This is a section from a paper I'm writing about hepatic glycogen control, this part concerns the effect of dietary fat type on the insulin response. Spoiler alert: you will be surprised how little sound evidence there is on a subject about which so many pronounce so confidently.
Carbohydrate feeding stimulates the release of glucagon from delta cells in the gut and pancreatic alpha cells.[1] Glucagon is the hormone that elevates blood glucose by stimulating gluconeogenesis, but this is a delayed response; the most immediate glucose-elevating effect of glucagon is to induce glycogenolysis. In healthy metabolism, after eating a carbohydrate meal the paracrine effect of the phase 1 insulin response rapidly suppresses this glucagon release and the hepatic endocrine action of insulin inhibits the action of glucagon in the hepatic parenchymal cell, so that both gluconeogenesis and glycogenolysis are fully inhibited.[2,3]
Figure 1: Showing glucagon and insulin response to carbohydrate in normal
metabolism
In type 2 diabetes, the delayed insulin response to a carbohydrate meal results in a longer elevation of glucagon; hepatic insulin resistance also reduces the inhibitory effect of insulin on glucagon action in the liver.
What is the value of this normal brief glucagon response to carbohydrate feeding? Glycogenolysis is a glycolytic process (glycogen -> glucose-6-phosphate -> lactate) which generates ATP in the glycogen-storing parenchymal cell; a brief and minor increase in glycogenolysis might be a preparatory adaptation, priming the cell for rapid glycogen synthesis from incoming glucose.
The delayed insulin peak from the beta cell of the diabetic pancreas (suggested mechanisms include ectopic fat accumulation in the beta cell, and/or cytokine interference with its function) allows a longer action of glucagon that is maladaptive in the context of a carbohydrate meal, and therefore the consumption of carbohydrate causes post-prandial hyperglycaemia by stimulating the release of glucose from glycogen and inhibiting its non-oxidative disposal in persons with type 2 diabetes.
This is an immediate cause of elevated PPPG that is rapidly corrected once carbohydrate is restricted.
In a study of 6 subjects with diabetes a simulated phase 1 and phase 2 insulin release during a hyperglycaemic clamp resulted in a 90% suppression of hepatic glucose production at 20 minutes, compared to a 50% suppression at 60 minutes from a simulated phase 2 response alone.[4]
However, a study of enhanced phase 1 insulin response in 14 elderly patients with diabetes found that phase 1 insulin response was not important in the regulation of hepatic glucose output or peripheral glucose disposal in these patients.[5]
1:02 The differential effect of fat type on the phase 1 insulin response
Does the type of fat in the diet influence the phase 1 insulin response? Below is the insulin response to a mixed meal containing two different fats – butter (SFA) and olive oil (MUFA) in 10 women with gestational diabetes mellitus. It will be seen that the butter-containing meal provoked a more rapid insulin response, and as a result both insulin and glucose area-under-the-curve (UAC) was reduced with the butter meal, and post-prandial plasma glucose at 2 and 3 hours was significantly lower compared with the olive oil meal.[6]
Figure 3: Plasma glucose response to a meal with olive oil (MUFA) or butter
(SFA) in women with gestational diabetes
This
difference may be due to other factors present in the fats, as butter contains
3% c9t11 CLA and olive oil supplies 11% linoleic acid (LA), compared to 2% in
butter. c9t11 CLA improves insulin sensitivity compared to LA in prediabetic
men.[7] Elevated plasma levels of trans-palmitoleic acid, mainly found
in dairy and ruminant fat, are also associated with a reduced incidence of
diabetes and insulin resistance.[8,9]
Wistar rats fed soybean oil (60% LA) for 4 weeks had significantly lower glucose-stimulated insulin responses compared to rats fed lard (10% LA) whose insulin responses were similar to those of rats fed a low fat control diet.[10] A study of inhibition of fasting FFAs by nicotinic acid (NA), replaced by soybean oil (Intralipid) and heparin, in 10 healthy male subjects found that FFAs were essential for insulin response to glucose in fasting humans.[11] A further study in rats in which serum FFAs were inhibited by NA and replaced by infusions of soybean oil or lard with heparin found that serum saturated fatty acids were essential for the first-phase insulin response to glucose, which was suppressed by high levels of unsaturated fatty acids, which only supported a second-phase response.[12]
Wistar rats fed soybean oil (60% LA) for 4 weeks had significantly lower glucose-stimulated insulin responses compared to rats fed lard (10% LA) whose insulin responses were similar to those of rats fed a low fat control diet.[10] A study of inhibition of fasting FFAs by nicotinic acid (NA), replaced by soybean oil (Intralipid) and heparin, in 10 healthy male subjects found that FFAs were essential for insulin response to glucose in fasting humans.[11] A further study in rats in which serum FFAs were inhibited by NA and replaced by infusions of soybean oil or lard with heparin found that serum saturated fatty acids were essential for the first-phase insulin response to glucose, which was suppressed by high levels of unsaturated fatty acids, which only supported a second-phase response.[12]
1.03 The differential effect of fat type on insulin
sensitivity
While some feeding studies show that meals high in saturated fat result in higher glucose levels than meals high in monounsaturated fat, others show the opposite, while yet other studies find no difference, as summarized in Jackson et al 2005.[13] The saturated fat source most likely to be used in such feeding studies is palm oil, which is the dietary fat with the highest concentration of palmitic acid, which was mixed with cocoa butter, the dietary fat with the highest concentration of stearic acid, in the saturated fat arm of the feeding study in that paper, which showed higher glucose AUC in the saturated fat arm. Palmitic and stearic acids are the main endogenous saturated fatty acid products of de novo lipogenesis (DNL) and serum levels of these fatty acids are known to be correlated with the carbohydrate content of the diet. Thus such a study may not accurately represent the effects of the mixture of fats found in normal diets, especially in the context of a low carbohydrate diet. Of randomised long-term studies, the LIPGENE study found no effect of fat type, whereas the KANWU study, a study cited as showing a worsening of insulin sensitivity (albeit non-significant) after feeding saturated fat compared to monounsaturated fat for 3 months, noted that the favourable effects of substituting a MUFA diet for a SFA acid diet on insulin sensitivity were only seen at a total fat intake below median 37E%.[14,15]
1.04 Recommendations regarding fat type in very low carbohydrate diets
The 2006 experiment by Krauss et al was a test of the hypothesis that saturated fat in a carbohydrate-restricted diet would influence the effect of the diet on the atherogenic dyslipidemia produced by hyperinsulinaemia in the context of insulin resistance.[16] Men (n=178) with a mean BMI of 29.2 (+/- 2) were randomized to four different diets – 54% CHO, 39% CHO, 29% CHO with 9% SFA, and 29 % CHO with 15% SFA, for twelve weeks, including a 5 week period of calorie restriction followed by a 4 week period of weight stabilization.
Concentrations of apo B, a measure of total atherogenic particle concentrations, as well as total:HDL cholesterol, an integrated measure of CVD risk, decreased similarly with both the higher- and lower-saturated-fat diets. Moreover, the changes in LDL cholesterol for both the lower- and higher-saturated-fat diets (−11 and 1 mg/dL, respectively) were considerably more beneficial than were those predicted on the basis of studies that used diets with a more conventional macronutrient composition (−1 and 9 mg/dL, respectively). The difference in LDL cholesterol between the two diets was due to the appearance of larger, less atherogenic LDL particles in those on the 15% SFA diet; both diets saw similar reductions in levels of atherogenic small, dense LDL (sdLDL) particles. The ratio between triglycerides and HDL cholesterol correlates with serum insulin and insulin sensitivity; the TG/HDL ratio was the same with both 9% and 15% SFA at 29% CHO.[17]
 |
| Fig 3: glucose response to fasting and carbohydrate-free diet |
It is considered that very low carbohydrate diets partially mimic the fasting state. In a 2015 randomised cross-over study by Nuttall et al, 7 men and women with untreated type 2 diabetes were placed on a control diet (55% CHO, 15% PRO, 30% FAT), a carbohydrate-free diet (3% CHO, 15% PRO, 82% FAT), or fasted for 3 days.[18] On the third day of the carbohydrate-free phase, overnight fasted blood glucose concentrations were 160 mg/dl compared with 196 mg/dl in the standard diet and 127 mg/dl in the fasting phases. Carbohydrate restriction also led to a rapid drop in post-prandial glucose concentrations and glucose area-under-the curve decreased by 35% in the carbohydrate-free phase compared to the standard diet. It was found that carbohydrate restriction accounted for 50% of the reduction in overnight glucose concentrations and 71% of the reduction in integrated glucose concentrations in the fasted phase compared with the standard diet phase. It is notable that human depot fat, which is the major fuel source in the fasting state, consists of (approximately) 55% monounsaturated fat and 30% long-chain saturated fat, with the remainder consisting of smaller amounts of polyunsaturated fats and medium-chain saturated fats. It has been noted that a 50:50 mixture of ghee and olive oil has a fatty acid composition of 32% saturated fat (some of which is short and medium chain fatty acids, leaving 25-28% from the long-chain saturated fats, palmitic and stearic acids), 50% monounsaturated fat, and 7% polyunsaturated fat, approximating reasonably well the composition of human depot fat. Thus there is insufficient evidence to support recommendations restricting saturated fat in very low carbohydrate diets. However, there is some evidence for preferring full-fat dairy foods to other sources of saturated fat in the diet, with regard not only to glycaemic control but also cardiovascular risk, based on observational studies [19,20,21].
Adherence to diets is likely to be greatest when the rationale for choices is simple and convincing, when the diet is adequately nutritious, and when food is culturally appropriate – that is, when the diet is made up of foods that are already familiar and liked.
It should also be noted that both carbohydrate-free diets and fasting appear to be well-tolerated in the feeding studies we have described, with no adverse events reported during or after any study.
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