Diabetes: Tale of 2 Mice Pinpoints Major Factor for Insulin Resistance

Joslin Diabetes Center scientists identify promising candidate for drugs treating type 2 diabetes and fatty liver disease

RESEARCHERS at Joslin Diabetes Center have identified an enzyme called PKC-delta as an important molecular modifier for development of insulin resistance, diabetes and fatty liver in mice. They also have found evidence suggesting a similar role for the enzyme in humans, making PKC-delta a promising new target for drugs for diabetes and related ailments.

It’s well known that insulin resistance typically occurs prior to type 2 diabetes. You can be insulin resistant for years before developing the disease, and often a diagnosis of type 2 diabetes is a person’s first sign that they are in fact insulin resistant.

The road to type 2 diabetes is paved with insulin resistance, a condition often associated with obesity in which the hormone begins to fail at its job helping to convert sugars to energy.

Investigators in the laboratory of C. Ronald Kahn, M.D., began with two existing strains of mice that are on opposite sides of the spectrum for insulin resistance. “The ‘B6’ mouse is very prone to develop both obesity and diabetes, and the ‘129’ mouse is quite protected from both, even if it possesses a genetic defect in insulin signaling,” says Dr. Kahn, Professor of Medicine at Harvard Medical School.

“Comparing the two models, it’s as if there’s an on/off switch for insulin resistance and diabetes between them. We reasoned that if we could find out the differences between B6 and 129 mice, we could identify a factor that could be a major modifier of insulin resistance, and a good drug target for treatment of type 2 diabetes,” he said

Dr C. Ronald Kahn, MD

In previous work, the Kahn lab created a genetic cross between these two mice models, did a genome-wide screening and found an area on mouse chromosome 14 that appeared to be important for insulin sensitivity. In the latest paper, published online in the Journal of Clinical Investigation, they followed up and found that PKC-delta stood out in activity among the genes in that region.

The researchers then showed that levels of the PKC-delta enzyme were about two times as high in the liver and other tissues in the B6 as in the 129 mouse. When both types were put on high-fat diets, levels of the enzyme stayed the same in the 129 mouse but rose to three times higher in the B6 mouse.

Could these differences be enough to make the profound change in insulin sensitivity? The scientists next created three new mice models to check.

In one model, they removed one of the two normal copies of the PKC-delta gene from B6 mice, thus cutting production of the enzyme in half, and the mice became much more insulin sensitive. In a second effort, they removed the gene entirely from the livers of B6 mice, and again the resulting mice were more insulin sensitive. In a third model, they inserted an extra copy of the PKC-delta gene in the liver of 129 mice, which became much more insulin resistant and diabetic.

In short, PKC-delta levels correlated closely with insulin resistance and the abnormalities in glucose tolerance in all three cases of mice. In addition, the insulin resistance correlated with increased fat in the liver, an increasing problem in people with insulin resistance.

Biopsies of human liver tissue, Dr. Kahn says, also showed that levels of the enzyme are heightened in people who are obese or have diabetes. “People with diabetes tend to get fatty liver and that also seems to correlate with the activity of PKC-delta,” he adds.

Overall, “drugs that inhibit the activity of PKC-delta in the liver and other tissues potentially could aid treatments for diabetes and fatty liver disease, which is second only to alcohol as a cause of liver failure,” Dr. Kahn says.

Via Eurekalert

IDF Endorses Early Bariatric Surgery

Return on Investment Make Gastric Bypass Cost-Effective, Claims Position Statement Issued at 2nd World Congress on Interventional Therapies for Type 2 Diabetes

The International Diabetes Federation (IDF) has issued a “radical statement” at an international conference today saying gastric banding and similar surgeries should no longer be a last resort for severely obese people with type 2 diabetes, it is recommending that surgery be considered at a much earlier stage.

“The statement highlights that there is increasing evidence that the health of obese people with type 2 diabetes, including their glucose control and other obesity related comorbidities (conditions), can benefit substantially from bariatric surgery under certain circumstances,” says the IDF press release.

The IDF says gastric banding and other surgeries to alter stomach anatomy should now be considered much earlier in the treatment of type 2 diabetes.

Gastric bypass surgery works by reducing the size of the stomach so a person can’t eat as much and shortening the length of the intestine so that the body doesn’t absorb too many calories. But it might also have the side effect of normalizing blood sugar.

Summary of the 39-Page Statement

• Obesity and type 2 diabetes are serious chronic diseases associated with complex metabolic dysfunctions that increase the risk for morbidity and mortality.

• The dramatic rise in the prevalence of obesity and diabetes has become a major global public health issue and demands urgent attention from governments, health care systems and the medical community.

• Continuing population-based efforts are essential to prevent the onset of obesity and type 2 diabetes. At the same time, effective treatment must also be available for people who have developed type 2 diabetes

• Faced with the escalating global diabetes crisis, health care providers require as potent an armamentarium of therapeutic interventions as possible.

• In addition to behavioral and medical approaches, various types of surgery on the gastrointestinal tract, originally developed to treat morbid obesity (“bariatric surgery”), constitute powerful options to ameliorate diabetes in severely obese patients, often normalizing blood glucose levels, reducing or avoiding the need for medications and providing a potentially cost-effective approach to treating the disease.

• Bariatric surgery is an appropriate treatment for people with type 2 diabetes and obesity not achieving recommended treatment targets with medical therapies, especially when there are other major co-morbidities.

• Surgery should be an accepted option in people who have type 2 diabetes and a BMI of 35 or more

• Surgery should be considered as an alternative treatment option in patients with a BMI between 30 and 35 when diabetes cannot be adequately controlled by optimal medical regimen, especially in the presence of other major cardiovascular disease risk factors.2

• In Asian, and some other ethnicities of increased risk, BMI action points may be reduced by 2.5 kg/m

• Clinically severe obesity is a complex and chronic medical condition. Societal prejudices about severe obesity, which also exist within the health care system, should not act as a barrier to the provision of clinically effective and cost-effective treatment options.

• Strategies to prioritize access to surgery may be required to ensure that the procedures are available to those most likely to benefit.

• Available evidence indicates that bariatric surgery for obese patients with type 2 diabetes is cost-effective.

• Bariatric surgery for type 2 diabetes must be performed within accepted international and national guidelines. This requires appropriate assessment for the procedure and comprehensive and ongoing multidisciplinary care, patient education, follow-up and clinical audit, as well as safe and effective surgical procedures. National guidelines for bariatric surgery in people with type 2 diabetes and a BMI of 35 or more need to be developed and promulgated.

• The morbidity and mortality associated with bariatric surgery is generally low, and similar to that of well-accepted procedures such as elective gall bladder or gall stone surgery.

• Bariatric surgery in severely obese patients with type 2 diabetes has a range of health benefits, including a reduction in all-cause mortality.

• A national registry of persons who have undergone bariatric surgery should be established in order to ensure quality patient care and to monitor both short and long-term outcomes. 1.17 In order to optimize the future use of bariatric surgery as a therapeutic modality for type 2 diabetes further research is required.

Although such operations cost anywhere from $20,000 to $30,000, they will reduce healthcare expenditures in the long run, according to a new IDF position paper on the subject. The surgery, the IDF explains, often normalizes blood glucose levels and reduces or avoids the need for medication.

In addition, curbing diabetes can stave off costly complications such as blindness, limb amputations, and dialysis, says Francesco Rubino, MD, director of the IDF’s 2nd World Congress on Interventional Therapies for Type 2 Diabetes.

“When we talk about whether we can afford bariatric surgery, we have to ask what will be the cost if we don’t treat the patient. Studies have shown the surgery to be cost-effective. So there is a return on investment,” says Francesco Rubino, MD, director of the IDF’s 2nd World Congress on Interventional Therapies for Type 2 Diabetes

The IDF puts the lifetime cost of diabetes in the United States at $172,000 for a person diagnosed at age 50 years and $305,000 at age 30 years. More than 60% of this amount is incurred in the first 10 years after diagnosis.

The new recommended indications for performing bariatric surgery on patients who are both diabetic and obese match those announced last month by the US Food and Drug Administration for expanded use of the Lap-Band Adjustable Gastric Banding System (Allergan) to treat obesity.

The IDF recommendations dovetail with Dr Rubino’s previous research on how bariatric surgery alleviates diabetes. He showed that the effect on diabetes is not entirely explained by a person’s weight loss. In fact, the gastrointestinal tract serves as an endocrine organ and a key player in the regulation of insulin secretion, body weight and appetite, which is why altering the GI tract has such profound metabolic effects.

However, the use of bariatric surgery to treat diabetes has sparked controversy in healthcare circles. Critics question the wisdom of wielding a scalpel to solve a medical problem, especially when clinicians have more drugs at their disposal to deal with diabetes.

A study published online last week in the Archives of Surgery has raised doubts about the efficacy of LAGB. Researchers following 151 patients who underwent LAGB for obesity concluded that the procedure yielded “relatively poor long-term outcomes,” with nearly half the patients needing their bands removed and 60% overall requiring some kind of reoperation. The authors, who performed the surgeries in question during the mid-1990s, added a caveat: they had used an older dissection technique.

Indeed, the biggest danger is that new weight-loss options like EndoBarrier (developed in the UK), Lap-Band,  Roux-en-Y gastric bypass and sleeve gastrectomy surgery have the potential to encourage overweight people to abandon traditional diet and exercise for procedures that carry some serious risks. That should be a big worry for all diabetes educators and activists.

South Asians’ Impaired Ability to Burn Fat Makes Them More Prone to Diabetes

With more than 50 million diabetics ‒ mainly type 2 ‒ India is facing a full-blown diabetes epidemic. Another100 million are at the stage of pre-diabetes. Only China suffers from far more cases of diabetes.

While anecdotal evidence suggests diabetes has assuming epidemic proportions in the subcontinent as a result of improved incomes but poorer lifestyle and dietary choices, especially among the middle class, a new study reveals that people from South Asia are at greater risk of developing type 2 diabetes because of the way their muscles burn and store body fat.

Researchers from the University of Glasgow, Scotland, analyzed the rates of fat metabolism in 20 men of South Asian origin and 20 white European men.

Their findings suggested that South Asian men have a lower rate of fat metabolism during exercise than their European counterparts, as well as reduced sensitivity to insulin – indicating a possible tendency towards glucose intolerance and type 2 diabetes.

The scientists said the association between fat metabolism rate and insulin sensitivity was due to key differences between the muscles of south Asians and Europeans.

They discovered that the expression of genes key to fat metabolism was lower in the muscles of south Asians, affecting their ability to process fat and thus increasing the risk of insulin resistance – a major factor in the development of type 2 diabetes.

Dr Jason Gill, who led the study, said: “Our results suggest that the ability of south Asians’ muscles to use fat as a fuel is lower than in Europeans.”

“In other words, if a south Asian man and a European man were walking alongside each other at the same speed, the south Asian man’s muscles would be burning less fat and this may contribute to a greater risk of developing diabetes.”

Dr Victoria King, from British charity Diabetes UK, said: “This new insight could provide the basis for future studies looking at lifestyle, or drug interventions to enhance the uptake and burning of fat in muscles, reducing the risk of type 2 diabetes in this high risk group.”

The study was published in the peer-reviewed medical journal PLoS One.

Diabetes Management: Metformin Gets Highest Marks in New Study

The cost of managing diabetes is going up all the time. And while pharmaceutical companies are doing a great job trying to develop new drugs, the overriding profit motive is sometimes prompting them to cut corners or suppress information that may prove to me inimical to their bottom line. A case in point is Avandia, which is now banned in many countries but still prescribed in the US, but with many caveats.

However, the safety of most diabetes drugs are time-tested — insulin was discovered in the early 1920s, and two of the other most commonly prescribed, metformin and sulfonylurea, have been around since the 1950s. Indeed, these drugs have five characteristics physicians look for in diabetes medications: few potential complications, safety, tolerability, ease of use and a low cost. (See my earlier post ‘Look to Older, Longer-Studied Treatments here.)

It’s not surprising, therefore, that Metformin, in combination or alone, remains the top choice for first-line treatment of type 2 diabetes because it demonstrates the best risk-benefit profile vs. other diabetes drugs, according to new data.

Most importantly, the newer drugs, which have no generic options, are significantly more expensive than older ones. One hundred metformin pills cost about $35.57, or 35 cents a pill, while 30 Januvia pills (a DPP-4 inhibitor) cost $192.52, or $6.42 a pill — nearly 18 times as much. Ask any diabetic and he’ll tell you why he shudders at the thought of taking the newer medication, especially if it’s out of pocket.

According to the new study, metformin, that has been around for more than 15 years, works just as well and has fewer side effects than a half-dozen other, mostly newer and more expensive classes of medication used to control the chronic disease, new Johns Hopkins research suggests.

In their report ‒ published online March 14 in the journal Annals of Internal Medicine ‒ the Johns Hopkins team found that metformin, an oral drug first approved by the US Food and Drug Administration (FDA) in 1995, not only controlled blood sugar, but was also less likely to cause weight gain or raise cholesterol levels.

“Metformin works for most people. It’s cheaper, there’s a generic form — it’s tried and true,” says study leader Wendy L. Bennett, M.D., M.P.H., an assistant professor in the Division of General Internal Medicine at the Johns Hopkins University School of Medicine. “Our study shows that even though there are all these newer drugs, metformin works just as well and has fewer side effects.”

The team looked at several popular classes of oral diabetes medication — metformin (sold as Glucophage, Fortamet and others), second-generation sulfonylureas (Amaryl, Glucotrol and more), thiazolidinediones (Avandia and Actos) and meglitinides (Starlix and Prandin) — and added two new classes of drugs, dipeptidyl peptidase-4 (DPP-4) inhibitors (Januvia and Onglynza) and glucagon-like peptide-1 (GLP-1) receptor agonists (Byetta and Victoza), which are given by injection.

Results indicated that most medications used as monotherapy yielded comparable decreases in HbA1c (about one absolute percentage point on average throughout the course of a study). Metformin alone, however, lowered HbA1c more than DPP-4 inhibitors alone, and any type of combination therapy reduced HbA1c by about one absolute percentage point more than monotherapy.

Weight loss with metformin was a mean 2.5 kg more vs. TZDs and sulfonylureas. Other data also showed that combination metformin and GLP-1 agonists induced greater weight loss than other combination therapies, but the researchers said evidence supporting this finding was weak.

When compared with pioglitazone, sulfonylureas and DPP-4 inhibitors, metformin also significantly lowered LDL. Further, the drug decreased triglycerides and moderately raised HDL.

The researchers reported that sulfonylureas raised the risk for hypoglycemia four-fold vs. metformin monotherapy. Combination treatment with metformin and a sulfonylurea also had a six-fold higher risk for hypoglycemia than combination metformin and TZDs.

Analysis of other adverse events revealed that risk for congestive heart failure was higher with TZDs than with sulfonylureas. Risk for bone fractures was also higher with TZDs than with metformin alone or metformin combined with sulfonylurea. Diarrhea, however, was more commonly associated with metformin than with other medications.

“Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line treatment agent,” the researchers wrote.

The study is an update of Hopkins research published in 2007 that also showed there were advantages to metformin. New classes of medication for adult-onset diabetes have been approved by the FDA since then, and Bennett and her colleagues wanted to know if the newer drugs were any better than the older crop.

The research team also looked for the first time at the efficacy of two-drug combinations to treat the chronic disease, which has become increasingly common with more than one-third of diabetes patients needing multiple medications.

Researchers found that while two drugs worked better than one in those patients whose blood sugar remained poorly controlled on a single medication, there were also side effects associated with adding a second medication.

“Diabetes is an enormous public health problem, and patients have difficult decisions to make about what medications they should be taking,” Bennett says. “Our study provides good information comparing drugs and can be used to inform those decisions.”

Bennett and her colleagues reviewed 166 previously published medical studies that examined the effectiveness and safety of diabetes drugs, as well as their impact on long-term outcomes including death, cardiovascular disease, kidney disease and nerve disease.

No drug or combination of drugs was shown to have an advantage in improving long-term outcomes, Bennett says, primarily because there weren’t enough long-term studies, particularly of newer medications.

While most drugs reduced blood sugar similarly, metformin was consistently associated with fewer side effects. Though metformin is associated with increased risk of gastrointestinal side effects, Bennett, an internist, says she finds many of her patients can overcome them by starting with a low dose and taking it with meals, though patients with severe kidney disease may avoid it.

The sulfonylureas and meglitinides were associated with increased risk for hypoglycemia, or dangerously low blood sugar levels. The thiazolidinediones increased risk of heart failure, weight gain and fractures. In September 2010, the FDA placed restrictions on the use of Avandia because of concerns that the drug increases the risk of heart attack.

While the drugs all reduce blood sugar levels, Bennett says more research is needed into whether they actually improve outcomes for diabetics in the long run. It remains an open question as to whether patients with type 2 diabetes who have their blood sugar controlled by medication will reduce their chances of having complications associated with the disease, including eye, kidney and nerve diseases, she says.

“Some of the drugs haven’t been on the market long enough to study the long-term effects or even some of the short-term rare side effects, so we need longer studies in patients who are at highest risk for complications” she says.

Long-Acting Drugs: Once-Monthly Exenatide Shows Promising Results in Phase 2 Trial

Long-acting diabetes drugs seem to have become the flavor of the season. After news of the successful Phase 2 trials of insulin degludec broke yesterday, newpapers reported today that Amylin Pharmaceuticals has also concluded trials of exenatide which can be taken monthly

According to reports, an experimental monthly version of Amylin’s type 2 diabetes drug exenatide worked as well as an experimental weekly version of the injected medication in a recent study.

Amylin is under pressure to get longer-term versions of exenatide onto the market to offset slowing sales of Byetta, the original twice-a-day version of the drug, which has been losing ground to longer-lasting competitors.

The weekly version, known as Bydureon, was rejected in October by FDA regulators who said they wanted new research data on how the weekly medication affects the heart. Amylin launched the study in February with plans to deliver results to the agency in the second half of this year.

In the latest test, the once-monthly version of exenatide reduced average blood-sugar levels, known as A1C, by between 1.3 percent and 1.5 percent in the Phase 2 clinical trial. Patients taking the weekly version of the drug, known as Bydureon, saw their A1C levels fall by 1.5 percent.

In the latest study, 121 patients were randomly given monthly doses of exenatide or weekly shots of Bydureon for 20 weeks. The trial was designed to measure the monthly drug’s effectiveness, safety and tolerability, the company said. The most common side effects from exenatide were headaches and nausea. The Amylin report said little about how well the monthly drug was tolerated among study participants.

The news came after another study showed that Bydureon didn’t control diabetes better than Victoza, a commercially available once-daily injectable drug made by Novo Nordisk.

All of the drugs are part of a class of injected diabetes medications known as GLP-1 agonists that has emerged in recent years to compete with orally administered therapies.

Amylin plans to open talks with the FDA about whether they need to conduct additional Phase 2 tests on the drug or can move on to larger Phase 3 trials.

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.

Diabetes: Is the ADA Shifting its Stance About Carbs?

Carbohydrates are a very touchy subject with diabetics. And for me at least, understanding carbs in a diabetic diet is more difficult than quantum mechanics (or double-entry accounting if you’re not a science type). Diabetologists and dieticians, too, have differing views. I found this article by LAURA DOLSON very instructive and am reproducing it here for those who may have missed it. You can find the lively discussion that followed the article’s publication here.

You may be surprised to know that for the past couple of decades, the American Diabetes Association has been sort of a cheerleader for carbs. Yes, I’m talking about the organization who’s mission it is to promote education and research in ways aimed at preventing diabetes and alleviating the suffering of diabetics.

What is diabetes? It is essentially a disorder of the body’s ability to process carbohydrates. This includes Type 1 and Type 2 diabetes, pre-diabetes, metabolic syndrome, insulin resistance, and all the other points on the diabetes spectrum. (The Endocrine Society suggests that anyone with a fasting blood glucose of 89 or above is at risk for damage to their health.)

In light of this, you’d think that limiting carbohydrate intake would be a priority in educating people about handling these disorders. And yet, the ADA jumped right onto the Food Pyramid bandwagon and began to advise people to get at least 55% of their calories from carbohydrate, such as in the Food Pyramid for Diabetes (see illustration above).

In 2008, they made one exception: diabetics trying to lose weight could follow a low-carb diet for up to one year; this was later loosened further to two years. But still they did not recommend a low-carb diet for health, blood sugar control, or preventing progression of the diabetes.

Now, in the March 2011 edition of the ADA magazine “Diabetes Forecast” are three rather remarkable articles. The first is called The “ADA Diet” Myth, which claims that there is no such thing as the ADA Diet! (Who else was having this hallucination?) Instead, Stephanie Duncare, director of nutrition and medical affairs for the ADA says, “For more than 15 years now, ADA has recognized that people with diabetes should eat in a way that helps them reach their blood glucose, cholesterol, blood pressure, and weight goals. For some, this means a relatively higher-carbohydrate diet, and for others, the diet may be lower in carbohydrate”. Well, hallelujah to that, especially if the goal is “normal blood glucose” (normal meaning “a blood glucose level that will not cause further damage in the pancreas”).

Even more bold is an article called, “Are Carbs the Enemy?” which attempts to cover the debate. They first present a sort of wimpy pro-carb stance. This section of the article has a notable absence of anything to do with science, instead relying on statements such as “Gone are the days of ‘diabetic diets’ that were meager and confining” and “as long as people eat less or cover their carb intake with medications, they can keep blood glucose levels in check with a healthy diet” (“healthy” in this case meaning “high-carb”).

The article then goes on to describe a low-carb approach, citing Dr. Richard Bernstein. This section cites actual evidence, and makes what I think is a much stronger case for controlling blood glucose by limiting carbohydrates. The article goes on to a section on saturated fats which is much more balanced than usual, and then the normal “we don’t have the long-term studies”. The article concludes with the statement: “In the end, the best diet is the healthy one you’re able to follow.”

The only thing I would add is that people need support in making those changes, and as far as I can tell they are still leaving an awful lot up to the individual to figure it out for themselves. There has been quite a defeatist attitude coming from the organization that is supposed to be helpful – along the lines that it is asking just too much of people to cut carbs in any significant way. Are dietitians now actually going to support people in finding a diet that achieves as close to a normal blood glucose as possible? It would be a very big change if this happened any time soon.

But wait, there’s more! A follow-on short piece called “Eating With Diabetes: 3 Approaches” lists the low-carb approach first, and then follows with “Moderate-Carb” and “Vegan/High-Carb”. The weird thing is that the three approaches are described as “less than 10% carb”, “40-50% carb” and “75% carb”. What about people who normalize their blood glucose with 20% carb or 30% carb? Why not just say, “it’s a spectrum disease, with a spectrum of carb that will treat it effectively”? In any case, I don’t want to complain too loudly, because this is SO great to see in an ADA publication!

Now, to be sure, the ADA is not yet changing their basic stance. Nowhere on the latest update of the diabetes.org Web site is it stated that diabetics should follow a low-carb diet. On the other hand, there is no longer anything I can find that says to eat over half of calories from carbohydrate, either. The former food pyramid, as far as I can tell, has vanished, and there are several hints that low-carb eating is becoming a bona-fide option.

There are statements such as, “Understanding the effect of carbohydrate on blood glucose levels is key to managing diabetes. The carbohydrate in food makes blood glucose levels go up.” Although diabetics are still advised that “a place to start is at about 45-60 grams of carbohydrate at a meal.”, (yikes) it goes on to say to adjust from there. Even though this is not what most of us would call a low-carb diet, for most people it is a reduction from their previous advice.

[Side note: I also notice it doesn’t actually say 45-60 g/meal is a good place to start. If that actually controls someone’s blood glucose, that’s great, but I would think that in the cases where it doesn’t, it would be more disheartening to subsequently take more carb away. Why not start lower, and then add? Also, most likely, the person for whom this works is losing weight – a phase which doesn’t last forever.]

To me this looks like the beginnings of a real change in approach from the ADA. The Titantic may actually be turning around! This could make a difference to the health of millions of people, and nothing could make me smile more than that.

By Laura Dolson/about.com

Image courtesy about.com

Diabetes & Steroids

Some conditions (e.g. Addison’s disease, severe asthma, rheumatoid arthritis, lupus) are treated with steroids. If you have diabetes, you may well find that your blood glucose levels rise while taking high-doses of steroids for periods of time.

This should not stop you taking steroids if your doctor has prescribed them, even if your blood glucose levels are affected, but you should discuss with your doctor how best to manage your diabetes while taking steroids. You may need an increase in medication or your medication to be changed.

If the steroids have been prescribed for a short period to manage a deterioration in your condition, your blood glucose levels will usually return to normal when you stop taking them. The drugs he’d been prescribed, glucocorticoids, are a type of steroid.  And many people will take glucocorticoids not knowing a common side-effect is type 2 diabetes.

In fact, steroid-induced diabetes is “very common”, says Dr David Price, a diabetes expert at the Morriston Hospital at Swansea, UK. “Glucocorticoids are life-saving in many situations. But the unavoidable consequence is that they raise blood sugar.” The drugs mimic the hormone cortisol, which is produced by the adrenal gland.

Cortisol is known for its anti-inflammatory effect, which is why these medications are prescribed for inflammatory conditions such as arthritis and asthma — but it also affects the way the body metabolizes sugar.

“Cortisol is a stress hormone,” says Dr Price. “When you’re stressed, it acts to free up glucose from the liver because you need this energy to get to the muscles.” As a result, blood sugar levels go up. And while many people on glucocorticoids see their blood sugars drop back to safe levels once they stop taking steroids.

When older people are put on a big dose of steroids, for example, a significant minority would become diabetic. And if someone is already diabetic, they may go from being on tablets to having to inject themselves. Patients should be warned of the risks.

This is what a British man ‒ who was asthmatic but did not have diabetes ‒ was not told.

Tony had developed asthma in 2000; he was then diagnosed with bronchiectasis, a condition where some of the air passages become permanently widened, meaning extra mucus builds up and the patient is more prone to chest infections.

He was given inhalers to keep the conditions under control, but these weren’t enough. “I ended up in hospital four times with severe attacks,” recalls Tony, 65, a semi-retired communications consultant from London.

In hospital he was given oral steroids in the form of prednisone, to reduce the inflammation in his airways. He then developed nasal polyps and so started taking prednisone more regularly. Polyps are swellings in the nasal cavity which can cause a runny nose and, in Tony’s case, loss of sense of smell. “Doctors told me the steroids could help to shrink the polyps,” he recalls. “I took them only if my chest was troubling me, or when I travelled overseas for business meetings, to spare myself the embarrassment of a dripping nose.”

Tony’s doctors warned him not to take them too often because of serious side-effects such as a hormone disorder called Cushing’s syndrome, so he kept to no more than once every three months. But his doctors never mentioned another serious risk: that, in fact, glucocorticoids can cause diabetes.

“During a trip to South Korea, a day after taking a dose, I found myself very thirsty and tired, and needing to go to the loo a lot. I didn’t think much of it, but when I got home my jet lag didn’t recover. I was exhausted and I started losing weight. After two weeks of this, I Googled my symptoms. Straight away, diabetes came up,” recalls Tony

Concerned, Tony bought a home blood sugar test and found his levels were much higher than normal. He went to see his GP, who did more tests and confirmed he had type 2 diabetes.

Not only was Tony showing the symptoms of diabetes, a urine test showed the presence of ketones — acids which build up in the blood when a diabetic patient’s insulin is dangerously low. Ketones can lead to ketoacidosis, a cause of diabetic coma and even death.

“I told my doctor about my medication and he said: ‘You’ve got steroid-induced diabetes.’ I’d never heard of it,” says Tony. The GP sent Tony to the diabetes clinic at the local hospital. He was given insulin and shown how to administer the injections. Within days his tiredness and thirst had faded.

Doctors told him his type 2 diabetes would be with him for life. The drugs he had taken to ease his chest problems had left him with a permanent and potentially life-threatening condition. “No one told me the steroids could cause diabetes,” says Tony. “I felt gutted that for the rest of my life I’d have to inject myself.”

“However, in some cases there may be a slight problem with insulin production anyway — this won’t have been an issue before. But the steroids cause an added strain on the pancreas, causing the patient to become permanently diabetic. It can depend on the dose you’re on, and underlying risks like whether you’re overweight and whether there’s a family history of diabetes,” adds Dr Price.

Tony, however, had no family history of diabetes and was not overweight. He’d also had regular blood tests for years during routine medical checks, which he says had always been normal.

Frustrated at his experience, Tony began to question whether there was anything he could do about his new condition. “I knew insulin is a very unstable thing. If you get your doses wrong and your blood sugar goes too low, you can get diabetic ‘hypos’, and if you don’t control your diabetes you can have strokes, amputations, problems with eyesight, all kinds of things.

“On my fourth visit to the diabetic clinic I asked the nurse if I could try reducing my insulin dose slowly over time and see how it went. I did and my blood sugar went back to near normal within two to three weeks.

“The clinic confirmed I no longer needed to inject, but said I was still mildly diabetic, so they put me onto a daily Metformin tablet. That’s been the case for four years.” Tony now avoids glucocorticoids and his asthma has been greatly improved thanks to an inhaled steroid called Seretide.

Tony is relieved he’s got his diabetes under control, but still wishes he’d been warned about the side-effects of glucocorticoids. “So many people have blind faith in their doctors. I wonder what would have happened if I hadn’t questioned my treatment.”

Adapted from a news report in the Daily Mail

Aggressive Diabetes Therapy May Raise Death Risk

The BIG news of the day is that intensive blood sugar control doesn’t benefit people with both type 2 diabetes and heart disease.  In fact, intensive treatment to lower blood sugar is linked to increased mortality, according to a long-running study whose findings were published today.

This reminds me of a discussion that I participated in a TuDiabetes forum a couple of week ago. The issue being discussed was A1c/eAG levels. I had written: “My diabetologist says that diabetics have higher eAG than normal, healthy individuals. Indeed, he says that it is better for diabetics to have an eAG of ~ 180 than ~ 140. He says in his experience diabetics who try to emulate normal eAG levels suffer more complications – cardio, renal, vascular, optho – than those with slightly higher values. He cites the example of a few patients (now age 80+) who have remained at 200+ for 30 years!”

Clinical trials now seem to have validated anecdotal evidence. The New England Journal of Medicine reported today that according to the latest analysis from the long-running ACCORD study, trying to maintain the blood sugar levels typical of people without diabetes can increase the risk of death for people with type 2 diabetes and heart disease by 19 percent.

ACCORD stands for Action to Control Cardiovascular Risk in Diabetes. This study was designed to assess whether intensive blood sugar interventions to bring A1C levels to under 6 percent would benefit people with type 2 diabetes and heart disease.

A1C is a long-term measure of blood sugar control, and the A1C level provides about two to three months of average blood sugar levels. A level of under 6 percent, which is considered normal or non-diabetic, can be difficult for someone with diabetes to achieve.

This brings me to the outlook of many TuDiabetes members (many of who take their management very seriously). Replying to my response mentioned above, one member wrote: “I disagree with the idea that lower blood sugar levels cause more complications….The largest intervention study to date, the DCCT pretty conclusively found that risks of “all” complications could be decreased by reducing blood sugars. Data from the DCCT conclusively substantiated that down to below 7% (154 mg/dl eAG). Further studies have found additional support that additional risk reductions occur all the way down to A1cs of even 5.5%. The American Association of Clinical Endochrinologists in fact suggests that patients “Encourage patients to achieve glycemic levels as near normal as possible without inducing clinically significant hypoglycemia”.”

Another quipped: “If your diabetologist is implying that averaging 180 is okay (over the Renal Threshold), then he desperately needs to go on a high-fiber diet.”

Fair enough. All of agree that BS levels should be as close to normal as possible. But do we have to adopt an aggressive approach to diabetes management just because the doctors says so? Ground Zero observations have revealed that many diabetics do NOT suffer complications. (See my earlier post on this here.)

It should not be forgotten that aggressive insulin therapy also necessitates the need of continuous monitors, a luxury most diabetics cannot afford (given the high cost of testing strips). In India where I live, only a minuscule number of people test BS on a daily or even weekly basis. The norm is to test fasting and post-prandial levels only when one visits a diabetologist, which is not more than 2-3 times in a year. (My diabetologist says most of his patients turn up only when they’re really sick.)

Of course I’m guilty of poorly paraphrasing my diabetologist’s observations. But essentially he’s right and the recent ACCORD study validates a diabetologist’s long experience of treating a variety of patients in a (clinically) ‘hostile’ environment.

It is interesting to note how the ACCORD study reached its conclusions. The people recruited for the study were between 40 and 79 years old, and their A1C levels were above 7.5 percent at the start of the study. Study volunteers were randomly assigned to either intensive blood sugar control or to a standard diabetes program striving for levels of 7 percent to 7.9 percent.

The study began in 2001 and was halted in February 2008 when researchers realized that people in the intensive treatment group had an increased risk of dying. By then, the intensive treatment group had received 3.7 years of treatment aimed at lowering their A1C levels to below 6 percent.

Achieving such tight blood sugar control often required numerous interventions, such as lifestyle changes along with medication, multiple medications or insulin therapy.

The analysis includes five years of data. For the intensive group, that meant an average of 3.7 years of intense treatment, followed by 1.3 years of standard therapy.

At the time the study was stopped, the intensive therapy group experienced a 21 percent reduction in the risk of heart attacks, but a 21 percent increase in the risk of all-cause mortality.

After five years, the researchers found that the risk of heart attacks was still decreased by 18 percent, but the increased risk of all-cause mortality also persisted. People in the intensive therapy group had a 19 percent increased risk of dying of any cause.

The study’s lead author, Dr. Hertzel C. Gerstein, the Population Research Health Institute Chair in Diabetes Research at McMaster University in Hamilton, Canada, said many researchers have tried to tease out why intensive blood sugar control might up the risk of death, and so far, no one has succeeded. Causes that have been ruled out include low blood sugar levels (hypoglycemia) and the rapid change in blood sugar levels.

“This study really reminds us that we always need to be prudent. Even if we think something is the right thing to do, sometimes we may have findings that are unexpected,” said Gerstein.

“This study confirms the results of the ACCORD trial over the full duration of the study,” said Dr. Vivian Fonseca, president-elect of medicine and science for the American Diabetes Association.

“Overall, this means that the recommendations of the American Diabetes Association hold true. In general, people with diabetes should aim for an A1C goal of less than 7 percent, but clearly individualization is important. One size does not fit all,” said Fonseca.

And, the findings suggest that people with type 2 diabetes and heart disease shouldn’t attempt to achieve an A1C below 6 percent, the study authors said.

Gerstein and Fonseca noted that the ACCORD findings should not be generalized for everyone with diabetes. People with type 1 diabetes and those with type 2 diabetes and no history of heart disease were not included in this study.

“There is no reason to change current guidelines because of this study, and this study certainly doesn’t support ignoring glucose control. We saw benefits in eye disease and many other outcomes with good control,” said Gerstein.

More information

To learn more about the connection between diabetes, heart disease and stroke, go to the U.S. National Institute of Diabetes and Digestive and Kidney Diseases

How Insulin-Producing Cells Die – Research Offers Potential for New Diabetes Diagnostic Test

The death of insulin-producing beta cells in the pancreas is a core defect in diabetes. Scientists in Italy and Texas now have discovered a new way that these cells die — by toxic imbalance of a molecule secreted by other pancreatic cells.

“Our study shows that neighboring cells called alpha cells can behave like adversaries for beta cells. This was an unexpected finding,” said Franco Folli, M.D., Ph.D., professor of medicine/diabetes at The University of Texas Health Science Center at San Antonio. He is co-lead author on the study with Carla Perego, Ph.D., assistant professor of physiology at the University of Milan.

Alpha and beta cells are grouped in areas of the pancreas called the islets of Langerhans. Alpha cells make glucagon, the hormone that raises blood sugar during fasting. In the same environment the beta cells make insulin, the hormone that lowers sugars after a meal. Imbalance ultimately leads to diabetes.

“We found that glutamate, a major signaling molecule in the brain and pancreas, is secreted together with glucagon by alpha cells and affects beta cell integrity,” Dr. Folli said. “In a situation where there is an imbalance toward more alpha cells and fewer beta cells, as in Type 1 and Type 2 diabetes, this could result in further beta cell destruction.”

Glutamate toxicity is a new mechanism of beta cell destruction not previously known, Drs. Perego and Folli said. It has not been typically thought that alpha cells could themselves be a cause of beta cell damage, they said.

The study also found a protection for beta cells, namely, a protein called GLT1 that controls glutamate levels outside the beta cells. “GLT1 is like a thermostat controlling the microenvironment of beta cells with respect to glutamate concentration,” Dr. Perego said.

A diagnostic test for glutamate toxicity in the islets of Langerhans is being developed by the authors, Dr. Folli said. Eventually an intervention to slow the process could follow.

Glutamate poisoning is a new candidate mechanism for beta cell destruction in diabetes. Others are high glucose, buildup of a protein called amyloid, and free fatty acids, which are found in patients with type 2 diabetes.

“The vicious cycle in diabetes is that there are several substances that have been shown, also by us, to be toxic to beta cells,” Dr. Folli said. “And now we have found a new one, glutamate.”