Current concept of type 2 DM

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Current concept of type 2 DM

  1. 1. Current Concepts of Type 2 DM 林文玉醫師 內科部新陳代謝內分泌科
  2. 2. Glucose Tolerance Categories 240 Diabetes Mellitus 220 200 180 Diabetes Mellitus 160 140 126 120 IFG Normal 100 80 Plasma glucose 60 (mg/dL) IGT Normal FPG 2-h PPG (OGTT)
  3. 3. mg/dl mg/d 100 108 144 160 200
  4. 4. Pathogenesis of type 2 diabetes: the triumvirate Insulin Resistance DeFronzo R A Diabetes 2009;58:773-795
  5. 5. Insulin Resistance Individuals destined to develop type 2 DM inherit a set of genes from their parents that make their tissues resistant to insulin. The epidemic of diabetes that has enveloped westernized countries is related to the epidemic of obesity and physical inactivity. DeFronzo R A Diabetes 2009;58:773-795
  6. 6. Euglycemic Hyperinsulinemic Clamp A prospective study carried out by Felber and colleages in Lausanne, Switzerland ( 1990 ). All subjects had a euglycemic hyperinsulinemic clamp to measure tissue sensitivity to insulin and OGTT to provide an overall measure of glucose homeostasis and β-cell function. The mean plasma glucose and insulin concentration during OGTT were 115 mg/dl and 62 μg/ml, while the mean rate of insulin stimulated glucose disposal (measured with a 40 mU/m² per min euglycemic insulin clamp ) was 265 mg/m² per minute. Obesity was associated with 29% decline in insulin sensitivity, but glucose tolerance remained perfectly normal….With time the obese NGT individuals progressed to IGT in association with a further 28% reduction in insulin sensitivity.
  7. 7. β-cell fails to compensate insulin resistance With time the β-cells cannot continue to produce these very large amounts of insulin and the obese IGT individuals progresses to overt diabetes. The decline in glucose tolerance is associated with a marked decrease in insulin secretion without further change in insulin sensitivity.
  8. 8. β-cell function Although the plasma insulin response to the development of insulin resistance typically increased during the nature history of type 2 dm, this does not mean that the β-cell is functioning normally. In SAM and VAGES studies, simply measuring the plasma insulin response to a glucose challenge does not provide a valid index of β-cell function. The β-cell responds to an increment in glucose (ΔG )with an increment in insulin (ΔI ). Thus the better measure of β-cell function is ΔI/ΔG. However, the β-cell also is very keenly aware of the body’s sensitivity to insulin and adjusts its secretion of insulin to maintain normoglycemia. Thus, the gold standard for measuring β-cell function is the insulin secretion/insulin sensitivity (ΔI/ΔG ÷IR ).
  9. 9. Natural history of type 2 diabetes DeFronzo R A Diabetes 2009;58:773-795
  10. 10. Insulin secretion/insulin resistance (disposition) index (ΔI/ΔG ÷ IR) in individuals with NGT, IGT, and type 2 diabetes (T2DM) as a function of the 2-h plasma glucose (PG) concentration in lean and obese subjects. Losing 2/3 of β-cell function at 2hr pc 120-140 mg/dl 80-85% loss of β-cell function at 2hrpc 180-199 DeFronzo R A Diabetes 2009;58:773-795
  11. 11. Natural log of the 2-h plasma glucose (PG) concentration versus natural log of the insulin secretion/insulin resistance index (measure of β-cell function). Biomedical phenomena DeFronzo R A Diabetes 2009;58:773-795
  12. 12. Natural History of Type 2 Diabetes Impaired glucose tolerance Undiagnosed diabetes Known diabetes Insulin resistance Insulin secretion Postprandial glucose Fasting glucose Microvascular complications Macrovascular complications Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789
  13. 13. Pre-diabetes In the DPP study, individuals with IGT and still had IGT 3 years later had a 7.9% incidence of background diabetic retinopathy at study end. Individuals with IGT progressed to diabetes after 3 years had a 12.6% incidence of BDR. Their A1cs were between 5.9 and 6.1%. Peripheral neuropathy in IGT as many as 5-10% individuals. DeFronzo R A Diabetes 2009;58:773-795
  14. 14. mg/dl mg/d 108 144 200
  15. 15. β-cell Failure
  16. 16. Pathogenesis of β cell failure Age ( Aging 1996;8:13-21, J Am geriatrics Soc 1982;30:562-567, Am j Physiol Endocrinol Metab 2003;284;E7-E12 ) Genes, clusters in families. – Type 2 diabetes runs in families. In part, this tendency is due to children learning bad habits — eating a poor diet, not exercising — from their parents. But there is also a genetic basis. In general, if you have type 2 diabetes, the risk of your child getting diabetes is 1 in 7 if you were diagnosed before age 50 and 1 in 13 if you were diagnosed after age 50. Some scientists believe that a child's risk is greater when the parent with type 2 diabetes is the mother. If both you and your partner have type 2 diabetes, your child's risk is about 1 in 2. ( from ADA ) – TCF7L2, T-allele of SNP rs7903146 is associated with impaired insulin secretion in vivo and reduced responsiveness to GLP-1. TCF7L2 encodes for a transcription factor involved in Wnt signaling, which plays a role in the regulation of β cell proliferation and insulin secretion. Insulin Resistance: the precise mechanism remains unknown.
  17. 17. Lipotoxicity   Excess deposition of fat ( LC-fatty acyl CoAs, diacylgycerol, and ceramide ) in liver and muscle has been shown to cause insulin resistance; deposition of fat in the β cell leads to impaired insulin secretion and β cell failure. Elevated plasma FFA levels impair insulin secretion, and this has been referred to as lipotoxicity.
  18. 18. Effect of physiological elevation (48 h) in the plasma FFA concentration (brought about by lipid infusion) on plasma C-peptide concentration (left) and insulin secretory response (deconvolution of the palsma C-peptide curve) (right) in offspring of two type 2 diabetic parents Impaired first and second phase C-peptide release after intralipid. Treatment with acipimox ( lower FFA ) improves insulin secretion. DeFronzo R A Diabetes 2009;58:773-795
  19. 19.   In vitro studies, human pancreas islets were incubated for48h in the presence of 2mmol/l FFA( oleate-to-palmitate 2:1 ), insulin secretion , especially the acute insulin response was markedly reduced. Exposure to FFA caused a marked a marked inhibition of insulin mRNA expression, glucosestimulated insulin secretion and reduction of islet insulin content. PPARr agonist prevented all of these deleterious effects of FFA.
  20. 20. Glucotoxicity  Chronically elevated plasma glucose levels impair β cell function, and this has been referred to as glucotoxicity.  Rosseti et al: partially pancreatectomized diabetic rats are characterized by severe defects in both first- and second-phase insulin secretion compared with control rats. Following treatment with phlorizin, an inhibitor of renal glucose transport, the plasma glucose profile was normalized, which was associated with restoration of both first-and second-phases of insulin. 投影片 19   In vitro studies with human islets, similar results. In rats, elevation of mean day-long plasma glucose concentration in vivo by as little as 16 mg/dl leads to a marked inhibition of glucose-stimulated insulin secretion.
  21. 21. Six biochemical pathways along which glucose metabolism can form ROS. Under physiologic conditions, glucose primarily undergoes glycolysis and oxidative phosphorylation . Robertson R P J. Biol. Chem. 2004;279:42351-42354
  22. 22. The glucotoxic effect on insulin gene expression via loss of PDX-1 and MafA. Robertson R P J. Biol. Chem. 2004;279:42351-42354
  23. 23. IAPP    Hypersecretion of islet amyloid polypeptide ( IAPP ), which is co-secreted in a one to one ratio with insulin, can lead to progressive β cell failure ( in rodents ). Chavez and colleagues: 150 baboons, 98% homology with the human genome. Relative amyloid area inversely correlates with HOMA- β. Insulin sensitizers leading to a reduction in insulin secretion would be expected to preserve β -cell function on a longterm base. Rosiglitazone protect human islets against IAPP toxicity by a PI-3K dependent pathway.
  24. 24. INCRETIN EFFECT ON INSULIN SECRETION IN HEALTHY SUBJECTS Oral Glucose Intravenous (IV) Glucose 2.0 C-peptide (nmol/L) Plasma Glucose (mg/dL) 200 100 0 1.5 Incretin Effect 1.0 0.5 0.0 0 60 Time (min) 120 180 0 60 120 Time (min) 180 N = 6; Mean ± SE; *P≤0.05 Source :Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.
  25. 25. LOSS OF INCRETIN EFFECT Control subjects (n=8) 60 Insulin (mU/l) 80 Insulin (mU/l) 80 People with Type 2 diabetes (n=14) 60 Incretin 40 effect 20 40 20 0 0 0 60 120 180 Time (min) 0 60 120 180 Time (min) Oral glucose load Intravenous glucose infusion Source : Nauck et al. Diabetologia. 1986
  26. 26. Incretins GLP-1 and GIP account for 90% of the incretin effect. In type 2 DM, there is a deficiency of GLP-1 and resistance to the action of GIP. The deficiency of GLP-1 can be observed in individuals with IGT and worsens progressively with progression to T2DM. Plasma levels of GIP are elevated in T2DM, yet circulating insulin levels are reduced. This can be interpreted as β-cell resistance to the stimulatory effect of GIP on insulin secretion. Tight glycemic control can restore GIP action. Thus β-cell resistance to GIP is a kind of glucotoxicity.
  27. 27. Insulin Resistance in liver      The brain has an obligate need for glucose and is responsible for~50% of glucose utilization under basal or fasting condition. The glucose demand is met, most from liver, to lesser extent from kidney. During overnight fast, the liver of nondiabetic subjects produces sugar at the rate of ~2mg/kg per min. In type 2 DM, the rate of basal HGP is increased , averaging ~2.5 mg/kg per min. In an average 80 kg person, this amounts to the addition of an extra 25-30 g of glucose to systemic circulation every night. The overproduction of glucose by the liver occurs in the presence of fasting plasma insulin levels that are increased 2.5 to 3.0X, indicating severe resistance to the suppressive effect of insulin.
  28. 28. Basal HGP (left) in control and type 2 diabetic (T2DM) subjects. DeFronzo R A Diabetes 2009;58:773-795
  29. 29. Acceleration of HGP Increased circulating glucagon levels and enhanced hepatic sensitivity to glucagon. Lipotoxicity: leading to increased expression and activity of phosphoenolpyruvate carboxykinase ( PEP-CK) and pyruvte carboxylase ( PC ), the rate limiting enzyme for gluconeogenesis. Glucotoxicity: leading to increased expression and activity of glucose-6-phosphatase, the rate limiting enzyme for glucose escape from liver.
  30. 30. Insulin Resistance in Muscle Original workup: euglycemic insulin clamp, tritiated glucose, femoral arterial and venous catheterization. Conclusion: muscle insulin resistance could account for over 85-90% of impairment in total body glucose disposal in type 2 DM subjects. The rate of insulin-stimulated glucose disposal remains 50% less than in normal control subjects. Impaired glucose transport and phosphorylation, reduced glycogen synthesis and decreased glucose oxidation.
  31. 31. Insulin-stimulated total body glucose uptake (left) and insulin-stimulated leg glucose uptake (right) in control (CON) and type 2 diabetic (T2DM) subjects . DeFronzo R A Diabetes 2009;58:773-795
  32. 32. Insulin Signal Transduction For insulin to work, it must first bind to and then activate the insulin receptor by phosphorylating key tyrosine residues on β chain. This results in the translocation of insulin receptor substrate( IRS)-1 to the plasma membrane. This leads to the activation of PI 3-kinase and Akt, resulting in glucose transport into the cell, activation of NO synthase with arterial vasodilation and stimulation of multiple intracellular metabolic processes. The defect in insulin signaling leads to decreased glucose transport, impaired release of NO with endothelial dysfunction…
  33. 33. In contrast to the severe defect in IRS-1 activation, mitogen-activated protein ( MAP) kinase pathway, which can be activated by Shc, is normally responsive to insulin. Activation of MAP kinase pathway leads to the activation of a number of intracellular pathways involved in inflammation, cellular proliferation and atherosclerosis. This, in part, explains the strong association between insulin resistance and atherosclerotic disease in nondiabetics and type 2 diabetics.
  34. 34. Relationship between impaired insulin signal transduction and accelerated atherogenesis in insulinresistant subjects, i.e., type 2 diabetes and obesity ? DeFronzo R A Diabetes 2009;58:773-795
  35. 35. There is only one class of oral antidiabetic drugs—TZDs– that simultaneously augment insulin signaling through IRS1 and inhibit the MAP kinase pathway. In CHICAGO and PERISCOPE study, pioglitazone halts the progression of carotid intima-media thickness and coronary atherosclerosis. PROactive study showed decreased 2nd end point of death, MI, and stroke by 16%, in pioglitazone group.
  36. 36. Hepatic glucose uptake in nondiabetic and diabetic (DIAB) subjects as a function of plasma glucose and insulin concentrations and route of glucose administration Insulin/Glucagon ratio DeFronzo R A Diabetes 2009;58:773-795
  37. 37. Fat cell (Dysharmonious Quartet )
  38. 38. Fat cells in type 2 diabetics are resistant to insulin’s antilipolytic effect, leading to day-long elevation of FFA. Dysfunctional fat cell produces excessive pro-inflammatory adipocytokines and indcing insulin resistance; and fails to secrete normal amounts of insulin-sensitizing adipocytokines such as adiponectin. Enlarged fat cells are insulin resistant, and have diminished capacity to store fat. When capacity is exceeded, lipid “overflow” into muscle, liver, and β cells. Lipid can also overflow into arterial vascular smooth muscles, leading to acceleration of atherosclerosis. DeFronzo R A Diabetes 2009;58:773-795
  39. 39. Randle Cycle
  40. 40. Liver steatosis
  41. 41. Effect of lipid infusion to cause a physiologicalpharmacological elevation in plasma FFA concentration on insulin signal transduction in healthy nondiabetic subjects. Under steady insulin infusion DeFronzo R A Diabetes 2009;58:773-795
  42. 42. PGC-1( PPAR coactivator 1 ) PGC-1 is the master regulator of mitochondrial biogenesis and augments the expression of multiple genes involved inithochondrial oxidative phosphorylation. Pioglitazone reduced intramyocellular lipid and fatty acyl CoA content was closely related to the improvement in insulinstimulated muscle glucose disposal. 48hr-Lipid infusion, incresing plasma FFA ~1.5 to 2.0X, inhibited the expression of PGC1α, PGC1 β, PDHA1 and multiple mitochondrial genes ( oxidative phosphorylation ) in muscle.
  43. 43. GI tract, the incretin effect (Quntessential Quintet )
  44. 44. Hepatic glucose uptake in nondiabetic and diabetic (DIAB) subjects as a function of plasma glucose and insulin concentrations and route of glucose administration Insulin/Glucagon ratio Approximately one half of the suppression of HGP following mixed meal is secondary to inhibition of glucagon secretion, The other one half is secondary to the increase in insulin secretion DeFronzo R A Diabetes 2009;58:773-795
  45. 45. Incretins
  46. 46. Because of its short half-life, native GLP-1 has limited clinical value DPP-IV i.v. bolus GLP-1 (15 nmol/l) 7 9 Val Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu Phe 37 Ile Ala Trp Leu Val Lys Gly Arg Gly Intact GLP-1 (pmol/l) 1000 His Ala Glu Gly Thr Phe Thr Ser Asp Healthy individuals Type 2 diabetes 500 0 –5 5 15 25 35 45 Time (min) Enzymatic cleavage High clearance (4–9 l/min) t½ = 1.5–2.1 minutes (i.v. bolus 2.5–25.0 nmol/l) Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.
  47. 47. GLP-1 enhancement GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life Add GLP-1 analogues with longer half-life: • exenatide • liraglutide Injectables Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003 Block DPP-4, the enzyme that degrades GLP-1: • Sitagliptin • Vildagliptin • Linagliptin Oral agents
  48. 48. Exenatide Trial 6-h meal tolerance test with double tracer technique (1-14Cglucose orally and 3-3H-glucose IV ) before and after 2 weeks of exenatide treatment. Findings: the increment in insulin secretory rate divided by the increment in plasma glucose increased more than 2X, demonstrating a potent stimulatory effect of β -cell function. The increase in insulin secretion, in concert with a decline in glucagon release, led to a significant reduction in HGP. Exenatide has no effect on delayed gastric emptying.
  49. 49. Alfa cell: role of glucagon ( Setaceous sextet ) The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 1 January 2012
  50. 50. Glucagon (pg/ml) Hyperglucagonemia through-out the day in people with type 2 diabetes Time Time Reaven et al. J. Clin. Endo. & Metab. 1987
  51. 51. Lowered glucose in glucagon receptor knockout mice Blood glucose (ad lib fed) *** *** *** 5.0 2.5 0.0 700 1000 1600 2000 Time of Day *** ** ** 18 Blood Glucose (mM) Blood Glucose (mM) ** 15 6 1000 * 12 9 AUC 1500 10.0 7.5 IP-GTT ** *** 500 0 GR+/+GR-/- ** ** * 3 0 2400 0 GR+/+ 25 50 75 100 125 Time (min) GR-/- RW Gelling et al. PNAS 100: 1438-1443, 2003
  52. 52. Inhibition of glucagon activity in hGCGR mice. hGCGR mice were dosed with vehicle (Veh) or Cpd 1 at 15 and 50 mg/kg (mpk) in the same vehicle via an intraperitoneal injection 1 h before glucagon challenge. Qureshi S A et al. Diabetes 2004;53:3267-3273
  53. 53. Renal Glucose Reabsorption The kidney filters ~ 162g ( GFR = 180 l/d X fasting plasma glucose 900 mg/l ) of glucose every day.
  54. 54. Targeting the Kidney Proximal tubule Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.
  55. 55. SGLT 2 transporter mRNA (left) and protein (middle) and glucose transport (α-methyl-d-glucopyranoside) (right) are increased in cultured renal proximal tubular epithelial cells of individuals with type 2 diabetes (T2DM) versus nondiabetic subjects (CON). DeFronzo R A Diabetes 2009;58:773-795
  56. 56. An adaptive response by the kidney to conserve glucose, which is essential to meet the energy demands of the body, especially the brain and other neural tissues, which have obligate need for glucose, becomes maladaptive in the diabetic patients.
  57. 57. Apple tree to SGLT2i John R. White, Jr., PA, PharmD CLINICAL DIABETES • Volume 28, Number 1, 2010     In 1835, French chemists isolated a substance, phlorizin, from the bark of apple trees. The compound was bitter in flavor and reminded them of similar extracts from the cinchona and willow tree and for a time was referred to as the “glycoside from the bark of apple trees.” Although the best thinking at the time concluded that phlorizin was a reasonable candidate for the treatment of fevers, infectious disease, and malaria, within 50 years, it was discovered that high doses of phlorizin caused glucosuria. Ultimately, it was determined that chronic administration of phlorizin in the canine model produced many of the same symptoms as observed in human diabetes (glucosuria, polyuria, and weight loss). Thus, the phlorizininduced diabetes animal model was proposed and utilized in the early 1900s ( Now Streptozotocin ). During the next several decades, phlorizin continued to be used in trials evaluating renal physiology. By the early 1970s, research with phlorizin revealed the location (proximal tubule brush border) of the active-transport system responsible for glucose reabsorption and that phlorizin had a much higher affinity for these transporters than did glucose. There was a resurgence of interest in phlorizin in the late 1980s to early 1990s concurrent with the characterization of SGLTs and the realization of a potential novel mechanism for reducing hyperglycemia. Animal studies carried out in 90% pancreatectomized diabetic rats demonstrated that phlorizin-induced glucosuria normalized fasting and postprandial glucose levels and reversed insulin resistance. Additionally, phlorizin administration was associated with reversal of first- and second-phase insulin secretory defects in this model
  58. 58. Invokana (canagliflozin)    Invokava™, canagliflozin, is a new once daily alternative for the maintenance treatment of Type 2 diabetes mellitus. Canagliflozin is the first and only medication in the class of Sodiumglucose co-transporter 2 (SGLT2) inhibitor. Usual dose is 100 mg orally once daily initially  May increase to 300 mg once daily  Max dose of 100 mg daily is recommended for GFR of 45-59 mL/min   Canagliflozin use may result in increased genitial mycotic infections Canagliflozin may have a place in therapy as a new third-line agent after metformin and sulfonylurea failure (possibly in front of DPP-IV inhibitors like sitagliptin).
  59. 59. The brain Ominous octet
  60. 60. 肚子餓很快吃得很急飽得很慢永遠覺得吃很少    Porte and colleagues: insulin was a powerful appetite suppressor. Even with compensatory hyperinsulinemia, food intake is increased in obese subjects and type 2 diabetics. That is to say, insulin resistance in peripheral tissues also extends to the brain. Functional MRI to localize areas responsible for impaired insulin regulation. After glucose ingestion, two hypothalamic areas with consistent inhibition were noted: VM nuclei and paraventricular nuclei ( appetite regulation center ). The inhibitory response was reduced in obese, insulin resistant, normal glucose tolerant subjects. And there was a delay in the time taken to reach maximal inhibitory response.
  61. 61. The ominous octet. DeFronzo R A Diabetes 2009;58:773-795
  62. 62. Treatment of type 2 diabetes: a therapeutic approach based upon pathophysiology. DeFronzo R A Diabetes 2009;58:773-795
  63. 63. Thanks for your Attention

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