BMS200 Week 1 Diabetes 2.pdf

Pathogenesis of Diabetes, Part 2 BMS 200 Week 1 The twin cycle hypothesis and T2DM What is the general model? What are the two cycles? Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 Background to the twin cycle hypothesis T...

Pathogenesis of Diabetes, Part 2 BMS 200 Week 1 The twin cycle hypothesis and T2DM What is the general model? What are the two cycles? Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 Background to the twin cycle hypothesis T2DM is thought to develop after many years of insulin resistance ▪ Key aspect of the transition from early insulin resistance to loss of beta cell mass is dysregulated lipid and glucose metabolism across multiple different organs Liver, muscle, pancreas, skeletal muscle, visceral adipose tissue, subcutaneous adipose tissue The twin cycle begins with early insulin resistance ▪ Easier to understand in a setting with: Excess caloric intake (exacerbated by leptin resistance, biopsychosocial factors… etc.) Impaired ability to “clear” nutrients by skeletal muscle The twin cycle hypothesis and T2DM Start here! Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 The “first” cycle – the liver Studies in humans seem to indicate that diabetic patients have a “tipping point”, where normal energy storage options are saturated Where should we store our energy? ▪ Lots in subcutaneous fat ▪ Some in muscle (what is the energy storage form?) ▪ Some in the liver (what is the energy storage form?) ▪ A bit in visceral fat Sensitive, effective insulin receptors aid “normal” energy storage in these “healthy” energy depots Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 The “first” cycle – the liver In the setting of positive energy/calorie balance and constant, “longer-term” insulin secretion, skeletal muscle and subcutaneous fat begins to experience insulin resistance ▪ This is the beginning of the first cycle Circulating nutrients – in particular glucose – remain in the bloodstream longer AND adipose tissue loses some of its ability to convert these calories into stored triglycerides (due to insulin resistance) ▪ The result is an increase in circulating free fatty acids (FFA) for long periods of time throughout the day Elevated FFAs then have to be dealt with by the liver Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201  The “first” cycle – the liver The liver seems to have 3 major options when it is “drowning” in these elevated levels of FFAs ▪ Burn the energy – (beta oxidation) ▪ Store the energy – hepatic steatosis (not good) ▪ Export the energy – VLDL production Recall – what are the characteristics of VLDL? What is its goal? What is its life cycle? Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 Summary –Endogenous Pathway Endogenous HDL Lipoprotein Liver synthesis Apoproteins Initial VLDL lipoprotein (ApoB-100, ApoA-V, from HDL (key ApoC-II) apoproteins) IDL LDL Intermediat IDL (ApoE, ApoB- VLDL e 100) lipoproteins  VLDL (key LDL (ApoB-100) apoproteins) LDL Cleared by Liver IDL (clearance (LDL receptor for B- mechanism) 100, ApoE clearance) Function Carry liver- synthesized lipids to other cells The twin cycle hypothesis and T2DM Step 2 Start here! Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 The “first” cycle – the liver Insulin resistance isn’t just “shutting insulin off” ▪ It’s an imbalance in the see-saw between glucagon and insulin signaling – which is especially important when considering liver physiology In those with longer-term insulin resistance/T2DM, the liver accumulates lipid (steatosis) and this may exacerbate insulin resistance in hepatocytes ▪ Steatosis → Inappropriate gluconeogenesis → increased blood glucose → increased pancreatic insulin secretion… ▪ You end up with the strange metabolic situation of fat accumulation in hepatocytes, increased VLDL export (both “insulin-driven” functions) and decreased ability of the liver to shut off gluconeogenesis (“glucagon- driven” function) Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 The “first” cycle – the liver Don’t forget the role of elevated circulating FFAs (from insulin-resistant adipocytes) ▪ The body has no choice but to deal with these – we don’t have an “energy excretion” mechanism ▪ The hepatocytes tend to take these FFAs out of circulation and “repackage” them as triglycerides in VLDL or incorporate them as lipid droplets – this activity is enhanced in T2DM ▪ Elevation of FFAs (in particular palmitic acid) activates TLRs and seems to exacerbate insulin resistance and “stress” the cell out Many of those with the metabolic syndrome/T2DM have “ectopic” deposition of fat oectopic: occurring in an abnormal ▪ Within skeletal muscle position or in an unusual manner or form ▪ Within the pancreas → next cycle Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 The twin cycle hypothesis and T2DM Step 2 Start here! Step 3 Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 The “second” cycle – the pancreas The changes to the pancreas in T2DM have been the most poorly characterized… until recently ▪ Pancreas is very “deep” in the body, hard to assess, hard to biopsy, and there has always been a conceptual “block” → The acinar cells and > 95% of pancreatic tissue don’t matter in T2DM… it’s all about the islets? Bad assump- ▪ Studies that examine the degree of adiposity tion? and fibrosis in the islets AND the surrounding acinar cells suggest that the pancreas is an important player – “the second cycle” Intrapancreatic fat accumulation is common in those with T2DM, and reversal of T2DM is associated with large decreases in pancreatic fat Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 The “second” cycle – the pancreas The liver delivers excess TGs (via VLDL) to the pancreas ▪ Linked to fibrosis and fatty accumulation in the pancreas in general (around acinar cells) ▪ Linked to accumulation of palmitic acid (FFA) in islet cells, specifically pancreatic beta-cells What are the consequences of “fatty pancreas”? ▪ Initially hypothesized to be apoptosis of beta-cells over time Increased ER stress, ROS production, apoptosis of beta cells “beta cell burnout” due to continuous insulin production This may be true Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 The “second” cycle – the pancreas What are the consequences of “fatty pancreas”? ▪ There are other possibilities beyond apoptosis – beta cell de-differentiation ▪ In animal and in vitro studies, excess fat and highly excessive glucose lead to beta cells that act more like alpha cells What does an alpha cell secrete? ▪ This is being intensely studied right now in humans Whatever the cause of beta cell dysfunction, resolution of fat deposition and fibrosis in the pancreas (as assessed by MRI) seems to be improved with dietary restriction and the resolution of T2DM, and is linked with resolution of hepatic steatosis Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 The twin cycle hypothesis and T2DM Step 2 Start here! Step 3 Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 Note the positive feedback loop Insulin resistance → increased hepatic steatosis and VLDL output → TG and FFA accumulation in the pancreas → compromised insulin secretion (impaired ability to secrete large, immediate “pulses of insulin) → hyperglycemia → conversion to fat, increased circulating FFAs… Elevations in VLDL and the general inflammation associated with T2DM… ▪ Describe the likely impact on atherosclerosis glucose sticky , glues the fat  Endogenous pathway (review slide) Initial lipoprotein: VLDL is synthesized by the liver – contains mostly TGs but also contains phospholipids, cholesteryl esters, vitamin E Contain ApoC-II and ApoA-V – these are important for the activity of LPL in peripheral tissues → as LPL “drains” triglycerides from VLDL, it becomes IDL and then LDL Also contains ApoB-100 – major structural protein and allows later clearance by the liver Intermediate forms: As TGs are removed from VLDL it becomes IDL – most IDL is cleared by the liver via ApoE binding to the LDL receptor (ApoE was transferred via HDL particles) IDL that loses TGs and becomes more and more cholesterol-rich becomes LDL LDL is cleared by the LDL receptor, and seems to have no useful physiologic role LDL receptor can bind to both ApoE and ApoB-100 Cleared by: Liver clears IDL and LDL via the LDL receptor on hepatocytes LDL receptor can bind to either ApoE or ApoB-100 If LDL is not cleared, it can become oxidized and becomes a major risk factor for the development of atherosclerosis Subcutaneous fat “saturation” Adipose tissue cannot take all the fat (VLDL) out of circulation – everyone has a limit ▪ Determined by genetics, sex, age In the setting of insulin resistance, the adipocytes are less able to build triglycerides, and instead release FFAs Our subcutaneous fat mass seems to be “good at” secreting adiponectin ▪ For reasons that are not clear, the subcutaneous fat store secretion of adiponectin cannot “keep up” with the secretion of leptin (from visceral and subcutaneous fat) ▪ In insulin resistance/T2DM, the ratio of leptin:adiponectin is increased… but many are resistant to leptin, so food intake becomes more poorly regulated The twin cycle hypothesis and T2DM That is a very detailed… and therefore hard-to-prove… hypothesis ▪ What is the evidence? ▪ How would we test it? With successful T2DM treatment do we observe: ▪ Improvement in fatty liver? ▪ Improvement in fatty pancreas? ▪ Weight loss? ▪ A drop in serum triglycerides? You would think that in long-term T2DM – when the vast majority of the pancreatic beta cell mass has been exhausted – the “twin cycles” would be difficult to stop Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 DiRECT trial in the UK 306 T2DM patients subjected to intense weight- loss program, supervised by dieticians and nurses ▪ All antihypertensive and antidiabetic meds stopped on first day of the trial, plus: 825 – 853 kcal/day for 3 months Structured food “reintroduction” to a more sustainable caloric content over the next 1 – 2 months ▪ Had to have been diagnosed with T2DM within the last 5 years (no long-term T2DM) ▪ Open-label study… but it got published in the Lancet (high-impact journal) because of the impressive results Al-Mrabeh, Card. Endo. Metab 2020, 9:132-142; doi: 10.1097/XCE.0000000000000201 https://doi.org/10.1016/S0140-6736(17)33102-1  DiRECT trial in the UK Results: 149 with dietary intervention, 149 control At 12 months, weight loss of 15 kg or more in 36 (24%) participants in the intervention group and no participants in the control group (p