Date: November 5th, 2009

Speaker's Name and Affiliation:

• Joseph R. Vasselli
• New York Obesity Research Center, St. Luke's Roosevelt Hospital

Seminar Title: "The role of insulin in the regulation of body weight"

Chair: Harry R. Kissileff, Ph.D.

Rapporteur: Kathleen L. Keller, Ph.D.

Attendees and their Affiliation:

Kathleen Keller	Columbia/Obesity Research Center
Harry Kissileff	Obesity Research Center
Tony Sclafani	Brooklyn College
Laurence Nolan	Wagner College
Miranda Johnson	VA-NJ Medical
Barry Levin	VA-NJ Medical
Joelle Grinker	University of Michigan
Carol Maggio	NY ORC
Allan Geliebter	NY ORC
Sami Hashim	St. Luke's Roosevelt Hospital
Michael Lewis	CUNY Hunter College
Charlisa Gibson	NYORC
Susan Carnell	NYORC
Sally Ann Lederman	IHN
Eugene Dinkevich	SUNY-Downstate
Martica Heaner	Teacher's College
Rhoda Gruen	Columbia University
Joanna Huang	SA
Angie Chong	CMMC

Summary: (Prepared by the Speaker)

Insulin is one of the major feedback signals for body weight regulation, and is perhaps the most complex one because its action includes peripheral anabolic effects and central catabolic effects, both of which can be shown to participate in the weight regulatory process under specific experimental conditions. In addition, resistance to both insulin's peripheral and central effects can be demonstrated in diabetic and obese animal models. These effects were reviewed, for the purpose of evaluating the action of a new long-acting analog of insulin which is acylated, and is currently in use in the treatment of diabetes (insulin detemir).

Insulin detemir has the unique property of preventing weight gain in treated diabetics, and the purpose of our studies was to identify the potential mechanisms involved. We demonstrated that insulin detemir prevents hypoglycemia and elevated feeding in normal and diabetic rats at doses at which another long-acting form of insulin (NPH) stimulates both of these effects. Also central microinjections of insulin detemir in normal rats at doses equimolar to regular insulin leads to significantly greater catabolic EE and RQ alterations for the insulin analog. Thus two potential weight-sparing mechanisms for insulin detemir were identified, although the exact role each plays inhibiting body weight gain in diabetes has yet to be identified. The basis for these unique effects of insulin detemir was hypothesized to be tissue-specific differences in the availability of detemir to the insulin receptor in liver, muscle, adipose tissue and brain. These tissue-specific effects may have the overall result of rendering the action of peripherally-injected insulin detemir closer to that of normal insulin released in response to a meal, thus providing protection from excess weight gain.

Question & Answers:

Q. Are there impediments to insulin transport in the brain?
A. No, there's actually an active transport mechanism.

Q. What is the mechanism of the effect of hypoglycemia on body weight?
A. This has yet to be determined. We would assume increased feeding is responsible, as shown by Woods, but lipogenic effects may be involved also.

Q. Is this peripheral insulin injections that have this effect?
A. In patients, yes. These are diabetics receiving long term insulin therapy.
Comment: This effect of hypoglycemia on feeding is rate dependent. If you infuse more slowly, you can get lower feeding thresholds.

Q. Have you looked at the animal's previous diet to see if it affects the hypoglycemic feeding threshold?
A. I haven't looked at diet and hypoglycemic thresholds yet that yet. It's a good question, there may well be some effects.

Q. What was the rationale for putting these patients on insulin to begin with?
A. They wanted to compare conventional treatment with metformin and insulin to determine weight gain and other outcomes.

Q. I thought that metformin causes weight loss?
A. Initially, but not over the long-term.

Q. Why were these modifications made?
A. To make a longer acting form of insulin. When injected it binds to albumin and then proceeds more slowly into plasma. This binding slows the release and prolongs the effects.

Q. Is it degraded in the same way as regular insulin?
A. I'm not sure.

Q. Is the insulin detimer injected once daily?
A. Yes, in our studies insulin is injected SQ once per day, but some human studies use two injections/day, and two injections are used in clinical practice as well.

Q. In this study, were the doses of insulin and detimer equal?
A. Yes. SC doses were equated for peripheral tissue glucose clearance, while central doses were equi-molar.

Q. Have these results been compared to Insulin glargine (Competitor)?
A. Yes, but insulin glargine actually doesn't have the same weight sparing effect.

Q. So, in other words, the NPH animals cannot eat enough to limit their hypoglycemia?
A. Yes, that's true initially following injection of regular insulin. But, even when their glucose is restored to normal, they will still continue to eat more.

Q. Did you see any sex differences?
A. We are just testing males.

Q. Is it thought that detimer is getting into the brain or into neurons differently?
A. I'll address that later, there are several possibilities.

Q. What about the counter hypothesis, that the Insulin detimer is stimulating counter regulatory hormones?
A. I'll also address that later.

Q. Are these animals na?ve to insulin?
A. In most cases, yes.
Comment: There is clearly a learning that goes on with hypoglycemia.

Q. How does that dose compare to the dose used in humans? It seems very high.
A. Yes, it is much higher than a dose that would be used in humans.

Q. How do we translate these data to human patients?
A. That's a fair question that should be explored.

Q. Are these Charles River Sprague Dawleys?
A. No, they are Taconics.

Q. How can you show cumulative food intake for 3 animals?
A. The BioDaq software allows us to calculate mean values.

Q. If you inject insulin IP, would you expect the same results?
A. Yes, that's supported by the literature and by our data.

Q. Would you conclude this to mean that degradation of insulin by the liver is greater?
A. No, the opposite, there is actually more insulin action in the liver following an IP injection than an SC injection, which would result in more glycogen synthesis.

Q. With respect to some of the brain effects of insulin detimer, have you looked at some of the other neuropeptides (eg. NPY, ARC)?
A. No, but that would be interesting to do.

Q. What do you mean by gradual loss of the ability to restore glycogen?
A. The mechanism by which insulin is able to restore glycogen may gradually become resistant. Essentially, liver insulin resistance in the face of high insulin levels, which is well known.

Q. You showed a slide on the difference between regular insulin and insulin detimer. How good is the evidence that the effects on food intake control are due to differences in blood sugar?
A. Niswender argues that insulin has no effect on body weight other than through hypoglycemia. But, insulin also has lipogenic effects that could indirectly affect body weight. It's not completely clear whether detemir minimizes these effects also.

Q. In several or your experiments, you compare High fat diets to chow. Has anyone done similar experiments looking at high carbohydrate diets?
A. Well, a chow diet is really a high carbohydrate diet. You could do this with a high sugar or polycose diets as well, that would be interesting.

Q. Are the hypoglycemic effects perceived to be a contributing factor of obesity that results from a high-fat diet?
A. Yes, according to Steve Woods, insulin injections leading to hypoglycemia would accelerate HF diet obesity.