Flashback Friday: What Causes Insulin Resistance and Diabetes?

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

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.

After about age 20, we may have all the insulin-producing beta cells we’re ever going to have in our pancreas, and so if we lose them, we may lose them for good. Autopsy studies show that by the time type 2 diabetes is diagnosed, we may have already killed off half of our beta cells.

You can do it right in a Petri dish. Expose human beta cells to fat; they suck it up and then start dying off. A chronic increase in blood fat levels is harmful, as shown by the important effects in pancreatic beta cell lipotoxicity. Fat breakdown products can interfere with the function of these cells, and ultimately lead to their death.

And not just any fat; saturated fat. The predominant fat in olives, nuts, and avocados gives you a tiny bump in death protein 5, but saturated fat really ramps up this contributor to beta cell death. Saturated fats are harmful to beta cells; harmful to the insulin-producing cells in our pancreas. Cholesterol too. The uptake of bad cholesterol, LDL, can cause beta cell death as a result of free radical formation.

So diets rich in saturated fats not only cause obesity and insulin resistance, but the increased levels of circulating free fats in the blood, called NEFAs, non-esterified fatty acids, cause beta cell death and may thus contribute to progressive beta cell loss in type 2 diabetes. And this isn’t just based on test tube studies. If you infuse fat into people’s bloodstream you can directly impair pancreatic beta cell function, and the same when we ingest it.

Type 2 diabetes is characterized by defects in both insulin secretion and insulin action, and saturated fat appears to impair both. Researchers showed saturated fat ingestion reduces insulin sensitivity within hours, but these were non-diabetics, so their pancreas should have been able to boost insulin secretion to match. But insulin secretion failed to compensate for insulin resistance in subjects who ingested the saturated fat. This implies the saturated fat impaired beta cell function as well, again within just hours after going into our mouth.

So increased consumption of saturated fats has a powerful short- and long-term effect on insulin action, contributing to the dysfunction and death of pancreatic beta cells in diabetes.

And saturated fat isn’t just toxic to the pancreas. The fats, found predominantly in meat and dairy—chicken and cheese are the two main sources in the American diet—are almost universally toxic, whereas the fats found in olives, nuts, and avocados are not. Saturated fat has been found to be particularly toxic to liver cells in the formation of fatty liver disease. You expose human liver cells to plant fat, and nothing happens. Expose liver cells to animal fat, and a third of them die. This may explain why higher intakes of saturated fat and cholesterol are associated with nonalcoholic fatty liver disease.

By cutting down on saturated fat consumption we may be able to help interrupt this process. Decreasing saturated fat intake may help bring down the need for all that excess insulin. So either being fat, or eating saturated fat can both cause that excess insulin in the blood. The effect of reducing dietary saturated fat intake on insulin levels is substantial, regardless of how much belly fat we have. And it’s not just that by eating fat we may be more likely to store it as fat. Saturated fats, independently of any role they have of making us fat, may contribute to the development of insulin resistance and all its clinical consequences. After controlling for weight, and alcohol, and smoking, and exercise, and family history, diabetes incidence was significantly associated with the proportion of saturated fat in our blood.

So what causes diabetes? The consumption of too many calories rich in saturated fats. Now just like everyone who smokes doesn’t develop lung cancer; everyone who eats a lot of saturated fat doesn’t develop diabetes—there’s a genetic component.  But just like smoking can be said to cause lung cancer, high-calorie diets rich in saturated fats are currently considered the cause of type 2 diabetes.

To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video. This is just an approximation of the audio contributed by Katie Schloer.

Please consider volunteering to help out on the site.

• H P Himsworth. The dietetic factor determining the glucose tolerance and senility to insulin of healthy men. Clinical Science 2, 67-94.
• H P Himsworth, E M Marshall. The diet of diabetics prior to the onset of the disease. Clinical Science 2, 95-115, 1935. NA.
• M Roden, T B Price, G Perseghin, K F Petersen, D L Rothman, G W Cline, G I Shulman. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. Jun 15, 1996; 97(12): 2859–2865.
• 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.
• M Roden, K Krssak, H Stingl, S Gruber, A Hofer, C Furnsinn, E Moser, W Waldhausl. Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans.
• M Krssak, K Falk Petersen, A Dresner, L Dipetro, S M Vogel, D L Rothman, M Roden, G I Shulman. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia. 1999 Jan;42(1):113-6.
• J Shirley Sweeney. DIETARY FACTORS THAT INFLUENCE THE DEXTROSE TOLERANCE TEST A PRELIMINARY STUDY. JAMA Int Med, Dec, 1927, Vol 40, No. 6.
• E W Kraegen, G J Cooney. Free fatty acids and skeletal muscle insulin resistance. Curr Opin Lipidol. 2008 Jun;19(3):235-41.
• A T Santomauro, G Boden, M E Silva, D M Rocha, FR F Santos, M J Ursich, P G Strassmann, B L Wajchenberg. Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes. 1999 Sep;48(9):1836-41.
• HP Himsworth. The dietetic factor determining the glucose tolerance and sensitivity to insulin of healthy men. J Physiol. 1934 Mar 29; 81(1): 29–48.
• W J Evans. Oxygen-carrying proteins in meat and risk of diabetes mellitus. JAMA Intern Med. 2013 Jul 22;173(14):1335-6. doi: 10.1001/jamainternmed.2013.7399.
• M Cnop. Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes. Biochem Soc Trans. 2008 Jun;36(Pt 3):348-52. doi: 10.1042/BST0360348.
• R Taylor. Banting Memorial lecture 2012: reversing the twin cycles of type 2 diabetes. Diabet Med. 2013 Mar;30(3):267-75. doi: 10.1111/dme.12039.
• A K Leamy, R A Egnatchik, J D Young. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog Lipid Res. 2013 Jan;52(1):165-74. doi: 10.1016/j.plipres.2012.10.004.
• D Estadella, C M da Penha Oller do Nascimento, L M Oyama, E B Ribeiro, A R Dâmaso, A de Piano. Lipotoxicity: effects of dietary saturated and transfatty acids. Mediators Inflamm. 2013;2013:137579. doi: 10.1155/2013/137579.
• R Taylor. Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause. Diabetologia. 2008 Oct;51(10):1781-9. doi: 10.1007/s00125-008-1116-7.
• D A Cunha, M Igoillo-Esteve, E N Gurzov, C M Germano, N Naamane, I Marhfour, M Fukaya, J M Vanderwinden, C Gysemans, C Mathieu, L Marselli, P Marchetti, H P Harding, D Ron, D L Eizirik, M Cnop. Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis. Diabetes. 2012 Nov;61(11):2763-75. doi: 10.2337/db12-0123.
• G Musso, R Gambino, F De Michieli, M Cassader, M Rizzetto, M Durazzo, E Fagà, B Silli, G Pagano. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003 Apr;37(4):909-16.
• J Cao, X X Feng, L Yao, B Ning, Z X Yang, D L Fang, W Shen. Saturated free fatty acid sodium palmitate-induced lipoapoptosis by targeting glycogen synthase kinase-3β activation in human liver cells. Dig Dis Sci. 2014 Feb;59(2):346-57. doi: 10.1007/s10620-013-2896-2.
• C Xiao, A Giacca, A Carpentier, G F Lewis. Differential effects of monounsaturated, polyunsaturated and saturated fat ingestion on glucose-stimulated insulin secretion, sensitivity and clearance in overweight and obese, non-diabetic humans. Diabetologia. 2006 Jun;49(6):1371-9.
• M Cnop, S J Hughes, M Igoillo-Esteve, M B Hoppa, F Sayyed, L van de Laar, J H Gunter, E J de Koning, G V Walls, D W Gray, P R Johnson, B C Hansen, J F Morris, M Pipeleers-Marichal, I Cnop, A Clark. The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia. 2010 Feb;53(2):321-30. doi: 10.1007/s00125-009-1562-x.
• M Ricchi, M R Odoardi, L Carulli, C Anzivino, S Ballestri, A Pinetti, L I Fantoni, F Marra, M Bertolotti, S Banni, A Lonardo, N Carulli, P Loria. Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. J Gastroenterol Hepatol. 2009 May;24(5):830-40. doi: 10.1111/j.1440-1746.2008.05733.x.
• C J Nolan, C Z Larter. Lipotoxicity: why do saturated fatty acids cause and monounsaturates protect against it? J Gastroenterol Hepatol. 2009 May;24(5):703-6. doi: 10.1111/j.1440-1746.2009.05823.x.
• D R Parker, S T Weiss, R Troisi, P A Cassano, P S Vokonas, L Landsberg. Relationship of dietary saturated fatty acids and body habitus to serum insulin concentrations: the Normative Aging Study. Am J Clin Nutr. 1993 Aug;58(2):129-36.
• D J Maron, J M Fair, W L Haskell. Saturated fat intake and insulin resistance in men with coronary artery disease. The Stanford Coronary Risk Intervention Project Investigators and Staff. Circulation. 1991 Nov;84(5):2020-7.
• L Wang, A R Folsom, Z J Zheng, J S Pankow, J H Eckfeldt, ARIC Study Investigators. Plasma fatty acid composition and incidence of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr. 2003 Jul;78(1):91-8.

Image in video thanks to Wess via Flickr.