Sorbitol increases muscle glucose uptake ex vivo and inhibits intestinal glucose absorption ex vivo and in normal and type 2 diabetic rats.

Previous studies have suggested that sorbitol, a known polyol sweetener, possesses glycemic control potentials. However, the effect of sorbitol on intestinal glucose absorption and muscle glucose uptake still remains elusive. The present study investigated the effects of sorbitol on intestinal glucose absorption and muscle glucose uptake as possible anti-hyperglycemic or glycemic control potentials using ex vivo and in vivo experimental models. Sorbitol (2.5% to 20%) inhibited glucose absorption in isolated rat jejuna (IC50 = 14.6% ± 4.6%) and increased glucose uptake in isolated rat psoas muscle with (GU50 = 3.5% ± 1.6%) or without insulin (GU50 = 7.0% ± 0.5%) in a concentration-dependent manner. Furthermore, sorbitol significantly delayed gastric emptying, accelerated digesta transit, inhibited intestinal glucose absorption, and reduced blood glucose increase in both normoglycemic and type 2 diabetic rats after 1 h of coingestion with glucose. Data of this study suggest that sorbitol exhibited anti-hyperglycemic potentials, possibly via increasing muscle glucose uptake ex vivo and reducing intestinal glucose absorption in normal and type 2 diabetic rats. Hence, sorbitol may be further investigated as a possible anti-hyperglycemic sweetener.

Moving toward the ideal insulin for insulin pumps.

Advances in insulin formulations have been important for diabetes management and achieving optimal glycemic control. Rapid-acting insulin analogs provide a faster time-action profile than regular insulin and are approved for use in pumps. However, the need remains for therapy to deliver a more physiologic insulin profile. New insulin formulations and delivery methods are in development, with the aim of accelerating insulin absorption to accomplish ultra-fast-acting insulin time-action profiles. Furthermore, the integration of continuous glucose monitoring with insulin pump therapy enables on-going adjustment of insulin delivery to optimize glycemic control throughout the day and night. These technological and pharmacological advances are likely to facilitate the development of closed-loop pump systems (i.e., artificial pancreas), and improve glycemic control and quality of life for patients with diabetes.

Metabolic implications when employing heavy pre- and post-exercise rapid-acting insulin reductions to prevent hypoglycaemia in type 1 diabetes patients: a randomised clinical trial.

AIM: To examine the metabolic, gluco-regulatory-hormonal and inflammatory cytokine responses to large reductions in rapid-acting insulin dose administered prandially before and after intensive running exercise in male type 1 diabetes patients. METHODS: This was a single centre, randomised, controlled open label study. Following preliminary testing, 8 male patients (24±2 years, HbA1c 7.7±0.4%/61±4 mmol.l-1) treated with insulin's glargine and aspart, or lispro attended the laboratory on two mornings at ∼08:00 h and consumed a standardised breakfast carbohydrate bolus (1 g carbohydrate.kg-1BM; 380±10 kcal) and self-administered a 75% reduced rapid-acting insulin dose 60 minutes before 45 minutes of intensive treadmill running at 73.1±0.9% VO2peak. At 60 minutes post-exercise, patients ingested a meal (1 g carbohydrate.kg-1BM; 660±21 kcal) and administered either a Full or 50% reduced rapid-acting insulin dose. Blood glucose and lactate, serum insulin, cortisol, non-esterified-fatty-acids, ß-Hydroxybutyrate, and plasma glucagon, adrenaline, noradrenaline, IL-6, and TNF-α concentrations were measured for 180 minutes post-meal. RESULTS: All participants were analysed. All glycaemic, metabolic, hormonal, and cytokine responses were similar between conditions up to 60 minutes following exercise. Following the post-exercise meal, serum insulin concentrations were lower under 50% (p<0.05) resulting in 75% of patients experiencing hyperglycaemia (blood glucose ≥8.0 mmol.l-1; 50% n = 6, Full n = 3). ß-Hydroxybutyrate concentrations decreased similarly, such that at 180 minutes post-meal concentrations were lower than rest under Full and 50%. IL-6 and TNF-α concentrations remained similar to fasting levels under 50% but declined under Full. Under 50% IL-6 concentrations were inversely related with serum insulin concentrations (r = -0.484, p = 0.017). CONCLUSIONS: Heavily reducing rapid-acting insulin dose with a carbohydrate bolus before, and a meal after intensive running exercise may cause hyperglycaemia, but does not augment ketonaemia, raise inflammatory cytokines TNF-α and IL-6 above fasting levels, or cause other adverse metabolic or hormonal disturbances. TRIAL REGISTRATION: ClinicalTrials.gov NCT01531855.

Influence of subcutaneous administration of rapid-acting insulin in the quality of (18)F-FDG PET/CT studies.

OBJECTIVE: The aim of this study was to develop a protocol for normalizing blood glucose levels in diabetic patients by subcutaneously administering rapid-acting insulin before administering (18)F-fluorodeoxyglucose ((18)F-FDG) without hindering the quality of PET/computed tomography (CT) studies. MATERIALS AND METHODS: The study included 120 patients, who were divided into four groups: Group I: This group comprised 30 diabetic patients with blood glucose levels lower than 160 mg/dl at the time of arrival at our center; in these patients, (18)F-FDG was injected without prior administration of subcutaneous rapid-acting insulin. Group II: This group comprised 30 diabetic patients with blood glucose levels ranging from 168 to 260 mg/dl; in these patients, subcutaneous rapid-acting insulin was administered and then (18)F-FDG was injected when blood glucose levels dropped below 160 mg/dl (30-115 min). Group III: This group included 30 diabetic patients with blood glucose levels ranging from 192 to 324 mg/dl; in these patients, subcutaneous rapid-acting insulin was administered and then (18)F-FDG was injected 4 h later. Blood glucose levels dropped below 160 mg/dl (range, 58-159 mg/dl) in all patients. CONTROL GROUP: This group included 30 nondiabetic patients with normal blood glucose levels (72-104 mg/dl). We calculated the mean standardized uptake value (SUV) of muscle from the maximum SUV in five consecutive axial slices in the proximal middle third of the rectus femoris muscle of the right thigh. RESULTS: The quality of the PET-CT studies was considered suboptimal when muscle uptake was more than 2 SDs greater than the mean muscle uptake in the control group (1.15±0.2). The mean SUV of muscle was as follows: Group I, 1.09 (σ=0,26); group II, 1.98 (σ=0,32); group III, 1.98 (σ=1,13); and control group IV, 1.15 (σ=0,2). The quality of PET-CT studies was considered suboptimal in 18 patients in group II (60%) and in four patients (13%) in group I. The quality was optimal in all studies conducted in group III patients. CONCLUSION: Subcutaneous administration of rapid-acting insulin normalizes blood glucose levels without compromising the quality of PET-CT studies when (18)F-FDG is administered not earlier than 4 h later.

Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice.

Long-acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients' individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost-effective not to use long-acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care.

Integrating advances in insulin into clinical practice: Overview of current insulin formulations.

Defects in both insulin secretion and function play a fundamental role in the pathophysiologic mechanisms underlying both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). As the most physiologic treatment option available, insulin plays a central role in the management of patients with T1DM and a growing role in the management of patients with T2DM, as is reflected in current treatment guidelines.

Pharmacodynamic effects of the oral glucokinase activator AZD6370 after single doses in healthy volunteers assessed with euglycaemic clamp.

AIMS: This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamic effects of the glucokinase activator (GKA) AZD6370 in non-diabetic subjects, using the euglycaemic clamp to avoid the risk of hypoglycaemia. METHODS: Oral single ascending doses of AZD6370 10-650 mg or subcutaneous short-acting insulin 4 or 12 U were given to healthy fasting subjects. AZD6370 safety, tolerability and pharmacokinetics were assessed. Pharmacodynamic effects on serum (S)-insulin and glucose infusion rate (GIR) were investigated with euglycaemic clamp. AZD6370 10-20 mg was also assessed when taken with food without euglycaemic clamp. RESULTS: AZD6370 was well tolerated and no safety concerns were raised. AZD6370 was rapidly absorbed and eliminated, and plasma concentration was proportional to dose. Both S-insulin and GIR increased following AZD6370 administration. The observed increase in GIR correlated with increasing AZD6370 area under the plasma concentration vs. time curve, demonstrating a dose-concentration-dependent pharmacodynamic effect. AZD6370 at doses of 50 and 80 mg had similar effects to short-acting insulin 4 U on peripheral S-insulin levels but greater effects on GIR, suggesting an effect beyond the increase of peripheral S-insulin levels at lower doses. In the food interaction part of the study, performed without euglycaemic clamp, dose escalation was stopped at a low dose (20 mg) because of hypoglycaemia. CONCLUSION: The euglycaemic clamp was successfully used to avoid hypoglycaemia and to demonstrate pharmacodynamic effects, that is, markedly increased insulin secretion and glucose utilisation, following administration of AZD6370 in healthy fasting subjects. In addition to the effect on pancreatic insulin secretion, the data support an extra-pancreatic (hepatic) component of GKA action.

Body mass index and the efficacy of needle-free jet injection for the administration of rapid-acting insulin analogs, a post hoc analysis.

We recently showed in a euglycaemic glucose clamp study among 18 healthy volunteers that using jet injectors rather than conventional pens significantly improved the time-action profiles of rapid-acting insulin analogs. Here, we investigated whether such profiles were modified by body mass index (BMI) and related weight parameters by comparing insulin administration by jet injection to that by conventional pen in subgroups defined by BMI, waist-to-hip ratio, waist circumference and insulin dose. After conventional administration, times to peak insulin levels (T-INS(max)) occurred 31.1 [95% confidence interval (CI) 13.7-48.5] min later and time to maximum glucose requirement (T-GIR(max)) 56.9 (95%CI 26.6-87.3) min later in more obese (BMI > 23.6 kg/m(2)) than in lean subjects (BMI < 23.6 kg/m(2)). In contrast, T-INS(max) and T-GIR(max) were similar in subjects with high and low BMI, when insulin was administered by jet injection. We conclude that using jet injection for insulin administration may especially benefit subjects with higher body weight.

Design of non-standard insulin analogs for the treatment of diabetes mellitus.

Structure-based protein design has enabled the engineering of insulin analogs with improved pharmacokinetic and pharmacodynamic properties. Exploiting classical structures of zinc insulin hexamers, the first insulin analog products focused on destabilization of subunit interfaces to obtain rapid-acting (prandial) formulations. Complementary efforts sought to stabilize the insulin hexamer or promote higher-order self-assembly within the subcutaneous depot toward the goal of enhanced basal glycemic control with reduced risk of hypoglycemia. Current products either operate through isoelectric precipitation (insulin glargine, the active component of Lantus; Sanofi-Aventis, Paris, France) or employ an albumin-binding acyl tether (insulin detemir, the active component of Levemir; Novo-Nordisk, Basværd, Denmark). In the past year second-generation basal insulin analogs have entered clinical trials in an effort to obtain ideal flat 24-hour pharmacodynamic profiles. The strategies employ non-standard protein modifications. One candidate (insulin degludec; Novo-Nordisk a/s) undergoes extensive subcutaneous supramolecular assembly coupled to a large-scale allosteric reorganization of the insulin hexamer (the TR transition). Another candidate (LY2605541; Eli Lilly and Co., Indianapolis, IN, USA) utilizes coupling to polyethylene glycol to delay absorption and clearance. On the other end of the spectrum, advances in delivery technologies (such as microneedles and micropatches) and excipients (such as the citrate/zinc-ion chelator combination employed by Biodel, Inc., Danbury, CT, USA) suggest strategies to accelerate PK/PD toward ultra-rapid-acting insulin formulations. Next-generation insulin analogs may also address the feasibility of hepatoselective signaling. Although not in clinical trials, early-stage technologies provide a long-range vision of "smart insulins" and glucose-responsive polymers for regulated hormone release.

Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin.

Barriers to the use of prandial insulin regimens include inadequate synchronization of insulin action to postprandial plasma glucose excursions as well as a significant risk of hypoglycemia and weight gain. Technosphere® insulin (TI) is an inhaled ultra-rapid-acting human insulin that is quickly absorbed in the alveoli. With a time to maximum plasma drug concentration of approximately 14 min and a time to maximum effect of 35 to 40 min, TI more closely matches the postprandial insulin concentrations seen in nondiabetic individuals. Studies have shown that long-term administration of prandial TI in combination with long-acting basal insulin results in reductions in hemoglobin A1c comparable to conventional subcutaneously injected prandial insulins but with improved control of early postprandial BG. Furthermore, TI has been associated with less weight gain and a lower incidence of hypoglycemia, which may enhance patient satisfaction and acceptability of insulin therapy. This review discusses the clinical properties of TI and proposes strategies for optimal use.

Improved pharmacokinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology.

OBJECTIVE: Insulin administered by jet injectors is dispensed over a larger subcutaneous area than insulin injected with a syringe, which may facilitate a more rapid absorption. This study compared the pharmacologic profile of administration of insulin aspart by jet injection to that by conventional insulin pen. RESEARCH DESIGN AND METHODS: Euglycemic glucose clamp tests were performed in 18 healthy volunteers after subcutaneous administration of 0.2 units/kg body wt of aspart, either administered by jet injection or by conventional pen, using a randomized, double-blind, double-dummy, cross over study design. Pharmacodynamic and pharmacokinetic profiles were derived from the glucose infusion rate (GIR) needed to maintain euglycemia and from plasma insulin levels, respectively. RESULTS: The time to maximal GIR was significantly shorter when insulin was injected with the jet injector compared with conventional pen administration (51 ± 3 vs. 105 ± 11 min, P < 0.0001). The time to peak insulin concentration was similarly reduced (31 ± 3 vs. 64 ± 6 min, P < 0.0001) and peak insulin concentrations were increased (108 ± 13 vs. 79 ± 7 mU/L, P = 0.01) when insulin was injected by jet injection compared with conventional pen injection. Jet injector insulin administration reduced the time to 50% glucose disposal by ∼40 min (P < 0.0001). There were no differences in maximal GIR, total insulin absorption, or total insulin action between the two devices. CONCLUSIONS: Administration of insulin aspart by jet injection enhances insulin absorption and reduces the duration of glucose-lowering action. This profile resembles more closely the pattern of endogenous insulin secretion and may help to achieve better meal insulin coverage and correction of postprandial glucose excursions.

Insulin X10 revisited: a super-mitogenic insulin analogue.

The molecular safety of insulin analogues has received a great deal of attention over the last year. In particular, attention has been directed to the mitogenic properties of insulin analogues as compared with human insulin. Understanding the mechanisms implicated in mediating mitogenic effects of insulin is therefore of particular interest. In this review we detail the story of the rapid-acting insulin analogue known as X10, which was the first insulin analogue in clinical development, but ended up being discontinued at an early clinical development stage following findings of mammary tumours in female Sprague-Dawley rats. The molecular characteristics of insulin X10, along with its interaction at both the IGF-1 receptor and the insulin receptor, have provided us with important insights into mechanisms implicated in metabolic and mitogenic signalling of insulin analogues.