Personalizing Type 2 Diabetes Management

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The MD Magazine Peer Exchange "Improving Management of Type 2 Diabetes Mellitus" features a panel of physician experts discussing current best practices to treating and managing patients with T2DM that generally includes lifestyle modifications as well as medication. The mechanisms of action, patient selection criteria, and side effects for various oral medication classes are included in the discussion.

This Peer Exchange is moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University College of Physicians and Surgeons, and an associate director of Surgical Intensive Care at New York-Presbyterian Hospital.

The panelists are:

• Robert Busch, MD, director of clinical research in the Community Endocrine Group at Albany Medical Faculty Practice in Albany, NY
• Ralph DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center in San Antonio, TX
• Pamela Kushner, MD, clinical professor at UC Irvine Medical Center and director of Kushner Wellness at UC Irvine Medical Center in Los Alamitos, CA
• Jeffrey Miller, MD, professor of medicine and clinical director of the Division of Endocrinology and Diabetes at Jefferson Medical School in Philadelphia, PA

Peter L. Salgo, MD: We’ve talked about talking to patients. We’ve talked about emphasizing to them how important it is to do the right thing, eat the right thing; I’ll say exercise because nobody else seems to want to. But, at some point, some of these patients are going to need medication. So, what’s the tipping point here, Dr. DeFronzo? How do you decide?

Ralph DeFronzo, MD: For me, it’s pretty simple. If you look at lifestyle intervention, it generally fails. I mean, you can cut it any way you want, but the data are very clear. Ninety percent of people who lose weight successfully in programs, once they’re out of the program, regain the weight within 3 to 4 years. I’ve created an ominous octet. When you understand what the ominous octet for obesity is, you’ll understand why it’s so difficult for people. Their brain becomes resistant to insulin. Insulin is a molecule that shuts off your appetite. You secrete insulin in a 1:1 ratio with Amylin—Amylin shuts off your appetite. You’re resistant to Amylin. The most powerful anorectic molecule in the human body is PYY. You are resistant to it. Every time you eat a meal, you release GLP-1, which is an appetite suppressant. You’re severely resistant in GLP-1. When your fat cells expand, you release leptin. Leptin goes to your brain and tells you to stop eating, you’re resistant to it. If you look within the brain, serotonin levels are increased, stimulates your appetite. Dopamine levels are low, which stimulates your appetite. They’re altered catecholamine levels. So, you’re asking people to psychologically overcome these eight powerful factors, and, on a long-term basis, we usually fail.

So, right from the beginning—in addition to lifestyle—I think you need to consider some of the anti-obesity medicines. The problem is they’re very expensive and they’re not on formularies. And, I personally don’t wait for the dietitian to convince my people to lose weight or for the person to get religious and lose weight. I’m going to initiate the diabetes therapy right from the beginning. And we’ll talk later about what I think medicines and don’t work. But I’m not going to wait to see if the person loses 20 pounds by the next time I see them.

Jeffrey Miller, MD: My correction, please, for the record. I believe, Dr. DeFronzo, you said insulin shuts off the appetite. I assume you mean stimulates the appetite.

Ralph DeFronzo, MD: Incorrect. I had been wrong once in my life and then 2 weeks later I found out I made a mistake. So, Dr. Daniel Port showed some 60 years ago that if you give rodents or humans low-dose insulin— one to two units, so you don’t change the blood sugar—that actually turns off your appetite. And obese people are markedly insulin resistant, as they’re diabetics. They have hyperinsulinemia and that insulin actually is now working in the opposite direction. These high doses, because we’ve become refractory to the insulin, actually then work the other way to stimulate your appetite. But low doses of insulin actually...

Jeffrey Miller, MD: I was referring to insulin resistance, which is what you said in the ominous octet.

Ralph DeFronzo, MD: No, no, it’s not insulin resistance. Insulin per se, if you give to normal healthy people in low doses, shuts off your appetite.

Jeffrey Miller, MD: No, I’m talking about your own endogenous insulin in the insulin- resistant individual. That stimulates appetite?

Ralph DeFronzo, MD: Your own insulin, if it’s in very low levels actually is an appetite suppressant.

Jeffrey Miller, MD: No, I understand that. But insulin-resistant people are hyperinsulinemic.

Ralph DeFronzo, MD: Correct. Despite the fact that they’re hyperinsulinemic, they still overeat and gain weight. So, the brain has become resistant to the anorectic effect of insulin, period.

Peter L. Salgo, MD: It’s a bad combination, bad, bad, bad. And then we’ve got these comorbidities, and I want to touch on them briefly because they do affect, I suspect, the way you approach diabetes care. I mean, there’s what, renal dysfunction and mental health issues and all of these things, Dr. Miller. How do you run through some of these things and decide, with that in mind, how you approach your diabetics care?

Jeffrey Miller, MD: It has been very eloquently brought out that one shoe size does not fit all, and the ADA and the ACE have not come out with guidelines where it’s personalized treatment. We’ve gone now from everybody getting the same treatment. We now have a number of different modalities working on different parts of the ominous octet. And if somebody has renal dysfunction, obviously they’re at increased risk of hypoglycemia, so I would be very careful in that individual with a long-acting sulfonylurea because that agent is potentially dangerous. We bring all these different factors in in terms of preventing hypoglycemia, etcetera, etcetera, and therefore we tailor our treatment to each individual person.