las

Welcome all seeking refuge from low carb dogma!

“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Sunday, February 13, 2011

Hypertension, Insulin and Free Fatty Acids (Part I)

Obesity Hypertension Is Related More to Insulin's Fatty Acid Than Glucose Action

Although resistance to insulin-mediated glucose disposal has emerged as a link between abdominal obesity and hypertension, abnormalities of nonesterified fatty acid metabolism may play a greater role. ... Fatty acid concentration and turnover were markedly more resistant to suppression by insulin in obese hypertensive than in lean or obese normotensive individuals. ... The data indicate that blood pressure is related to the effects of insulin on fatty acid metabolism. The findings raise the possibility that resistance of hormone-sensitive lipase to insulin participates in elevating the blood pressure of abdominally obese hypertensive subjects by increasing fatty acid concentration and turnover.
I'm C&P'ing the entire Introduction because it contains live links to background references some readers may be interested in.


Obese hypertensive patients are more likely than obese normotensive subjects to have abdominal obesity, which is associated with hyperinsulinemia, insulin resistance, and coronary risk.1 Although some mechanistic studies have linked hyperinsulinemia and insulin resistance to hypertension,2 3 4 others have not confirmed this association.5 6 7 8 9 10 Our strategy was to focus on abdominally obese subjects, since not all of them are hypertensive. We sought to identify metabolic differences between abdominally obese subjects that are related to interindividual differences in BP.

NEFAs are one factor that may link abdominal obesity to hypertension. For example, postprandial and/or 24-hour fatty acid values are elevated insubjects with diabetes11 ; obesity,12 especially the abdominal fat pattern13 ; and familial combined hyperlipidemia,14 conditions that are all associated with an increased prevalence of hypertension. NEFAs may increase vascular tone and BP by increasing sympathetic drive15 and vascular {alpha}1-adrenergic receptor reactivity and tone16 17 while impairing endothelium-dependent vasodilation.18
We measured fatty acid concentration and turnover, which are indicative of postprandial13 19 and 24-hour11 20 regulation of NEFAs, during a euglycemic, hyperinsulinemic clamp. In reanalyzing existing data,21 22 we found that NEFA concentration and turnover during the euglycemic hyperinsulinemia were related to BP in abdominally obese subjects independently of insulin-mediated glucose disposal. After these correlations were found, data were reanalyzed on another group of 30 subjects who also had multiple determinations of BP as well as plasma NEFAs and glucose measurements during an insulin tolerance test23 to determine whether the correlation of fatty acids to BP could be confirmed.

Diabetics were excluded from the study (had to "pass" an OGT test).  They compared 3 groups:.

  1. Abdominally obese hypertensive (9 men, 4 women)  - 2 excluded from insulin test results
  2. Abdominally obese normotensive (6 men)
  3. Lean normotensive (5 men, 1 woman)
I have some criticisms of this study.  The study size is not impressive here, and the gender mismatch between groups doesn't make sense to me, especially given the differences between genders and abdominal obesity.

In any case, all subjects ceased taking medications and followed a standard diet (energy balanced) for four weeks.  All food and beverages were supplied for the last week before the study to enhance compliance.

Protocol #1:

0-2 hours baseline:  Euglycemic clamp (infusion of 20% dextrose to maintain constant BG) with radiolabeled glucose and palmitate (fatty acid) infusions  {the concentrations of the radiolabels are not significant compared to total}  
2-4 hours:  10 mU/m2min insulin infusion   
4-6 hours:  40 mU/m2min insulin infusion
From 2-6 hours, the radiolabel infusions were maintained, dextrose infusion was adjusted as needed to maintain constant  BG which was monitored every 5 min.

Throughout the study they measured BG, insulin, NEFA, and radiolabel concentration (3H for glucose, 14C for palmitate) every 10 minutes.  O2 consumption and CO2 production were measured by indirect calorimetry for the last 30 min of each 2 hour period.

Results of Protocol #1:  (I've rearranged the table a bit)

  • Both groups of obese subjects have elevated NEFA levels at baseline (though only the OH group reached statistical significance, stat.sig.) compared to LN.  
  • Both groups of obese subjects had significantly higher NEFA turnover rates compared to LN.  
  • The OH group had both higher NEFA levels and turnover rates vs. ON, but not stat.sig.  
  • With the normal insulin-level infusion (clamp10) we see NEFA significantly reduced in the LN group but reduced significantly less for both ON and OH.  
  • The failed suppression NEFA by insulin was stat.sig. in OH vs. ON.  
  • The NEFA turnover rate for  clamp10 is greater in ON vs. LN (not ss) but stat.sig. greater in OH vs. both LN and ON.  
  • The NEFA turnover rate  for OH-normal insulin is closer to baseline for the ON group than the LN group.   With hyperinsulinemic clamp (clamp40) we now see the ON group return to near-normal NEFA levels and turnover rates.
  • OH group demonstrated a persistent suppression of insulin action with clamp40, this was significant compared with both LN and ON groups.  
  • The NEFA levels of OH under hyperinsulinemic conditions are more than double those of the LN group.
  • The NEFA turnover rate for OH under hyperinsulinemic conditions was close to 3X that of the ON group, and more than 3.5X that of the LN group.

The authors then went on to look at correlations between BP & NEFA levels, and BP & NEFA turnover rates.  
NEFA concentration and turnover during the 40–mU·m-2·min-1 insulin infusion were generally significantly correlated with BP, whereas glucose metabolized (M) and glucose disposal corrected for insulin concentration (M/I) were not. Correlations between BP and NEFA concentration and turnover at baseline and NEFA values during the 10–mU·m-2·min-1 insulin infusion were less robust (data not shown), whereas NEFA turnover at the lower insulin infusion rate correlated significantly with BP. The value for M and M/I obtained during the 10–mU·m-2·min-1 insulin infusion did not correlate significantly with BP (data not shown).
The independent correlations of NEFA turnover during the 40–mU·m-2·min-1 insulin infusion and BP were obtained by multiple stepwise linear regression analysis, while fasting insulin, the insulin AUC during the oral glucose tolerance test, and glucose disposal during the 40–mU·m-2·min-1clamp were controlled for separately (Table 2Up). The correlations between NEFA flux and BP remained significant after the other variables shown were controlled for. 
So both NEFA concentration and turnover rates correlated significantly with BP  in the OH group under hyperinsulinemic conditions, while only NEFA turnover was significantly correlated with BP under normal insulin level conditions.

Now I'm looking at these results and it seems that the turnover rate (flux) response to insulin is closer to normal in the ON group at normal insulin levels and essentially normal at high insulin levels.  This indicates a certain degree of insulin sensitivity to where the fat tissue in these individuals "sees" the elevated insulin more.  The OH group, however, exhibits significant insulin resistance as quadrupling the dose still does not elicit an anywhere near normal response.

If I get around to it around to it at some point I'll address the second leg of the study.  But for now I'll leave it here with my "reading".