Disclaimer: Always consult your diabetes care team before making changes to medication. The following blog post is not medical advice, nor is it a comprehensive review of medication, it is intended to make you the reader think about the diabetes medication you are taking or prescribing.
Research is essential to good medical practice, but sometimes logic gets short shrift in a time when more people 'know' the importance of randomised controlled trials than understand why these are important and what their limitations are.
In this blog I'll begin by asking the question – are medications that increase insulin production a good idea in type 2 diabetes? Let's think for a moment...
Type 2 diabetes is often described as having two core components (yes, there is more to it, but let's keep it simple):
1) insulin resistance, meaning that the cells receiving instructions from the hormone insulin aren't very responsive (or selectively responsive in some cases); and
2) a reduction in the insulin producing capabilities of our pancreas, specifically the insulin producing beta-cells.
The common metaphor is that our body becomes 'deaf' to insulin (selective hearing might be more accurate), and our pancreas gets worn out from constantly having to ‘shout’, i.e. produce abnormally large amounts of insulin.
Research has shown that both marked insulin resistance and a reduced capacity to produce insulin are present, potentially for many years, before type 2 diabetes is diagnosed (1-3).
Post-mortem studies suggest a large reduction in beta-cell number at the time of diagnosis with further reductions over time (4,5), and recent work in living volunteers with type 2 diabetes showed an average 33% reduction in pancreas size compared to volunteers with normal glucose tolerance (6).
NB: although the capacity to produce insulin is impaired before diagnosis, in an attempt to overcome insulin resistance average insulin production is still much higher in most cases of ‘pre-diabetes’ and early type 2 diabetes than in those with normal metabolism. Translation – most people with type 2 diabetes have excessive blood insulin to go along with their excessive blood glucose.
So when you consider this, does it make sense to use medication that directly or indirectly stimulates the insulin producing beta-cells to produce more insulin? Is it a good idea to motivate the already ‘hoarse’ pancreas to ‘shout’ a little louder, say as opposed to addressing the prevailing deafness or doing something to help the pancreas rest, repair, and regrow to its original size?
I would have suggested the default answer is no it does not make sense, and the burden of evidence was on anyone who suggested otherwise.
The latest research by Professor Per-Olof Berggren’s group published in the journal Cell Metabolism set out to address this question (7).
In quite an intricate experiment, his team first introduced human beta-cells into a ‘humanised’ mouse model, and then gave either liraglutide or saline.
Liraglutide is a glucagon-like peptide-1 (GLP-1) agonist, and basically makes beta-cells produce more insulin in response to glucose, among other effects.
When the above mentioned mice were given Liraglutide over 200 or more days, the effects at first were as expected, i.e. improved glucose control, but over time the medication made insulin production, and with it glucose control, worse.
As with all such studies, it’s hard to know how well such a finding in an animal model reflects what happens in humans, but bare in mind that human beta-cells were used to get as close as possible.
This isn’t the only concern with this and other GLP-1 analogues coming through in the research, but it is the finding that directly addresses the question at hand.
Our bodies are very intricate systems with hormones and hormone-like substances sending multiple instructions to multiple sites, and the effects being the result of a fine balance between all the hormones/signals floating around during any given time.
Given this complexity, it is unsurprising that simply giving or stimulating the production of a hormone using a pill or injection never, by itself, restores normal function.
I see these findings as another important lesson to treat type 2 diabetes, which is a lifestyle related condition, with lifestyle modification when and wherever possible. That is after all what virtually all treatment guidelines have as step 1.
The recognised goal should be to reverse and not just ‘manage’ the condition, and restore health, not just delay disease a little longer.
Read more on that here:
Can Type 2 Diabetes be Reversed?
Very Low Calorie Diets & Type 2 Diabetes Reversal Part 1: Blood Glucose
References
1. Cnop, M. et al. Progressive loss of beta-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes Care 30, 677–682 (2007).
2. Festa, A., Williams, K., D'Agostino, R., Wagenknecht, L. E. & Haffner, S. M. The natural course of beta-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study. Diabetes 55, 1114–1120 (2006).
3. Ferrannini, E. et al. Mode of onset of type 2 diabetes from normal or impaired glucose tolerance. Diabetes 53, 160–165 (2004).
4. Butler, A. E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).
5. Rahier, J., Guiot, Y., Goebbels, R. M., Sempoux, C. & Henquin, J. C. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab 10 Suppl 4, 32–42 (2008).
6. Macauley, M., Percival, K., Thelwall, P. E., Hollingsworth, K. G. & Taylor, R. Altered volume, morphology and composition of the pancreas in type 2 diabetes. PLoS ONE 10, e0126825 (2015).
7. Abdulreda, M. H., Rodriguez-Diaz, R., Caicedo, A. & Berggren, P.-O. Liraglutide Compromises Pancreatic b Cell Function in a Humanized Mouse Model. Cell Metab 1–7 (2016). doi:10.1016/j.cmet.2016.01.009
In this blog I'll begin by asking the question – are medications that increase insulin production a good idea in type 2 diabetes? Let's think for a moment...
Type 2 diabetes is often described as having two core components (yes, there is more to it, but let's keep it simple):
1) insulin resistance, meaning that the cells receiving instructions from the hormone insulin aren't very responsive (or selectively responsive in some cases); and
2) a reduction in the insulin producing capabilities of our pancreas, specifically the insulin producing beta-cells.
The common metaphor is that our body becomes 'deaf' to insulin (selective hearing might be more accurate), and our pancreas gets worn out from constantly having to ‘shout’, i.e. produce abnormally large amounts of insulin.
Research has shown that both marked insulin resistance and a reduced capacity to produce insulin are present, potentially for many years, before type 2 diabetes is diagnosed (1-3).
Post-mortem studies suggest a large reduction in beta-cell number at the time of diagnosis with further reductions over time (4,5), and recent work in living volunteers with type 2 diabetes showed an average 33% reduction in pancreas size compared to volunteers with normal glucose tolerance (6).
NB: although the capacity to produce insulin is impaired before diagnosis, in an attempt to overcome insulin resistance average insulin production is still much higher in most cases of ‘pre-diabetes’ and early type 2 diabetes than in those with normal metabolism. Translation – most people with type 2 diabetes have excessive blood insulin to go along with their excessive blood glucose.
So when you consider this, does it make sense to use medication that directly or indirectly stimulates the insulin producing beta-cells to produce more insulin? Is it a good idea to motivate the already ‘hoarse’ pancreas to ‘shout’ a little louder, say as opposed to addressing the prevailing deafness or doing something to help the pancreas rest, repair, and regrow to its original size?
I would have suggested the default answer is no it does not make sense, and the burden of evidence was on anyone who suggested otherwise.
The latest research by Professor Per-Olof Berggren’s group published in the journal Cell Metabolism set out to address this question (7).
In quite an intricate experiment, his team first introduced human beta-cells into a ‘humanised’ mouse model, and then gave either liraglutide or saline.
Liraglutide is a glucagon-like peptide-1 (GLP-1) agonist, and basically makes beta-cells produce more insulin in response to glucose, among other effects.
When the above mentioned mice were given Liraglutide over 200 or more days, the effects at first were as expected, i.e. improved glucose control, but over time the medication made insulin production, and with it glucose control, worse.
As with all such studies, it’s hard to know how well such a finding in an animal model reflects what happens in humans, but bare in mind that human beta-cells were used to get as close as possible.
This isn’t the only concern with this and other GLP-1 analogues coming through in the research, but it is the finding that directly addresses the question at hand.
Our bodies are very intricate systems with hormones and hormone-like substances sending multiple instructions to multiple sites, and the effects being the result of a fine balance between all the hormones/signals floating around during any given time.
Given this complexity, it is unsurprising that simply giving or stimulating the production of a hormone using a pill or injection never, by itself, restores normal function.
I see these findings as another important lesson to treat type 2 diabetes, which is a lifestyle related condition, with lifestyle modification when and wherever possible. That is after all what virtually all treatment guidelines have as step 1.
The recognised goal should be to reverse and not just ‘manage’ the condition, and restore health, not just delay disease a little longer.
Read more on that here:
Can Type 2 Diabetes be Reversed?
Very Low Calorie Diets & Type 2 Diabetes Reversal Part 1: Blood Glucose
References
1. Cnop, M. et al. Progressive loss of beta-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes Care 30, 677–682 (2007).
2. Festa, A., Williams, K., D'Agostino, R., Wagenknecht, L. E. & Haffner, S. M. The natural course of beta-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study. Diabetes 55, 1114–1120 (2006).
3. Ferrannini, E. et al. Mode of onset of type 2 diabetes from normal or impaired glucose tolerance. Diabetes 53, 160–165 (2004).
4. Butler, A. E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).
5. Rahier, J., Guiot, Y., Goebbels, R. M., Sempoux, C. & Henquin, J. C. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab 10 Suppl 4, 32–42 (2008).
6. Macauley, M., Percival, K., Thelwall, P. E., Hollingsworth, K. G. & Taylor, R. Altered volume, morphology and composition of the pancreas in type 2 diabetes. PLoS ONE 10, e0126825 (2015).
7. Abdulreda, M. H., Rodriguez-Diaz, R., Caicedo, A. & Berggren, P.-O. Liraglutide Compromises Pancreatic b Cell Function in a Humanized Mouse Model. Cell Metab 1–7 (2016). doi:10.1016/j.cmet.2016.01.009
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