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University Tulane University
Doctors have long known that men with low testosterone are more likely to develop type 2 diabetes.
Now, for the first time, they have identified how the hormone helps men regulate blood sugar by triggering key signaling mechanisms in islets, clusters of cells within the pancreas that produce insulin.
The results, published in the journal Cell Metabolism, could help identify new treatments, researchers say.
“We have found the cause—and a potential treatment pathway—for type 2 diabetes in testosterone-deficient men,” says senior author Franck Mauvais-Jarvis, professor of medicine at Tulane University School of Medicine. “Our study shows that testosterone is an anti-diabetic hormone in men. If we can modulate its action without side effects, it is a therapeutic avenue for type 2 diabetes.”
Researchers used specially bred male mice with pancreatic beta cells lacking the receptor to testosterone (the androgen receptor). They fed them a diet rich in fats and sugar, and tested their response to glucose. The mice without androgen receptors all developed lower insulin secretion, leading to glucose intolerance compared with normal mice in the control group.
To better understand how testosterone interacted with insulin production within the pancreas, researchers administered the hormone and glucose directly to human islet cells treated with an androgen receptor inhibitor and islets cells harvested from mice without androgen receptors. In both cases the islet cells showed decreased insulin production compared to islet cells whose receptor to testosterone was not inhibited or missing.
Further experiments in cultured mouse and human islet cells showed the insulin-producing effect of testosterone could be abolished by inhibiting glucagon-like peptide-1 (GLP-1), a hormone the body produces after a meal. The study suggests that testosterone amplifies the islet impact of the hormone, which is currently used as a diabetes treatment.
Other researchers from Tulane and from Northwestern University, Vanderbilt University, University of Chicago, University of Illinois, and Catholic University of Leuven in Belgium are coauthors of the study.
Source: Tulane University
- Testosterone Prevents Progression to Diabetes in Hypogonadal Men
- A Complete List of Diabetes Medications
- FDA Approves Ozempic, A Powerful Once-Weekly Type 2 Diabetes Medication
Testosterone Prevents Progression to Diabetes in Hypogonadal Men
Normalizing testosterone levels through replacement therapy could prevent men with low testosterone levels, or hypogonadism, and prediabetes from progressing to type 2 diabetes, the results of a registry study suggest.
Aksam Yassin, MD, Institute for Urology and Andrology, Norderstedt, Germany, and colleagues looked at more than 300 men from two registries who had low testosterone levels, symptoms of hypogonadism, and raised HbA1c levels.
Of almost 90 men, 40% who opted out of testosterone therapy went on to develop type 2 diabetes over 8 years, but none of the more than 200 men who took testosterone replacement therapy progressed to diabetes, according to the results, published online March 12 in Diabetes Care.
Crucially, the vast majority of the treated men achieved normal glucose regulation, in addition to which they saw improvements in lipid levels and quality of life.
The team writes that “to our knowledge, this study is the first to show that testosterone therapy can completely prevent prediabetes progression to overt type 2 diabetes.”
They add: “Interventions that aim to prevent prediabetes progression to diabetes ideally should restore normoglycemia rather than just maintain the prediabetes state.
“In this regard, it is particularly notable that 90% of men treated with testosterone achieved regression to normal glucose regulation.”
“Dramatic” Results That Will Have “Impact”
Study author W. Timothy Garvey, MD, Department of Nutrition Sciences, University of Alabama at Birmingham, told Medscape Medical News that he was “surprised” by the “dramatic results,” which he believes are “going to have a lot of impact.”
He nevertheless cautioned that testosterone therapy should not be given to “any man with prediabetes who has low total testosterone,” as testosterone levels are lower in men with insulin resistance because of the reduced production of sex hormone binding globulin.
The “important issue” is that the men in the study had symptoms of hypogonadism, and so had “true hypogonadism.”
He added: “It’s really the presence of symptoms that make the difference.”
Overall, Garvey believes the results add “another reason” to treat men with hypogonadism “and get testosterone levels up to normal.”
Approached for comment, Louis Philipson, MD, PhD, director of the Kovler Diabetes Center at the University of Chicago, Illinois, told Medscape Medical News that, despite a number of limitations, “it is a study that grabs one’s attention.”
He pointed out that it was a nonrandomized, unblinded study supported by a drug company and there were baseline differences between the treatment and control groups, yet “the editors clearly felt this was a study worth publishing because this is a win.”
Philipson continued that the take home message is that “if men have symptoms of low testosterone, they should by all means discuss it with their doctor and, if it is low, testosterone replacement could have multiple benefits.”
He also agreed with Garvey that treatment should be reserved for men who have proven hypogonadism.
“This is not about the general population,” he said. “We don’t want to run around giving people testosterone. Lord knows the world has enough testosterone.”
“But in those men who are, by blood test, low it turns out they have a higher chance then of getting diabetes, but if you replace it those chances go down.”
Testosterone-Treated Men Less Likely to Die or Have a Heart Attack
The researchers say that men with hypogonadism have an increased risk of developing insulin resistance and, subsequently, type 2 diabetes.
With long-term testosterone therapy also leading to sustained weight loss, the researchers examined whether treating men with hypogonadism and prediabetes would slow their progression to type 2 diabetes.
They pooled data from two ongoing urological registries on 316 men with prediabetes, defined as an HbA1c level between 5.7% and 6.7%, and total testosterone level ≤ 12.1 nmol/L, as well as symptoms of hypogonadism.
After a 6-week interval, 229 men were given parenteral testosterone undecanoate (TU) 1000 mg every 12 weeks. The 87 men who chose not to have testosterone therapy acted as controls.
Anthropometric and metabolic measures, including total testosterone, fasting glucose, and HbA1c levels, were assessed at least twice a year.
The group treated with testosterone were significantly younger than those who opted out of treatment, at a mean of 58.2 years versus 66.4 years (P < .0001).
Men given testosterone therapy had also significantly lower high-density lipoprotein cholesterol (HDL-C), higher triglycerides, and worse scores on the Aging Males’ Symptoms (AMS) quality of life scale (P < .0001 for all).
In addition, the testosterone group had lower mean testosterone levels at baseline than the untreated group, at an average of 8.2 nmol/L versus 9.6 nmol/L (P < .0001).
Over 8 years, contributing 1993 patient-years of follow-up, HbA1c levels decreased by an average of 0.39% in the testosterone group compared with a mean increase of 0.63% in the untreated group (P < .0001).
In addition, the testosterone group had a reduced waist circumference of 6.8 cm versus an increase of 7.4 cm in the untreated group.
There was also reductions in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels and an increase in HDL-C levels in the treated group. AMS scores also improved.
Discussing the findings, the team says that weight loss of 10% through diet and exercise interventions “is notoriously difficult to achieve, and even harder to maintain long term.”
Multifactorial Risk Reduction in Hypogonadism With Prediabetes
Noting that their attrition rate, at only two men overall, was “extremely low,” they say that “long-term testosterone therapy with TU injections is effective for achieving marked lasting weight loss and prevention of diabetes and feasible long term in real life.”
Nevertheless, they suggest that the “main mechanism explaining how testosterone therapy prevents development of diabetes is likely improvement in insulin sensitivity,” as indicated by the impact on HDL-C and triglyceride levels, among other parameters.
“In summary, given the observed improvements in glycemia, insulin resistance, body weight, and lipids, our study shows that testosterone therapy provides a multifactorial and comprehensive cardiovascular disease risk reduction in men with hypogonadism and prediabetes.”
Philipson noted, however, “For anybody contemplating this kind of therapy, one has to balance the good with the bad, and testosterone we know can increase prostate size.”
He added: “There’s a small fear that testosterone replacement could, say, enhance prostate cancer, but in this study they were careful to give a low dose of testosterone.”
“And also, of course, it has to be given by injection…so men either have to learn how to give it themselves at home or come into the doctor at some interval…anywhere from every 2 weeks to once a month.”
The study was financially supported by Bayer AG. Yassin and Ahmad Haider received financial contributions for data entry, travel grants, and speakers honoraria from Bayer AG. Karim S. Haider received travel grants and speakers honoraria from Bayer AG. Gheorghe Doros received payment for statistical analyses from Bayer AG. Farid Saad is a full-time employee of Bayer AG.
Diabetes Care. March 12, 2019. Full text
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A Complete List of Diabetes Medications
If you have type 2 diabetes, your body makes insulin but no longer uses it well.
Your body can’t make enough insulin to keep your blood sugar levels normal. The goal of treatment for you is to help your body use your insulin better or to get rid of extra sugar in your blood.
Most medications for type 2 diabetes are oral drugs. However, a few come as injections. Some people with type 2 diabetes may also need to take insulin.
These medications help your body break down starchy foods and table sugar. This effect lowers your blood sugar levels.
For the best results, you should take these drugs before meals. These drugs include:
- acarbose (Precose)
- miglitol (Glyset)
Biguanides decrease how much sugar your liver makes. They decrease how much sugar your intestines absorb, make your body more sensitive to insulin, and help your muscles absorb glucose.
The most common biguanide is metformin (Glucophage, Metformin Hydrochloride ER, Glumetza, Riomet, Fortamet).
Metformin can also be combined with other drugs for type 2 diabetes. It’s an ingredient in the following medications:
- metformin-alogliptin (Kazano)
- metformin-canagliflozin (Invokamet)
- metformin-dapagliflozin (Xigduo XR)
- metformin-empagliflozin (Synjardy)
- metformin-glyburide (Glucovance)
- metformin-linagliptin (Jentadueto)
- metformin-pioglitazone (Actoplus)
- metformin-repaglinide (PrandiMet)
- metformin-rosiglitazone (Avandamet)
- metformin-saxagliptin (Kombiglyze XR)
- metformin-sitagliptin (Janumet)
Bromocriptine (Cycloset) is a dopamine agonist.
It’s not known exactly how this drug works to treat type 2 diabetes. It may affect rhythms in your body and prevent insulin resistance.
Dipeptidyl peptidase-4 (DPP-4) inhibitors
DPP-4 inhibitors help the body continue to make insulin. They work by reducing blood sugar without causing hypoglycemia (low blood sugar).
These drugs can also help the pancreas make more insulin. These drugs include:
- alogliptin (Nesina)
- alogliptin-metformin (Kazano)
- alogliptin-pioglitazone (Oseni)
- linagliptin (Tradjenta)
- linagliptin-empagliflozin (Glyxambi)
- linagliptin-metformin (Jentadueto)
- saxagliptin (Onglyza)
- saxagliptin-metformin (Kombiglyze XR)
- sitagliptin (Januvia)
- sitagliptin-metformin (Janumet and Janumet XR)
- sitagliptin and simvastatin (Juvisync)
Glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists)
These drugs are similar to the natural hormone called incretin.
They increase B-cell growth and how much insulin your body uses. They decrease your appetite and how much glucagon your body uses. They also slow stomach emptying.
These are all important actions for people with diabetes.
For some people, atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease may predominate over their diabetes. In these cases, the American Diabetes Association (ADA) recommends certain GLP-1 receptor agonists as part of an antihyperglycemic treatment regimen.
These drugs include:
These medications help your body release insulin. However, in some cases, they may lower your blood sugar too much.
These drugs aren’t for everyone. They include:
- nateglinide (Starlix)
- repaglinide (Prandin)
- repaglinide-metformin (Prandimet)
Sodium-glucose transporter (SGLT) 2 inhibitors
Sodium-glucose transporter (SGLT) 2 inhibitors work by preventing the kidneys from holding on to glucose. Instead, your body gets rid of the glucose through your urine.
In cases where atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease predominate, the ADA recommends SGLT2 inhibitors as a possible treatment option.
- dapagliflozin (Farxiga)
- dapagliflozin-metformin (Xigduo XR)
- canagliflozin (Invokana)
- canagliflozin-metformin (Invokamet)
- empagliflozin (Jardiance)
- empagliflozin-linagliptin (Glyxambi)
- empagliflozin-metformin (Synjardy)
- ertugliflozin (Steglatro)
These are among the oldest diabetes drugs still used today. They work by stimulating the pancreas with the help of beta cells. This causes your body to make more insulin.
These drugs include:
Thiazolidinediones work by decreasing glucose in your liver. They also help your fat cells use insulin better.
These drugs come with an increased risk of heart disease. If your doctor gives you one of these drugs, they’ll watch your heart function during treatment.
- rosiglitazone (Avandia)
- rosiglitazone-glimepiride (Avandaryl)
- rosiglitazone-metformin (Amaryl M)
- pioglitazone (Actos)
- pioglitazone-alogliptin (Oseni)
- pioglitazone-glimepiride (Duetact)
- pioglitazone-metformin (Actoplus Met, Actoplus Met XR)
FDA Approves Ozempic, A Powerful Once-Weekly Type 2 Diabetes Medication
By Ben Pallant and Payal Marathe
US Launch Expected in Early 2018; weight loss, major A1c reduction, and the convenience of a once-weekly injection in this new GLP-1 agonist
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The FDA has approved the once-weekly injectable Ozempic (semaglutide) for use in type 2 diabetes. Ozempic, a GLP-1 agonist, demonstrated significant A1c reductions (nearly 2%!) as well as weight loss in clinical trials. Though the approval was anticipated following a unanimous vote in favor of approval by an FDA advisory committee in October, it happened faster than expected. Ozempic will be available in the US within the first three months of 2018.
The one concern that came up during the FDA approval process was a slightly higher rate of retinopathy (eye damage) observed in Ozempic users in one clinical trial – 3% of Ozempic users experienced retinopathy compared to 1.8% of those taking placebo. The FDA addressed this by including a warning on Ozempic’s label about this risk, especially when first starting the drug. The slightly higher retinopathy risk may be linked to very rapid reductions in A1c when starting the medication. Many insulins feature a similar warning. This warning is especially relevant for people who already have some history of retinopathy prior to starting Ozempic.
Ozempic is now the fourth once-weekly injectable GLP-1 agonist to be approved in the US, joining Trulicity (dulaglutide), Bydureon (exenatide), and soon-to-be discontinued Tanzeum (albiglutide). In a recently-reported “head-to-head” trial, Ozempic showed greater A1c reduction than Trulicity (1.8% versus 1.4%) as well as greater weight loss (10-14 pounds versus 5-7 pounds). Ozempic had similarly shown greater A1c and weight reductions than Bydureon in an earlier trial. There are also once-daily GLP-1 agonists, Victoza (liraglutide) and Adlyxin (lixisenatide).
Novo Nordisk has indicated that Ozempic will be priced “on par” with other once-weekly GLP-1 agonists, meaning those with insurance coverage should pay a similar amount to other drugs in this class. We’d guess copay savings cards will be available for those without insurance coverage, similar to Victoza’s Instant Savings Card. Ozempic will come in a prefilled, disposable FlexTouch pen.
Following this FDA approval, Novo Nordisk is also working towards two more possible developments for this drug
- A study to assess whether Ozempic has benefits for heart health
- A study in 2018 on the use of Ozempic specifically as a weight-loss therapy for obesity.
A pill version of Ozempic is also in clinical trials; this could very likely be the first GLP-1 agonist not to require any injections at all.
When your doctor says you have type 2 diabetes, you may worry about getting shots of insulin to control the disease. But that’s seldom the first step, and some people don’t need insulin for years — or ever.
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When you have type 2 diabetes, your body doesn’t make enough insulin, as the body is unable to use it properly. Without insulin, blood glucose (sugar) levels rise. High blood glucose levels can damage your organs, including blood vessels, nerves, kidneys and eyes.
But with lifestyle changes and medications, many people are staying healthier longer with type 2 diabetes. Endocrinologist Richard Shewbridge, MD, says there is lot you can do to live well with diabetes.
What’s behind type 2 diabetes?
Type 2 diabetes develops because the body becomes resistant to insulin. Insulin is a hormone made by the pancreas to turn blood sugar into energy. “Type 2 diabetes means the process to turn food into energy isn’t working as well,” says Dr. Shewbridge.
Poor choices in diet and lack of exercise work to worsen insulin resistance, he says. And genetics can play a role, too. Additionally, people with type 2 diabetes tend to make less and less insulin over time and that causes a rise in blood sugar after meals.
The role of eating right and exercising
Many people with type 2 diabetes aren’t put on medication right away. Your doctor will likely suggest changes in your eating and exercise habits first.
“Once someone is put on medication, they may need it for the rest of their life. But, they also can treat diabetes with a healthy lifestyle and exercise,” says Dr. Shewbridge.
Healthier eating habits are a good place to start. “Cut out simple sugars. Eat less starchy bread, pasta, noodles and cereal. These foods don’t necessarily taste sweet, but they break down quickly,” he says.
If someone is overweight, trimming down also helps improve blood sugar control. Dr. Shewbridge says that losing as little as 5 percent of one’s total body weight can improve the body’s ability to convert blood sugar into energy.
Another benefit of a healthy diet and regular exercise is that you may need less medication. And taking less medication means you’ll likely see fewer side effects, he says.
When medications are necessary
If diet and exercise don’t stabilize your blood glucose levels, there are several prescription medication options. There are many types of oral medications to help boost insulin production, reduce glucose or help your body use insulin more effectively.
Dr. Shewbridge explains that most people will need medication eventually. Some “might do fine for years and years” without medication, while others need it sooner, he says.
If that time comes, there are many medication options:
- A biguanide (metformin) is a first-line treatment for type 2 diabetes. “Its primary job is to make insulin work better in the body,” says Dr. Shewbridge. It is effective in lowering blood sugar without causing hypoglycemia, and does not cause weight gain as a side effect. Also, the drug is relatively safe and available in generic form, he says.
- Sulfonylureas (e.g., glipizeide or glimepiride) help the pancreas produce more insulin to lower blood glucose. Dr. Shewbridge says doctors prescribe these drugs alone or with other diabetes medications. Possible side effects include hypoglycemia and weight gain.
- Meglitinides (such as Prandin® or Starlix®) help the pancreas produce insulin specifically with meals, as they act faster than sulfonylureas.
- Insulin is prescribed in type 1 diabetes but sometimes also for people who have type 2 diabetes. This drug is not usually a first-line treatment, Dr. Shewbridge says. Insulin can cause hypoglycemia and requires an injection, which is inconvenient and may cause hypoglycemia if not dosed carefully.
And that brings us back to the subject of shots and insulin.
If your doctor says you have type 2 diabetes, don’t worry about insulin shots. Instead, take control of your condition by learning more about it and making a plan for a healthy diet and regular exercise — and you’ll likely need fewer medications in the long run.