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Incretins and Pathogenic Abnormalities

Nov 06, 2012

In my last blog, I shared with you what I learned at a meeting on Metformin.  I was in shock and awe when I saw that 15 kind people commented on that entry.  I hope not to bore you, but I thought I would try once more to share what I learned at an early morning breakfast meeting presented by Dr. Ralph DeFronzo (a diabetes rock star). 

According to Dr. DeFronzo -
1.  Beta cell failure occurs much earlier in the natural history of type 2 diabetes and is more severe than previously appreciated.
2.  Individuals with impaired glucose tolerance are maximally or near maximally insulin resistant, have lost approximately 80 percent of their beta cell function (DeFronzo) and have lost significant beta cell mass (Butler)
3.  Our primary goal should be to prevent beta cell failure. Interventions should target pathogenic mechanisms known to promote beta cell failure and cause insulin resistance.
4.  Treatments of type 2 dm will require multiple drugs in combination to correct multiple pathophysiologic defects, should be based upon known pathogenic abnormalities and not simply on reduction of A1c and must be started early in the natural history of type 2 dm, if progressive beta cell failure is to be prevented.
(For more detailed information, review Dr. DeFronzo’s Banting lecture on the Ominous Octet).

Dr. DeFronzo addressed incretins and how they correct multiple abnormalities
1.  Glucagon-like Peptide 1 (GLP-1) and Glucose-dependent Insulinotrophic Polypeptide (GIP) account for approximately 90 percent of the incretin effect
2.  In response to equivalent hyperglycemic stimuli, oral glucose elicits a greater insulin response than IV glucose. Thus, the gut becomes more important.
When we eat, K-cells of the intestine secrete GIP and L-cells secrete GLP-1.
GLP-1 is responsible for delaying gastric emptying, increasing satiety , increasing insulin secretion by the beta cells, and shutting off glucagon production by the pancreas.
One good point is that these drugs do not cause hypoglycemia.
4.  There are also cardiovascular benefits of the GLP-1 analogues. These include:

  • improved plasma lipid levels 
  • reduction of blood pressure
  • decreased CRP and BNP
  • improvement in endothelial dysfunction
  • reduction in infarct size – this has been shown by Robert Chilton in the cath lab

5.  In the liver, GLP-1 analogues decreased fat accumulation and hepatic glucose production.

The incretin mimetic drugs are Exenatide, Liraglutide  and Bydureon. Another drug class associated with incretins are the DPP IVs  (read DPP 4s). I am sure there are more complex explanations, but this is how I understand them to work.  DPP IV breaks down the action of GIP and GLP-1 thus causing incretins to be biologically inactive.  As stated above, you do not want the GIP and GLP-1 to be inactive because they do lots of good things to assist in controlling diabetes.  So you would give a DPP IV Inhibitor to slow the degrading action of the DPP IV - thus, the GIP and GLP-1 can remain biologically active longer and do their thing to assist in controlling glucose and diabetes.

That is my drug lesson for today.  Hope you have a wonderful holiday season!


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  1. Dec 03, 2012

    I really like your up to date information on drugs. Thanks for the information and keep it coming.
  2. Dec 03, 2012

    This was a great summary of this drug class and nicely organizes the key components of Dr. DeFronzo's lecture. thanks for sharing. Elaine
  3. Nov 15, 2012

    I have been a diabetes educator for 6 years. I am taking Victoza for about two years now and have lost 40 lbs and may blood sugars are amazing. My last A1C was 6.1. I can exercise and do not have to eat at a certain time and still never go low. Before Victoza, I was on 2000 mg of Metformin, 68 units of Lantus, Januvia 100 mg, and Actos. After gradually losing weight I was able to come off of Lantus, Actos, and Januvia, and am now only taking Metformin and Victoza. Many of our patients have also had great success and have lost weight, usually around 40 lbs. A girl I work with had an A1C of 11 and had pretty much given up trying to control her blood sugars. She was started on Victoza, lost 40 lbs after about a year, and her last A1C was 6.0. Unfortunately, we do not see a lot of the primary doctors using GLP-1 analogues, so I was very glad to see your article. Hopefully, the word will get out and more MDs will start prescribing these to patients.
  4. Nov 07, 2012

    Who is on your (diabetes) team? My name is Shari Liesch, a Nurse Practitioner in diabetes and endocrine at CHW Fox Valley. In clinic visits I try to focus on heart healthy living. To maintain health, we need to eat balanced meals, get daily exercise and plenty of rest. These are also important in taking care of your diabetes. Diabetes care can be demanding. When first diagnosed, there are many “jobs” to learn to maintain sugar control. As persons become more experienced, these “jobs” (blood sugar testing and insulin administration) become part of the daily routine. While routine is important, we must also prepare for the unexpected. This week I had the privilege of seeing Cara, a 13 ½ year old student who is also a figure skater. She eats healthy, exercises and tries hard to get plenty of rest, but struggles with fitting it all in, plus continue to get good grades. Along with reviewing the plan (testing, insulin dosing, activity), I asked “Who’s on your diabetes team?” As Cara verbalized those who could assist with cares, it was a great reminder that although she is fairly independent, she is not alone in diabetes care. We discussed the importance of the team in synchronous skate, and the importance of a team approach in diabetes management. No matter what team we are on, persons who are part of a team are more likely to be accountable or do their part. For skating, Cara is motivated by her love of skating and the knowledge that there are alternates in training; ready to step in if needed. For diabetes she is motivated by energy, as if numbers are high she gets fatigued more easily, and if low she has to stop skating until it is fixed. These are powerful motivators for her. What are your motivators? To evaluate how anything in life is working, I use the strategy of plan, do, check, adjust (PDCA) as a way of continued improvement. One key piece of a successful team is attention to the game plan. Parents (guardians) are the head coach (es), while health care team providers are the assistant coaches. While we know a lot about diabetes, the parent is with them 24/7, and sees firsthand the relationship between food, activity, stress and sugar variations. To encourage review of the game plan, it is recommended there be family “time-outs” to look at what is working, and what may need to be adjusted. For Cara I used the analogy of tightening her skates. She quickly listed how important proper skate fit and tight laces are to safely perform all the “tricks” in the routine. For her diabetes plan, evaluating the pump download on a weekly basis was compared to tightening her skates. The family will look at specific days of the week, especially when the demand is high (Monday nights), to determine if changes are needed. Meeting times need to be when the family is able to focus. It should be brief, and information learned (what worked, what did not) should be used to direct future care. Adjustments are made, so highs and lows can be prevented. The day and time are written on the take home instructions as a reminder of their commitment to plan, do check adjust. If family meetings are scheduled and put in the family weekly planner, it becomes part of their routine. This allows the family to adjust the plan as needed between appointments. This strategy keeps the home team vested and can prevent “surprises” in A1c results at clinic visits. Whether it is tightening skates or evaluating the diabetes plan, we can use the PDCA model for successful management. Evaluating and adjusting the plan is important to be successful in achieving goals in any area of life. What are your goals? Who is encouraging you to “tighten your skates”? How are your teammates helping you achieve your goals? This is a link to the PDCA process and how it can be applied to any area of life.

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