Benchmark Cambridge Trial In Quest For Ambulatory Artificial Pancreas

I had reported earlier that once perfected and approved by regulators, safe and robust ambulatory artificial pancreas ‒ or to use the scientific term ‘closed loop insulin delivery system’ ‒ has the potential to greatly improve the health and lives of people with type 1 diabetes. The idea itself is not new but the old generation closed loop insulin delivery systems were cumbersome and unsuitable for long term or outpatient use.

Artificial pancreas concept

The newer systems link a continuous glucose monitor and a subcutaneous insulin infusion pump via a control algorithm, which retrieves continuous glucose monitoring data in real time (for example, every five minutes) and uses a mathematical formula to compute insulin delivery rates that are then transmitted to the insulin pump.

However, artificial pancreas that can be worn by diabetics on their person as they go about their daily lives is still in development, with the first in-clinic studies now being reported. Preliminary results have been promising ‒ the most notable improvement is in overnight control of type 1 diabetes, with improvements in safety and a reduction in nocturnal hypoglycemia being reported.

These improvements result from the fine adjustment of insulin delivery provided by closed loop control overnight being superior to a generally fixed basal rate and less likely to cause hypoglycemia. The first application of closed loop control is therefore likely to be in glucose regulation overnight, a step that has the potential to improve dramatically the safety of insulin delivery during crucial, generally unsupervised, periods.

Now a University of Cambridge research tem led by Roman Hovorka has demonstrated the safety and efficacy of overnight closed loop insulin delivery with conventional insulin pump therapy in adults with type 1 diabetes.

Artificial Pancreas Best Hope For Diabetics In Near Term

The trial group consisted of 24 adults (10 men and 14 women) aged 18-65, who had used insulin pump therapy for at least three months and the research team used two protocols ‒ a medium sized meal (60 g carbohydrate) and a large size meal (100 g carbohydrate + alcohol) ‒ to see whether artificial pancreas were effective in overcoming nocturnal hypoglycemia.

As in previous studies carried out by Boris Kovatchev and others in the U.S. and France, the Cambridge closed loop system significantly increased the time that plasma glucose was in the target range (70-144 mg/dl), reduced incidence of hypoglycemia, and better overnight control.

But what makes the Cambridge study important is that the randomized crossover trial design is virtually unique in the field of closed loop control. Because this design is the gold standard for clinical research, the results set a benchmark for future studies.

The only other randomized controlled trial of closed loop control was recently presented by the University of Virginia research team led by Kovatchev at the 4th International Conference on Advanced Technologies and Treatments for Diabetes. This study recruited 24 adults and adolescents with type 1 diabetes in the United States and in France and achieved results similar to those reported by Hovorka and colleagues ‒ more time within the target range of 70-180 mg/dl and a threefold reduction in hypoglycemia.

Dr Roman Hovorka

Moreover, the control algorithm used by Hovorka and colleagues belongs to an advanced class of closed loop control technologies known as “model predictive control”. Algorithm designs for artificial pancreas have generally used either “proportional-integral-derivative control” or “model predictive control”.

Proportional-integral-derivative control algorithms are reactive, responding to changes in glucose levels with adjustment in insulin delivery. Model predictive control algorithms are built over a model of the human metabolic system and are therefore proactive, delivering insulin in anticipation of changes in glucose concentrations.

This compensates partially for the time delays inherent in subcutaneous glucose control (the time delay in insulin action, which can amount to 60 minutes or more). For this reason, model predictive control has become the approach of choice more recently.

The algorithm developed by Hovorka and colleagues has certain distinct features, such as real time adaptation of the underlying model to changing patient parameters implemented as a selection from several predefined models. However, this potential advantage remains to be evaluated.

Most importantly, this is one of the first studies to test realistic meal scenarios and challenge the participants with a large dinner that included alcohol. As such, the study is a clear advance in the quest for an artificial pancreas that can be used by a diabetic while performing normal daily activity.

However, as the authors admit, one limitation is the exclusivelymanual control of the artificial pancreas used relied on study personnel to transmit data manually from the continuous glucose monitor (CGM) to the computer running the closed loop control, and to transmit insulin injection recommendations from the computer to the insulin pump because of technological and regulatory barriers

In fully automated systems ‒ which is what researchers and medical device makers are hoping to make a reality for diabetics ‒ these processes are handled by data transmission and pump control devices, respectively. However, Cambridge method limited the investigation to testing only the control algorithm, not the artificial pancreas as a whole. The testing of other key components, such as sensor-pump communication and error mitigation, would require much more effort and thorough system validation.

Studies using fully automated systems have already been reported by the Artificial Pancreas Project and offer hope for the future of ambulatory systems i.e. devices that be worn by diabetics on their person in their daily lives.

Lastly, despite the sophistication of the control algorithm and the significant reduction in nocturnal hypoglycemia, four episodes of severe hypoglycemia (<70 mg/dl) occurred, three of which the authors thought were attributable to the preceding prandial insulin dose and could not be prevented by the artificial pancreas suspending insulin delivery.

This finding reinforces the recently proposed idea that a dedicated hypoglycemia safety system ‒ a separate algorithm responsible solely for the assessment and mitigation of the risk of hypoglycemia ‒ may need to accompany closed loop control. Such safety systems already exist, and have proved useful.

Based on ‘Boris Kovatchev: Closed Loop Control For Type 1 Diabetes (BMJ 2011; 342:d1911)

Related Post: Killer Apps That Are Revolutionizing Diabetes Care

Individualized Care Plans Important for Treating Diabetes, Says AACE

The American Association of Clinical Endocrinology (AACE) on April 14 released new clinical practice guidelines for developing comprehensive care plans for patients with type 1 and type 2 diabetes mellitus, developed by a panel of 23 of the leading diabetes experts in the U.S.

Debunking one-size-fits-all care plans, the guidelines emphasize the importance of achieving a treatment plan that avoids hypoglycemia, now considered to be a continual and pressing concern for many patients with diabetes. The implications of the new guidelines for practicing physicians, as well as new data on low blood sugar in patients with diabetes, are being discussed at the AACE 20th Annual Meeting and Clinical Congress, now in session in San Diego.

Caring Doctors Improve Patients' A1c, LDL Scores

The new AACE guidelines are also published in supplement 2 of the March/April issue of the association's official medical journal, Endocrine Practice.

The guidelines emphasize a personalized approach to controlling diabetes and achieving blood glucose targets with care plans that take into account patients' risk factors for complications, comorbid conditions, and psychological, social, and economic status. Although the guidelines recommend a blood glucose target of an HbA1c level of 6.5%, if it can be achieved safely, a treatment plan should take into account a patient's risk for the development of severe hypoglycemia.

CGM is the New Standard

The new guidelines also provide information on the appropriate use of new technologies such as insulin pumps and continuous glucose monitoring, as well as managing conditions that may not be immediately obvious to treating physicians, such as sleep and breathing disturbances and depression.

Millions Risk Early Death Because of Poor Diagnosis and Ineffective Treatment

In a statement, Yehuda Handelsman, MD, AACE president-elect and co-chair of the AACE Diabetes Guidelines Writing Committee, said that it was crucial for physicians to address not just hyperglycemia in patients with diabetes but also associated cardiovascular risk factors. "These state-of-the-art guidelines provide the most up-to-date evidence-based answers to real-life (clinical) questions," Dr. Handelsman said.

Tight Cholesterol, BP Control Does Little Good for Diabetics

In the guidelines, AACE recommends comprehensive diabetes lifestyle management education at the time of diagnosis, as well as throughout the course of diabetes. The importance of medical nutrition therapy, physical activity, avoidance of tobacco products, and adequate quantity and quality of sleep should be discussed with patients who have prediabetes, as well as type 1 and type 2 diabetes, according to the new guidelines.

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Hypoglycemia: Many Diabetics Do Not Know Most Common Symptoms Like Dizziness and Shakiness Linked to Low Blood Sugar

NEW survey data released today at the American Association of Clinical Endocrinologists (AACE) 20th Annual Meeting and Clinical Congress reveal that more than half (55%) of people with type 2 diabetes across the country report they have experienced hypoglycemia, or low blood sugar. But, surprisingly, many patients remain uneducated about the risks for hypoglycemia.

The survey also highlighted why hypoglycemia may be more of a health hazard than previously reported, as patients said they often experience low blood sugar during daily activities such as working and driving. Indeed, hypoglycemia has clear risks, as well as being an expensive burden for the healthcare system.

This survey of 2,530 adults diagnosed with type 2 diabetes assessed patients’ personal experience with and knowledge about low blood sugar, and was conducted online in November and December 2010 by Harris Interactive. (See details below)

Hypoglycemia occurs when the level of glucose in the blood is too low for the body’s needs. Symptoms that may be caused by low blood sugar include nervousness or anxiety, shakiness, sweating, tiredness, confusion, hunger, fast heartbeat and dizziness. Low blood sugar usually is caused by eating less or later than usual, changes in physical activity, or a diabetes medicine that is not matched to your needs.

Many diabetics experienced hypoglycemia during typical daily activities such as working (42%), exercising (26%) and driving (19%), according to the survey designed by the American College of Endocrinology (ACE). Recognizing symptoms like nervousness, sweating or shakiness before engaging in common activities is important to help reduce the risk of serious consequences, such as fainting or loss of consciousness.

(These eye-popping results can be extrapolated to other countries as well. I mean, if this is happening in America where the level of diabetes awareness is high thanks to a widespread education program, one can only speculate about the scenario in less developed countries like India and China.) 

Hypoglycemia: Don'y Rely on the Doctor's Prognosis - Tell Him What Needs to be Done to Save Your Life

The fact that patients with diabetes experience hypoglycemia while working and driving is especially problematic, as these activities require focus and concentration, and experiencing hypoglycemia during driving can be life-threatening, said Etie Moghissi, MD, vice president and president-elect of AACE, and an associate clinical professor of medicine at the University of California in Los Angeles, at a press conference.

Although the study clearly showed that at least half (52%) of the patients surveyed were concerned about experiencing a future episode of hypoglycemia, some did not know that the most common symptoms are dizziness (22%) and shakiness (17%), and 39% incorrectly thought that thirst was the primary symptom of hypoglycemia. "Many patients are unable to name the leading causes of hypoglycemia, which is also a great cause for concern," Moghissi confirmed.

Low blood sugar can be caused by skipping meals or irregular mealtimes, sudden increase in or excessive exercise, or certain diabetes medications. In this survey, a number of patients with type 2 diabetes were unable to identify the leading causes, including skipping meals, such as breakfast (27%), and certain diabetes medications (35%). Forty-six percent of patients with type 2 diabetes also remained unaware that excessive exercise may bring on hypoglycemia, particularly when combined with some medications for type 2 diabetes.

These results suggest there is a need for better education and understanding of the common causes, signs and symptoms of low blood sugar. Learning to recognize the symptoms of low blood sugar and quickly treating them is important – symptoms may be mild at first but may worsen quickly if not treated. According to the survey, 6 percent of patients with type 2 diabetes have had to go to the emergency room at some point as a result of low blood sugar.

To help bridge this knowledge gap, ACE recently launched the Blood Sugar Basics program, which aims to help people living with diabetes, their families and loved ones learn about the importance of understanding and managing low and high blood sugar. While the program is focused on type 2 diabetes, the most common type of diabetes, it also may be useful for people with other types of diabetes.

Although hypoglycemia has long been known to be a risk associated with diabetes and its treatment, it often falls under the radar of busy physicians, particularly those in primary care, who may be treating patients for other conditions, Moghissi noted. "The survey shows that it's important to inform patients about the causes, symptoms, and how to address hypoglycemia," Moghissi stressed.

“Low blood sugar can be an alarming experience for people with type 2 diabetes, and failure to recognize and treat symptoms in a timely manner can cause serious complications,” says Moghissi, adding, “Low blood sugar can be avoided, so it’s important for patients to know what can cause blood sugar levels to drop and talk with their doctor about how they can reduce the frequency of future episodes.”

The need for emergency care is just one of the potential consequences resulting from untreated low blood sugar. The survey also indicated that about one in five (21%) patients who have experienced it have needed assistance from others. It is important that patients and their friends, family and caregivers recognize and understand the symptoms of low blood sugar and what to do if it occurs.

Survey Design
This survey was conducted online by Harris Interactive between November 17 and December 14, 2010, among 2,530 adults diagnosed with type 2 diabetes mellitus in the United States. This included 1,308 nationally sampled respondents, as well as oversamples in the following metropolitan statistical areas (MSAs): Cleveland (n=261), Dallas (n=208), Detroit (n=222), Houston (n=211), St. Louis (n=200), San Diego (n=120). Results were weighted as needed for age, sex, race/ethnicity, education, region and household income. Propensity score weighting also was used to adjust for respondents’ propensity to be online. A full methodology is available upon request. The survey was developed by the American College of Endocrinology (ACE) and supported by Merck.

About Blood Sugar Basics
Blood Sugar Basics is an educational program aimed to help people living with diabetes, their families and loved ones learn about the importance of blood sugar control as part of a successful diabetes treatment plan. The program was developed by the American College of Endocrinology (ACE) and supported by Merck.

Efficacy of HbA1c Results Questioned; CGM is the New Standard, Claim Experts

WHILE HbA1c tests have been considered the gold standard for years, these tests do not necessarily correlate to good diabetes control. But HbA1c is only an average of glucose levels over time. A person can have major highs and lows every day, yet still have a "good" HbA1c level.

This is one reason why recent clinical trials reveal that HbA1c tests alone do not necessarily correlate to good diabetic control. It is also important to know that the more often you are outside your target range, the higher your risk of diabetes-related complications.

Indeed, there are many diabetics who experience hypoglycemia and hyperglycemia so often that they no longer realize when they have symptoms. Large-scale studies have shown, over time, these glycemic excursions cause major complications to the vascular system and organs.

Writing in his Endocrine Today blog, Michael Kleerekoper, MD, MACE wonders whether HbA1c is a reliable measure of glycemic control in an individual patient. His answer is: “It depends.”

As far as I can gather, the HbA1c is reliable in patients with fairly stable home blood glucose values, but too few patients measure blood glucose often enough to know this. It’s not the patient’s fault — their insurance carrier is very niggardly about the number of times a day a patient is allowed to measure blood sugar. If only the carrier would recognize the longer-term health care costs in those patients! All too often the patient leaves the glucose meter at home — that’s like going to the pediatrician without the baby.

Serial HbA1c is far less reliable in patients with widely fluctuating blood glucose values. Continuous glucose monitoring (CGM) is being utilized more frequently to document widely fluctuating blood glucose values, and patients learn a lot from the graphical illustration of how well or not well they are taking care of their diabetes.

Point-of-care HbA1c instruments are available and are also being used more often in the clinic. It makes sense to have the data available while the patient is still in the clinic rather than wait 24 hours for the lab result to come back.

Caveat emptor! If you are of a mind to get a handheld HbA1c device for your clinic, I encourage you to first read the editorial and article published in Clinical Chemistry about 1 year ago. Only two of the eight available devices were reliable!

Kleerekoper’s reservations bring us back to the question posed in the headline of this article: Are HbA1c results reliable enough?

Goals of Diabetes Self-Management
Basically, the goal of diabetes self-management is to help patients optimally manage their diabetes based on:

• Individual needs

• Customized goals

• Personal lifestyle considerations

So, do diabetics stick with the old fingerstick monitoring or shift tocontinuous glucose monitoring (CGM)?

Improving Diabetes Management
Over a decade ago, a landmark study called the Diabetes Control and Complications Trial — the largest study of its kind — revealed the importance of good glucose control. New, large-scale studies are revealing even more improvements in glucose control with the use of CGM technology.

In a recent study, people who were considered to be in "good control" showed distinct improvements in time spent within their target zone while using a CGM device. And subjects who were considered to be in "poor control" before the study, had even more impressive improvements with a 70% increase in time they spent in their target zone.

A recent study by the Juvenile Diabetes Research Foundationshowed that using a CGM, for at least 6 days a week can lead to significant decreases in HbA1c and can provide a greater ability to reach the ADA recommended goal of 7%.

Revealing Unnoticed Highs and Lows
A CGM device can call attention to highs and lows that you may often experience, but not recognize. Sometimes people have"hypoglycemia unawareness" — they no longer feel their symptoms of going low. And some people are also unable to feel symptoms of high glucose. Over time, frequently swerving outside of your target range can lead to severe consequences, such as damage to your nerves, eyes, kidneys, and other organs.

Fingerstick vs. CGM: Revealing Unnoticed Highs & Lows

Recent studies reveal that fingerstick testing alone does not provide enough information to stay within their target range — even people who monitor frequently. In contrast, the use of a CGM device does a better job of helping people to stay between the lines. Indeed, CGM, especially in conjunction with HbA1c, helps to show a more complete picture of glucose control.

Real-Time Trending = 288 Fingersticks!
Fingerstick monitoring alone does not provide enough information for patients to act preemptively to avoid hyper- and hypoglycemic events. A major benefit of CGM is that it can help patients identify fluctuations and trends that would otherwise go unnoticed with standard fingerstick testing.

A CGM measures glucose levels and sends a glucose value every 5 minutes from the Transmitter to the Receiver. This is equivalent to a patient taking 288 fingerstick readings daily. However, unlike fingersticks, patients see real-time trending of glucose levels and patterns.

A CGM system shows patients their current glucose value, as well as their glucose trend over the past several hours (1-, 3-, 6-, 12-, and 24-hour trends). It also tells them how quickly their glucose is changing. And when glucose levels go above or below the set target range, alerts notify patients so they are able to take corrective action before going too low or too high — helping them stay between the lines.

Damage Caused By Glucose Variability
There is a growing body of clinical evidence showing that glucose variability itself — independent of HbA1c — initiates a cascade ofphysiological damage. Over time, hyper- and hypoglycemic events significantly increase the risk of diabetic complications, such as retinopathy and general microvascular pathogenesis, at least partially due to increases in oxidative stress and pro-inflammatory cytokines that are triggered by hyper- and hypoglycemic swings.

A CGM device can call attention to dangerously low overnight glucose levels that often go undetected, reveal previously unnoticed hyperglycemia spike trends between meals, show early morning highs in glucose, clarify the way diet and exercise affect your patients' glucose levels and provide a long-term comprehensive assessment of the effects of adjustments in diabetes management.

It is not surprising, therefore, that in recent years CGM has gained acceptance among diabetes experts as an effective tool for helping people achieve their diabetes goals:

• Achieve HbA1c targets without adding hypoglycemia

• Reduce glucose highs and lows

• Reduce hypoglycemia

Indeed, when using a continuous glucose monitoring (CGM) device, study results demonstrate that the patients were actually experiencing extensive fluctuations in glucose levels. CGM, especially in conjunction with HbA1c, helps to show a more complete picture of glucose control.

Incretin Secretion, Action in the Natural History Of Type 2 Diabetes

INCRETIN hormones contribute a major portion to the insulin secretory responses after meals in healthy people. The incretin effect describes the phenomenon that oral glucose elicits approximately threefold greater insulin responses than the elevation in glucose (achieved with glucose administered intravenously) alone.

(Incretins are gastrointestinal hormones that influence insulin secretion, and which have been the basis for the development of new medications for type 2 diabetes.)

The incretin effect is the result of nutrient-stimulated secretion of the incretin hormones glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 and their insulinotropic effect (ie, the augmentation of insulin secretion at elevated plasma glucose concentrations). In patients with type 2 diabetes, this incretin effect is severely impaired or even absent.

It is the purpose of this commentary to highlight current knowledge in incretin research and to answer the question of whether and to which degree abnormalities in incretin hormone secretion and action accompany the development of type 2 diabetes or even contribute to this process.

The reduced incretin effect in patients with type 2 diabetes was first noticed in 1967 and was clearly established in 1986.

Three types of questions arose from this finding:

• What is the mechanism behind the reduced incretin effect? Is the secretion or insulinotropic action of GIP and GLP-1 at fault?

• Are defects in the enteroinsular axis (the signaling system between the gut, from where incretin hormones are secreted, and the endocrine pancreas, the main target tissue that incretin hormones act on) important for the development and/or progression of type 2 diabetes?

• Can the pathophysiological characterization of the incretin system in type 2 diabetes provide clues for the development of new approaches for the treatment of this metabolic disease?

A severe impairment in the insulinotropic (stimulating or affecting the production and activity of insulin) activity of GIP in type 2 diabetes explains the reduced incretin effect.

A large cross-sectional study by Toft-Nielsen and colleagues comparing GLP-1 responses after meal stimulation suggested a reduced release of GLP-1 in patients with type 2 diabetes and, to a lesser extent, impaired glucose tolerance (“prediabetes”).

This widely quoted study was sometimes interpreted to indicate a progressive loss in the capacity of GLP-1 secretion in the natural history of type 2 diabetes, starting from normal secretion as long as glucose tolerance was normal with slight impairments when IGT develops, with a further deterioration after the diagnosis of type 2 diabetes and little residual capacity for GLP-1 secretion when the condition has progressed.

The logical consequence was to replace a missing hormone by advocating incretin-based antidiabetic agents (GLP-1 receptor agonists [mimicking the action of a naturally occurring substance] or DPP-4 inhibitors [medicines like Januvia(sitagliptin), Onglyza (saxagliptin), and Galvus (vildagliptin) that contain DPP-4].

However, not all studies that have compared the secretion of GLP-1 in patients with type 2 diabetes and in matched healthy people come to the same conclusions.

A recent meta-analysis suggested no uniform reduction in L-cell secretion between healthy and type 2 diabetic patients, but a large interindividual variation, in part determined by age, obesity and plasma levels of glucagon and free fatty acids.

In nondiabetics, the amount of GIP and GLP-1 secreted is significantly correlated to the incretin effect in quantitative terms. Thus, a low secretion of GLP-1 may determine a reduced incretin effect on an individual level, but does not explain the reduced incretin effect in patients with type 2 diabetes by and large.

If secretion is not the culprit, is there any peculiarity regarding the action of incretin hormones in type 2 diabetes? As originally described using GIP of the porcine amino acid sequence, and later confirmed using synthetic human GIP, the endocrine pancreas shows very little secretory response, even if exposed to supraphysiological concentrations of GIP.

This inability to respond to GIP appears to be acquired, since populations at high risk for developing type 2 diabetes do not display a similar defect. Basically, the response to GIP seems to be normal in any form of prediabetes (first-degree relatives, patients recovering from gestational diabetes, etc.), but after diagnosis (ie, with a fasting glucose ≥126 mg/dL), the incretin effect is reduced or lost, as is the ability to respond to exogenous GIP.

Most likely, the inability to elicit insulin secretory responses with GIP, even at hyperglycemia, is explained by a generalized impairment in beta-cell secretory capacity, as is typical for type 2 diabetes, no matter which stimulus is looked at (hyperglycemia, amino acids, sulfonylureas, etc).

Furthermore, rodent studies have suggested a down-regulation of the GIP receptor by chronic hyperglycemia. The fact that this defect becomes apparent when glucose concentrations rise above the normal level has raised the question of whether this phenomenon is reversible by glucose normalization.

A recent study by Højberg and colleagues suggested that this may be the case. However, although the insulin secretory responses to GIP and GLP-1 were significantly improved, normalization was not achieved after improved glucose control.

Abnormalities in the incretin system accompany the development of type 2 diabetes and may contribute to the velocity of progression. Figure 1 depicts the natural history of developing type 2 diabetes and also the progression of the disease after the diagnosis has been made.

Changes in insulin secretory capacity, based on homeostasis model assessment (HOMA) estimation of beta-cell function, and insulin sensitivity preceding the diagnosis were taken from a recent analysis by Tabak and colleagues. The development after the diagnosis of diabetes was based on analyses from the UKPDS and ADOPT study.

Regarding the secretion of GIP and GLP-1, we refer to our recent review indicating no general abnormalities in K-cell (GIP) and L-cell (GLP-1) secretion associated with a diagnosis of type 2 diabetes.

The fact that in none of the studies examining prediabetic populations, insulinotropic GIP effectiveness was impaired, but after the diagnosis, uniformly, a severe inability to respond to GIP with secreting insulin was documented, is the basis for assuming a substantial drop in beta-cell responsiveness to GIP around the time of diagnosis, with no further changes afterward (Figure 1).

In a recent review, we have explained reasons to assume that this inability to secrete insulin in response to GIP stimulation goes along with a general impairment of beta-cell function, which is demonstrable with most other secretagogues as well.

Whether this inability of the endocrine pancreas to respond to GIP contributes to the natural history of type 2 diabetes can only be evaluated by quantitative considerations. If a mechanism to stimulate insulin secretion after meals that normally contributes two-thirds of the overall secretory responses is at fault, this almost certainly has the effect to accelerate the progression of type 2 diabetes because without the additional incretin stimulus, overall insulin secretion should be further impaired.

In the case of GLP-1, the insulinotropic activity is somewhat reduced after the diagnosis of type 2 diabetes, and even worse under the condition of uncontrolled hyperglycemia compared with healthy controls.

High pharmacological doses of GLP-1, nevertheless, have the potential to raise insulin concentrations and to suppress glucagon secretion, with the overall result of normalizing glucose concentrations in the fasting state and after meals over a wide range of patients with type 2 diabetes, ranging from those treatable with lifestyle modification (“diet and exercise”) to those requiring insulin treatments.

Thus, the “resistance” to GIP of the type 2 diabetic beta-cell can be overcome by a compensatory exposure to high concentrations of the incretin hormone, GLP-1. GLP-1 itself appears to be less important than GIP for postprandial glucose control in healthy people and does not seem to be involved in the pathogenesis (origination and development) of type 2 diabetes.

However, because of its preserved efficacy in type 2 diabetes, GLP-1 is an effective agent to treat hyperglycemia in type 2 diabetic patients, with the added benefits of inducing weight loss and avoiding hypoglycemia.

By Michael A. Nauck, MD, PhD, Irfan Vardarli, MD (Diabeteszenstrum Bad Lauterberg), and Juris J. Meier, MD (St. Josef-Hospital, Ruhr-University of Bochum, Germany)

Source: Endocrine Today

Diabetes: Artificial Pancreas Best Hope For Diabetics In Near Term

The realization that breakthroughs in biology-based therapies for diabetes are not imminent is spurring tech-based innovation in insulin delivery mechanisms
The days when ‘the only choice open to diabetes sufferers was that between death by coma and death by starvation’ passed unmourned into history in 1922, when insulin was first used therapeutically.

Even today, however, diabetes has lost none of its fearsomeness, because even today diabetics live in constant fear of overdosage or underdosage of their medicines, especially insulin, and of consequent hypoglycemic episodes and late complications that can result from inadequate treatment and prolonged elevation of blood glucose level.

Artificial Pancreas Project concept

Patients with diabetes whose blood glucose levels are kept close to normal by means of suitable therapeutic measures avoid the risk of dangerous hypoglycemic episodes and develop complications of diabetes considerably less frequently and later than their less successfully treated counterparts. But there is realization that breakthroughs in biology-based therapies for diabetes are not imminent. Sure, there is hope that they’re going to happen, but more long-term research is needed.

In the meanwhile, technology that can meet this need is available and is spurring innovation in insulin delivery mechanisms. As a result, diabetes technology, and particularly the artificial pancreas, has become an area of very rapid academic and industrial development.

A precondition for this success is close monitoring of blood glucose levels. Therefore, a great deal of research activity has been directed towards the development of sensors that permit near-painless, continuous measurement of blood glucose level. The objective is to develop a system that pairs continuous blood glucose monitoring with an insulin pump and thus acts as an ‘artificial pancreas’.

Why Continuous Blood Glucose Monitoring Is Desirable
It is difficult to achieve good metabolic control in diabetics. Especially in patients on intensive insulin therapy, good metabolic control calls for frequent blood glucose determinations by patients themselves. The timing and dose of insulin injections have to be adapted to a variety of factors that influence blood glucose level, such as carbohydrate intake, physical exertion, sporting activities, stress (including operations, injuries and infections) and also rest periods such as periods spent asleep.

Insulin Pump

In addition to being painful and unpleasant, individual determinations of blood glucose by patients themselves using the conventional invasive techniques provide no more than a snapshot of the patient’s blood glucose level at the moment the blood sample was taken.

Continuous glucose monitoring (CGM), by contrast, would detect fluctuations in blood glucose level over a prolonged period and indicate when major deviations from the normal range occur. Every diabetic could benefit from continuous monitoring of their blood glucose level.

What Is An Artificial Pancreas?

An artificial pancreas is essentially a device that would both measure sugar levels and dispense appropriate amounts of insulin to keep blood sugar levels in optimal range. It would take much of the guesswork out of daily management of the disease and in the long-run, controlled sugar levels will help to lessen or avert the devastating complications from diabetes.

An artificial pancreas will integrate two currently available technologies ‒ continuous glucose monitors and insulin pumps ‒ with an algorithm that provides the right amount of insulin at the right time. It will enable people with diabetes to achieve tight blood glucose control avoiding both highs and dangerous lows, thereby significantly reducing the risk of the disease's devastating complications.

Why Is An Artificial Pancreas Needed?
The current diabetes treatment market comprises three related but distinct submarkets that address different aspects of the condition. Products in the market are currently comprised of blood glucose monitors, lancets & test strips, continuous blood glucose monitors, insulin, insulin pumps, syringes, and other insulin delivery devices & anti-diabetic drugs. Right now, the most significant growth in the U.S. market is in continuous blood glucose meters, insulin pumps, and anti-diabetic drugs.

An artificial pancreas could potentially revolutionize diabetes care and management, significantly improving the ability of people with diabetes to maintain strict blood glucose control, and ‒ as a direct result ‒ helping reduce kidney disease, heart attacks and stroke, amputations, blindness, and death from severe hypoglycemia.

Extensive research shows that glucose control is the primary factor in avoiding the devastating complications of diabetes. The landmark Diabetes Control and Complications Trial (conducted 1983-1993) showed that intensive diabetes management and improved glycemic control reduces major long-term complications of diabetes.

A later study published in the New England Journal of Medicinefound that intensive diabetes therapy aimed at achieving good control reduced the risk of any heart disease event by 42 percent, and the risk of nonfatal myocardial infarction, stroke, or death from heart disease by 57 percent.

However, clinical research shows that most people with diabetes are not controlling blood glucose levels nearly well enough. The risk of complications ‒ and the economic burden placed on our health care system ‒ could be significantly lowered with devices that improve blood glucose control. And good glucose control will probably enhance the effectiveness of promising new cure therapies such as beta cell regeneration and islet transplantation.

Diabetes Technology To The Rescue
There are several classes of technologies used for diabetes care at home. In general, the devices include monitoring of blood glucose levels and delivery of insulin. The monitoring can happen with finger sticks or with the newer generation of continuous glucose monitoring that permanently attach to the person.

Insulin delivery, the old-fashioned way, is through injections several times a day. The newer devices are insulin pumps. They attach to the person with little needles under the skin that deliver insulin at continuous rates.

But the current problem with even the most advanced treatment of diabetes is that these devices don’t talk to each other. Even the most sophisticated insulin pumps will keep delivering insulin regardless of the blood sugar level of the person because it doesn’t have any information coming from the monitors. That can cause severe reactions.

Dr Boris Kovatchev

Boris Kovatchev, director of the Center for Diabetes Technology at the University of Virginia, has focused on diabetes technology for more than a decade. His contribution to this area is to make these devices talk to each other in a smart fashion, to insert an algorithm that can take the reading from the monitoring device and tell the insulin pump to deliver insulin in a smart way.

The Artificial Pancreas Project is the most advanced application of the device. It connects the most advanced continuous monitoring device to the most advanced insulin pumps available in a continuous fashion — all the time. This is the top of the line integrated technology — and that means continuous monitoring of the person’s blood sugar levels and the reaction to changes.

The system's "smart" algorithm, developed by Kovatchev’s team and collaborators from the University of Padova in Italy, uses existing continuous glucose monitoring and insulin pump technology to automatically regulate a patient's insulin levels, with no action required on behalf of the user. The algorithm is currently being tested in clinical trials at the U-Va. Health System and 10 other centers spanning seven countries.

This project ‒ initiated by the Juvenile Diabetes Research Foundation (JDRF) ‒ has been going on since 2006. Kovatchev’s group was one of the first to join this project. Since then, it has grown significantly. Now, there are government initiatives in several countries and a lot of companies are interested in this technology.

The U-Va group has undertaken some extensive clinical trials on around 60 patients on that system for short periods of time for testing purposes. Besides, there are ongoing clinical trials in eight countries, all using Kovatchev’s patented technology or components of it.

The most challenging aspect of this technology is predicting the future. The reason that the future must be predicted accurately in this particular technology is that insulin delivery under the skin and glucose monitoring under the skin have delays.

“The monitoring of the blood sugar level generally works with a one-hour delay. Imagine you’re driving a car and you’re reacting to oncoming traffic with a one-minute delay. In situations like that, you have outdated data and delayed action. You have to anticipate what is going on in the next hour,” explains Kovatchev.

A device developed by Kovatchev and collaborators to automatically regulate a patient's insulin levels as part of the Artificial Pancreas Project (right) is shown with a continuous glucose monitor (left)

To make his device predict the near future for diabetes management, Kovatchev is developing a class of control strategies called model predictive control. Every human is assigned a mathematical model that mimics the functioning of the metabolic system of that person.

“Based on what that model says, we can predict the future. It’s similar to weather forecasts. But instead of weather models, we have models of a particular human,” he says with confidence.

New Ultra-Long-Acting Insulin Taken Thrice a Week Will Reduce Pain of Daily Jabs

A thrice-a-week insulin shot instead of the once-a-day shot at present could soon be a reality.

Doctors from India, Canada, US and South Africa have jointly tested the most promising new form of long- acting insulin ‒ degludec ‒ needed once every 48 hours, and found it to be as good in controlling blood sugar as the presently used insulin of choice, glargine (e.g. Lantus), which is a 24-hour shot.

This means that once in the market, the number of injections needed by a type-2 diabetic patient would be cut by half every week. It will also make insulin shots cheaper for patients. Pharma giant Novo Nordisk of Denmark, which funded the study, hopes to apply for licensing approval to market the drug in 2013.

However, the findings still need to be confirmed in another phase of research, and it's not clear how much the drug would cost if it were approved for this use. The Phase 2 trial results were published this week in the medical journal The Lancet.

Nonetheless, the findings are promising because most patients with diabetes don't want to have injections at all, if they can help it. And those who have to take them would prefer less. Moreover, each additional injection per day is a financial burden.

Announcing the results of their 16-week, phase-II trial of degludec in the medical journal Lancet, scientists said, "In this 16-week randomized trial, participants aged 18-75 years with type-2 diabetes and glycosylated hemoglobin (HbA1C) of 7-11% were enrolled and treated at 28 clinical sites in Canada, India, South Africa and US. At study end, mean HbA1c levels were much the same across treatment groups and insulin degludec provided comparable glycemic control to insulin glargine without additional adverse events. This might reduce dosing frequency due to its ultra-long action profile.”

The novel insulin releases over several days appears as effective as once-daily standard insulin in type 2 diabetes, an open-label trial found. HbA1c levels reached a similar 7.2% to 7.5% over 16 weeks whether patients got the novel insulin degludec three times a week or once daily, or standard insulin glargine (e.g. Lantus) once daily, Bernard Zinman, MD, of Mount Sinai Hospital at the University of Toronto, and colleagues reported online in The Lancet.

Adverse events, including hypoglycemia, were likewise comparable across the insulin groups in the phase II study, mirroring what Zinman initially presented at the American Diabetes Association meeting last summer.

"Insulin degludec is an ultra-long-acting insulin in clinical development. Its features suggest that the risk of hypoglycemia might be reduced and clinical effectiveness might be achievable with dosing three times a week in people with type-2 diabetes who were previously insulin-naive which could help with early initiation of and adherence to insulin treatment," the study says.

"It's an exciting new insulin, it's an ultra-long-acting insulin and the real issue is, of course, this is a small study, a proof-of-concept study, and we have to wait for the results of much larger studies to know where its place will be in a clinical setting," Zinman said in an interview. "It just has a much longer half-life, much more than 24 hours, compared to the other insulin and may provide some additional advantage."

However, Zinman said he doesn't see that three-times-per-week injections will be a common way to treat diabetes. "When you inject three times a week, the doses have to be increased so that it covers the full week, and in those circumstances, the benefits with respect to reducing the rates of hypoglycemia are not there," he said.

"Personally, I wouldn't use it that way. I would use it as once-daily insulin,” said Zinman, but he thinks if people do forget to take their insulin on occasion, this would be more forgiving. "We find people do occasionally forget their insulin, so this may — because it has a longer half-life and hangs around longer — that may be an advantage. I think we need to do studies to really see if that's the case."

However, topline results from a more recent phase III study comparing insulin degludec to insulin glargine again showed virtually identical glycemic control without a significant difference in hypoglycemia between groups.

While it had been hoped that the ultra-long-acting formulation might actually reduce hypoglycemia episodes, the chance to cut down on dosing frequency would be a valuable feature for clinical practice even without a safety or efficacy advantage over current basal insulin choices, Zinman's group suggested.

"A three-times-a-week, weekend-off, dosing regimen might appeal to some people with type 2 diabetes who are inadequately controlled on oral anti-diabetic drug treatments, potentially helping with acceptance and early initiation of insulin therapy," they wrote in the paper.

A longer dosing interval could be important in boosting adherence as well, and with less disruption to patients' lifestyle, Yogish C. Kudva, MBBS, and Ananda Basu, MBBS, both of the Mayo Clinic in Rochester, Minn., noted in an accompanying commentary.

But regardless of increasing numbers of long-acting options in diabetes treatment, lifestyle changes can't be overlooked, they urged.

"It is extremely worthwhile to remember that therapeutic lifestyle changes are inexpensive and favorable on a risk–benefit basis and need persistent re-emphasis, as is being done for the financial benefits accruing to patients from their employer and insurance by doing so," Kudva and Basu wrote in the commentary.

The proof-of-concept study by Zinman's group randomized 245 insulin-naive patients with inadequately controlled type 2 diabetes to open-label treatment at 28 centers internationally with one of the following regimens in combination with metformin:

• Insulin degludec three times a week ‒ Monday, Wednesday, and Friday evenings -- with a starting dose of 20 U per injection

• Insulin degludec in a 600 nmol/mL formulation once a day, with a starting dose of 10 U per injection

• Insulin degludec in a 900 nmol/mL formulation once a day, also at a starting dose of 10 U per injection

• Insulin glargine once a day, at a starting dose of 10 U per injection

Mean reductions in HbA1c over 16 weeks of treatment hit 1.3% to 1.5% in all the groups without significant differences among them. Nor were fasting plasma glucose concentrations any different between groups by the end of the study.

Confirmed hypoglycemia episodes of glucose falling below 55.8 mg/dL or requiring assistance occurred among 23% of patients on thrice-weekly insulin degludec or insulin glargine but 8% to 15% of those on once-daily insulin degludec. Although the difference between the highest and lowest rates was significant, the researchers noted that the 95% confidence intervals overlapped among all the between-group comparisons.

Nocturnal hypoglycemia by the same measure was uncommon, at 0% to 5% across groups, which the researchers attributed in part to the short duration of diabetes in the cohort.

However, as was pointed out at the ADA presentation of the data, the 55.8 mg/dL threshold may have missed hypoglycemia cases by the more standard 70 mg/dL criteria.

Diabetes specialist Dr. Vivian Fonseca, who chairs the endocrinology section at Tulane University Health Sciences Center, cautioned that more research is needed to determine if people who take the drug will face a higher risk of low blood sugar.

That's a major problem for people who currently take insulin medications, she said, as is the unpredictability of the drugs. "You give the same dose to the same person every day, and the next morning you get a different result," Fonseca said. "That is challenging for patients."

The researchers also reported that body weight remained stable throughout the trial for all treatment groups, and they pointed to "no apparent treatment-specific patterns or clustering of adverse events."

However, they cautioned about drawing firm conclusions on safety or efficacy based on the phase II data and noted that the open-label design used because of the different insulin-injection systems for the drugs might have impacted efforts to get glucose under control, as well as reporting of hypoglycemia and adverse events.

Dr Anoop Misra, chairman of Fortis Hospital's Centre of Excellence for Diabetes in New Delhi, India, said, "This is quite a breakthrough. For the first time, we have a ultra-long acting insulin with stable action. This will lead to lesser injections (once in two days) for the patients with good blood sugar control…Till now, all long acting insulin shots are for 24 hours."

It typically takes years for a drug to go through research and get approval from the U.S. government. The three-times-a-week degludec needs just one more phase of research, however, meaning that it could be on the market fairly soon if it's found to be effective. There's no indication of how much it would cost, although Kudva said it's fair to assume that it will be more expensive than insulin is today.

But one thing remains clear, Kudva said: "The most effective treatment for diabetes, a treatment that is worth doing throughout life, is attention to diet and exercise and working on one's weight. These are difficult to achieve, but even as every new medication comes, there's no getting away from that."

The study was sponsored by the drug maker Novo Nordisk of Denmark, and three of the paper's authors are employees of the company and own stock. Zinman, who helped design the study and obtain and interpret the data, has received fees for consultancy and honoraria for membership of advisory boards from Novo Nordisk and a number of other drug companies.

Hypoglycemia: Don'y Rely on the Doctor's Prognosis - Tell Him What Needs to be Done to Save Your Life

Here’s yet another episode of doctors who are clueless about treating complications arising from diabetes. If only the doctors at the hospital attending on him had more knowledge of treating hypoglycemia (low blood sugar), the 46-year-old man would have been alive today.

The diabetic, a self-employed electrical technician, identified only as Mr H, weighed 150kg and was taken by ambulance to the North West Regional Hospital in Burnie, Tasmania, Australia with a very low blood sugar level of just 27 mg/dl (a normal blood sugar level is about 90 mg/dl).

Three sets of clinical observations were taken, at 5.52pm, 6.35pm and 6.40pm, including his blood pressure, which was low. He was provided with sandwiches to eat, which he tolerated, and was observed for an hour and remained well.

After being discharged at 7pm, Mr H went home. About 12.34am, Mrs H awoke but could not rouse her husband. She called an ambulance but, by the time they arrived, Mr H was in cardiac arrest.

An investigation by Coroner Rod Chandler found the 46-year-old was discharged at 7pm and died at home about 1.45am the next day. "Mr H was considered to have suffered a hypoglycemic episode, most likely related to poor oral intake combined with his oral anti-diabetic medication," the post-mortem report said. In these circumstances the decision to permit Mr H to go home about 7pm on 10 January, 2009, was a regrettable misjudgment," the coroner said.

"Had he remained in hospital for a longer period and been subject to close monitoring and to more intensive investigations, then it is likely in my view that the seriousness of his condition would have become evident and life-saving treatment put in place. These matters give rise to the question whether the decision to permit Mr H to go home without further monitoring and/or investigation was, in all the circumstances, a reasonable one."

After carrying out an autopsy, pathologist Terry Brain recommended the case be reviewed by an experienced diabetic physician, "particularly [whether] the decision to allow him to go home played a significant role in his death and what could have been done to prevent this outcome".

Royal Hobart Hospital Diabetes and Endocrine Services clinical director Tim Greenaway said severe hypoglycemia was a "clinical red flag" and should have attracted careful assessment. "Mr H's falling blood sugar at the time he was allowed to leave hospital should have resulted in action by the emergency department staff," he said, adding there were measures that could have been implemented by the medical staff. "Such investigation and treatment is standard practice," he said.

Indeed, such investigation and treatment is standard practice around the world. Even an intern should know them. But the doctors on duty at the emergency room were ignorant of these procedures. “Regrettable misjudgment” is a terrible understatement, to say the least.

It was reported that the health authorities have implemented new procedures (sic) after Mr H’s death. But that’s no relief for his family.

My advice to all diabetics: If you suffer a hypo episode, instruct your family members to tell the doctors what to do. Also carry a note detailing the measures to be taken ‒ in case you have passed out ‒ in your wallet along with your card that identifies you as a diabetic. Unlike Mr H, you may not be another victim of an ill-trained doctor’s regrettable misjudgment.

Based on a news report in themercury.com.au

Hospitalized Diabetics Should Have Higher Than Normal Sugar Levels

After hospitalization for hernia surgery two months ago, my blood sugar levels, which had been reasonably good, suddenly went haywire. Readings of 200+ mg/dl were common for a couple of days after surgery. My doctors said they were looking at a target of around 180 mg/dl, which they said was optimal. Still, I was unhappy that my A1c levels would be compromised.

So it was with interest that I read the new guidelines released by the American College of Physicians recommending that doctors not attempt intensive insulin therapy designed to achieve normal blood sugar levels in patients in medical or surgical intensive care units. These guidelines are for both people with diabetes and without the condition.

The college recommends that doctors should maintain blood sugar levels between 140 and 200 milligrams per deciliter (mg/dl) for anyone in medical or surgical intensive care.

These recommendations ‒ published in the February 15 issue of Annals of Internal Medicine ‒ are similar to the guidelines from the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE). However, those guidelines recommend that blood sugar levels should be kept below 180 mg/dl to reduce the risk of infection and other complications.

For reference, in a healthy person with type 2 diabetes, normal blood sugar levels would be between 70 mg/dl and 130 mg/dl before eating. And, even after eating (postprandial), the recommendation from the ADA is to keep blood sugar levels under 180 mg/dl.

Talking to Serena Gordon of Health.com Dr. Amir Qaseem, director of clinical policy in the medical education division of the American College of Physicians explained, “[High blood sugar] is a common finding in hospitalized patients, and it’s associated with a lot of complications, like delayed healing, increased infection, cardiovascular events, you name it. The prevailing thought in the past was that tightly controlling the blood sugar levels would reduce inflammation, clotting and other problems. But, there are also harms that are associated with lowering the blood glucose levels too much. [Low blood sugar] can be very dangerous.”

“The evidence isn’t clear on what range of blood sugar is best, but 140 to 200 mg/dl seems to minimize the risk of hypoglycemia [in surgical or medical units],” said Qaseem. “We felt it was better to stick with a range that is a little bit higher.”

The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) have also published updated guidelines for treating high blood glucose while avoiding low blood glucose in hospitalized patients.

The main objectives of the 2009 AACE/ADA recommendations were to identify reasonable, achievable, and safe glycemic targets and to describe the protocols, procedures, and system improvements needed to facilitate their implementation. For most patients a blood glucose target of 140-180 mg/dl is recommended and appropriate use of insulin is the preferred approach for achieving safe, optimal glucose control.

“Hyperglycemia in hospitalized patients is common and associated with increased risk of infection, mortality, and increased cost,” said AACE President Daniel Einhorn, MD, FACP, FACE. “Although near normalization of glucose in these patients appears to be of no greater benefit than moderate glycemic targets, ignoring hyperglycemia in this population is no longer acceptable.”

There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes. Although initial small studies suggested that intensive glycemic control (insulin infusion with goal blood glucose targets of 80-110 mg/dl) improved outcomes in surgical ICU and medical ICU patients, subsequent trials have failed to show a benefit or have even shown increased mortality of intensive targets compared to more moderate targets (140-180 mg/dl). Moreover, these recent studies have highlighted the risk of severe hypoglycemia resulting from attempts to completely normalize blood glucose.

“Both over treatment and under treatment of hyperglycemia in hospitalized patients are patient safety issues,” said Robert R. Henry, MD, President, Medicine and Science for the American Diabetes Association. “Coordinated, interdisciplinary teams have been shown to achieve both safe and effective control of hyperglycemia in hospitalized patients.”

The recent ACP guidelines are for the most part consistent with the AACE/ADA recommendations. AACE/ADA maintains that the upper limit of 180 mg/dl is safe and justified by data on benefits of glycemic control and the harms of uncontrolled hyperglycemia. Practitioners should take heart in the commonality of recommendations among all the organizations to address hospital hyperglycemia in the safest manner.

Dr. Mary Korytowski, a professor of medicine at the University of Pittsburgh School of Medicine, and a member of the board of directors of the American Diabetes Association, concurs that intensive insulin management in medical and surgical units isn’t the best way to manage blood sugar any more. “(But) 200 mg/dl is probably too high. The 2009 ADA/AACE guidelines recommend 180 mg/dl, which is consistent with postprandial numbers in diabetes care. The problem is that if you set the target too high, those numbers may be even higher when someone starts giving insulin to bring those numbers down,” she explains.

“These guidelines should not be interpreted to mean that glucose control isn’t important for critically ill patients: It is. And it’s important not to let the blood sugar get too high because of the risk of complications, like a higher risk of infection and fluid and electrolyte abnormalities,” she says, adding that it’s important to remember these guidelines give a range of options. “Managing blood sugar closer to the lower end is probably better,” she concludes.

Also see how illness can affect blood sugar levels in people with diabetes from the American Diabetes Association.

Are You Diabetic? It May be Time for Insulin!

If you have type 2 diabetes and have had difficulty achieving blood sugar control, it may be time to find out if insulin is right for you.

Why Consider Insulin

Insulin is proven to lower blood sugar levels when used as part of an overall diabetes treatment plan. In fact, over 5 million people take insulin every day. 

Adding insulin replaces what your body isn't making naturally to help control blood sugar. Insulin is a hormone that is naturally produced in the body that helps convert your blood sugar (or blood glucose) into energy.

When you have diabetes your body doesn't make enough insulin and/or your body doesn't properly use the insulin it does make. As diabetes progresses it can get harder to manage your blood sugar.

Insulin should not necessarily be viewed as a sign of personal failure, or viewed as a last resort.

When diet, exercise, and oral diabetes medications alone don’t bring your blood sugar levels under control, insulin may be an effective tool to help with uncontrolled blood sugar. Do not take insulin if you are allergic to insulin or any of its ingredients. You must test your blood sugar levels when using insulin. 

Choose To Know More About Insulin & Overcome Common Fears

Many people, including you, may be afraid of insulin. However, insulin may help you achieve better blood sugar control. 

It is important to talk to your doctor about the potential benefits and realistic risks associated with insulin use. Hypoglycemia is the most common side effect of insulin therapy, which may be serious. Some fears of insulin may be based on misperceptions. Do any of these concern you?

• It's painful. Today's insulin needles are smaller and thinner than in the past. Generally injections cause little discomfort. You may be surprised by how soon you get used to injections.
• It's a sign of failure. Adding insulin does not necessarily mean that you failed with your current diabetes treatment plan. Over time, your body may have trouble producing what it needs to lower blood sugar.
• It's a "last resort." Insulin should not be seen as a "last resort." With diabetes, your doctor may change your treatment plan over time to find what works best for you. Controlling your blood sugar is what’s most important.
• It's a lifestyle change. Insulin is an effective option that you can add to your diabetes treatment plan to help you reach your daily blood sugar goals and lower your A1C. Most people find that insulin becomes a part of their routine. 
• It's forever. Insulin is not physically addictive or habit-forming. Many patients stay on insulin because they see the effect it has on lowering blood sugar.  

Talk to your doctor sooner, rather than later, if you have uncontrolled blood sugar. Together you can decide if insulin is right for you. Insulin works as part of an overall diabetes treatment plan, which includes diet, exercise and other diabetes medications, to help control blood sugar.

Remember, controlling blood sugar may help reduce the risk of developing diabetes-related complications.

Diabetes: Taking The Sting Out Of Insulin

Physicians hear a common refrain from patients with Type 2 diabetes: "Not the needle! Not yet. Give me three more months. I'll be good!" So they try with renewed vigor to control their disease without insulin through diet, exercise and oral medications. Inevitably, many patients lapse and their diabetes again slips out of control, doing invisible damage to their kidneys, nervous systems and cardiovascular health.

This cycle of fear and denial has little to do with insulin itself, a normal human protein, but rather its method of delivery: a hypodermic needle.

Many patients are afraid of needles or embarrassed at the prospect of carrying syringes and the associated stigma of " shooting up" before a meal. But pain and inconvenience aside, injectable insulin also carries a medical risk — hypoglycemia. This occurs when blood glucose falls too low, a common occurrence in people who've injected insulin that acts longer than needed, and one that can, in extreme circumstances, prove fatal.

For the nation's 23 million diabetics and 57 million pre-diabetics, many of whom use insulin, a better way to deliver insulin could be life-changing, enabling them to use insulin therapy earlier in the progression of their disease and reducing the long-term damage. And it could be possible.

Two products that could get insulin into the bloodstream without needle sticks are in the latter stages of clinical trials, with their makers hoping for Food and Drug Administration approval in the next two years.

One is administered via oral spray; the other is delivered via inhaler. Still more are in earlier phases of development. Together they offer the potential for treating the disease in a less onerous, less obvious, less painful fashion.

"Soon after insulin was discovered in the 1920s, doctors immediately recognized that it would be an advantage if they could get it into the body without injection," says Dr. Gerald Bernstein, vice president for medical affairs for Generex, which developed the spray.

But getting insulin, a very large protein, past the body's protective barriers and absorbed across small patches of surface area has proved difficult.

Better Delivery System

Injectable insulin is familiar — it's been around for 80 years — but it has drawbacks. The hormone must be injected multiple times throughout the day to help the body store glucose properly and keep bloodstream levels low. Uncontrolled high blood-sugar can destroy eyesight, nerves and kidney function.

But insulin injected under the skin has to work its way through fat, muscle and connective tissue to reach the bloodstream. Because of this, insulin activity can persist long after a meal, shuttling too much sugar out of the blood and creating hypoglycemia. Fear of the resulting dizziness, fainting or possible coma can keep some patients from using injectable insulin.

There have been many attempts historically to create an insulin pill, but the digestive tract is, well, digestive to large proteins like insulin; after all, the stomach is designed to break down the proteins in our meals.

The new products would speed insulin to the bloodstream in a more consistently absorbed fashion without being destroyed by the digestive system.

The oral spray, called Oral-lyn, delivers liquid bubbles containing insulin to the lining of the mouth, also called the buccal mucosa. "It goes right into the bloodstream; there's no place to hang out," Bernstein says. "The advantage is that [its activity] peaks much faster than even the most rapid-acting injectable insulin. It's got a two-hour window, and when it's finished, it's finished."

That, he says, enables patients to take it immediately before a meal, with a reduced risk of experiencing low blood sugar hours later. Oral-lyn is delivered in a puff of medicine much like an asthma inhaler.

Afrezza, the other product in the latter stages of testing, also uses a small inhaler device but one that directs the medication toward the lungs. Its maker, MannKind Corp., believes it can succeed where other inhaled insulins have failed.

One inhaled insulin, called Exubera, was actually approved by the FDA in 2006, but it failed to generate sufficient sales and was pulled from the market by Pfizer the next year.

The Exubera device was about the size of a tennis ball canister — almost as embarrassing to whip out at a restaurant table as a syringe — and calculating the insulin dose proved confusing and complex. In addition, some patients and doctors were concerned that the relatively large insulin particles delivered by Exubera might leave deposits in the lungs that would increase cancer risk.

Peter Richardson, chief scientific officer of Valencia-based MannKind, says his company learned from the Exubera missteps. Afrezza comes in a palm-sized inhaler with simple four- or eight-unit doses.

Afrezza's insulin catches a ride on nanoparticles. The nanoparticles and the insulin get absorbed rapidly through the lung's air sacs into the bloodstream, and the inert nanoparticles eventually are eliminated from the body via urine, he says.

Trial Results

Data from ongoing Phase III trials on both devices were presented at a meeting of the American Diabetes Assn. in June. And an Afrezza study was published in the medical journal the Lancet in June. In that research, 448 patients took either Afrezza or injected insulin at mealtimes for one year. Afrezza controlled blood sugar levels as well as injected insulin and resulted in less of the weight gain associated with starting injected insulin — about 2 pounds for patients on Afrezza compared with 5.5 pounds for patients on injected insulin. In addition, Afrezza patients experienced fewer episodes of mild-to-moderate hypoglycemia (48% of the group, compared with 69% of the injected insulin group) and fewer episodes of severe hypoglycemia (4%, compared with 10%).

Oral-lyn is still enrolling people in Phase III trials, scheduled to be completed early next year, but the preliminary results announced in June showed similar benefits when compared with injected insulin — less weight gain and fewer episodes of severe hypoglycemia. MannKind says it expects Afrezza to become available in 2011.

Both companies say their products do a better job of mimicking the natural, fast-acting spike of insulin released from the pancreas during mealtimes.

"Faster yet than injectable insulin is a good thing," says Dr. Daniel Lorber, an endocrinologist in Queens, N.Y., who completed the published trial of Afrezza and has consulted for MannKind. Also, unlike injected insulin, neither product must be refrigerated.

Dr. Richard Bergenstal, president of medicine and science for the diabetes association, notes that other insulin products are also being developed — for delivery through the nasal membranes and as oral pills.

"The biggest problem we have with insulin is hypoglycemia," he says. "If these mimic more closely how insulin is delivered from the pancreas and avoid that, to me that's the potential benefit here."

But whether the convenience factors along with the potential of these products to lower the risk for hypoglycemia will translate into a real advantage over injected insulin has yet to be proved, Bergenstal says. Further, he notes, the new devices are somewhat wasteful in that they need to use more insulin to deliver the same dose as an injection, which will push their cost up.

Still, he's pleased to see progress in making insulin more convenient. "Even as we develop other therapies, insulin is still our tried and true. It's a valuable treatment that has been around for 80 years, and we know what it does."

Thank you Kendall Powell/ latimes.com

Diabetes: The Perils Of Hypoglycemia

I came across this very good article on the perils of Hypoglycemia. While T1 cases are discussed, all of us insulin-dependent T2 types must also know the consequences of "tight control".

I have always wondered why just about everyone insists that diabetics MUST have BS levels associated with non-diabetics! Indeed, my diabetologist says: "One incident of Hypoglycemia is worse than 10 days of Hyperglycemia."

In my case, BS levels went haywire (plus 9 on the A1C scale) after intestinal surgery 2 years ago. I started a strict regimen and brought down A1C level to 7.2 in 3 months. However, my doctor was unimpressed!

According to him, his experience of 30 years showed that diabetics live healthy lives even if A1C levels are between 7-8. Less than that, frequent bouts of Hypoglycemia lead to more complications. His prognosis is that the body "learns to live with diabetes" by adjusting accordingly.

In fact, I have noted that obits of many famous people dying of "diabetes complications" involve individuals over 80!

While the jury is out on such an assertion, we know that most diabetics lead normal lives without attaining "optimal" BS scores.

In my own case, after 8 years of insulin dependence, I'm so far outside the danger zone vis-a-vis retinopathy, neuropathy, kidney malfunction, heart disease and foot complications. 

Here are excerpts from the article by Robert J Tanenberg, MD, outlining the perils of Hypoglycemia: 
Over 80 years ago, famed diabetologist Elliot Joslin said about the treatment of patients with type 1 diabetes: "Ketoacidosis may kill a patient, but frequent hypoglycemic reactions will ruin him."

Unfortunately, hypoglycemia continues to be the most difficult problem facing most patients, families, and caregivers who deal with the management of type 1 diabetes on a daily basis.

Frequent hypoglycemia episodes not only can "ruin," or adversely impact the quality of life for patients, but also, when severe, can cause seizures, coma, and even death.

One needs to first understand hypoglycemia as a biological event. When blood sugars fall below normal, there are two important consequences, which are identified by the blood sugar level at which they occur and the type of symptoms involved.

 
Mild and Moderate Hypoglycemia
The first consequence triggers a prompt release of hormones that work to raise the blood sugar.

These so-called counter-regulatory hormones include epinephrine (adrenaline), glucagon, cortisol, and growth hormone. The clinical responses to these hormones, which are well known to patients who have had hypoglycemic reactions, include sweating, palpitations, tremor, hunger, nervousness, and tingling sensations. These "fight, or flight" symptoms are often called sympathetic or adrenergic to emphasize their origin in the autonomic nervous system and from the adrenal gland. They are non-specific and may also occur in response to other stressors.

When hormones are released normally (in response to a low or rapid fall in blood sugar), patients experience the symptoms and usually take action by eating or drinking carbohydrates. Typically, the symptoms resolve within five minutes as the blood sugar rises.
 
Severe Hypoglycemia
However, if the hormones are not released and there are no warning symptoms, the blood sugar will continue to fall.  As the blood sugar drops below 55 mg/dL, the second consequence of hypoglycemia occurs.

The brain becomes deprived of glucose and can no longer function normally. This condition, called neuroglycopenia, leads to cognitive dysfunction that presents as confusion. There is a slowing of reflexes, and the hypoglycemic individual loses the ability to comprehend and act appropriately. The patient is no longer able to treat the hypoglycemia himself.

The need for assistance from another person to treat the hypoglycemia fulfills the definition of severe hypoglycemia. When driving a car, for example, patients with severe hypoglycemia often become lost even in a familiar neighborhood. If they are not able to quickly recognize the insulin reaction and pull off the road, they may lose control of their vehicle, with potentially catastrophic consequences.

Loss of Protective Hormones
Several hormonal changes occur in patients with type 1 diabetes. Usually within a few years of the onset of the disease, the patient's pancreas fails to secrete glucagon when the blood sugar falls below 70 mg/dL.

When this happens, only epinephrine is left to respond to the low blood sugar until it drops below 60 mg/dL. At that level, cortisol and growth hormone are secreted. Unfortunately, these hormones are "too little, too late" to help during the first 10 minutes of the insulin reaction.

Patients with both a diminished glucagon and a diminished epinephrine response have a 25-fold increase in the frequency of severe hypoglycemia.

Diabetes specialists use the term hypoglycemic unawareness to describe patients who have lost the ability to trigger the classic sympathetic symptoms. Sleep, which naturally suppresses epinephrine, makes the patient vulnerable to severe nocturnal hypoglycemia. 

If the blood sugar drops falls below 30 mg/dL, it may lead to seizures, coma, and ultimately death (as it did in our patient). Occasionally, patients with tightly controlled type1 diabetes (e.g., A1c under 6.5%) may be reasonably lucid with blood sugars below 40 mg/dL.

Apparently, the brain has a capability to lower the natural clinical set point. This situation places the patient in great danger. The only treatment is to back off on glycemic control (in other words, raise the target blood sugars), which should raise the set point back to normal. In fact, it is well known that each episode of severe hypoglycemia increases the possibility of a future episode occurring at an even lower blood glucose level.

Causes of Hypoglycemia
In type 1 diabetes, the most common cause of hypoglycemia is a mismatch of insulin, food intake, and physical activity. Whenever there is a change in the amount of food or exercise in a nondiabetic individual, the body adjusts by changing the hormones to keep the glucose as close to normal as possible.

This is why people without diabetes rarely become hypoglycemic when fasting or running marathons. In patients taking insulin, however, vigorous physical activity may cause hypoglycemia both during the activity and for several hours afterward. In fact, late afternoon exercise is a well known cause of nocturnal hypoglycemia.

Regimens using the newer analogue insulins (e.g., glargine and lispro) reduce the incidence of hypoglycemia compared to those using regular and NPH insulin. But any insulin, even when dosed correctly, can cause severe hypoglycemia. If patients taking insulin increase their physical activity, they must either eat more or reduce the insulin dose before and after their activity.

Similarly, patients on insulin who eat much less than usual need to reduce their insulin dose to prevent hypoglycemia. Furthermore, the indiscriminate use of alcohol can also lead to severe hypoglycemia.

Treatment of Hypoglycemia
Mild hypoglycemia should be treated with 15 grams of fast-acting carbohydrate, such as four ounces of juice or three to four dextrose tablets. If the blood sugar is still low in 10 to 15 minutes another 15 grams of carbohydrate should be given (known as the Rule of 15).

Moderate hypoglycemia typically responds to oral carbohydrates, but may take as long as 30 minutes to fully resolve. Frequent fingerstick blood glucose testing is mandatory to be sure the glucose does not continue to fall.

Patients with severe hypoglycemia who are not yet comatose may respond to liquid or buccal oral carbohydrates, but injectable glucagon is the best treatment in the home setting. Since glucagon may not raise the glucose levels to normal, giving fast-acting carbohydrates after the patient becomes more responsive is essential. 

Rescue squads and emergency room physicians administer 50-percent dextrose intravenously, which usually reverses the condition very quickly. In some cases, repeated doses of intravenous dextrose are needed.

Prevention of Severe Hypoglycemia
To help prevent severe hypoglycemia, diabetes specialists recommend the following:

• For physically active persons, it is important to check fingerstick blood sugars after exercise in anticipation of possible hypoglycemia. It is especially important to check at bedtime and 3:00 am if the activity is after 4:00 pm.
• Bedtime insulin should be decreased after exercise.
• Physicians should be cautious about recommending near-normal blood glucose control and A1c targets to patients with type 1 diabetes and a history of hypoglycemia, particularly if they sleep alone.
• If severe hypoglycemia occurs, the physician should raise the glucose targets immediately to prevent another episode.
• Patients with nocturnal hypoglycemia, hypoglycemic unawareness, and/or a history of seizures are candidates for the newer real-time subcutaneous sensors with low glucose alarms.

Final Thoughts
We want to better inform physicians and patients of this potential danger. Severe hypoglycemia, in very rare cases, can lead to death while driving a car, swimming in the ocean, or even sleeping in ones' own bed.

If patients who take insulin learn nothing else, they should learn to always test their blood sugar at bedtime, before driving, and any time there is a change in activity or food intake.

Early treatment of mild hypoglycemia must be emphasized so that progression to more severe consequences can be avoided. As physicians and diabetes educators learn more about the hazards of nocturnal hypoglycemia, they will educate their patients to anticipate and prevent it.

Thank you Robert J. Tanenberg, MD