Insulin secretagogues: Who,what, when,and how?

Sulfonylurea compounds were the first available oral antidiabetic agents and they remain an important tool in our quest for optimal glycemic control. The more recent introduction of meglitinides offers an approach to short-term insulin release with minimal hypoglycemic risk during fasting periods. Published trials suggest that individuals with a hemoglobin A_1c above 8.5% are unlikely to reach currently recommended targets (6.5% to 7%) without the use of one of these insulin secretagogues. Starting and probable maximally effective doses for glimepiride are 1 to 2 mg initially and 4 mg thereafter. For glyburide and glipizide, these are 2.5 to 5 mg initially, and 10 mg effective at a maximum. The large majority of the effect can be seen within a week, making them very attractive when rapid lowering of glucose is needed. An understanding of the principles will facilitate more effective use of initial and combination therapy.     

Insulin pump therapy, should we consider it more often?

Erratic blood glucose control, hypoglycaemia unawareness and optimisation of glycaemic control during pregnancy are widely recognised indications for commencing diabetic patients on continuous subcutaneous insulin infusion (CSII) using an insulin pump. In patients without such a specific condition, the benefit of CSII over other forms of intensified treatment on glycaemic control and hypoglycaemic rate is generally viewed as too modest to warrant a change of regimen. However, the impact of the treatment regimen on psychosocial parameters is often undervalued, at least in randomised trials. This is unfortunate as quality of life and treatment satisfaction probably determine the patient's preferences more than metabolic parameters. To truly appreciate all potential benefits of either strategy (CSII or injection therapy), these data are urgently required. In the meantime, doctors should keep an open eye for the specific needs of the individual patient to find the best treatment available for that person.     

Insulin resistance in HIV infection: drugs, host responses, or restoration to health?

Protease inhibitors (PIs) are widely assumed to be associated with a syndrome of insulin resistance accompanied by hyperlipidemia and fat redistribution. Insulin resistance in HIV infection has numerous other causes, however, which include not only the direct effects of antiretroviral drugs but also factors such as aging and restoration to health accompanied by fat accumulation. Studies of PIs in HIV-infected and noninfected patients indicate that some of these drugs are associated with reduced insulin sensitivity (greater acute versus chronic effects) that may be due to direct blockade of the insulin-sensitive glucose transporter in muscle and fat cells. Other studies have shown that insulin levels increase over time with antiretroviral therapy, likely the result of improved health, fat accumulation, and aging, and that increases in visceral fat and upper trunk fat are associated with a higher risk of insulin resistance in HIV-infected and -uninfected individuals alike. This article summarizes a presentation on insulin resistance in HIV infection made by Carl Grunfeld, MD, PhD, at the 10th Annual Ryan White HIV/AIDS Program Clinical Update in Phoenix in June 2007.     

Effect of the Vasodilatory β-Blocker,Nipradilol, and Ca-Antagonist,Barnidipine, on Insulin Sensitivity in Patients with Essential Hypertension

Objectives To assess the effects of a vasodilatory β -adrenoceptor blocker, nipradilol, and a long-acting Ca channel blocker, barnidipine, on insulin sensitivity.

Design Insulin sensitivity was determined using a euglycemic hyperinsulinemic clamp technique before and after a 12-week treatment period in eighteen patients with essential hypertension.

Results Both drugs decreased blood pressure without affecting any serum parameters of glucose and lipid metabolism. Nipradilol significantly augmented glucose infusion rate (GIR) from 3.11 ± 0.28 to 4.69 ± 0.57 mg/kg/min (p=0.027). Barnidipine also increased GIR from 3.91 ± 0.43 to 5.29 ± 0.43 mg/kg/min (p=0.028). Plasma norepinephrine concentrations significantly increased with barnidipine treatment, while nipradilol had no effect on plasma norepinephrine levels. No adverse events were reported during the study.

Conclusions These results suggest that vasodilatory /3 -blockers such as nipradilol and long-acting Ca channel blockers such as barnidipine may be usefui in the treatment of insulin resistant hypertensive patients.     

Intra-Individual Variability of the Metabolic Effect of a Novel Rapid-Acting Insulin (VIAject?) in Comparison to Regular Human Insulin

Background

The variability of the metabolic action of insulin after subcutaneous (sc) injection hampers optimal insulin therapy. Insulin formulations with a reduced tendency to form hexamers might exhibit a reduced variability of absorption from the sc insulin depot into the blood stream.

Methods

We investigated the within-subject variability of pharmacodynamic and pharmacokinetic properties of an ultra-fast insulin (UFI) formulation and regular human insulin (RHI) in patients with type 1 diabetes. Fourteen patients participated in six 10-hour euglycemic glucose clamp experiments. In this double-blind, crossover study, subjects were randomly assigned to a sequence of two experimental blocks: each block consisted of three doses of 0.1 IU/kg UFI or RHI, respectively, administered on separate days by abdominal sc injection.

Results

Ultra-fast insulin has an earlier onset of action and shorter time to maximal plasma insulin concentration when compared to RHI (tGIR_max 99 ± 36 min vs. 154 ± 74 min, p = 0.002; tC_max 33 ± 16 min vs. 97 ± 39 min, p = 0.00001). The within-subject variability of plasma insulin tC_max (p = 0.027) and of tGIR_max (p = 0.022) was less for UFI than for RHI.

Conclusions

In patients with type 1 diabetes, this UFI showed reduced within-subject variability when compared with RHI.     

Insulin and atherosclerosis: How are they related?

The relationship between insulin and atherosclerosis is complex. People with type 2 diabetes are affected by three main glycaemic disorders: chronic hyperglycaemia; glycaemic variability; and iatrogenic hypoglycaemia. In addition to this triumvirate, the diabetic condition is characterized by lipid disorders, chronic low-grade inflammation and activation of oxidative stress. All these associated disorders reflect the insulin-resistant nature of type 2 diabetes and contribute to the development and progression of cardiovascular (CV) diseases. By both lowering plasma glucose and improving the lipid profile, insulin exerts beneficial effects on CV outcomes. In addition, insulin has several pleiotropic effects such as anti-inflammatory, antithrombotic and antioxidant properties. Insulin per se exerts an inhibitory effect on the activation of oxidative stress and seems able to counteract the pro-oxidant effects of ambient hyperglycaemia and glycaemic variability. However, insulin actions remain a subject of debate with respect to the risk of adverse CV events, which can increase in individuals exposed to high insulin doses. Evidence from the large-scale, long-term ORIGIN trial suggests that early implementation of insulin supplementation therapy in the course of glycaemic disorders, including type 2 diabetes, has a neutral impact on CV outcomes compared with standard management. Thus, the answer to the question “What impact does insulin have on atherosclerosis?” remains unclear, even though it is logical to deduce that insulin should be initiated as soon as possible and that small doses of insulin early on are better than higher doses later in the disease process.     

Oral Insulin Delivery: How Far Are We?

Oral delivery of insulin may significantly improve the quality of life of diabetes patients who routinely receive insulin by the subcutaneous route. In fact, compared with this administration route, oral delivery of insulin in diabetes treatment offers many advantages: higher patient compliance, rapid hepatic insulinization, and avoidance of peripheral hyperinsulinemia and other adverse effects such as possible hypoglycemia and weight gain. However, the oral delivery of insulin remains a challenge because its oral absorption is limited. The main barriers faced by insulin in the gastrointestinal tract are degradation by proteolytic enzymes and lack of transport across the intestinal epithelium.Several strategies to deliver insulin orally have been proposed, but without much clinical or commercial success. Protein encapsulation into nanoparticles is regarded as a promising alternative to administer insulin orally because they have the ability to promote insulin paracellular or transcellular transport across the intestinal mucosa. In this review, different delivery systems intended to increase the oral bioavailability of insulin will be discussed, with a special focus on nanoparticulate carrier systems, as well as the efforts that pharmaceutical companies are making to bring to the market the first oral delivery system of insulin. The toxicological and safety data of delivery systems, the clinical value and progress of oral insulin delivery, and the future prospects in this research field will be also scrutinized.     

Insulin glargine compared to NPH among insulin-naïve, U.S. inner city, ethnic minority type 2 diabetic patients

Aims

We compared basal regimens of glargine or NPH among insulin-naïve, U.S. inner city, ethnic minority type 2 diabetic patients who were sub-optimally controlled on maximally tolerated doses of combination oral agents.

Methods

Eighty-five subjects were randomized to 26 weeks of open-label, add-on therapy using single doses of bedtime NPH, bedtime glargine, or morning glargine; initially through an 8-week dose titration phase, followed by a 16-week maintenance phase during which insulin doses were adjusted only to avoid symptomatic hypoglycemia.

Results

All three groups were comparable at baseline (mean HbA_1c 9.3 ± 1.4%), and improved their HbA_1c (to 7.8 ± 1.3%), fasting, and pre-supper glucose readings, with no significant between-group differences. Weight gain was greater with either glargine regimen (+3.1 ± 4.1 kg and +1.7 ± 4.2 kg) compared to NPH (−0.2 ± 3.9 kg), despite comparable total insulin doses. Pre-supper hypoglycemia occurred more frequently with morning glargine, but nocturnal hypoglycemia and improvements in treatment satisfaction did not differ among groups.

Conclusions

Among inner city ethnic minority type 2 diabetic patients in the U.S., we found no differences in basal glycemic control or nocturnal hypoglycemia between glargine and NPH, although glargine precipitated greater weight gain.     

Advances in Insulin Pen Technologies: Lessons Learned during the Development of HumaPen? Memoir?, an Insulin Pen with a Memory Feature

Insulin pens are developed to address specific needs of diabetes patients for their pens, such as ease of use, portability, and discreetness. Like many consumer-based products, the development of insulin pens can pose significant challenges to the development team in that they must balance substantial accuracy requirements with aesthetic desires. The HumaPen^® Memoir™ team learned valuable lessons throughout the development process that may be worth highlighting. A keen understanding of the unmet needs of the patient population and a skillfully planned product generation map are critical to successful device development. A development team must decide whether to use a Quality Functional Deployment or system engineering-based development plan and, additionally, recognize where proof of concept ends and product development begins to maintain a strict timeline for the project. A proficiency in understanding and managing technical risk is critical to ensure a timely and high-quality product launch to the marketplace.