1 00:00:00,090 --> 00:00:02,490 The following content is provided under a Creative 2 00:00:02,490 --> 00:00:04,030 Commons license. 3 00:00:04,030 --> 00:00:06,330 Your support will help MIT OpenCourseWare 4 00:00:06,330 --> 00:00:10,720 continue to offer high quality educational resources for free. 5 00:00:10,720 --> 00:00:13,320 To make a donation or view additional materials 6 00:00:13,320 --> 00:00:17,280 from hundreds of MIT courses, visit MIT OpenCourseWare 7 00:00:17,280 --> 00:00:18,450 at ocw.mit.edu. 8 00:00:21,000 --> 00:00:23,280 PROFESSOR: We're now at storyboard 23. 9 00:00:23,280 --> 00:00:26,550 Let's look at panel A. Our last metabolism 10 00:00:26,550 --> 00:00:31,140 topic under the general umbrella of catabolism is ketone bodies. 11 00:00:31,140 --> 00:00:34,140 Ketone bodies are only covered in two pages in the book, 12 00:00:34,140 --> 00:00:36,230 but they're medically very important. 13 00:00:36,230 --> 00:00:38,500 The medical relevance of ketone bodies 14 00:00:38,500 --> 00:00:40,770 stems from their role in starvation 15 00:00:40,770 --> 00:00:42,870 and their role in diabetes. 16 00:00:42,870 --> 00:00:47,340 Let's look at panel A. This panel shows various sources of 17 00:00:47,340 --> 00:00:49,680 and uses of acetyl CoA. 18 00:00:49,680 --> 00:00:53,280 It shows that ketone bodies are made from Acetyl coenzyme A. 19 00:00:53,280 --> 00:00:55,680 So let's start this part of the lecture 20 00:00:55,680 --> 00:00:59,280 with a discussion of where acetyl CoA comes from, 21 00:00:59,280 --> 00:01:01,140 and what its various states are including 22 00:01:01,140 --> 00:01:03,330 the formation of ketone bodies. 23 00:01:03,330 --> 00:01:06,610 We just finished talking about fatty acid catabolism. 24 00:01:06,610 --> 00:01:08,950 So let's start on the right of this figure. 25 00:01:08,950 --> 00:01:11,085 We see that a fatty acid can be broken down 26 00:01:11,085 --> 00:01:14,130 to form acetyl CoA by beta oxidation, 27 00:01:14,130 --> 00:01:17,040 usually with the objective of generating energy. 28 00:01:17,040 --> 00:01:19,890 If we follow the acetyl CoA from beta oxidation 29 00:01:19,890 --> 00:01:22,380 down into the TCA cycle, we see that it 30 00:01:22,380 --> 00:01:25,650 will be fully oxidized to carbon dioxide with the generation 31 00:01:25,650 --> 00:01:27,510 of a lot of energy that can be used 32 00:01:27,510 --> 00:01:30,840 for mechanical work, biosynthesis, and other things. 33 00:01:30,840 --> 00:01:32,730 A second source of Acetyl CoA can 34 00:01:32,730 --> 00:01:34,620 be seen to the left, where we see 35 00:01:34,620 --> 00:01:37,050 glycogen breakdown to glucose or glucose 36 00:01:37,050 --> 00:01:39,480 can be directly imported into a cell. 37 00:01:39,480 --> 00:01:42,330 In either case, the glucose that we take in or liberate 38 00:01:42,330 --> 00:01:44,100 from its storage depot, glycogen, 39 00:01:44,100 --> 00:01:47,580 can be converted into acetyl coenzyme A. 40 00:01:47,580 --> 00:01:50,070 Glycerol can be generated from the backbone 41 00:01:50,070 --> 00:01:52,950 of a metabolized triacylglyceride. 42 00:01:52,950 --> 00:01:56,310 It enters glycolysis as dihydroxyacetone phosphate 43 00:01:56,310 --> 00:02:00,840 and then can progress to acetyl CoA by way of glycolysis. 44 00:02:00,840 --> 00:02:04,050 Alanine can transiminate into pyruvate, 45 00:02:04,050 --> 00:02:06,300 which is converted subsequently to acetyl CoA 46 00:02:06,300 --> 00:02:08,910 by pyruvate dehydrogenase. 47 00:02:08,910 --> 00:02:12,480 This diagram shows us that many pathways converge 48 00:02:12,480 --> 00:02:17,130 to generate acetyl coenzyme A. Carbohydrates, amino acids, 49 00:02:17,130 --> 00:02:19,290 fatty acids, all can act as a source 50 00:02:19,290 --> 00:02:22,980 of this important precursor to energy. 51 00:02:22,980 --> 00:02:26,890 Aside from being processed by the TCA cycle, on the left, 52 00:02:26,890 --> 00:02:28,980 we see a broken line pathway involving 53 00:02:28,980 --> 00:02:31,050 fatty acid biosynthesis. 54 00:02:31,050 --> 00:02:33,060 This is going to be the next topic we come to 55 00:02:33,060 --> 00:02:36,660 after this discussion of ketone body formation. 56 00:02:36,660 --> 00:02:39,030 The pathway on the right with the broken lines 57 00:02:39,030 --> 00:02:41,490 is the pathway leading to ketone bodies 58 00:02:41,490 --> 00:02:43,740 which is called ketogenesis. 59 00:02:43,740 --> 00:02:46,770 In the box at the top of panel A is a cartoon reminding me 60 00:02:46,770 --> 00:02:49,980 to tell you that acetyl CoA cannot escape from the cell. 61 00:02:49,980 --> 00:02:54,300 Moreover, it cannot even easily escape from the mitochondrion. 62 00:02:54,300 --> 00:02:56,430 In order for acetyl CoA to leave the cell 63 00:02:56,430 --> 00:02:58,515 and be transported from one organ to another, 64 00:02:58,515 --> 00:03:00,990 it needs to be converted into ketone bodies. 65 00:03:00,990 --> 00:03:02,850 Another way to look at ketone bodies 66 00:03:02,850 --> 00:03:05,160 is that these are mobile or portable forms 67 00:03:05,160 --> 00:03:08,700 of Acetyl CoA that can go from a source organ, which is usually 68 00:03:08,700 --> 00:03:12,000 the liver, to a target organ, which may need them in order 69 00:03:12,000 --> 00:03:15,030 to generate energy by way of the TCA cycle. 70 00:03:15,030 --> 00:03:17,130 The target organ for example could be brain 71 00:03:17,130 --> 00:03:18,855 under conditions of starvation, or it 72 00:03:18,855 --> 00:03:20,400 could be skeletal muscle if you have 73 00:03:20,400 --> 00:03:22,560 to run away from something. 74 00:03:22,560 --> 00:03:25,740 Let's look at panel B. There are five key facts that we need 75 00:03:25,740 --> 00:03:27,570 to know about ketone bodies. 76 00:03:27,570 --> 00:03:30,600 First, Ketogenesis mainly occurs in the liver. 77 00:03:30,600 --> 00:03:32,670 The liver manufactures ketone bodies 78 00:03:32,670 --> 00:03:36,090 and then exports them to other organs for use. 79 00:03:36,090 --> 00:03:39,810 These reactions typically happen when the levels of oxaloacetate 80 00:03:39,810 --> 00:03:42,210 become limiting in their mitochondrion. 81 00:03:42,210 --> 00:03:43,740 And I'll give you an example of why 82 00:03:43,740 --> 00:03:46,470 this is the case when I talk about starvation a little later 83 00:03:46,470 --> 00:03:47,370 in this lecture. 84 00:03:47,370 --> 00:03:49,860 The second important fact is that these 85 00:03:49,860 --> 00:03:52,770 are the primary metabolic fuels of the heart and skeletal 86 00:03:52,770 --> 00:03:55,110 muscle under normal conditions. 87 00:03:55,110 --> 00:03:56,850 The third fact is that ketone bodies 88 00:03:56,850 --> 00:04:00,000 become the major metabolic fuel of all cells 89 00:04:00,000 --> 00:04:01,920 under conditions of starvation, even 90 00:04:01,920 --> 00:04:04,710 cells of the brain after a few days of starvation 91 00:04:04,710 --> 00:04:07,920 will convert from glucose being the preferred metabolic fuel 92 00:04:07,920 --> 00:04:11,370 to accepting ketone bodies as their major source of energy. 93 00:04:11,370 --> 00:04:13,500 The fourth fact I want to talk about with regard 94 00:04:13,500 --> 00:04:14,910 to ketone bodies is that they are 95 00:04:14,910 --> 00:04:17,519 produced in excess in diabetes. 96 00:04:17,519 --> 00:04:19,320 I'll talk a little bit more about that 97 00:04:19,320 --> 00:04:20,910 later in the lecture. 98 00:04:20,910 --> 00:04:24,810 Finally, ketogenesis occurs in the mitochondrion, primarily 99 00:04:24,810 --> 00:04:26,520 the mitochondrion of the liver. 100 00:04:26,520 --> 00:04:29,550 So these are mitochondrial reactions. 101 00:04:29,550 --> 00:04:33,240 Panel C shows the three classical ketone bodies, 102 00:04:33,240 --> 00:04:36,990 acetoacetate, beta hydroxybutyrate, and acetone. 103 00:04:36,990 --> 00:04:39,090 From the standpoint of chemical accuracy, 104 00:04:39,090 --> 00:04:41,670 it's obvious that beta hydroxybutyrate 105 00:04:41,670 --> 00:04:43,590 is an alcohol and not a ketone. 106 00:04:43,590 --> 00:04:46,500 Nevertheless, it's lumped in with the ketone bodies 107 00:04:46,500 --> 00:04:48,130 for historical reasons. 108 00:04:48,130 --> 00:04:50,640 Acetoacetate and beta hydroxybutyrate 109 00:04:50,640 --> 00:04:52,890 are what I'll call quote unquote "useful" ketone 110 00:04:52,890 --> 00:04:55,410 bodies from the standpoint of serving as precursors 111 00:04:55,410 --> 00:04:57,000 to metabolic energy. 112 00:04:57,000 --> 00:05:00,930 Acetone by contrast, is not useful by this criterion. 113 00:05:00,930 --> 00:05:04,620 Acetone however, is a useful biomarker, 114 00:05:04,620 --> 00:05:08,340 because sometimes its presence can help diagnose diabetes. 115 00:05:08,340 --> 00:05:11,730 On a personal note, I come from a long line of diabetics. 116 00:05:11,730 --> 00:05:14,760 I remember when I was a little kid, my dad before he 117 00:05:14,760 --> 00:05:16,530 was diagnosed, would come home from work 118 00:05:16,530 --> 00:05:18,090 at the end of the day. 119 00:05:18,090 --> 00:05:19,650 He had very poor circulation. 120 00:05:19,650 --> 00:05:21,510 So my two sisters and I would try 121 00:05:21,510 --> 00:05:24,030 to rub his legs to give him a kind of massage 122 00:05:24,030 --> 00:05:26,490 to make his circulation a little bit better. 123 00:05:26,490 --> 00:05:30,940 I remember very clearly my older sister saying, "gee, 124 00:05:30,940 --> 00:05:34,560 dad smells like mom's nail polish remover," 125 00:05:34,560 --> 00:05:37,140 and that's because he was a diabetic producing 126 00:05:37,140 --> 00:05:39,540 acetone, which was used at the time at least 127 00:05:39,540 --> 00:05:41,280 as nail polish remover. 128 00:05:41,280 --> 00:05:44,130 We had no idea at the time what was going on. 129 00:05:44,130 --> 00:05:47,730 A few months later, my dad was diagnosed as a type 2 diabetic. 130 00:05:47,730 --> 00:05:50,790 I now know that the fruity odor we smelled on his breath 131 00:05:50,790 --> 00:05:52,140 was acetone. 132 00:05:52,140 --> 00:05:56,640 As I said, acetone is a biomarker of this disease. 133 00:05:56,640 --> 00:05:59,370 One last point with regard to the story board. 134 00:05:59,370 --> 00:06:03,750 Note that the acetoacetate and beta hydroxybutyrate molecules 135 00:06:03,750 --> 00:06:05,010 are acids. 136 00:06:05,010 --> 00:06:07,200 In diabetics, these acids can be produced 137 00:06:07,200 --> 00:06:09,900 as we'll see later in sufficiently 138 00:06:09,900 --> 00:06:12,840 high concentrations to lower the pH of the blood 139 00:06:12,840 --> 00:06:14,940 quite substantially. 140 00:06:14,940 --> 00:06:17,070 Keep in mind that lowering the pH 141 00:06:17,070 --> 00:06:20,010 is the same thing as increasing the concentration of protons 142 00:06:20,010 --> 00:06:21,760 in the blood. 143 00:06:21,760 --> 00:06:25,050 These concentrated protons will have physiological relevance 144 00:06:25,050 --> 00:06:26,730 that I'll discuss later. 145 00:06:26,730 --> 00:06:29,730 When a diabetic enters the phase where the pH of their blood 146 00:06:29,730 --> 00:06:34,080 is dangerously low, that's called diabetic acidosis. 147 00:06:34,080 --> 00:06:36,630 Let's now turn to Panel D. At this point 148 00:06:36,630 --> 00:06:39,780 I want to describe the detailed biochemical reactions that 149 00:06:39,780 --> 00:06:41,820 give rise to ketone bodies. 150 00:06:41,820 --> 00:06:43,320 To make a ketone body we're going 151 00:06:43,320 --> 00:06:45,816 to need three molecules of acetyl coenzyme 152 00:06:45,816 --> 00:06:48,660 A. One of these molecules is going to be catalytic. 153 00:06:48,660 --> 00:06:51,960 That is, it's going to be restored at the overall end 154 00:06:51,960 --> 00:06:54,270 of the process of ketogenesis. 155 00:06:54,270 --> 00:06:56,520 Let's start by imagining a scenario 156 00:06:56,520 --> 00:06:58,770 in the mitochondrion of a liver cell 157 00:06:58,770 --> 00:07:01,230 where oxaloacetate becomes limiting. 158 00:07:01,230 --> 00:07:04,770 I'll talk about physiological states under which oxaloacetate 159 00:07:04,770 --> 00:07:08,410 becomes limiting or sparse a little bit later. 160 00:07:08,410 --> 00:07:11,130 Acetyl CoA cannot enter the TCA cycle, 161 00:07:11,130 --> 00:07:15,000 because citrate synthase lacks oxaloacetate as a reaction 162 00:07:15,000 --> 00:07:16,200 partner. 163 00:07:16,200 --> 00:07:20,080 The concentration of acetyl CoA starts to accumulate. 164 00:07:20,080 --> 00:07:22,680 Then the beta ketothiolase reaction 165 00:07:22,680 --> 00:07:27,330 that is the last step in fatty acid bio oxidation 166 00:07:27,330 --> 00:07:31,515 reverses owing to the high concentration of product acetyl 167 00:07:31,515 --> 00:07:32,730 CoA. 168 00:07:32,730 --> 00:07:35,790 So two acetyl CoAs come together in order 169 00:07:35,790 --> 00:07:39,330 to form acetoacetyl coenzyme A. Note 170 00:07:39,330 --> 00:07:41,610 that I put markers on each of the carbons 171 00:07:41,610 --> 00:07:45,980 of the acetoacetyl coenzyme A. A third acetoacetyl coenzyme 172 00:07:45,980 --> 00:07:48,720 A is then added to the gamma carbon 173 00:07:48,720 --> 00:07:52,680 of the acetoacetyl coenzyme A. That's the carbon that 174 00:07:52,680 --> 00:07:54,360 has the filled-in square. 175 00:07:54,360 --> 00:07:56,700 The enzyme that catalyzed this last reaction 176 00:07:56,700 --> 00:08:00,720 is HMG Coenzyme A reductase, where HMG stands 177 00:08:00,720 --> 00:08:03,120 for hydroxymethylglutaryl. 178 00:08:03,120 --> 00:08:07,249 HMG CoA is a six-carbon branch chain molecule. 179 00:08:07,249 --> 00:08:08,790 In the present situation, we're going 180 00:08:08,790 --> 00:08:12,180 to look at HMG CoA as the source of ketone bodies 181 00:08:12,180 --> 00:08:14,220 in the mitochondrion, but I want you 182 00:08:14,220 --> 00:08:16,470 to keep in mind that if this reaction were 183 00:08:16,470 --> 00:08:18,210 to occur not in the mitochondrion 184 00:08:18,210 --> 00:08:21,660 but in the cytoplasm, the resulting HMG CoA could 185 00:08:21,660 --> 00:08:23,310 be used for other pathways. 186 00:08:23,310 --> 00:08:26,070 For example, HMG CoA in the cytosol 187 00:08:26,070 --> 00:08:28,455 is the precursor to cholesterol. 188 00:08:28,455 --> 00:08:30,330 With that in mind, let's return our attention 189 00:08:30,330 --> 00:08:32,789 to the mitochondrion and ketogenesis. 190 00:08:32,789 --> 00:08:35,970 The mitochondrial enzyme HMG CoA lyase 191 00:08:35,970 --> 00:08:39,090 will split the HMG CoA, knocking off 192 00:08:39,090 --> 00:08:42,210 an acetyl CoA in liberating as the final product 193 00:08:42,210 --> 00:08:46,710 acetoacetate, which is our first of three ketone bodies. 194 00:08:46,710 --> 00:08:49,560 Acetoacetate is a beta keto acid and hence, 195 00:08:49,560 --> 00:08:52,250 prone to spontaneous decarboxylation. 196 00:08:52,250 --> 00:08:55,440 Non enzymatically, this will happen at some slow rate 197 00:08:55,440 --> 00:08:59,130 in order to liberate CO2 and produce acetone, which 198 00:08:59,130 --> 00:09:01,470 is our second ketone body. 199 00:09:01,470 --> 00:09:03,360 This acetone gives the fruity smell 200 00:09:03,360 --> 00:09:05,580 to the breath of a diabetic whose disease is out 201 00:09:05,580 --> 00:09:06,870 of control. 202 00:09:06,870 --> 00:09:09,810 Acetone is not going to be biochemically useful to us, 203 00:09:09,810 --> 00:09:13,790 for example it's not going to be metabolized to generate energy. 204 00:09:13,790 --> 00:09:16,210 The second chemical fate of the acetoacetate 205 00:09:16,210 --> 00:09:20,770 is its reduction by NADH using the enzyme beta hydroxybutyrate 206 00:09:20,770 --> 00:09:22,180 dehydrogenase. 207 00:09:22,180 --> 00:09:24,880 This reduction forms our third ketone body beta 208 00:09:24,880 --> 00:09:28,780 hydroxybutyrate, which is a biochemically useful molecule 209 00:09:28,780 --> 00:09:31,770 in that it serves as a good metabolic fuel. 210 00:09:31,770 --> 00:09:34,420 Acetoacetate and beta hydroxybutyrate 211 00:09:34,420 --> 00:09:37,210 do not need any kind of special transporter 212 00:09:37,210 --> 00:09:39,530 to get out of the cell into the blood. 213 00:09:39,530 --> 00:09:41,620 They diffuse through the mitochondrial membrane 214 00:09:41,620 --> 00:09:43,810 and later through the cell membrane. 215 00:09:43,810 --> 00:09:46,360 They are then transported by the circulatory system 216 00:09:46,360 --> 00:09:49,300 from the liver to organs that need them for energy. 217 00:09:49,300 --> 00:09:51,190 As you mentioned above, ketone bodies 218 00:09:51,190 --> 00:09:53,920 are portable forms of acetyl CoA. 219 00:09:53,920 --> 00:09:56,770 In a real sense, the liver by making these ketone bodies 220 00:09:56,770 --> 00:09:59,050 is acting as a food caterer where 221 00:09:59,050 --> 00:10:01,330 ketone bodies represent food that's 222 00:10:01,330 --> 00:10:03,780 delivered to other organs. 223 00:10:03,780 --> 00:10:06,800 At this point let's look at storyboard 24 224 00:10:06,800 --> 00:10:09,240 panel A. Now let's take a look what 225 00:10:09,240 --> 00:10:11,850 happens when the ketone bodies travel by the blood 226 00:10:11,850 --> 00:10:14,580 and are taken up by another organ such as muscle. 227 00:10:14,580 --> 00:10:17,700 Acetoacetate, which I'll refer to as ketone body 228 00:10:17,700 --> 00:10:20,220 one is good to go and is ready to enter 229 00:10:20,220 --> 00:10:21,990 the main stream of metabolism. 230 00:10:21,990 --> 00:10:24,420 So I'm going to come back to it in a minute. 231 00:10:24,420 --> 00:10:26,790 The beta hydroxybutyrate, by contrast, 232 00:10:26,790 --> 00:10:28,830 has to be processed in order for it 233 00:10:28,830 --> 00:10:32,250 to be useful to the target organ skeletal muscle in this case. 234 00:10:32,250 --> 00:10:37,370 In step two, the muscle form of beta hydroxybutyrate 235 00:10:37,370 --> 00:10:40,560 dehydrogenase will use NAD plus to oxidize 236 00:10:40,560 --> 00:10:44,220 the beta hydroxybutyrate into acetoacetate, which 237 00:10:44,220 --> 00:10:47,190 joins the pool of acetoacetate that came in directly 238 00:10:47,190 --> 00:10:48,150 from the blood. 239 00:10:48,150 --> 00:10:52,380 We now have to put a thioester group on the acetoacetate, 240 00:10:52,380 --> 00:10:54,840 and that comes from an unusual source. 241 00:10:54,840 --> 00:10:58,470 In step three you'll see a succinyl coenzyme A 242 00:10:58,470 --> 00:11:01,290 from the TCA cycle giving its coenzyme 243 00:11:01,290 --> 00:11:04,440 A residue to acetoacetate, which results 244 00:11:04,440 --> 00:11:08,100 in the formation of acetoacetyl coenzyme A. 245 00:11:08,100 --> 00:11:11,340 This reaction happens in the mitochondrion of the cell. 246 00:11:11,340 --> 00:11:14,790 At step four acetyl coenzyme A is 247 00:11:14,790 --> 00:11:18,690 converted by beta ketothiolase into two molecules 248 00:11:18,690 --> 00:11:21,180 of acetyl coenzyme A. And again, we're 249 00:11:21,180 --> 00:11:23,220 going to need another coenzyme A group 250 00:11:23,220 --> 00:11:26,730 to come in at this point as part of the beta ketothiolase 251 00:11:26,730 --> 00:11:28,140 reaction. 252 00:11:28,140 --> 00:11:30,240 Remember that beta ketothiolase is 253 00:11:30,240 --> 00:11:32,730 the last enzyme that's operative in beta oxidation 254 00:11:32,730 --> 00:11:34,230 of fatty acids. 255 00:11:34,230 --> 00:11:36,360 Here it's doing the same chemistry 256 00:11:36,360 --> 00:11:37,980 that it does in beta oxidation. 257 00:11:37,980 --> 00:11:42,780 It splits acetoacetyl CoA into two acetyl CoA molecules. 258 00:11:42,780 --> 00:11:44,880 And in steps five and six, those molecules 259 00:11:44,880 --> 00:11:47,430 integrate into the TCA cycle. 260 00:11:47,430 --> 00:11:50,610 In the TCA cycle they're oxidized to carbon dioxide 261 00:11:50,610 --> 00:11:52,980 with the generation of energy. 262 00:11:52,980 --> 00:11:55,080 Let me review for a minute before going 263 00:11:55,080 --> 00:11:58,290 into a physiological scenario. 264 00:11:58,290 --> 00:12:00,540 Way over to the left at step one, 265 00:12:00,540 --> 00:12:03,600 the liver has made acetyl CoA and packaged it 266 00:12:03,600 --> 00:12:06,560 into two ketone bodies, acetoacetate 267 00:12:06,560 --> 00:12:08,640 and beta hydroxybutyrate. 268 00:12:08,640 --> 00:12:10,830 They travel in the blood to target tissues, 269 00:12:10,830 --> 00:12:14,160 for example, the muscle, or heart, or the brain. 270 00:12:14,160 --> 00:12:17,790 In these target tissues these ketone bodies are internalized, 271 00:12:17,790 --> 00:12:22,380 converted to acetoacetate, and then to acetoacetyl coenzyme A 272 00:12:22,380 --> 00:12:27,450 and then ultimately to several molecules of acetyl coenzyme A. 273 00:12:27,450 --> 00:12:30,360 The acetyl coenzyme A that started in the liver, 274 00:12:30,360 --> 00:12:33,240 ends up in the target tissue and then can 275 00:12:33,240 --> 00:12:35,260 be used to generate energy. 276 00:12:35,260 --> 00:12:38,130 This is a particularly important reaction under conditions 277 00:12:38,130 --> 00:12:41,450 of starvation and diabetes. 278 00:12:41,450 --> 00:12:45,590 Let's now look at panel b of storyboard 24. 279 00:12:45,590 --> 00:12:48,650 As you know, I like to look at physiological scenarios 280 00:12:48,650 --> 00:12:52,430 because at least to me, they helped make biochemistry real. 281 00:12:52,430 --> 00:12:55,355 The scenario I want to look at is that of diabetes. 282 00:12:55,355 --> 00:12:58,500 In Type 2 diabetes, which is the type that I have, 283 00:12:58,500 --> 00:13:02,390 my cells have become resistant to taking up glucose. 284 00:13:02,390 --> 00:13:04,910 My cells are insulin insensitive. 285 00:13:04,910 --> 00:13:07,880 After a meal I have very, very high concentrations 286 00:13:07,880 --> 00:13:11,150 of glucose in my blood, because the cells of my tissues 287 00:13:11,150 --> 00:13:13,670 are not capable of taking it in. 288 00:13:13,670 --> 00:13:17,000 Hence, if I do not take my anti-diabetic medication 289 00:13:17,000 --> 00:13:18,530 the sugar concentration in my blood 290 00:13:18,530 --> 00:13:22,190 stays high, which leads to some of the medical complications 291 00:13:22,190 --> 00:13:23,090 of diabetes. 292 00:13:23,090 --> 00:13:24,800 More on that later. 293 00:13:24,800 --> 00:13:28,410 Given that there's a lot of glucose in my blood, 294 00:13:28,410 --> 00:13:30,290 but it's not getting into my cells, 295 00:13:30,290 --> 00:13:34,010 my cells are actually in a technical state of starvation. 296 00:13:34,010 --> 00:13:37,290 Take a look at the pathway I've drawn in panel b. 297 00:13:37,290 --> 00:13:40,270 Glucose on the left is not getting into the cell. 298 00:13:40,270 --> 00:13:43,020 I've used broken lines for the pathway from glucose 299 00:13:43,020 --> 00:13:46,590 to pyruvate and then from pyruvate in the cytoplasm 300 00:13:46,590 --> 00:13:48,600 into the mitochondrial matrix. 301 00:13:48,600 --> 00:13:51,870 These broken lines are meant to indicate 302 00:13:51,870 --> 00:13:54,960 that the pathways involved are just not very active. 303 00:13:54,960 --> 00:13:57,120 The sparse activity of these pathways 304 00:13:57,120 --> 00:13:59,700 means that acetyl CoA levels are becoming somewhat 305 00:13:59,700 --> 00:14:01,520 limiting in the mitochondrion. 306 00:14:01,520 --> 00:14:03,930 Because pyruvate is also limiting, 307 00:14:03,930 --> 00:14:05,970 the enzyme pyruvate carboxylase doesn't 308 00:14:05,970 --> 00:14:08,160 have sufficient pyruvate in order 309 00:14:08,160 --> 00:14:10,710 to maintain the oxaloacetate concentration 310 00:14:10,710 --> 00:14:13,240 within the mitochondrial matrix. 311 00:14:13,240 --> 00:14:16,980 Once again, oxaloacetate is the TCA cycle intermediate 312 00:14:16,980 --> 00:14:20,860 that that's at the lowest, that is micromolar concentration. 313 00:14:20,860 --> 00:14:23,220 I'm focusing here on the liver, although I 314 00:14:23,220 --> 00:14:25,320 should add at this point that all tissues are 315 00:14:25,320 --> 00:14:27,840 similarly limited in the pathways indicated 316 00:14:27,840 --> 00:14:29,460 by the broken lines. 317 00:14:29,460 --> 00:14:31,890 The liver's response to sensing this limitation 318 00:14:31,890 --> 00:14:36,030 in carbohydrate processing is to either take in lipid 319 00:14:36,030 --> 00:14:38,460 or to break it down from internal stores, 320 00:14:38,460 --> 00:14:43,260 for example, triacylglycerides in order to produce acetyl CoA. 321 00:14:43,260 --> 00:14:45,870 But because oxaloacetate is limiting, 322 00:14:45,870 --> 00:14:48,420 the step at beta ketothiolase backs up, 323 00:14:48,420 --> 00:14:51,300 producing a large amount of ketone bodies. 324 00:14:51,300 --> 00:14:53,910 The ketone bodies are produced in excess, 325 00:14:53,910 --> 00:14:56,580 so you can see them escaping into the mitochondrion 326 00:14:56,580 --> 00:15:00,300 and later out of the cell, and they go off into the blood. 327 00:15:00,300 --> 00:15:02,700 Consequently, the liver of diabetics 328 00:15:02,700 --> 00:15:05,610 produces a lot of ketone bodies, because it senses 329 00:15:05,610 --> 00:15:08,710 that the body is starving, 330 00:15:08,710 --> 00:15:12,400 To the right of panel B, I have some blood chemistry values 331 00:15:12,400 --> 00:15:14,890 that are of relevance to diabetics. 332 00:15:14,890 --> 00:15:18,460 In a non-diabetic person, blood sugar concentrations, 333 00:15:18,460 --> 00:15:20,320 that is blood glucose is maintained 334 00:15:20,320 --> 00:15:22,540 at about 100 milligrams of glucose 335 00:15:22,540 --> 00:15:25,030 per 100 milliliters of blood. 336 00:15:25,030 --> 00:15:26,590 When I was diagnosed with diabetes, 337 00:15:26,590 --> 00:15:31,690 my blood sugar was over 300 milligrams per 100 milliliters. 338 00:15:31,690 --> 00:15:34,210 As I recall the symptoms were disorientation. 339 00:15:34,210 --> 00:15:36,730 I couldn't walk very easily, I was thirsty, 340 00:15:36,730 --> 00:15:38,890 and I urinated a lot. 341 00:15:38,890 --> 00:15:41,050 Normal ketone body concentrations 342 00:15:41,050 --> 00:15:43,540 are less than 0.2 nanomolar. 343 00:15:43,540 --> 00:15:47,470 In a severe diabetic situation, your ketone body concentrations 344 00:15:47,470 --> 00:15:51,850 could be 15 to 25 millimolar and the pH of your blood 345 00:15:51,850 --> 00:15:56,470 could drop from the mid 7 range down to about 6.8. 346 00:15:56,470 --> 00:15:59,710 The kidney responds to the high concentration of glucose 347 00:15:59,710 --> 00:16:01,780 and the high concentration of protons, 348 00:16:01,780 --> 00:16:06,700 that is the low pH, by increasing urine volume output 349 00:16:06,700 --> 00:16:11,020 in order to try to urinate out the glucose and protons. 350 00:16:11,020 --> 00:16:14,560 The results are that the diabetic becomes excessively 351 00:16:14,560 --> 00:16:17,470 thirsty which again is one of the biomarkers 352 00:16:17,470 --> 00:16:19,540 or symptoms of the disease. 353 00:16:19,540 --> 00:16:22,080 The classic historical treatment of diabetes 354 00:16:22,080 --> 00:16:25,660 is to give insulin, which will push more glucose into the cell 355 00:16:25,660 --> 00:16:28,960 and thus offset the biochemical defect that leads ultimately 356 00:16:28,960 --> 00:16:31,810 to ketone bodies and to the high concentration of glucose 357 00:16:31,810 --> 00:16:32,890 in the blood. 358 00:16:32,890 --> 00:16:35,230 Aside from giving insulin by injection 359 00:16:35,230 --> 00:16:36,820 there are other medications that will 360 00:16:36,820 --> 00:16:39,370 result in a sort of reactivation of the beta cells 361 00:16:39,370 --> 00:16:42,640 in the pancreas in order to produce more insulin naturally. 362 00:16:42,640 --> 00:16:45,040 Alternatively, there are medications 363 00:16:45,040 --> 00:16:47,200 that will block gluconeogenesis and thus 364 00:16:47,200 --> 00:16:50,350 stop the ability of the liver and other gluconeogenic organs 365 00:16:50,350 --> 00:16:52,390 from producing glucose. 366 00:16:52,390 --> 00:16:55,090 So by blocking gluconeogenesis, one 367 00:16:55,090 --> 00:16:57,910 can lower the glucose concentration of the blood. 368 00:16:57,910 --> 00:17:01,930 As you see there are many, many ways to treat this disease. 369 00:17:01,930 --> 00:17:05,650 Let me add that it can be a very debilitating disease, leading 370 00:17:05,650 --> 00:17:09,880 to blindness, amputation, and cardiovascular difficulties. 371 00:17:09,880 --> 00:17:12,130 It's a good idea to try to avoid the risk 372 00:17:12,130 --> 00:17:14,230 factors for this disease. 373 00:17:14,230 --> 00:17:16,089 It's not fully preventable at least 374 00:17:16,089 --> 00:17:19,300 in people who come from families in which nearly everybody gets 375 00:17:19,300 --> 00:17:21,369 it, for example, my situation. 376 00:17:21,369 --> 00:17:24,490 But by avoiding risk factors you can push off the date of onset 377 00:17:24,490 --> 00:17:26,417 by many years.