 and 4 (6.3 vs. 8.4 mmol/l, P < 0.0001) for nocturnal fasting periods. CONCLUSIONS: The deterioration of glucose homeostasis in individuals with type 2 diabetes progressed from postprandial to fasting hyperglycemia following a three-step process. The first step related to the three diurnal postmeal periods considered as a whole, the second step occurred during the morning period, and the third and final step corresponded to sustained hyperglycemia over the nocturnal fasting periods. Such a description of the key stages in the evolution of type 2 diabetes may be of interest for implementing antidiabetes treatment.

Branched-Chain Amino Acid Database Integrated in MEDIPAD Software as a Tool for Nutritional Investigation of Mediterranean Populations.

Branched-chained amino acids (BCAA) are essential dietary components for humans and can act as potential biomarkers for diabetes development. To efficiently estimate dietary intake, we developed a BCAA database for 1331 food items found in the French Centre d'Information sur la Qualité des Aliments (CIQUAL) food table by compiling BCAA content from international tables, published measurements, or by food similarity as well as by calculating 267 items from Greek, Turkish, Romanian, and Moroccan mixed dishes. The database embedded in MEDIPAD software capable of registering 24 h of dietary recalls (24HDR) with clinical and genetic data was evaluated based on archived 24HDR of the Saint Pierre Institute (France) from 2957 subjects, which indicated a BCAA content up to 4.2 g/100 g of food and differences among normal weight and obese subjects across BCAA quartiles. We also evaluated the database of 119 interviews of Romanians, Turkish and Albanians in Greece (27⁻65 years) during the MEDIGENE program, which indicated mean BCAA intake of 13.84 and 12.91 g/day in males and females, respectively, comparable to other studies. The MEDIPAD is user-friendly, multilingual, and secure software and with the BCAA database is suitable for conducting nutritional assessment in the Mediterranean area with particular facilities for food administration.