Can glucosamine lower CVD risk by lowering insulin?
A possible mechanism for glucosamine's association with reduced CVD and mortality in this population may be that it mimics the glucokinase mutations that cause benign diabetic states.
Infused into rats, glucosamine causes severe impairment in glucose-induced insulin secretion. This glucosamine-induced beta-cell secretory dysfunction extends to nonglycemic stimuli like arginine.[1]
Conventional wisdom has it that elevated glucose is the feature of diabetes that leads to cardiovascular risk, and there are good mechanistic reasons why this is true of very high glucose levels - however, persistent mildly elevated glucose levels in the pre-diabetic range, if they are due to a slightly impaired insulin response (i.e. insulin response to glucose elevations only occurs at a higher-than-usual serum glucose level) do not seem to be harmful in glucokinase mutations.
"Patients with GCK had a low prevalence of clinically significant macrovascular complications (4% [95% CI, 1%-10%]) that was not significantly different from controls (11% [95% CI, 5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95% CI, 21%-41%], P<.001)."[2]
This set of correlations seems to support the view that CVD is promoted by the hyperinsulinaemia that accompanies type 2 diabetes, pre-diabetes, and the metabolic syndrome. Anecdotally, glucosamine can elevate LDL levels in some cases, but this has not been confirmed by RCTs - however, the effect is seem in mouse models of atherosclerosis.[3]
Therefore glucosamine potentially has two metabolic effects that should be consistent with increased CVD risk (increased glucose and increased LDL cholesterol), yet is associated with reduced CVD mortality (0.78, 95% CI: 0.70 to 0.87), because insulin is the dominant driver of this pathology and both the elevation in glucose and any elevation in LDL-C in the case of glucosamine are due to a reduced insulin response, and thus differ from glucose and LDL-C elevations in normal metabolic syndromes.
Of course a low-carbohydrate diet requires a reduced insulin response to maintain homeostatis, so the authors' claim that glucosamine is a low-carb diet mimic seems correct.
[1] Shankar RR, Zhu JS, Baron AD. Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism. 1998 May;47(5):573-7.
[2] Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. JAMA. 2014 Jan 15;311(3):279-86. doi: 10.1001/jama.2013.283980. http://www.ncbi.nlm.nih.gov/pubmed/24430320
[3] Lisa R. Tannock, Elizabeth A. Kirk, Victoria L. King, Renee LeBoeuf, Thomas N. Wight, Alan Chait, Glucosam ine Supplementation Accelerates Early but Not Late Atherosclerosis in LDL Receptor–Deficient Mice, The Journal of Nutrition, Volume 136, Issue 11, November 2006, Pages 2856–2861, https://doi.org/10.1093/jn/136.11.2856
[4] Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia. 1991 Jun;34(6):416-22. https://www.ncbi.nlm.nih.gov/pubmed/1884900
Rapid Response:
Can glucosamine lower CVD risk by lowering insulin?
A possible mechanism for glucosamine's association with reduced CVD and mortality in this population may be that it mimics the glucokinase mutations that cause benign diabetic states.
Infused into rats, glucosamine causes severe impairment in glucose-induced insulin secretion. This glucosamine-induced beta-cell secretory dysfunction extends to nonglycemic stimuli like arginine.[1]
Conventional wisdom has it that elevated glucose is the feature of diabetes that leads to cardiovascular risk, and there are good mechanistic reasons why this is true of very high glucose levels - however, persistent mildly elevated glucose levels in the pre-diabetic range, if they are due to a slightly impaired insulin response (i.e. insulin response to glucose elevations only occurs at a higher-than-usual serum glucose level) do not seem to be harmful in glucokinase mutations.
"Patients with GCK had a low prevalence of clinically significant macrovascular complications (4% [95% CI, 1%-10%]) that was not significantly different from controls (11% [95% CI, 5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95% CI, 21%-41%], P<.001)."[2]
This set of correlations seems to support the view that CVD is promoted by the hyperinsulinaemia that accompanies type 2 diabetes, pre-diabetes, and the metabolic syndrome. Anecdotally, glucosamine can elevate LDL levels in some cases, but this has not been confirmed by RCTs - however, the effect is seem in mouse models of atherosclerosis.[3]
Therefore glucosamine potentially has two metabolic effects that should be consistent with increased CVD risk (increased glucose and increased LDL cholesterol), yet is associated with reduced CVD mortality (0.78, 95% CI: 0.70 to 0.87), because insulin is the dominant driver of this pathology and both the elevation in glucose and any elevation in LDL-C in the case of glucosamine are due to a reduced insulin response, and thus differ from glucose and LDL-C elevations in normal metabolic syndromes.
Of course a low-carbohydrate diet requires a reduced insulin response to maintain homeostatis, so the authors' claim that glucosamine is a low-carb diet mimic seems correct.
[1] Shankar RR, Zhu JS, Baron AD. Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism. 1998 May;47(5):573-7.
[2] Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. JAMA. 2014 Jan 15;311(3):279-86. doi: 10.1001/jama.2013.283980. http://www.ncbi.nlm.nih.gov/pubmed/24430320
[3] Lisa R. Tannock, Elizabeth A. Kirk, Victoria L. King, Renee LeBoeuf, Thomas N. Wight, Alan Chait, Glucosam ine Supplementation Accelerates Early but Not Late Atherosclerosis in LDL Receptor–Deficient Mice, The Journal of Nutrition, Volume 136, Issue 11, November 2006, Pages 2856–2861, https://doi.org/10.1093/jn/136.11.2856
[4] Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia. 1991 Jun;34(6):416-22.
https://www.ncbi.nlm.nih.gov/pubmed/1884900
Competing interests: No competing interests