Dr. Ron’s Research Review – July 23, 2014

© 2014

This week’s research review focuses on insulin resistance and blood viscosity.

Jean-Frederic Brun from Montpellier University in France has been publishing articles on insulin from the late 80s and early 90s. (Brun et al., 1995) (Brun et al., 1996)

Two recent studies confirms that red cell aggregability is associated with insulin resistance and hyperinsulinemia, but plasma viscosity seems to be more related to overall glucose tolerance than to either SI or insulinemia. (Brun et al., 2012b) (Brun et al., 2012a)

Low insulin sensitivity is associated with increased erythrocyte aggregability. When low insulin sensitivity is associated with hyperinsulinemia there is an increase in plasma viscosity. Among those factors, plasma viscosity appears, in multivariate analysis, to be "independently" related to insulin resistance. (Brun, 2009)

Overall adiposity increases plasma viscosity and RBC aggregability, while abdominal adiposity increases hematocrit. When glucose tolerance declines, there is also an increase in plasma viscosity. (Brun, 2010)

A study using the hyperinsulinemic isoglycemic glucose clamp demonstrated for the first time that there is a negative relationship between directly measured whole-blood viscosity and insulin sensitivity as a part of the insulin-resistance syndrome. (Hoieggen et al., 1998)

 

Dr. Ron

 


Articles

 

Effects of oral zinc gluconate on glucose effectiveness and insulin sensitivity in humans.
            (Brun et al., 1995) Download
Zinc improves both insulin secretion and insulin sensitivity, and exerts insulin-like effects. We investigated its acute effects on the parameters of glucose assimilation determined with the minimal model technique from frequent sampling intravenous glucose tolerance test (FSIVGTT) in seven healthy volunteers. FSIVGTTs (0.5 g/kg of glucose, followed by 2 U insulin i.v. injection at 19 min) were performed after the subjects had taken 20 mg zinc gluconate twice (the evening before and 30 min before the beginning of the test) or placebo pills (simple blind randomized protocol). Glucose assimilation was analyzed by calculating Kg (slope of the exponential decrease in glycemia), glucose effectiveness Sg (i.e., ability of glucose itself to increase its own disposal independent of insulin response), and SI (insulin sensitivity, i.e. the effect of increases in insulinemia on glucose disposal). The two latter parameters were calculated by fitting the experimental data with the two equations of Bergman's "minimal model." Zinc increased Kg (p < 0.05) and Sg (p < 0.05), whereas SI and insulin first-phase secretion did not significantly increase. This study suggests that zinc improves glucose assimilation, as evidenced by the increase in Kg, and that this improvement results mainly from an increase in glucose effectiveness (insulin-like effect), rather than an action on insulin response or insulin sensitivity.

[Blood viscosity is correlated with insulin resistance].
            (Brun et al., 1996) Download
The insulin resistance syndrome (or syndrome X) is a cluster of symptoms (dyslipidemia, impaired glucose tolerance, overweight, hypertension) associated with a higher risk of atherosclerosis. It has been suggested that hemorheological abnormalities, often found in association with most of these symptoms, may be a part of this syndrome, and possibly play a role in the circulatory abnormalities. In 22 nondiabetic women (20-54 years) presenting a wide range of body mass index (from 20 to 48 kg/m2), insulin sensitivity was assessed with the minimal model procedure, over a 180 min intravenous glucose tolerance test with frequent sampling. The insulin sensitivity index SI (i.e. the slope of the dose-response relationship between insulin increased above baseline and glucose disposal) ranges between 0.1 and 20.1 x 10(-4) min-1/microU/ml) i.e all the range of insulin sensitivity. SI was negatively correlated with blood viscosity (r = -0.530 p < 0.02), body mass index (r = 0.563 p < 0.01) and baseline insulinemia (r = 0.489 p < 0.05). These correlations were independent of each other and were not explained by relationships between SI and fibrinogen or blood lipids. Thus, blood fluidity is correlated with insulin sensitivity when it is measured with an accurate technique, suggesting that blood hyperviscosity is a symptom of insulin resistance that might be involved in the cardiovascular risk of this syndrome.

Hemorheology in Insulin Resistance
(Brun, 2009) Download
The insulin resistance syndrome is associated with hemorheologic abnormalities whose understanding is complex, since rheological properties of plasma and blood cells are to a large extent determined by the surrounding milieu: physicochemical factors, metabolism and hormones. It is thus difficult to delineate the specific role of adiposity, endothelial dysfunction, and the hormonal disturbance by its own in this complex picture. Nevertheless, low insulin sensitivity which is associated with both increased body fat and increased circulating lipids, together with impaired fibrinolysis, is characterized by a mild hyperviscosity syndrome. Those rheological alterations are more closely related to insulin resistance than to the clinical scoring of the metabolic syndrome. Low insulin sensitivity is associated with increased erythrocyte aggregability. When low insulin sensitivity is associated with hyperinsulinemia there is an increase in plasma viscosity. Among those factors, plasma viscosity appears, in multivariate analysis, to be "independently" related to insulin resistance. Moreover, plasma hyperviscosity is corrected by insulin-sensitizing procedures (such as exercise training) and is thus to some extent a marker of this disease.

Insulin resistance as a hemorheologic disease
            (Brun, 2010) Download
The insulin resistance syndrome is associated with hemorheologic abnormalities whose understanding is complex, since rheological properties of plasma and blood cells are to a large extent determined by the surrounding milieu: physicochemical factors, metabolism and hormones. It is thus difficult to delineate the specific role of adiposity, endothelial dysfunction, and the hormonal disturbance by its own in this complex picture. Nevertheless, low insulin sensitivity which is associated with both increased body fat and increased circulating lipids, together with impaired fibrinolysis, is characterized by a mild hyperviscosity syndrome. Those rheological alterations are more closely related to insulin resistance than to the clinical scoring of the metabolic syndrome. Overall adiposity increases plasma viscosity and RBC aggregability, while abdominal adiposity increases hematocrit. Low insulin sensitivity is associated with increased erythrocyte aggregability. When glucose tolerance declines, there is also an increase in plasma viscosity. Red cell aggregability is a marker of obesity, insulin resistance and hyperinsulinemia, while plasma viscosity seems to be more related to overall glucose tolerance than to either SI or insulinemia.

Minimal model-derived insulin sensitivity, insulin secretion and glucose tolerance: relationships with blood rheology.
            (Brun et al., 2012b) Download
Insulin resistance is associated with a mild hyperviscosity syndrome, which is more closely related to insulin resistance than to the clinical scoring of the metabolic syndrome. In studies using the intravenous glucose tolerance test with minimal model analysis we reported that low insulin sensitivity (SI) is associated with increased erythrocyte aggregability (EA). Actually, this issue is confusing because insulin resistance is often associated with compensatory hyperinsulinemia (insulin being a hormone with reported hemorheologic effects) and that a decline in insulin secretion has marked metabolic effects that modify blood rheology. From the intravenous glucose tolerance test (IVGTT) the minimal model allows the calculation of SI, insulin response, and an overall glucose tolerance parameter termed "disposition index" (DI) that measures whether insulin response is adequate or not for the level of insulin sensitivity. In this study we assessed SI, insulin response, and DI during an IVGTT in 335 subjects of both genders (age 8-77 yr; BMI 14-67 kg/m2). SI was only correlated (negatively) with EA (Myrenne M r = -0.285; p = 0.0001; M1 r = -0.240 p = 0.003). Fasting insulin was also correlated (positively) with EA (Myrenne M r = 0.233, 0.00880; M1 r = 0.320 p = 0.0003; SEFAM TA r = -0.342 p = 0.04; SEFAM S60 r = 0.419 p = 0.01) and SEFAM RBC disaggregation thresholds (gammaS = r = 0.372 p = 0.025; gammaD = r = 0.504 p = 0.002). Fasting DI (SI x fasting insulin) is negatively correlated to M (r = -0.274; p = 0.002) and M1 (r = -0.225; p = 0.01) but also positively to whole blood viscosity (r = 0.168; p = 0.01) and hematocrit (r = 0.142; p = 0.05). Stimulatory DI (SI x insulin peak) fails to be correlated with any parameter of EA but is negatively correlated to whole blood viscosity (r = -0.150; p = 0.02) and plasma viscosity (r = -0.163; p = 0.01). This study confirms that red cell aggregability is associated with insulin resistance and hyperinsulinemia, but plasma viscosity seems to be more related to overall glucose tolerance than to either SI or insulinemia.


 

Relationships between insulin sensitivity measured with the oral minimal model and blood rheology.
            (Brun et al., 2012a) Download
In studies using the intravenous glucose tolerance test with minimal model analysis we reported that low insulin sensitivity (SI) is associated with increased erythrocyte aggregability and plasma viscosity, that appeared to be markers of insulin resistance. Recently, development of modelling has made available a new approach of insulin sensitivity from oral glucose tolerance test data (oral minimal model). We aimed at determining in 111 subjects (51 men, 62 women, age 11-77 yr), insulin sensitivity with this approach together with blood viscosity parameters. With this approach the Myrenne indexes of red cell aggregation were negatively correlated to SI (M; r = -0.456; p = 0.0007; M1; r = -0.397; p = 0.004) while plasma viscosity was not. Correlations with fasting insulin levels (Ib) were weaker (M; r = 0.2711; p = 0.05; M1; r = 0.373; p = 0.007). Accordingly, a stepwise regression analysis selects M as the best correlate of SI and M1 as the best correlate of Ib. With this approach plasma viscosity does not exhibit any clear relationship with SI. This study supports the concept that RBC hyperaggregability is the prominent hemorheologic symptom of insulin resistance.

Whole-blood viscosity and the insulin-resistance syndrome.
            (Hoieggen et al., 1998) Download
BACKGROUND: In a previous study we found that elevated blood viscosity was linked to the insulin resistance syndrome, and we proposed that high blood viscosity may increase insulin resistance. That study was based on calculated viscosity. OBJECTIVE: To determine whether directly measured whole-blood viscosity was related to the insulin-resistance syndrome in the same way as calculated viscosity had been found to be. METHODS: Healthy young men were examined with the hyperinsulinemic isoglycemic glucose clamp technique, and we related insulin sensitivity (glucose disposal rate) to other metabolic parameters and to blood viscosity. We established a technique for direct measurement of whole-blood viscosity. RESULTS: There were statistically significant negative correlations between glucose disposal rate and whole-blood viscosity at low and high shear rates (r = -0.41, P = 0.007 for both, n = 42). Whole-blood viscosity was correlated positively (n = 15) to serum triglyceride (r = 0.54, P = 0.04) and total cholesterol (r = 0.52, P = 0.05), and negatively with high-density lipoprotein cholesterol (r = -0.53, P = 0.04) concentrations. Insulin sensitivity index was correlated positively to high-density lipoprotein cholesterol (r = 0.54, P = 0.04) and negatively to serum triglyceride (r = -0.69, P = 0.005) and to total cholesterol (r = -0.81, P = 0.0003) concentrations. CONCLUSIONS: The present results demonstrate for the first time that there is a negative relationship between directly measured whole-blood viscosity and insulin sensitivity as a part of the insulin-resistance syndrome. Whole-blood viscosity contributes to the total peripheral resistance, and these results support the hypothesis that insulin resistance has a hemodynamic basis.

Relationship between hemorrheologic factors and insulin sensitivity in healthy young men.
            (Moan et al., 1994) Download
The present study aimed at testing a possible relationship between hemorrheologic factors, such as hematocrit, fibrinogen, and whole-blood viscosity, and insulin sensitivity in healthy humans. Twenty-one 21-year-old men were studied with the hyperinsulinemic euglycemic glucose clamp technique. We found statistically significant negative correlations between the glucose disposal rate (GDR) and calculated whole-blood viscosity at both high (r = -.55, P = .01) and low (r = -.51, P = .01) shear rates. We observed negative associations between GDR and fibrinogen (r = -.66, P = .002), GDR and hematocrit (r = -.63, P = .002), GDR and body mass index (r = -.51, P = .007), and GDR and resting heart rate (r = -.46, P = .04). Using stepwise multiple regression considering whole-blood viscosity, body mass index, mean arterial blood pressure, and heart rate as independent variables, we found that only whole-blood viscosity and body mass index were independent explanatory variables of the GDR. Together they accounted for 63% of the variability in the GDR in our subjects. These results suggest hemorrheologic, and therefore indirectly hemodynamic, factors as correlates to insulin sensitivity.

 


 

References

 

Brun, J. (2009), ‘Hemorheology in Insulin Resistance’, in Wiernsperger (ed.), Microcirculation and Insulin Resistance (Bentham Science), 99-106.
——— (2010), ‘Insulin resistance as a hemorheologic disease’, Series on Biomechanics, 25 (1-2), 83-90. PubMedID:
Brun, JF, et al. (1996), ‘[Blood viscosity is correlated with insulin resistance].’, J Mal Vasc, 21 (3), 171-74. PubMedID: 8965046
Brun, JF, E Varlet-Marie, and E Raynaud de Mauverger (2012a), ‘Relationships between insulin sensitivity measured with the oral minimal model and blood rheology.’, Clin Hemorheol Microcirc, 51 (1), 29-34. PubMedID: 22240352
Brun, JF, et al. (2012b), ‘Minimal model-derived insulin sensitivity, insulin secretion and glucose tolerance: relationships with blood rheology.’, Clin Hemorheol Microcirc, 51 (1), 21-27. PubMedID: 22240354
Brun, JF, et al. (1995), ‘Effects of oral zinc gluconate on glucose effectiveness and insulin sensitivity in humans.’, Biol Trace Elem Res, 47 (1-3), 385-91. PubMedID: 7779574
Hoieggen, A, et al. (1998), ‘Whole-blood viscosity and the insulin-resistance syndrome.’, J Hypertens, 16 (2), 203-10. PubMedID: 9535148
Moan, A, et al. (1994), ‘Relationship between hemorrheologic factors and insulin sensitivity in healthy young men.’, Metabolism, 43 (4), 423-27. PubMedID: 8159097