These are notes from lecture 12 of Harvard Extension’s biochemistry class.
The first priority is to provide enough glucose to tissues that are solely dependent on glucose – the brain and red blood cells. It was long thought that fatty acids cannot be converted to glucose, though there is now some evidence that this conversion may occur under some circumstances. Amino acids are a poor fuel source because they’re not stored (no equivalent of glycogen or triacylglycerol), so you’d just be catabolizing proteins you need to live.
Starvation occurs in stages. Exogenous glucose can be used for the first 4 hours after a meal. Then glycogen reserves kick in from hour 4 to hour ~28. As the glycogen mobilization peaks around hour 8, gluconeogenesis begins, and can continue full steam for about 2 days, after which it dampens slightly but can continue for up to 40 days at a lower level. During days 2-24, the kidney begins gluconeogenesis and the brain begins using ketone bodies. In Stage V (days 24-40), the liver and kidney continue to do gluconeogenesis and the brain relies solely on ketone bodies.
Muscle protein degradation is about 75 g/day at day 3 of starvation, 20 g/day at day 40 of starvation. The initial sources of proteins are rapid turnover proteins from the intestinal epithelium and secreted pancreatic proteins. After three days, the liver forms ketone bodies (from fatty acid catabolism) which become the predominant energy source, preventing additional protein degradation. After an average of 40 days (more if you have more adipose tissue), TAG stores are depleted, and protein degradation increases again, impacting heart, liver and kidney function and leading ultimately to death.
See [Berg 2002] for an overview of all this, esp. muscle protein degradation. Here’s a quick review of ketone bodies. Fatty acids are mobilized from adipose tissue and transported to the liver, where they are degraded into acetyl-CoA. However under starvation conditions, oxaloacetate in the liver is being removed from the citric acid cycle for gluconeogenesis, thus slowing down citric acid cycle capacity. Therefore this acetyl-CoA from fatty acid catabolism cannot always be run in the CAC, so it is instead converted to ketone bodies, which are exported to other tissues. Those other tissues are not performing gluconeogenesis, so they are still running the CAC and they actually convert the ketone bodies back to acetyl-CoA in order to use them in the CAC.
Diabetes is a metabolic disorder characterized by hyperglycemia (high blood glucose levels). A quick comparison of the two types:
- Type 1 is an autoimmune disorder that kills pancreatic beta cells, resulting in insulin deficiency – it can be treated with insulin. It results in the presence of antibodies against beta cells, though the ultimate cause is not known. It is usually onset < 30 years of age, no association with obesity, low to undetectable plasma levels of insulin, associated with loss of beta cells, leads to ketoacidosis, comprises ~5% of U.S. diabetics, and its prevalence is stable.
- Type 2 is associated with impaired response to insulin – adding more insulin doesn’t help. It is usually onset > 30 years of age, associated with obesity, variable plasma levels of insulin, islet cells are smaller than usual for unknown reasons, no ketoacidosis is observed, currently ~95% of U.S. diabetics and its prevalence is rising.
In Type 1 diabetes, glucose doesn’t get taken up into tissue nor phosphorylated in the liver. The liver continues to mobilize glycogen even right after a meal, and plasma glucose levels get very high. Glucose starts to be lost into urine, alone with water and electrolytes, resulting in excessive urination and excessive thirst. And because your tissues haven’t taken up glucose, your body thinks you’re starving and you get increased appetite and food intake. (Note that the brain constitutively uses glucose, and is not insulin-sensitive, so the brain is still able to take up glucose even under these conditions). Type 1 is also associated with elevated glucagon because insulin, if it were present, would have suppressed glucagon.
The body accordingly fails to store lipids in adipocytes, fails to synthesize TAGs in hepatocytes. Instead it mobilizes TAGs from adipocytes, oxidizes them and produces acetyl-CoA and ketone bodies, and also catabolizes proteins. The ketone bodies lower blood pH (ketoacidosis). Low blood pH is a common cause of death in untreated Type 1 diabetes. This disorder is described as “starvation in the midst of plenty.”
Type 1 is treated by insulin injections. This causes tissues to take up glucose, thus lowering blood glucose levels. However, insulin also suppresses glucagon release, thus preventing the liver from breaking down glycogen. In other words, dosing is really important, and if you get a little too much insulin you can have hypoglycemia.
The rise in T2D prevalence can be attributed to a couple factors: (1) overnutrition, obesity, inactivity; (2) treatment of T2D has improved, and therefore people live longer with it. T2D risk factors include obesity (particularly abdominal fat), age (> 45), blood pressure (high is bad), inactivity (even if not obese), genetics (family history), and ethnic background.
Two hours after you eat a meal, your blood glucose should be back to fasting levels. In the 10 years leading up to T2D onset, your post-meal glucose gradually rises, and more and more insulin is secreted in response, but you develop insulin resistance. Fasting glucose also starts to rise (I think because the liver performs glycogen breakdown or gluconeogenesis but cells are slow to take this glucose up too, and/or because the liver has to produce higher levels of glucose in order to get cells to take up the glucose). Around year 0 (where onset is defined), beta cells start to fail, and insulin secretion goes back down, declining gradually over 30 years.
“Prediabetes” is a marker for risk. Impaired Glucose Tolerance (IGT) is when your glucose levels ~2 hours after a meal are higher than they should be. Impaired Fasting Glucose (IFG) is elevated hepatic glucose production. HbA1c is glycosylated hemoglobin – hemoglobin is ordinarily unglycosylated but becomes glycosylated if there is too much glucose in the blood. HbA1c is another risk marker. Increased risk for heart disease and stroke, as measured by low HDL, high LDL, and/or high blood TAGs, are also considered risk factors.
mechanisms in T2D
There are 3 hypotheses about how insulin resistance arises:
- Adipose tissue dysfunction – the lipid burden hypothesis. PPARγ expression (which determines ability to store TAGs) is reduced in obese individuals’ adipose tissue but elevated in their liver and muscle, meaning that now liver and muscle can now store fat (which they shouldn’t normally; this is ectopic). Meanwhile, all tissues (adipose, liver and muscle) become less insulin sensitive for reasons this lecture didn’t explain.
- Adipose tissue dysfunction – the role of inflammation. When adipocytes get too large (in overweight people), the overloading of TAG causes release of MCP-1, a chemoattractant. The MCP-1 attracts macrophages which release TNFα and other cytokines, reducing insulin signaling. TAG storage becomes impaired, resulting in lipolysis and increasing the circulating TAGs and free fatty acids, allowing them to accumulate ectopically in muscle.
- Insulin resistance in liver and muscle – the role of mitochondria. In either case 1 or 2 above, fatty acids accumulate in the liver. Overnutrition also increases malonyl-CoA in the liver, and malonyl-CoA inhibits CPT1 (carnitine palomitoyltransferase 1) which inhibits fatty acid oxidation. In lieu of oxidation, TAG storage increases. Fatty acid metabolism during CPT1 inhibition also produces diacylglycerol and ceramide. DAG activates stress-induced kinases, and both these and ceramide reduce insulin signaling. Meanwhile in the muscle, fatty acid accumulation increases beta oxidation thereof, and reduces citric acid cycle activity. Products of incomplete fat oxidation (acylcarnitines and reactive oxygen species) activate stress-induced kinases, which reduce insulin signaling.
After insulin resistance, impaired insulin secretion and beta cell failure follow next. There are likewise a few hypotheses about these:
- Role of mitochondria and pyruvate cycling. Pyruvate cycling refers to how pyruvate generated in the cytosol enters the mitochondria, is converted to intermediates such as malate and then exported back to the cytosol where they are converted back to pyruvate. During overnutrition, increased fatty acids lead to increased acetyl-CoA which activates pyruvate carboxylase. Meanwhile there is also additional pyruvate due to additional glucose from overnutrition. Together, the added glucose and the activated pyruvate carboxylase increase the volume of pyruvate cycling. Because metabolites from pyruvate cycling are responsible for insulin secretion, an increase in cycling leads to insulin hypersecretion by beta cells.
- Role of ER stress. Insulin hypersecretion means you have to produce a ton of insulin, which stresses out the ER, leading to protein misfolding and ultimately apoptosis.
- Role of amyloid fibrils. When insulin is secreted, amylin (gene: IAPP) is also secreted. Amylin helps slow gastic emptying, thus resulting in a slower release of glucose and of insulin into the bloodstream. If amylin production gets too high, it forms amylin fibrils, which can kill the cell.
- Dedifferentiation. This is a very recent theory that during diabetes, mature beta cells undergo dedifferentiation to beta cell progenitors [Talchai 2012].
potential drug targets
From class discussion:
- PPARγ to maintain fatty acid storage in adipose tissue instead of liver and muscle.
- Promote beta cell differentiation
- Transplantation of beta cells
- RXR in muscle
- Inhibit beta cell uptake of fatty acids
- Inhibit migration of macrophages to adipocytes
- Inhibit TNFα secretion
- Inhibit amylin fibril formation… or conversely provide more amylin to inhibit glucagon
- Increase oxaloacetate levels
- Reduce malonyl-CoA
- Inhibit pyruvate carboxylase
- Inhibit gluconeogenesis to keep blood glucose low
treatments in use
- Weight loss reduces TAG content in adipose tissue, reducing lipid burden and increasing available capacity for lipid storage, restoring insulin sensitivity.
- Exercise increases [AMP]/[ATP], activating AMPK. This increases GLUT4 localization at the cell surface.
- Sulfonylureas such as glimepiride inhibit ATP-sensitive K+ channels in beta cells, leading to depolarization and promoting insulin release. This is helpful in late stages of T2D when not much insulin is being secreted.
- Biguanides such as metformin activate APMK, which has several effects: promoting glucose uptake in muscle and inhibiting gluconeogenesis while reducing expression of lipogenic enzymes in the liver, thus reducing fatty liver.
- Thiazolidinediones such as pioglitazone activate PPARγ in adipose tissue, reducing fatty acid mobilization. A side effect is the redistribution of TAG stores from visceral fat to subcutaneous fat and some amount of net weight gain. However in terms of diabetes, visceral fat is a bigger risk than subcutaneous fat, so you’re better off on net.
- α-glucosidase inhibitors prevent polysaccharides from being broken down in the intestines, thus reducing the amount of nutrition absorbed from a meal.