Prediabetes and type 2 diabetes are caused by a drop in insulin sensitivity attributed in part to “intramyocellular lipid,” the buildup of fat inside muscle cells.
Studies dating back nearly a century noted a striking finding. If you take young, healthy people and split them up into two groups, half on a fat-rich diet, and the other half on a carb-rich diet, within just two days, this is what happens. The glucose intolerance skyrockets in the fatty diet group. In response to the same sugar water challenge, the group that had been shoveling in fat ended up with twice the blood sugar.
As the amount of fat in the diet goes up, one’s blood sugar spikes. It would take scientists nearly seven decades to unravel this mystery, but it would end up holding the key to our current understanding of the cause of type 2 diabetes.
When athletes carb-load before a race, they’re trying to build up the fuel supply within their muscles. They break down the starch into glucose in their digestive tract. It circulates as blood glucose—blood sugar—and is taken up by our muscles, to be stored and burned for energy.
Blood sugar, though, is like a vampire. It needs an invitation to come into our cells. And, that invitation is insulin. Here’s a muscle cell. Here’s some blood sugar outside, waiting patiently to come in. Insulin is the key that unlocks the door to let sugar in our blood enter the muscle cell. When insulin attaches to the insulin receptor, it activates an enzyme, which activates another enzyme, which activates two more enzymes, which finally activate glucose transport, which acts as a gateway for glucose to enter the cell. So, insulin is the key that unlocks the door into our muscle cells.
What if there was no insulin, though? Well, blood sugar would be stuck out in the bloodstream, banging on the door to our muscles, and not able to get inside. And so, with nowhere to go, sugar levels would rise and rise.
That’s what happens in type 1 diabetes; the cells in the pancreas that make insulin get destroyed, and without insulin, sugar in the blood can’t get out of the blood into the muscles, and blood sugar rises.
But, there’s a second way we could end up with high blood sugar. What if there’s enough insulin, but the insulin doesn’t work? The key is there, but something’s gummed up the lock. This is called insulin resistance. Our muscle cells become resistant to the effect of insulin. What’s gumming up the door locks on our muscle cells, preventing insulin from letting sugar in? Fat. What’s called intramyocellular lipid, or fat inside our muscle cells.
Fat in the bloodstream can build up inside the muscle cells, create toxic fatty breakdown products and free radicals that can block the signaling pathway process. So, no matter how much insulin we have out in our blood, it’s not able to open the glucose gates, and blood sugar levels build up in the blood.
This mechanism, by which fat (specifically saturated fat) induces insulin resistance, wasn’t known until fancy MRI techniques were developed to see what was happening inside people’s muscles as fat was infused into their bloodstream. And, that’s how scientists found that elevation of fat levels in the blood “causes insulin resistance by inhibition of glucose transport” into the muscles.
And, this can happen within just three hours. One hit of fat can start causing insulin resistance, inhibiting glucose uptake after just 160 minutes.
Same thing happens to adolescents. You infuse fat into their bloodstream. It builds up in their muscles, and decreases their insulin sensitivity—showing that increased fat in the blood can be an important contributor to insulin resistance.
Then, you can do the opposite experiment. Lower the level of fat in people’s blood, and the insulin resistance comes right down. Clear the fat out of the blood, and you can clear the sugar out of the blood. So, that explains this finding. On the high-fat diet, the ketogenic diet, insulin doesn’t work as well. Our bodies are insulin-resistant.
But, as the amount of fat in our diet gets lower and lower, insulin works better and better. This is a clear demonstration that the sugar tolerance of even healthy individuals can be “impaired by administering a low-carb, high-fat diet.” But, we can decrease insulin resistance—the cause of prediabetes, the cause of type 2 diabetes—by decreasing saturated fat intake.
TEXT UNDER CONSTRUTION
J Clin Invest. 1996 Jun 15; 97(12): 2859–2865.
Mechanism of free fatty acid-induced insulin resistance in humans.
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To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13C and 31P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (approximately 5.2 mM) hyperinsulinemic (approximately 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be approximately 46% of control values after 6 h (P < 0.00001). Augmented lipid oxidation was accompanied by a approximately 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to approximately 50% of control values (4.0 +/- 1.0 vs. 9.3 +/- 1.6 mumol/[kg.min], P < 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at approximately 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mM; P < 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an approximately 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation
Metabolism. 2013 Mar;62(3):417-23. doi: 10.1016/j.metabol.2012.09.007. Epub 2012 Nov 1.
Effects of an overnight intravenous lipid infusion on intramyocellular lipid content and insulin sensitivity in African-American versus Caucasian adolescents.
To explain the predisposition for insulin resistance among African American (AA) adolescents, this study aimed to: 1) examine changes in intramyocellular lipid content (IMCL), and insulin sensitivity with intralipid (IL) infusion; and 2) determine whether the increase in IMCL is comparable between AA and Caucasian adolescents.
MATERIALS AND METHODS:
Thirteen AA and 15 Caucasian normal-weight adolescents (BMI <85th) underwent a 3-h hyperinsulinemic-euglycemic clamp, on two occasions in random order, after an overnight 12-h infusion of: 1) 20% IL and 2) normal saline (NS). IMCL was quantified by (1)H magnetic resonance spectroscopy in tibialis anterior muscle before and after IL infusion.
During IL infusion, plasma TG, glycerol, FFA and fat oxidation increased significantly, with no race differences. Hepatic insulin sensitivity decreased with IL infusion with no difference between the groups. IL infusion was associated with a significant increase in IMCL, which was comparable between AA (Δ 105%; NS: 1.9±0.8 vs. IL: 3.9±1.6 mmol/kg wet weight) and Caucasian (Δ 86%; NS: 2.8±2.1 vs. IL: 5.2±2.4 mmol/kg wet weight), with similar reductions (P<0.01) in insulin sensitivity between the groups (Δ -44%: NS: 9.1±3.3 vs. IL: 5.1±1.8 mg/kg/min per μU/ml in AA) and (Δ -39%: NS: 12.9±6.0 vs. IL: 7.9±3.8 mg/kg/min per μU/ml in Caucasian) adolescents.
In healthy adolescents, an acute elevation in plasma FFA with IL infusion is accompanied by significant increases in IMCL and reductions in insulin sensitivity with no race differential. Our findings suggest that AA normal-weight adolescents are not more susceptible than Caucasians to FFA-induced IMCL accumulation and insulin resistance.
Copyright © 2013 Elsevier Inc. All rights reserved.
S Lee, C Boesch, J L Kuk, S Arsianian. Effects of an overnight intravenous lipid infusion on intramyocellular lipid content and insulin sensitivity in African-American versus Caucasian adolescents. Metabolism. 2013 Mar;62(3):417-23.
Diabetes. 1999 Feb;48(2):358-64.
Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans.
The initial effects of free fatty acids (FFAs) on glucose transport/phosphorylation were studied in seven healthy men in the presence of elevated (1.44 +/- 0.16 mmol/l), basal (0.35 +/- 0.06 mmol/l), and low (<0.01 mmol/l; control) plasma FFA concentrations (P < 0.05 between all groups) during euglycemic-hyperinsulinemic clamps. Concentrations of glucose-6-phosphate (G-6-P), inorganic phosphate (Pi), phosphocreatine, ADP, and pH in calf muscle were measured every 3.2 min for 180 min by using 31P nuclear magnetic resonance spectroscopy. Rates of whole-body glucose uptake increased similarly until 140 min but thereafter declined by approximately 20% in the presence of basal and high FFAs (42.8 +/- 3.6 and 41.6 +/- 3.3 vs.
52.7 +/- 3.3 micromol x kg(-1) x min(-1), P < 0.05). The rise of intramuscular G-6-P concentrations was already blunted at 45 min of high FFA exposure (184 +/- 17 vs.
238 +/- 17 micromol/l, P = 0.008). At 180 min, G-6-P was lower in the presence of both high and basal FFAs (197 +/- 21 and 213 +/- 18 vs.
286 +/- 19 micromol/l, P < 0.05). Intramuscular pH decreased by -0.013 +/- 0.001 (P < 0.005) during control but increased by +0.008 +/- 0.002 (P < 0.05) during high FFA exposure, while Pi rose by approximately 0.39 mmol/l (P < 0.005) within 70 min and then slowly decreased in all studies. In conclusion, the lack of an initial peak and the early decline of muscle G-6-P concentrations suggest that even at physiological concentrations, FFAs primarily inhibit glucose transport/phosphorylation, preceding the reduction of whole-body glucose disposal by up to 120 min in humans.
Diabetes reversal, not just treatment, should be a goal in the management of type 2 diabetes. Type 2 diabetes can be reversed with an extremely low calorie diet. Type 2 diabetes can also be reversed with an extremely healthy diet, but is that because it’s also low in calories? The study subjects lost as much weight on the green leafy vegetable-packed plant-based diet as the semi-starvation diet based on liquid meal replacements. So, does it matter what we’re eating as long as we’re eating few enough calories to lose 15 pounds a month?
Even if diabetes reversal is just about calorie restriction, instead of subsisting off largely sugar, powdered milk, corn syrup, and oil, on the plant-based diet at least one can eat food, in fact, pounds of food a day, as many low-cal veggies as we can stuff in our face. So, even if it only worked because it’s just another type of calorie restricted diet, it’s certainly a healthier version. But even participants who did not lose weight, or even gained weight eating enormous quantities of whole healthy plant foods, appeared to improve their diabetes. Thus, the beneficial effects of this kind of diet appear to extend beyond weight loss.
The successful treatment of type 2 diabetes with a plant-based diet goes back to the 1930’s, providing incontestable evidence that a diet centered around vegetables, fruits, grains, and beans was more effective in controlling diabetes than any other dietary treatment. Randomized controlled trial: insulin needs were cut in half. A quarter ended up off insulin altogether, but again this was a low-calorie diet. Kempner reported similar results 20 years later with his rice and fruit diet, for the first time showing documented reversal of diabetic retinopathy in a quarter of his patients, something never even thought possible. An example was a 60-year-old diabetic woman already blind in one eye and could only see contours of large objects with the other. Five years later, on the diet, instead of it getting worse, it got better. She could make out faces, see signs, and read large newspaper print, in addition to being off insulin, with normal blood sugars and a 100 point drop in her cholesterol. Another patient went from just being able to read the big headlines to being able to read newsprint four months later. What was behind these remarkable reversals? Was it because the diet was extremely low-fat, no animal protein, no animal fat—or, was it because the diet was so restrictive and monotonous that the patients lost weight and improved their diabetes that way?
To tease that out, what we need is a study where they switch people to a healthy diet, but force them to eat so much that they don’t lose any weight. Then, we can see if a plant-based diet has benefits independent of all the weight loss. For that, we had to wait another 20 years, but here it is. Diets were designed to be weight-maintaining. Participants were weighed every day, and if they started losing weight, the researchers made them eat more food. In fact, so much food some of the participants had trouble eating it all, but they eventually adapted; so, there was no significant alterations in body weight despite restrictions of meat, dairy, and eggs, and enough whole plant foods—whole grains, beans, vegetables, and fruit—to provide 65 grams of fiber a day, four times what the Standard American Diet provides.
The control diet they used was the conventional diabetic diet, which actually had nearly twice the fiber content of the Standard American Diet; so, it was probably healthier than what they were used to eating. So, how did they do? With zero weight loss, did the dietary intervention still help? Here’s the before and after insulin requirements of the 20 people they put on the diet. This is the number of units of insulin they had to inject themselves with before and after going on the plant-based diet. Overall, insulin requirements were cut about 60%; half were able to get off insulin altogether, despite no change in weight. So, was this after five years, or seven months, like in the other studies I showed? No, 16 days.
So, we’re talking diabetics who’ve had diabetes as long as 20 years, injecting 20 units of insulin a day, and then, as few as 13 days later, they’re off insulin altogether, thanks to less than two weeks on a plant-based diet. Patient 15: 32 units of insulin on the control diet, and then, 18 days later, none. Lower blood sugars on 32 units less insulin. That’s the power of plants.