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The first preparation of insulin extracted from a pancreas and made suitable for use in humans after purification was achieved 100 years ago in Toronto, an epoch-making achievement, which has ultimately provided a life-giving treatment for millions of people worldwide. The earliest animal-derived formulations were short-acting and contained many impurities that caused adverse reactions, thereby limiting their therapeutic potential. However, since then, insulin production and purification improved with enhanced technologies, along with a full understanding of the insulin molecule structure. The availability of radio-immunoassays contributed to the unravelling of the physiology of glucose homeostasis, ultimately leading to the adoption of rational models of insulin replacement. The introduction of recombinant DNA technologies has since resulted in the era of both rapid- and long-acting human insulin analogues administered via the subcutaneous route which better mimic the physiology of insulin secretion, leading to the modern basal-bolus regimen. These advances, in combination with improved education and technologies for glucose monitoring, enable people with diabetes to better meet individual glycaemic goals with a lower risk of hypoglycaemia. While the prevalence of diabetes continues to rise globally, it is important to recognise the scientific endeavour that has led to insulin remaining the cornerstone of diabetes management, on the centenary of its first successful use in humans., (© 2022. Springer-Verlag Italia S.r.l., part of Springer Nature.)

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., (© 2021 John Wiley & Sons Ltd.)

The first insulin preparation injected in humans in 1922 was short-acting, extracted from animal pancreas, contaminated by impurities. Ever since the insulin extracted from animal pancreas has been continuously purified, until an unlimited synthesis of regular human insulin (RHI) became possible in the '80s using the recombinant-DNA (rDNA) technique. The rDNA technique then led to the designer insulins (analogs) in the early '90s. Rapid-acting insulin analogs were developed to accelerate the slow subcutaneous (sc) absorption of RHI, thus lowering the 2-h post-prandial plasma glucose (PP-PG) and risk for late hypoglycemia as comparing with RHI. The first rapid-acting analog was lispro (in 1996), soon followed by aspart and glulisine. Rapid-acting analogs are more convenient than RHI: they improve early PP-PG, and 24-h PG and A1C as long as basal insulin is also optimized; they lower the risk of late PP hypoglycemia and they allow a shorter time-interval between injection and meal. Today rapid-acting analogs are the gold standard prandial insulins. Recently, even faster analogs have become available (faster aspart, ultra-rapid lispro) or are being studied (Biochaperone lispro), making additional gains in lowering PP-PG. Rapid-acting analogs are recommended in all those with type 1 and type 2 diabetes who need prandial insulin replacement., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in relation to this article. G.B.B. has received honoraria for lectures and advisory boards from Sanofi and Menarini; F.P. has received honoraria for lecturing and consultations from Sanofi, Lilly, Novo Nordisk, MSD; P. L. declares no conflict of interest; C.G.F. has received honoraria for lecturing and consultations from Sanofi, Lilly and travel grants from Menarini; D.R.O. has received honoraria for lectures and advisory board activities from Boehringer Ingelheim, Novo Nordisk, Roche Diagnostics and Sanofi., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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%., (© 2020 by the American Diabetes Association.)

Due to the progressive nature of type 2 diabetes (T2DM), initiation of insulin therapy is very likely in the disease continuum. This article aims at highlighting the current situation with regard to insulin therapy in people with T2DM in Europe and at presenting the associated unmet need. Challenges for both people with T2DM and healthcare professionals include clinical inertia also derived from fear of hypoglycaemia, weight gain and injections as well as increased need for a comprehensive diabetes management. We compare national and international guidelines and recommendations for the initiation and intensification of insulin therapy with the real-world situation in six European countries, demonstrating that glycaemic targets are only met in a minority of people with T2DM on insulin therapy. Furthermore, this work evaluates currently recorded numbers of people with T2DM treated with insulin in Europe, the proportion not achieving the stated glycaemic targets and thus in need to enhance insulin therapy e.g. by a change in means of insulin delivery including, but not limited to, insulin pens, wearable mealtime insulin delivery patches, patch pumps, and conventional insulin pumps with continuous subcutaneous insulin infusion., Competing Interests: Declaration of Competing Interest The author(s) declared the following potential conflicts of interest: AC, HWdV, BG, TH and DO are members of the BD Switzerland Sàrl Advisory Board. MC is a full-time employee of BD Italy SpA. KF and CS have no conflicts of interest. OS is a member of the BD Switzerland Sàrl Advisory Board and is CEO and founder of Sciarc GmbH. All authors have approved the final article., (Copyright © 2020. Published by Elsevier B.V.)

Aims: To evaluate the efficacy and safety of adding a single bolus dose of insulin glulisine to basal insulin ('basal-plus') in persons with type 2 diabetes., Methods: Data from patients with poor glycemic control on oral antihyperglycemic drugs who were initiated on a 'basal-plus' regimen for up to 6 months were pooled from four randomized, multicenter studies. Glycated hemoglobin (HbA1c), fasting blood glucose, postprandial glucose (PPG), insulin dose and demographics were measured at baseline and end of study., Results: 711 patients with a mean age of 59.9 years and a mean duration of diabetes of 11.0 years were included in the analysis population. A 'basal-plus' regimen was associated with significant decreases in HbA1c and PPG at 6 months, an increase in glargine and glulisine doses and small, but statistically significant, changes in body weight and BMI in all patient subsets. The proportion of patients with HbA1c<7% also increased in all populations studied, while the prevalence of severe hypoglycemia was low and did not significantly differ across patient groups., Conclusions: These results suggest that the use of 'basal-plus' can achieve a good therapeutic response with a low risk of hypoglycemia and weight gain, regardless of a patient's age or BMI., (Copyright © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

The natural history of type 2 diabetes mellitus (T2DM) is a relentless progression of β-cell failure and dysregulation of β-cell function with increasing metabolic derangement. Insulin remains the only glucose-lowering therapy that is efficacious throughout this continuum. However, the timing of introduction and the choice of insulin therapy remain contentious because of the heterogeneity of T2DM and the well-recognized behavioral and therapeutic challenges associated with this mode of therapy. Nevertheless, the early initiation of basal insulin has been shown to improve glycemic control and affect long-term outcomes in people with T2DM and is a treatment strategy supported by international guidelines as part of an individualized approach to chronic disease management. The rationale for early initiation of insulin is based on evidence demonstrating multifaceted benefits, including overcoming the glucotoxic effects of hyperglycemia, thereby facilitating "β-cell rest," and preserving β-cell mass and function, while also improving insulin sensitivity. Independent of its effects on glycemic control, insulin possesses anti-inflammatory and antioxidant properties that may help protect against endothelial dysfunction and damage resulting in vascular disease. Insulin therapy and the achievement of good glycemic control earlier in T2DM provide long-term protection to end organs via "metabolic memory" regardless of subsequent treatments and degree of glycemic control. This is evidenced from long-term observations continuing from trials such as the United Kingdom Prospective Diabetes Study. As such, early initiation of insulin therapy may not only help to avoid the effects of prolonged glycemic burden, but may also positively alter the course of disease progression.

Several biopharmaceuticals, including insulin and insulin analogs, are, or shortly will be, off-patent, thereby providing an opportunity for companies to attempt to manufacture "copies" commonly referred to as biosimilars and also known as follow-on biologics. Reassurance that such copy biologics are equally safe and effective as the conventional products is essential. It is important for the clinician to consider what information is therefore necessary for such assurances. Biopharmaceuticals, produced from living organisms and manufactured by complex processes, differ in many respects from chemically derived drugs. The biological source materials and manufacturing processes for non-innovator biologics may differ considerably from those used for producing the innovator substance. Differences between innovator and non-innovator products can be identified analytically (e.g., batch-to-batch consistency, product stability along side clinical safety). This provides a strong argument for caution before automatic substitution of conventional products (e.g., insulin by biosimilars). Several non-innovator insulins, including insulin analogs (while still patent-protected), are already available in many countries. Many of these lack rigorous regulations for biosimilar approval and pharmacovigilance. Recently an application for a biosimilar recombinant human insulin was withdrawn by the European Medicines Agency because of safety and efficacy concerns. Therefore, every biosimilar insulin and insulin analog should be assessed by well-defined globally harmonized preclinical and clinical studies followed by post-marketing pharmacovigilance programs, in the interest of people with diabetes worldwide.

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., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: A pooled analysis of randomized controlled trials of individuals with type 2 diabetes mellitus (T2DM) was conducted to compare dosing and impact of two basal insulin analogs, insulin glargine (glargine) and insulin detemir (detemir), on weight and hemoglobin A1c (A1c)., Methods: Twenty-two studies of at least 20 weeks in duration in individuals with T2DM initiating glargine/detemir were included. Results were combined using a weighted-average method and a bivariate random effect model. Outcomes included changes in weight, A1c, and insulin dose from study start to end., Results: One study was head-to-head comparison of glargine and detemir. Detemir (four studies) was administered once or twice daily, with 50% starting on detemir once daily but needing therapy intensification. Glargine was used once daily in all 22 studies. The Egger test was borderline significant for change in weight over the course of the treatment for glargine (0.29; 90% confidence interval [CI] -0.01, 0.58), and heterogeneity was not observed for detemir (-0.18; 90% CI -0.59, 0.23). Heterogeneity was observed for change in A1c over the course of the treatment (glargine, -1.19, 90% CI -1.74, -0.63; detemir, -2.65, 90% CI -4.86, -0.45). Nonheterogeneity for change in A1c over the course of the treatment was achieved by excluding five studies for glargine and one study for detemir; however, all studies were included in subsequent analyses. In the unadjusted model, glargine and detemir showed similar results for mean A1c change (-1.4% vs. -1.4%), weight gain (2.5 vs. 1.7 kg), and weight/A1c (1.8 vs. 1.2 kg/%). A significantly higher detemir dose was needed to achieve the same A1c change (51.5 vs. 38.8 U/day)., Conclusions: Although absolute weight gain was higher with glargine versus detemir, weight gain per A1c change was similar. A higher detemir dose was required to achieve a similar A1c reduction.

Background: New-onset diabetes after transplantation is an important complication of renal transplantation. Few studies have examined nondiabetic renal transplant recipients for occult defects in insulin sensitivity or secretion. The aims of this study were to identify abnormalities of glucose metabolism in nondiabetic, tacrolimus-treated renal transplant recipients more than 6 months posttransplantation and characterize determinants., Methods: Eighteen nondiabetic renal transplant recipients and 20 healthy control subjects were examined with a frequently sampled intravenous glucose tolerance test and meal tolerance test to derive first-phase insulin secretion (FPIR), insulin sensitivity, and second-phase insulin secretion., Results: FPIR was higher in controls compared with transplant recipients (2225 vs. 1173 pmol/L; P=0.003). In transplant subjects, there was a strong positive linear correlation between glomerular filtration rate (GFR) and FPIR (Pearson correlation r=0.7; P=0.002). There were strong negative correlations between trough tacrolimus concentration at study entry (r=-0.56; P=0.01) and 3-month tacrolimus exposure (r=-0.49; P=0.02) with GFR, but not with FPIR., Conclusions: Nondiabetic renal transplant recipients had lower FPIR than controls with normal renal function. Declining FPIR predicts type 2 diabetes in the general population. Interpreting the relationship between FPIR and GFR requires exploration of dual tacrolimus toxicity on both renal and pancreatic beta-islet cell function.

Background: As type 2 diabetes mellitus progresses, oral hypoglycaemic agents often fail to maintain blood glucose control and insulin is needed. We investigated whether the addition of once-daily insulin glargine is non-inferior to three-times daily prandial insulin lispro in overall glycaemic control in adults with inadequately controlled type 2 diabetes mellitus taking oral hypoglycaemic agents., Methods: In the 44-week, parallel, open study that was undertaken in 69 study sites across Europe and Australia, 418 patients with type 2 diabetes mellitus that was inadequately controlled by oral hypoglycaemic agents were randomly assigned to either insulin glargine taken once daily at the same time every day or to insulin lispro administered three times per day. The primary objective was to compare the change in haemoglobin A(1c) from baseline to endpoint (week 44) between the two regimens. Randomisation was done with a central randomisation service. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00311818., Findings: 205 patients were randomly assigned to insulin glargine and 210 to insulin lispro. Mean haemoglobin A(1c) decrease in the insulin glargine group was -1.7% (from 8.7% [SD 1.0] to 7.0% [0.7]) and -1.9% in the insulin lispro group (from 8.7% [1.0] to 6.8% [0.9]), which was within the predefined limit of 0.4% for non-inferiority (difference=0.157; 95% Cl -0.008 to 0.322). 106 (57%) patients reached haemoglobin A(1c) of 7% or less in the glargine group and 131 (69%) in the lispro group. In the glargine group, the fall in mean fasting blood glucose (-4.3 [SD 2.3] mmol/L vs -1.8 [2.3] mmol/L; p<0.0001) and nocturnal blood glucose (-3.3 [2.8] mmol/L vs -2.6 [2.9] mmol/L; p=0.0041) was better than it was in the insulin lispro group, whereas insulin lispro better controlled postprandial blood glucose throughout the day (p<0.0001). The incidence of hypoglycaemic events was less with insulin glargine than with lispro (5.2 [95% CI 1.9-8.9] vs 24.0 [21-28] events per patient per year; p<0.0001). Respective mean weight gains were 3.01 (SD 4.33) kg and 3.54 (4.48) kg. The improvement of treatment satisfaction was greater for insulin glargine than for insulin lispro (mean difference 3.13; 95% CI 2.04-4.22)., Interpretation: A therapeutic regimen involving the addition of either basal or prandial insulin analogue is equally effective in lowering haemoglobin A(1c). We conclude that insulin glargine provides a simple and effective option that is more satisfactory to patients than is lispro for early initiation of insulin therapy, since it was associated with a lower risk of hypoglycaemia, fewer injections, less blood glucose self monitoring, and greater patient satisfaction than was insulin lispro., Funding: Sanofi-Aventis.

A comparison of the plasma glucose and insulin day profiles between two prandial rapid-acting insulin analogues, insulin glulisine (glulisine) and insulin lispro (lispro), in 18 obese subjects with Type 2 diabetes. Subjects (body mass index: males, 36.7 [33.2-43.8] kg/m(2); females, 40.0 [35.7-46.5] kg/m(2)) received subcutaneous glulisine or lispro (0.15 U/kg) at 4-h intervals immediately (within 2 min) before three standard test meals during each of two 12-h, randomised, open-label, crossover studies (7+/-2-day interval between each). Overall, preprandial-subtracted glucose concentrations (area under the curve) were similar on the glulisine and lispro study days. However, the mean of the three maximal preprandial subtracted plasma glucose concentrations (DeltaGLU(max)) were lower with glulisine versus lispro (12%; p<0.01). Mean concentrations of insulin analogue were significantly higher post-meal with glulisine (p<0.01 for all). Post hoc analysis showed a significantly faster absorption rate for glulisine versus lispro in the first 30 min post-meal (estimated difference 0.48 microU/min; p<0.0001). Only two cases of hypoglycaemia were reported; both from one subject during the lispro day. When glulisine is injected immediately before a meal in obese patients with Type 2 diabetes, glulisine achieves significantly lower glucose excursions over lispro. Significantly faster absorption with higher and sustained post-meal levels of insulin analogue was achieved at every meal with glulisine versus lispro.

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 acids(0-24 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.

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by co-existing insulin deficiency (relative) and insulin insensitivity. Both fasting and post-prandial blood glucose are elevated, exposing the patient to acute and chronic complications due to micro- and macro-vascular angiopathy. Improving glycaemic control has been demonstrated to lower the risk of these complications. Owing to the progressive nature of the disease, an evolving treatment strategy is necessary to maintain glycaemic control. Insulin therapy is required when dietary and lifestyle modifications combined with oral hypoglycaemic agents fail to provide adequate glycaemic control. Adding an optimized dose of basal insulin to the existing oral therapy is a simple and widely used method for initiating insulin therapy. However, despite an effective control of fasting hyperglycaemia, further intervention to control post-prandial hyperglycaemia may become necessary to achieve HbA1c targets. Strategies for the addition of prandial insulin include administering short-acting (or rapid-acting) insulin analogues before each meal or twice-daily administration of pre-mixed insulin. As a single large meal often contributes to the greatest part of daytime hyperglycaemia, an alternative strategy is emerging with the addition of a single injection of prandial insulin prior to the meal that induces the largest post-prandial blood glucose excursion measured 2 h after the start of the meal. Over time, additional prandial boluses of insulin may be required to sustain daytime glycaemic control. This strategy offers a simple, stepwise approach to progress from basal insulin to a basal-bolus regimen. Studies are needed to validate this method and better define specific titration tactics., (Copyright 2007 John Wiley & Sons, Ltd.)

Insulin aspart, an analogue of human insulin, which is approved for use in people with diabetes, is more rapidly absorbed and achieves higher plasma concentrations than human soluble insulin following subcutaneous injection. Hence, it has a faster and more effective glucose-lowering action, with superior control of postprandial hyperglycaemia compared with human soluble insulin. Its shorter duration of action makes interprandial and nocturnal hypoglycaemia less of a problem than with human soluble insulin. Insulin aspart is approved for use in continuous subcutaneous infusion and offers a valuable treatment option during pregnancy.

Objective: To study the effects of exercise on the absorption of the basal long-acting insulin analog insulin glargine (Lantus), administered subcutaneously in individuals with type 1 diabetes., Research Design and Methods: A total of 13 patients (12 men, 1 woman) with type 1 diabetes on a basal-bolus insulin regimen were studied. (125)I-labeled insulin glargine at the usual basal insulin dose was injected subcutaneously into the thigh on the evening (2100) before the study day on two occasions 1 week apart. Patients were randomly assigned to 30 min intense exercise (65% peak oxygen uptake [Vo(2peak)]) on one of these visits. The decay of radioactive insulin glargine was compared on the two occasions using a thallium-activated Nal gamma counter. Blood samples were collected at regular intervals on the study days to assess plasma glucose and insulin profiles., Results: No significant difference was found in the (125)I-labeled insulin glargine decay rate on the two occasions (exercise vs. no exercise; repeated-measures ANOVA, P = 0.548). As expected, a significant fall in plasma glucose was observed over the exercise period (area under curve above fasting [DeltaAUC] glucose: -0.39 +/- 0.11 vs. -1.30 +/- 0.16 mmol . l(-1) . h(-1); nonexercise vs. exercise; P = 0.001), but insulin levels did not differ significantly on the two occasions (DeltaAUC insulin: -2.1 +/- 3.9 vs. 1.5 +/- 6.2 pmol . l(-1) . h(-1); nonexercise versus exercise; P = 0.507)., Conclusions: An intense 30-min period of exercise does not increase the absorption rate of the subcutaneously injected basal long-acting insulin analog insulin glargine in patients with type 1 diabetes.

Historically, the objective of insulin replacement has been to simulate the 2 major components of insulin secretion in individuals without diabetes mellitus: the low-level basal secretion during the night and periods of fasting, and the prandial secretion in response to food intake. The variable pharmacokinetic and pharmacodynamic characteristics of conventional insulin preparations have made mimicking these physiologic profiles virtually impossible. Balancing the effects of diet, exercise, and the numerous factors contributing to intra- and inter-individual variations in insulin absorption and action, such as type, site of injection, and dosage of insulin, while avoiding the very serious side effect of hypoglycemia in seeking normoglycemia, presents a further challenge. Recently, these limitations have been addressed by recombinant DNA-mediated development of insulin analogues, such as rapid-acting insulin lispro, aspart and glulisine, and the long-acting insulin preparations, insulin glargine and detemir. The molecular structures of these analogues have produced time-action profiles that better approach prandial and basal insulin secretion, thus allowing for easier, safer, and more flexible treatment regimens.

Population approaches are more robust estimators of insulin sensitivity (SI) and glucose effectiveness (SG) with the minimal model of glucose kinetics during an intravenous glucose tolerance test (IVGTT). We assessed the performance of 3 population methods, iterative two-stage (ITS), Bayesian hierarchical Markov chain Monte Carlo (MCMC), and NONMEM first-order conditional estimation (FOCE) with interaction (NM), and made a comparison with the standard two-stage method (STS) employing the weighted nonlinear regression analysis. To evaluate accuracy of individual and population estimates, 40 simulated insulin-modified frequently sampled IVGTTs (IM-FSIVGTT) were derived from real IM-FSIVGTTs (0.3 g glucose per kg body weight with 0.02 U/kg insulin at 20 minutes; 30 samples over 180 minutes) performed in 40 healthy Caucasian subjects (male/female, 22/18; age, 46 +/- 9 years; body mass index [BMI], 26.7 +/- 5.7 kg. m(-2); mean +/- SD). The population methods assumed a log-normal population distribution of parameters. All methods gave a similar but overestimated population SG by 9% to 13%. Population SI was underestimated to a different degree by the methods (STS 6%, ITS 10%, MCMC 13%, and NM 7%). The between-subject variability of SG was overestimated by STS and underestimated by the population methods (true 33%, STS 40%, ITS 19%, MCMC 24%, NM 24%; coefficient of variation). For SI, this quantity was well estimated by all methods (true 79%, STS 80%, ITS 82%, MCMC 83%, NM 82%). The results for individual estimates indicate that STS performs better than the population methods when estimating SI (STS 12%, ITS 16%, MCMC 16%, NM 16%; 1 outlying subject excluded; root mean squared error expressed as percent of mean) but worse for SG (STS 28%, ITS 21%, MCMC 20%, NM 19%). We conclude that the robust performance of population approaches, preventing parameter estimation failures associated with the nonlinear regression analysis, is not required with IM-FSIVGTT in subjects with normal glucose tolerance. The standard two-stage technique is the preferred method under such circumstances.

Objective: To compare the effects of repaglinide, glipizide, and glibenclamide on insulin secretion and postprandial glucose after a single standard 500-kcal test meal., Research Design and Methods: A total of 12 type 2 diabetic patients with early diabetes (mean HbA(1c) of 6.1%) and 12 matched control subjects were enrolled in this randomized, double-blind, crossover trial. Subjects received placebo, 2 mg repaglinide, 5 mg glipizide, and 5 mg glibenclamide in a random fashion during the trial. Administration of each drug was followed by a single standard 500-kcal test meal. A washout period of 7-12 days existed between the four study visits., Results: All three drugs were equally effective on the total prandial insulin secretion (area under the curve [AUC] -15 to 240 min). However, clear differences were noted in the early insulin secretion (AUC -15 to 30 min); both repaglinide and glipizide increased secretion in nondiabetic subjects by approximately 61 and 34%, respectively, compared with placebo. In the diabetic patients, the difference versus placebo was 37 and 47%, respectively. The difference between glipizide and glibenclamide reached significance in both groups of subjects, whereas repaglinide was more effective than glibenclamide only in the healthy nondiabetic subject group. All three drugs were effective in decreasing total glucose AUC in the nondiabetic and diabetic population. In the nondiabetic subjects, however, repaglinide was significantly more effective than glibenclamide. The differences disappeared in the diabetic subjects, probably as a result of increased prevalence of insulin resistance in this group., Conclusions: Repaglinide and glipizide but not glibenclamide significantly enhanced the early insulin secretion in both nondiabetic and diabetic subjects with preserved beta-cell function after a single standard meal.

Since the introduction of insulin therapy 80 years ago, the lives of millions of patients with diabetes have been saved, prolonged and immeasurably improved. However, restoring normal glucose levels in diabetic patients through administering insulin by subcutaneous injection has proved virtually impossible. The consequences for patients are serious complications, including diabetic retinopathy and nephropathy, which tend to result from persistent hyperglycaemia. Maximizing glucose control in diabetic patients requires several daily injections. In an effort to reduce this burden, alternative and less-intrusive routes for the administration of insulin are being explored.

We examined the ability of indices of insulin sensitivity and pancreatic beta-cell responsiveness to explain interindividual variability of clinical measures of glucose control in newly presenting type 2 diabetes. Subjects with newly presenting type 2 diabetes (n = 65; 53 males and 12 females; age, 54 +/- 1 yr; body mass index, 30.5 +/- 0.7 kg/m(2); mean +/- SE) underwent an insulin-modified iv glucose tolerance test to determine minimal model-derived insulin sensitivity (S(I)), glucose effectiveness, first-phase insulin secretion, and disposition index. Subjects also underwent a standard meal tolerance test (MTT) to measure fasting/basal (M(0)) and postprandial (M(I)) pancreatic beta-cell responsiveness. Stepwise linear regression used these indices to explain interindividual variability of fasting and postprandial plasma glucose and insulin concentrations and glycated hemoglobin (HbA(1C)). All measures of pancreatic beta-cell responsiveness (M(0), M(I), and first-phase insulin secretion) were negatively correlated with fasting plasma glucose (P < 0.01) and positively correlated with fasting plasma insulin (FPI) and insulin responses to MTT (P < 0.05). S(I) demonstrated negative correlation with FPI (P < 0.001) but failed to correlate with any glucose variable. M(I) followed by disposition index (composite index of insulin sensitivity and pancreatic beta-cell responsiveness) were most informative in explaining interindividual variability. It was possible to explain 70-80% interindividual variability of fasting plasma glucose, FPI, HbA(1C), and insulin responses to MTT, and only 25-40% interindividual variability of postprandial glucose. In conclusion, postprandial insulin deficiency is the most powerful explanatory factor of deteriorating glucose control in newly presenting type 2 diabetes. Indices of insulin sensitivity and pancreatic beta-cell responsiveness explain fasting glucose and HbA(1C) well but fail to explain postprandial glucose.

Introduction: To compare responses to basal insulin glargine 300 U/ml (IGlar‐300) and 100 U/ml (IGlar‐100) in newly defined subphenotypes of type 2 diabetes. Methods: Insulin‐naive participants (n = 858) from the EDITION 3 trial were assigned to subphenotypes 'Mild Age‐Related Diabetes (MARD)', 'Mild Obesity Diabetes (MOD)', 'Severe Insulin Resistant Diabetes (SIRD)' and 'Severe Insulin Deficient Diabetes (SIDD)'. Key variables were analysed at baseline and 26 weeks. Results: Participants were comprised of MOD 56.1% (n = 481), SIDD 22.1% (n = 190), MARD 18.2% (n = 156) and SIRD 3.0% (n = 26). After 26 weeks a similar decrease in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) of 16‐19 mmol/mol and 1.4‐1.7 mmol/L, respectively, occurred in MARD and MOD with both insulins. SIDD had the most elevated HbA1c and FPG (80‐83 mmol/mol/11.1‐11.4 mmol/L) and reduction in both HbA1c and FPG was greater with IGlar‐100 than with IGlar‐300 (−18 vs. −15 mmol/mol and −1.6 vs. −1.3 mmol/L, respectively; each p =.03). In SIDD, despite receiving the highest basal insulin doses, HbA1c decline (57‐60 mmol/mol/7.3‐7.6%) was suboptimal at week 26. In MOD and SIDD lower incidences with IGlar‐300 were found for level 1 nocturnal hypoglycaemia [odds ratio (OR) 0.59, 95% confidence intervals (CI) 0.36‐0.97; OR 0.49, 95% CI 0.24‐0.99]. In addition, fewer level 2 hypoglycaemia episodes occurred at any time with IGlar‐300 in SIDD (OR 0.31, 95% CI 0.13‐0.77). Conclusion: Both insulins produce comparable outcomes in type 2 diabetes subphenotypes, but in SIDD, add‐on treatment to basal insulin is required to achieve glycaemic targets. [ABSTRACT FROM AUTHOR]

The class of rapid‐acting insulin analogues were introduced more than 20 years ago to control postprandial plasma glucose (PPG) excursions better than unmodified regular human insulin. Insulins, lispro, aspart and glulisine all achieved an earlier onset of action, greater peak effect and shorter duration of action resulting in lower PPG levels and a reduced risk of late postprandial hypoglycaemia. However, the subcutaneous absorption rate of these analogues still fails to match the physiological profile of insulin in the systemic circulation following a meal. Recent reformulations of aspart and lispro have generated a second generation of more rapid‐acting insulin analogue candidates, including fast‐acting aspart (faster aspart), ultra‐rapid lispro and BioChaperone Lispro. These modifications have the potential to mimic physiological prandial insulin secretion better with an even earlier onset of action with improved PPG control, shorter duration of effect and reduced risk of hypoglycaemia. Recent phase 3 trials in type 1 and type 2 diabetes show that faster aspart and ultra‐rapid lispro compared with conventional aspart and lispro, achieved fewer PPG excursions with a small increase in post‐meal hypoglycaemia but similar or marginally superior glycated haemoglobin levels, and suggest the need for parallel optimization of basal insulin replacement. Phase 1 trials for BioChaperone Lispro are equally encouraging with phase 3 trials yet to be initiated. Comparative analysis of the clinical and pharmacological evidence for these new prandial insulin candidates in the treatment of type 1 and type 2 diabetes is the main focus of this review. [ABSTRACT FROM AUTHOR]

Aim: To examine the relationship between baseline fasting C‐peptide (FCP) and outcomes in insulin‐naïve people with type 2 diabetes initiating basal insulin glargine 100 U/mL (Gla‐100). Materials and methods: Post hoc pooled analysis of nine randomized, treat‐to‐target trials in patients with type 2 diabetes inadequately controlled on oral antihyperglycaemic drugs initiating once‐daily Gla‐100. Participants (n = 2165) were stratified at baseline according to FCP (≤0.40, >0.40–1.20, >1.20–2.00, >2.00 nmol/L). Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 24 weeks. Results: At baseline low FCP levels were associated with longer known diabetes duration, lower body mass index and higher fasting plasma glucose (FPG). Following Gla‐100 introduction, the mean HbA1c reduction at week 24 was similar in all four FCP groups, albeit fewer people in the lowest FCP group achieved HbA1c <7.0% versus FCP groups >0.40 nmol/L. By contrast, FPG reduction and proportion reaching FPG ≤5.6 mmol/L were greatest in the lowest FCP group, diminishing at higher FCP levels. Gla‐100 dose at week 24 was lowest in the ≤0.40 nmol/L FCP group and highest in the >1.20 nmol/L FCP group. Incidence and event rate of overall, nocturnal and severe hypoglycaemia were higher at week 24 in groups with lower FCP levels. In multivariable regression analysis baseline FCP, concomitant sulphonylurea use and endpoint HbA1c were strong predictors of hypoglycaemia. Conclusions: FCP levels identified patients with type 2 diabetes experiencing different responses to basal insulin Gla‐100. A low FCP identifies a markedly insulin‐deficient, insulin‐sensitive subgroup/phenotype with an enhanced risk of hypoglycaemia, which requires a low initial basal insulin dose, cautious titration and earlier addition of prandial glucose‐lowering therapy. [ABSTRACT FROM AUTHOR]

Objective: To define the threshold for excess glucose variability (GV), one of the main features of dysglycemia in diabetes.Research Design and Methods: A total of 376 persons with diabetes investigated at the University Hospital of Montpellier (Montpellier, France) underwent continuous glucose monitoring. Participants with type 2 diabetes were divided into several groups-groups 1, 2a, 2b, and 3 (n = 82, 28, 65, and 79, respectively)-according to treatment: 1) diet and/or insulin sensitizers alone; 2) oral therapy including an insulinotropic agent, dipeptidyl peptidase 4 inhibitors (group 2a) or sulfonylureas (group 2b); or 3) insulin. Group 4 included 122 persons with type 1 diabetes. Percentage coefficient of variation for glucose (%CV = [(SD of glucose)/(mean glucose)] × 100) and frequencies of hypoglycemia (interstitial glucose <56 mg/dL [3.1 mmol/L]) were computed.Results: Percentages of CV (median [interquartile range]; %) increased significantly (P < 0.0001) from group 1 (18.1 [15.2-23.9]) to group 4 (37.2 [31.0-42.3]). In group 1, the upper limit of %CV, which served as reference for defining excess GV, was 36%. Percentages of patients with %CVs above this threshold in groups 2a, 2b, 3, and 4 were 0, 12.3, 19.0, and 55.7%, respectively. Hypoglycemia was more frequent in group 2b (P < 0.01) and groups 3 and 4 (P < 0.0001) when subjects with a %CV >36% were compared with those with %CV ≤36%.Conclusions: A %CV of 36% appears to be a suitable threshold to distinguish between stable and unstable glycemia in diabetes because beyond this limit, the frequency of hypoglycemia is significantly increased, especially in insulin-treated subjects. [ABSTRACT FROM AUTHOR]

Aims: Evaluate efficacy and hypoglycaemia according to concomitant oral antidiabetes drug (OAD) in people with type 2 diabetes initiating insulin glargine 100U/mL (Gla-100) or neutral protamine Hagedorn (NPH) insulin once daily.Methods: Four studies (target fasting plasma glucose [FPG] ⩽100mg/dL [⩽5.6mmol/L]; duration ⩾24weeks) were included. Standardised data from 2091 subjects (Gla-100, n=1024; NPH insulin, n=1067) were analysed. Endpoints included glycated haemoglobin (HbA1c) and FPG change, glycaemic target achievement, hypoglycaemia, weight change, and insulin dose.Results: Mean HbA1c and FPG reductions were similar with Gla-100 and NPH insulin regardless of concomitant OAD (P=0.184 and P=0.553, respectively) and similar proportions of subjects achieved HbA1c <7.0% (P=0.603). There was a trend for more subjects treated with Gla-100 achieving FPG ⩽100mg/dL versus NPH insulin (relative risk [RR] 1.09 [95% confidence interval (CI) 0.97-1.23]; P=0.135). Plasma glucose confirmed (<70mg/dL) overall and nocturnal hypoglycaemia incidences and rates were lower with Gla-100 versus NPH insulin (overall RR 0.93 [95% CI 0.87-1.00]; P=0.041; nocturnal RR 0.73 [95% CI 0.65-0.83]; P<0.001). After 24weeks, weight gain and insulin doses were higher with Gla-100 versus NPH insulin (2.7kg vs 2.3kg, P=0.009 and 0.42U/kg vs 0.39U/kg; P=0.003, respectively). Insulin doses were higher when either insulin was added to sulfonylurea alone.Conclusions: Pooled results from treat-to-target trials in insulin-naïve people with type 2 diabetes demonstrate a significantly lower overall and nocturnal hypoglycaemia risk across different plasma glucose definitions with Gla-100 versus NPH insulin at similar glycaemic control. OAD therapy co-administered with Gla-100 or NPH insulin impacts glycaemic control and overall nocturnal hypoglycaemia risk. [ABSTRACT FROM AUTHOR]

The epoch-making discovery of insulin heralded a new dawn in the management of diabetes. However, the earliest, unmodified soluble insulin preparations were limited by their short duration of action, necessitating multiple daily injections. Initial attempts to protract the duration of action of insulin involved the use of various additives, including vasoconstrictor substances, which met with limited success. The subsequent elucidation of the chemical and three-dimensional structure of insulin and its chemical synthesis and biosynthesis allowed modification of the insulin molecule itself, resulting in insulin analogs that are designed to mimic normal endogenous insulin secretion during both fasting and prandial conditions. Insulin glargine was the first once-daily, long-acting insulin analog to be introduced into clinical practice more than 10 years ago and is specifically designed to provide basal insulin requirements. It has a prolonged duration of action and no distinct insulin peak, making it suitable for once-daily administration and reducing the risk of nocturnal hypoglycemia that is seen with intermediate-acting insulins. Insulin glargine can be used in combination with prandial insulin preparations and non-insulin anti-diabetic agents according to individual requirements. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the effectiveness of either a standard care programme (n = 9) or a 12-week supported exercise programme (n = 10) on glycaemic control, β-cell responsiveness, insulin resistance, and lipid profiles in newly diagnosed Type 2 diabetes patients. The standard care programme consisted of advice to exercise at moderate to high intensity for 30 min five times a week; the supported exercise programme consisted of three 60-min supported plus two unsupported exercise sessions per week. Between-group analyses demonstrated a difference for changes in low-density lipoprotein cholesterol only (standard care programme 0.01 mmol · L-1, supported exercise programme -0.6 mmol · L-1; P = 0.04). Following the standard care programme, within-group analyses demonstrated a significant reduction in waist circumference, whereas following the supported exercise programme there were reductions in glycosylated haemoglobin (6.4 vs. 6.0%; P = 0.007), waist circumference (101.4 vs. 97.2 cm; P = 0.021), body mass (91.7 vs. 87.9 kg; P = 0.007), body mass index (30.0 vs. 28.7 kg · m-2; P = 0.006), total cholesterol (5.3 vs. 4.6 mmol · L-1; P = 0.046), low-density lipoprotein cholesterol (3.2 vs. 2.6 mmol · L-1; P = 0.028), fasting β-cell responsiveness (11.5 × 10-9 vs. 7.0 × 10-9 pmol · kg-1 · min-1; P = 0.009), and insulin resistance (3.0 vs. 2.1; P = 0.049). The supported exercise programme improved glycaemic control through enhanced β-cell function associated with decreased insulin resistance and improved lipid profile. This research highlights the need for research into unsupported and supported exercise programmes to establish more comprehensive lifestyle advice for Type 2 diabetes patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To assess the effects of incremental doses of repaglinide on postprandial insulin and glucose profiles after a standard 500-kcal test meal. RESEARCH DESIGN AND METHODS -- Sixteen diet-treated Caucasians with type 2 diabetes (mean HbA1c] 8.4%) were enrolled in this randomized, open-label, crossover trial. Subjects received 0.5, 1, 2, and 4 mg repaglinide or placebo in a random fashion, followed by a standard 500-kcal test meal on 5 separate study days, 1 week apart. RESULTS -- The insulinogenic index (ΔI30/ΔG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC0-30) were higher with the 4-mg drug dose compared with the two lower doses and with 2 mg compared with 0.5 mg. On subgroup analysis, the incremental insulin responses were apparent only in the fasting plasma glucose (FPG) <9-mmol/l subgroup of subjects and not in the FPG >9-mmol/l subgroup. There was a significant dose-related increase in t he late postprandial insulin secretion (insulin AUC 120-240), which resulted in hypoglycemia in four subjects. Proinsulin-to-insulin ratios at 30 and 60 min improved with increasing doses of repaglinide; higher drug doses (2 and 4 mg) were more effective than the 0.5- and 1-mg doses. CONCLUSIONS -- Significant dose-related increases in early insulin secretion were found only in less advanced diabetic subjects. In advanced diabetic patients, only the maximum dose (4 mg) was significant compared with placebo. Better proinsulin-to-insulin processing was noted with increasing drug doses. [ABSTRACT FROM AUTHOR]

Background: To reduce the likelihood of complications in persons with type 2 diabetes, it is critical to control hyperglycaemia. Monotherapy with metformin or insulin secretagogues may fail to sustain control after an initial reduction in glycemic levels. Thus, combining metformin with other agents is frequently necessary. These analyses model the potential long-term economic and health impact of using combination therapy to improve glycemic control. Methods: An existing model that simulates the long-term course of type 2 diabetes in relation to glycosylated haemoglobin (HbA1c) and post-prandial glucose (PPG) was used to compare the combination of nateglinide with metformin to monotherapy with metformin. Complication rates were estimated for major diabetes-related complications (macrovascular and microvascular) based on existing epidemiologic studies and clinical trial data. Utilities and costs were estimated using data collected in the United Kingdom Prospective Diabetes Study (UKPDS). Survival, life years gained (LYG), quality-adjusted life years (QALY), complication rates and associated costs were estimated. Costs were discounted at 6% and benefits at 1.5% per year. Results: Combination therapy was predicted to reduce complication rates and associated costs compared with metformin. Survival increased by 0.39 (0.32 discounted) and QALY by 0.46 years (0.37 discounted) implying costs of £6,772 per discounted LYG and £5,609 per discounted QALY. Sensitivity analyses showed the results to be consistent over broad ranges. Conclusion: Although drug treatment costs are increased by combination therapy, this cost is expected to be partially offset by a reduction in the costs of treating long-term diabetes complications. [ABSTRACT FROM AUTHOR]

AimThe aim of this study was to compare glucose, insulin and proinsulin profiles during nateglinide and gliclazide treatment over an extended postprandial period.Materials and methodsThis double-blind crossover trial was conducted in 23 type 2 diabetic patients (mean HbA1C 6.6%; range 6.0—7.4%) who received, for one week each, nateglinide 120 mg t.i.d., gliclazide 80 mg b.i.d. and placebo, with a one week wash out period between treatments.ResultsThe 2-hour postprandial glucose concentration was markedly lower with nateglinide than with gliclazide (5.83 vs. 7.21 mmol/L; p<0.05), as was the post-meal peak glucose elevation (8.63 vs. 9.72 mmol/L; p=0.085), which was associated with earlier, higher and shorter-lived insulin and proinsulin secretory responses. However, 0—7-hour AUCs during standardised meal test for glucose and insulin between the two drugs did not statistically differ. No symptomatic hypoglycaemic events occurred during the 7-hour test period.ConclusionNateglinide was more effective than gliclazide in controlling postprandial hyperglycaemia and showed a faster effect on insulin and proinsulin secretion. [ABSTRACT FROM PUBLISHER]

The advent of insulin almost 80 years ago revolutionised treatment of diabetes and must be one of the most outstanding achievements of twentieth century medicine. Since then, there has been an ever-increasing awareness and acceptance of the need to achieve and sustain near-normoglycaemia to delay onset and retard progression of diabetic angiopathy. Physiological insulin replacement is therefore central to management of patients with diabetes who are unable to take insulin. Insulin formulations, treatment strategies, and methods and routes of delivery have changed much, with more and more options for monitoring the effect on blood glucose concentrations. Patients with type 1 and type 2 diabetes need insulin much more aggressively than previously. Parallel developments in glucose-sensing technologies are welcomed as an integral part of safe and optimum implementation of insulin replacement therapy. [ABSTRACT FROM AUTHOR]

Presents a study which determined the subcutaneous absorption rates and appearance in plasma of 3 formulations of the long-acting human insulin analog insulin glargine. Difference in zinc content of the formulations; Research design and methods; Discussion on the results.

The article comments on studies on the pharmacokinetics of insulin glargine in individuals with type 1 and type 2 diabete. It has been informed that according to a study insulin glargine has an enhanced affinity to IGF-1 receptors in a human osteosarcoma cell line and it is associated with increased mitogenicity.

Postabsurptive plasma glucose concentrations are regulated not just by insulin secretion but also glucagon concentrations. Both fasting and postprandial glucagon concentrations are elevated in subjects with impaired glucose tolerance (IGT) compared to subjects with normal glucose tolerance. The aim of the study was to investigate the effects of pioglitazone on glucagon secretion in subjects with IGT. 15 subjects (9 male) with IGT (WHO criteria) were recruited into this randomised, double-blind, placebo controlled study. All subjects undertook a standard 500kcal meal tolerance (MTT) and intravenous glucose tolerance (FSIVGTT) test on consecutive days following an overnight fast. Plasma glucose (PGs) and glucagon (PGn) were measured following the MTT. Insulin sensitivity (SI) was calculated from the FSIVGTT using the CIBA GEIGY programme. Following 6 months treatment with either placebo or Pioglitazone (Pio 30mg od) all tests were repeated. In the placebo group, subjects were aged (mean±SEM) 60.3±4.2years, with weight 75.7±7.1kg, BMI 27.4±1.6 kg/m² and HbA[sub 1c]5.6±0.2% and in the Pio group age 61.7±3.3years, weight 74.8±3.9kg, BM127.8 ±1. 1 kg/m² and HbA[sub 1c] 5.8±0:1%. There were no significant differences between groups or between baseline and follow up. There was a significant decrease in fasting PGs following Pin (5.8±0.2 vs 5.5±0.1 mmol/L; p=0.018) compared to placebo (6.0±0.2 vs 5.6 ±0.2 mmol/L; 10=0.398). However there were no differences in area under the prandial PGs profiles (AUC[sub PGs-0-4hr])) after 6 months in either treatment group. There was a significant increase in SI following Pio (0.53±0.26x10[sup -4] vs. 1.06±0.35 1/min*microU/ml p--0.043) with a significant decrease in the placebo treated group (2.48±0.22 vs. 1.554-0.24 xl0[sup -4] 1/min*microU/ml p=0.043). Compared to the change observed on placebo (82.5q-8.7 vs 88.8±6.9), Pio significantly decreased (p=0.046) fasting glucagon concentrations after 6 months (124.8±22.4 vs 113.8±23.0pg/ml). There were no differences in AUC[sub PGn-0-4hr) after 6 months in either the placebo (358.9±28.3vs.363.4±19. lpg.h/ml) or Pio (479.3±64.1 vs.445.8±64.2pg.h/ml) groups. In this small cohort of subjects with impaired glucose tolerance, pioglitazone improved insulin sensitivity and thereby lowered both fasting glucagon and glucose concentrations. [ABSTRACT FROM AUTHOR]

The pharmacokinetic (PK) and pharmacodynamic (PD) properties of oral insulin in a capsule form (Capsulin, Cap) and regular human insulin (Actrapid, Act) were compared in persons with type 2 diabetes during two 6h isoglycaemic glucose clamp studies conducted 11 days apart. Subjects were randomised into one of two groups: Group 1 received 150U Capsulin (Cap 150) on study day 1 and 12U subcutaneous (sc) Actrapid on study day 2:Group 2 received 12U sc Actrapid on study day 1 and 300U Capsulin (Cap 300) on study day 2. The night before the clamp study day all OHA treatment was stopped. Subjects were fasted (apart from water) for 12 hours prior to each study day. Capsulin was given with 200ml carbonated water; insulin Actrapid by subcutaneous administration into the anterior abdominal wall. The glucose infusion rates (GIR), plasma insulin and C-peptide concentrations were estimated throughout each 6h study period. 16 subjects (12 male) participated; mean (SD) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m[sup 2], HbA1c 7.5 (1.3) %. On all glucose clamp study days the overall plasma glucose concentration remained constant (within 3% of target concentration). Following Cap 150 GIR increased reaching a maximum of 1.14 (0.12) mg/kg/min at 6h compared to Act which reached a higher peak of 1.90 (0.19) mg/kg/min at 5h 30min. Following Cap300 GIR increased reaching a maximum of 1.23 (0.17) mg/kg/min at 4h 40min compared to Act which reached a peak of 2.21 (0.48) mg/kg/min also at 4h 40min. The overall GIR (AUC0-6h) for Cap 150 vs Act was 0.31(0.09) vs 0.50(0.15) g/kg (p<0.05) and for Cap 300 0.29(0.11) vs 0.58(0.25) g/kg (p<0.05). The peak incremental plasma insulin were 26 pmol/L reached at 2h 50 min and 109 pmol/L at 2h 30min for Cap 150 vs Act respectively, and 38 pmol/L at 1h 40min and III pmol/L at 3h 40min for Cap300 vs Act respectively. The overall plasma insulin (AUC0-6h) following Cap150 and Cap300 was significantly lower than Act 472(245) vs 910(270) pmol/L/h, p<0.05 and 433(218) vs 950(446) pmol/L/h, p<0.05, respectively. Suppression of endogenous insulin secretion (C-peptide) was seen only following the injections of Act. Administration of the oral insulin Capsulin demonstrated a significant increase in GIR over a period of 6 hours associated with only a small increase in circulating plasma insulin concentrations. No related dose effect was observed, however with both doses (150 & 300U) of Capsulin used the glucose lowering effect lasted greater than 6 hours. [ABSTRACT FROM AUTHOR]

The use of univariate and multivariate techniques to derive estimates of insulin sensitivity from the insulin modified FSIGT were investigated in 12 Type 2 diabetic subjects aged (mean±S.D.) 59±9.5 years and BMI 28.1±2.2 kg m−2, who underwent both a FSIGT and an isoglycemic hyperinsulinemic clamp. Reproducibility of the FSIGT was tested in four patients on three separate occasions. FSIGT data were assessed by both univariate and multivariate techniques. The sensitivity index for the FSIGT ranged from 0.162 to 3.292 (mean 1.378)×10−4·l min−1 mU−1 for the univariate approach and from 0.163 to 2.727 (mean 1.378)×10−4·l min−1 mU−1 for the multivariate method. Mean SIclamp was 44.41×10−4·l−2 min−1·mU−1 (range 22.0–77.92). The correlation of the insulin sensitivity indices between the clamp and the FSIGT was 0.51 (P=0.056) for the univariate and 0.67 (P=0.017) for the multivariate analyses. Repeated FSIGTs showed a lower variability for the multivariate than for the standard approach. [Copyright &y& Elsevier]