Diabetes Mellitus Dr. CAI Mengyin Department of Endocrinology 3 rd  Affiliated Hospital Sun Yat-sen University
<ul><li>Populous country with westernized lifestyle </li></ul><ul><li>Limited resources for healthcare expenditure </li></...
Economy taking-off like a rocket  with dramatic lifestyle change State “on Bicycle” Traffic jam in Beijing Coupon for food...
Prevalence rate of Diabetes Throughout the world: 150 millions ? 2% USA: 15 millions China:  9.7 % --  N Engl J Med 2010;3...
What is Diabetes Mellitus? Definition: Syndrome Metabolic disorder of multiple etiology (causes) characterized by hypergly...
Hyperglycemia X or Metabolic Syndrome Metabolic abnormalities and by long-term  complications involving  eyes, kidneys, ne...
Genetic factors Environmental factors Chinese  population  9% Monogenic Polygenic Aging Lifestyle Infections Diabetes Typ...
Defect of β Cell in Insulin Secretion & Action
Non - diabetes Pre - diabetes Diabetes IGT/IFG Fasting plasma  glucose Insulin  requirement Insulin  production <6.1mmol/L...
Derangements are due to relative or absolute insulin deficiency and glucagon excessiveness. Normally, it is a rise in the ...
 
Spectrum of Diabetes Mellitus Insulin receptor gene mutations (<1%) Insulin gene mutations (<1%) Mitochondrial gene mutati...
1  yr 10  yr 21  yr 32  yr 45  yr 60  yr Age at diagnosis TYPE1 TYPE2 MODY LADA MIDD DIDMOAD ? Variable Faces of Diabetes ...
Type 1 diabetes mellitus Usually onset before age of 40.  In USA, peak incidence is around 14 years old.  Onset of symptom...
Type 2 Diabetes Mellitus Usually  starts in middle age or older.  Symptoms begin more gradually than in type 1 diabetes, a...
Type 1 vs. Type 2 Type 1 Type 2 Age of onset Childhood, young adult Adulthood, elder people Body cells Responsive to insul...
 
Maturity-onset diabetes of the young (MODY) 45 33 22 12 16 17 10 INS OHA OHA DIET DIET DIET INS Classical MODY-criteria: 1...
History of MODY genes MODY2 GCK MODY1 Linkage to chr20 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 MODY2 Linkage to ...
 
Severe insulin resistance syndrome Insulin signaling associated mutation Lypodystrophy syndrome linked mutation Other gene...
Type A insulin resistance syndrome <ul><li>Autosomal recessive inheritance  </li></ul><ul><li>Autosomal dominant inheritan...
Sequencing of IR exon20 Black Arrow : P1174W Green Arrow : P1178P Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. E...
Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. Epub 2009 Jan 19.
HGPS, RD the  “most”  complicated and lethal type of laminopathies HGPS RD Hum Mol Genet, 2004, 13: 2493-2503. N Engl Med,...
In some other secondary identifiable condition, a diabetic syndrome can develop <ul><ul><li>Pancreatic diseases,  pancreat...
Gestational Diabetes Mellitus ◆  Definition: Carbohydrates intolerance of variable severity with  onset or first recogniti...
Clinical manifestation   The manifestations of symptomatic diabetes mellitus vary from patient to patient.  Most often med...
But, the first event may be an acute metabolic decompensation resulting in diabetic coma. More occasionally, the initial e...
Classifications of Diabetic Vascular Disease <ul><li>Macrovascular disease:  an accelerated form of athersclerosis, accoun...
Increased coagulability Platelet hypersensitivity Increased blood viscosity Impaired microvascular flow Increased microvas...
<ul><li>Microaneurysms </li></ul><ul><li>Scattered exudates </li></ul><ul><li>Haemorrhages </li></ul><ul><ul><li>Flame-sha...
Background Proliferative Diabetic Retinopathy
Diabetic Nephropathy <ul><li>※ Mechanism : thickening of capillary basement membranes and of the mesangium of renal glomer...
Diabetic Neuropathy <ul><li>Peripheral neuropathy </li></ul><ul><ul><li>Distal, symmetric sensory loss </li></ul></ul><ul>...
Limited joint mobility Motor damage  Sensory damage  Autonomic damage Microcirculatory disease Macrovascular disease Diabe...
Foot ulceration Charcot arthropathy Diabetic Foot
Laboratory Findings <ul><li>◇   Analysis of urine glucose : </li></ul><ul><ul><li>Factors affecting the result: </li></ul>...
<ul><li>◇  Blood glucose testing: </li></ul><ul><ul><li>venous blood sample for diagnosis </li></ul></ul><ul><ul><li>capil...
Insulin (mU/L) 30  60  90  120  150  180  210  min  T2DM Normal T1DM <ul><li>◇  Serum insulin concentration: </li></ul><ul...
C peptide A chain B chain <ul><li>◇  Serum C peptide concentration: </li></ul><ul><ul><li>in equimolar amounts with insuli...
Diagnosis of Diabetes Mellitus <ul><li>Symptoms of diabetes plus a random plasma glucose concetration >11.1 mmol/L. </li><...
Treatment of Diabetes Mellitus Management Goals <ul><li>Obtain optimal glycemic control </li></ul><ul><li>Prevent and reta...
LDL-c mmol/L <2.5 2.5-4.4 >4.5 ★ According to UKPDS data . Targets for Diabetic Control Good Moderate Poor FPG mmol/L 4.4-...
Major Therapeutic Trials 1 <ul><li>DCCT (Diabetes Control & Complications Trial) 1983-1993 </li></ul><ul><li>1441 Type 1 p...
Major Therapeutic Trials 2 <ul><li>UKPDS (UK Prospective Diabetes Study) 1977-1997 </li></ul><ul><li>5102 newly diagnosed ...
<ul><li>◆   Set total calorie Intake </li></ul><ul><ul><ul><ul><ul><li>according to ideal body weight (IBW) and working st...
Food Pyramid <ul><li>Food Group/Servings </li></ul><ul><li>starch 6 - 11  </li></ul><ul><li>vegetable 3 - 5  </li></ul><ul...
Physical Activities <ul><li>◇ Benefits: </li></ul><ul><ul><li>※ Lowers glucose levels in blood </li></ul></ul><ul><ul><li>...
Exercise Guidelines ※   Monitor BG before and after exercise. ※ Avoid exercise if BG >250 mg/dl, ketones present. ※   Use ...
Oral Hypoglycemic Agents
Sulphonylureas <ul><li>Mode of action: </li></ul><ul><li>Increase pancreatic insulin secretion  </li></ul><ul><li>May impr...
Sulfonylurea Activates Insulin Secretion Small figure shows the site of action.
<ul><li>◇ Contra-indications :  </li></ul><ul><ul><li>pregnancy, surgery, severe renal failure, </li></ul></ul><ul><ul><li...
Secondary Failure <ul><li>Secondary failure rate 5% to 10% a year (UKPDS 7% a year) </li></ul><ul><ul><li>Decreasing β-cel...
Biguanides (Metformin) Mode of action: ◇ reduces hepatic glucose production ◇ decreased intestinal absorption of glucose ◇...
Precautions:   ● chronic renal or cardiac failure    ● hepatic impairment   ● elderly   ● excessive alcohol intake Side ef...
Alpha Glucosidase Inhibitor  (Acarbose) <ul><li>Mode of action: </li></ul><ul><ul><li>Delays breakdown of CHO such as star...
Thiazolidinedione <ul><li>Mode of action: </li></ul><ul><li>Peroxisome proliferator-activated receptor gamma agonist (PPAR...
Insulin <ul><li>Indications: </li></ul><ul><ul><li>Type 1 diabetes  </li></ul></ul><ul><ul><li>Type 2 diabetes whose hyper...
Insulin preparations and time of reaching peak and duration
Lipoatrophy due to long term injection of ‘impure’ insulin preparations.
Novopen Inhaled insulin Insulin pump
Oral Agents + Insulin in Type 2 Diabetes <ul><li>Simplifies insulin regimen </li></ul><ul><li>Improves glycemic control </...
Diabetic Ketoacidosis Presentation Physical examination Laboratory results Polyuria, polydipsia Nausea, vomiting Diarrhea,...
Precipitating Factors of DKA <ul><li>Noncompliance with medication </li></ul><ul><li>Infection  </li></ul><ul><li>myocardi...
Treatment of DKA – IV fluid Normal saline 1 liter/hr until not orthostatic hypotensive,  then  NS at 500 ml/hr Electrolyte...
Treatment of DKA – Insulin IV insulin at 5-10 u/hr in adult, 0.1 u/kg/hr in child Check glucose hourly, if no change in 2 ...
Treatment of DKA – Potassium Potassium repletion if initial K is normal or low at 10-40 mEq/hr Check potassium every 2- 4 ...
Treatment of DKA – Bicarbonate, Phosphorus Bicarbonate replacement if pH less than 6.90 Check phosphorus 12 hrs into treat...
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C:\documents and settings\administrator\桌面\35 ndiabetes mellitus

  1. 1. Diabetes Mellitus Dr. CAI Mengyin Department of Endocrinology 3 rd Affiliated Hospital Sun Yat-sen University
  2. 2. <ul><li>Populous country with westernized lifestyle </li></ul><ul><li>Limited resources for healthcare expenditure </li></ul><ul><li>Increasing prevalence of obesity </li></ul>The official mascots of the Beijing 2008 Olympic Games Populous country with obesity pandemic Asia countries are facing challenge from Diabetes
  3. 3. Economy taking-off like a rocket with dramatic lifestyle change State “on Bicycle” Traffic jam in Beijing Coupon for food in Guangzhou One week’s food for a family in Beijing Exercise less Eat More
  4. 4. Prevalence rate of Diabetes Throughout the world: 150 millions ? 2% USA: 15 millions China: 9.7 % -- N Engl J Med 2010;362:1090-101. China: 1980 0.609% in 304537 Canton: 1980 0.411% in 42788
  5. 5. What is Diabetes Mellitus? Definition: Syndrome Metabolic disorder of multiple etiology (causes) characterized by hyperglycemia with carbohydrates, fat, and protein metabolic alterations, which result in defects in the secretion or action of insulin, or both.
  6. 6. Hyperglycemia X or Metabolic Syndrome Metabolic abnormalities and by long-term complications involving eyes, kidneys, nerves, and blood vessels Acute complications: diabetic ketoacidosis, hyperosmolar nonketotic diabetic coma. homogenous Heterogeneous
  7. 7. Genetic factors Environmental factors Chinese population  9% Monogenic Polygenic Aging Lifestyle Infections Diabetes Type I <10% Type II >90% Etiology and Development
  8. 8. Defect of β Cell in Insulin Secretion & Action
  9. 9. Non - diabetes Pre - diabetes Diabetes IGT/IFG Fasting plasma glucose Insulin requirement Insulin production <6.1mmol/L >7.0 mmol/L
  10. 10. Derangements are due to relative or absolute insulin deficiency and glucagon excessiveness. Normally, it is a rise in the molar ratio of glucagon to insulin which leads to diabetic decompensation . Why does metabolic derangement happen?
  11. 12. Spectrum of Diabetes Mellitus Insulin receptor gene mutations (<1%) Insulin gene mutations (<1%) Mitochondrial gene mutations (2%) Type 2 (70%) Type 1 (10%) LADA (10-12% ?) MODY (2-4% ?)
  12. 13. 1 yr 10 yr 21 yr 32 yr 45 yr 60 yr Age at diagnosis TYPE1 TYPE2 MODY LADA MIDD DIDMOAD ? Variable Faces of Diabetes Mellitus
  13. 14. Type 1 diabetes mellitus Usually onset before age of 40. In USA, peak incidence is around 14 years old. Onset of symptoms may be abrupt, with thirst, excessive urination, increased appetite and weight loss developing over a several-day period. In some cases, the disease is heralded by the appearance of DKA during and intercurrent illness or following surgery.
  14. 15. Type 2 Diabetes Mellitus Usually starts in middle age or older. Symptoms begin more gradually than in type 1 diabetes, and diagnosis is frequently made when an asymptomatic person is found to have an elevated plasma glucose on routine lab. Exam..
  15. 16. Type 1 vs. Type 2 Type 1 Type 2 Age of onset Childhood, young adult Adulthood, elder people Body cells Responsive to insulin Resistant to insulin Autoantibodies Positive Negative Body fatness Low to average High Endogenous insulin Little or none Normal or too much Pancreatic function Beta cells not functional Beta cell normal Severity of symptoms Severe; liable to DKA Mild; few or none, not liable to DKA Insulin shots? Yes, indispensable Not during early and middle stage Drugs? Not solely Yes
  16. 18. Maturity-onset diabetes of the young (MODY) 45 33 22 12 16 17 10 INS OHA OHA DIET DIET DIET INS Classical MODY-criteria: 1. Two patients diagnosed with diabetes before the age 25 years. 2. Autosomal dominant inheritance of diabetes (  3 generations) Note: Yellow figures indicating ages at on-set.
  17. 19. History of MODY genes MODY2 GCK MODY1 Linkage to chr20 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 MODY2 Linkage to chr7 MODY3 Linkage to chr12 MODY3 HNF-1  MODY1 HNF-4  MODY5 HNF-1  MODY4 IPF1
  18. 21. Severe insulin resistance syndrome Insulin signaling associated mutation Lypodystrophy syndrome linked mutation Other gene IR gene AKT2 gene BSCL FPLD MAD CaR gene AGPAT2 gene Seipin gene LMNA PPARγ gene LMNA ZMPSTE24 gene
  19. 22. Type A insulin resistance syndrome <ul><li>Autosomal recessive inheritance </li></ul><ul><li>Autosomal dominant inheritance </li></ul><ul><li>Penetrance is not constant </li></ul>
  20. 23. Sequencing of IR exon20 Black Arrow : P1174W Green Arrow : P1178P Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. Epub 2009 Jan 19.
  21. 24. Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. Epub 2009 Jan 19.
  22. 25. HGPS, RD the “most” complicated and lethal type of laminopathies HGPS RD Hum Mol Genet, 2004, 13: 2493-2503. N Engl Med, 2008,358: 552-555.
  23. 26. In some other secondary identifiable condition, a diabetic syndrome can develop <ul><ul><li>Pancreatic diseases, pancreatitis </li></ul></ul><ul><ul><li>Hormonal causes: pheochromocytoma, acromegaly, </li></ul></ul><ul><ul><li>Cushing syndrome and therapeutic administration </li></ul></ul><ul><ul><li>Stress hyperglycemia: severe burns, acute myocardial </li></ul></ul><ul><ul><li>infarctions and other life-threatening illnesses </li></ul></ul>Mechanism of Stress of Hyperglycemia <ul><ul><li>Endogenous release of glucagon and catecholamines </li></ul></ul><ul><li>Combinations of impairment of insulin release and induction </li></ul><ul><li>of insulin resistance </li></ul>
  24. 27. Gestational Diabetes Mellitus ◆ Definition: Carbohydrates intolerance of variable severity with onset or first recognition during pregnancy ◆ Screening: American Diabetic Association(ADA) Recommend screening all pregnant women at 24-26 wks using 50g oral glucose test with 1 hour blood glucose value of 140mg or more as an indication for standard oral glucose tolerance test. No stipulations as to the time of last meal.
  25. 28. Clinical manifestation The manifestations of symptomatic diabetes mellitus vary from patient to patient. Most often medical help is sought because of symptoms related to hyperglycemia: polyuria, polydipsia, polyphagia.
  26. 29. But, the first event may be an acute metabolic decompensation resulting in diabetic coma. More occasionally, the initial expression can be a degenerative complication such as neuropathy in the absence of symptomatic hyperglycemia.
  27. 30. Classifications of Diabetic Vascular Disease <ul><li>Macrovascular disease: an accelerated form of athersclerosis, accounts for the increased incidence of myocardial infarction, stroke and peripheral gangrene . </li></ul><ul><li>B. Microvascular disease: basement membrane thickening of the small blood vessles, the capillary and the precapillary arteriols, involving the retina leads to diabetic retinopathy, the kindney causes diabetic nephropathy, also the heart, resulting in the cardiomegaly with heart failure in diabetic patients. </li></ul>
  28. 31. Increased coagulability Platelet hypersensitivity Increased blood viscosity Impaired microvascular flow Increased microvascular pressure and flow Microvascular sclerosis Limitation of maximum perfusion Failure of autoregulation Raised capillary pressure Tissue damage Hypothesis for Diabetic Microangiopathy
  29. 32. <ul><li>Microaneurysms </li></ul><ul><li>Scattered exudates </li></ul><ul><li>Haemorrhages </li></ul><ul><ul><li>Flame-shaped </li></ul></ul><ul><ul><li>Dot and blot </li></ul></ul><ul><li>Cotton-wool spots(<5) </li></ul><ul><li>Venous dilatation </li></ul>Background <ul><li>Rapid increase in microaneurysm count </li></ul><ul><li>Multiple haemorrhages </li></ul><ul><li>Cotton-wool spots(>5) </li></ul><ul><li>Venous beading, looping and duplication </li></ul>Preproliferative <ul><li>New vessels </li></ul><ul><li>On disc (NVD) </li></ul><ul><li>Elsewhere (NVE) </li></ul><ul><li>Fibrous proliferation </li></ul><ul><li>On disc (FPD) </li></ul><ul><li>Elsewhere (FPE) </li></ul><ul><li>Haemorrhages </li></ul><ul><li>Preretinal </li></ul><ul><li>Vitreous </li></ul>Proliferative <ul><li>Retinal </li></ul><ul><li>detachment </li></ul><ul><li>Rubeosis </li></ul><ul><li>iridis </li></ul><ul><li>Neovascular </li></ul><ul><li>glaucoma </li></ul>Advanced diabetic eye disease <ul><li>Macular oedema </li></ul><ul><li>Focal </li></ul><ul><li>Diffuse </li></ul><ul><li>Ischaemic maculopathy </li></ul>Maculopathy Stages of Diabetic Retinopathy
  30. 33. Background Proliferative Diabetic Retinopathy
  31. 34. Diabetic Nephropathy <ul><li>※ Mechanism : thickening of capillary basement membranes and of the mesangium of renal glomeruli, produces varying degrees of glomerulosclerosis and renal insufficiency. Proteinurea is the initial manifestation. </li></ul><ul><li>※ Natural history : </li></ul><ul><ul><li>Initial stage of normoalbuminuria : enlargement of the kidney with increased filtration rate, but the urinary albumin excretion rate (AER) is within the normal range (<15 ug/min). </li></ul></ul><ul><ul><li>Microalbuminuria : 20 ug/min <AER<200 ug/min. </li></ul></ul><ul><ul><li>Clinical proteinuria : AER>200 ug/min (or 300 mg/24hr), dip-stick-positive proteinuria. </li></ul></ul><ul><ul><li>End-stage renal disease : renal dysfunction with increased serum creatine level, edema, hypertension, etc. </li></ul></ul>
  32. 35. Diabetic Neuropathy <ul><li>Peripheral neuropathy </li></ul><ul><ul><li>Distal, symmetric sensory loss </li></ul></ul><ul><ul><li>Motor neuropathy </li></ul></ul><ul><ul><ul><li>Foot drop, wrist drop </li></ul></ul></ul><ul><ul><ul><li>Mononeuropathy multiplex (diabetic amyotrophy) </li></ul></ul></ul><ul><ul><ul><li>Cranial nerves III, IV, VI, VII </li></ul></ul></ul><ul><li>Autonomic neuropathy </li></ul><ul><ul><li>Postural hypotension </li></ul></ul><ul><ul><li>Resting tachycardia </li></ul></ul><ul><ul><li>Loss of sweating </li></ul></ul><ul><ul><li>Gastrointestinal neuropathy </li></ul></ul><ul><ul><ul><li>Gastroparesis </li></ul></ul></ul><ul><ul><ul><li>Diabetic diarrhea </li></ul></ul></ul><ul><ul><li>Urinary bladder atony </li></ul></ul><ul><ul><li>Erectile dysfunction </li></ul></ul>
  33. 36. Limited joint mobility Motor damage Sensory damage Autonomic damage Microcirculatory disease Macrovascular disease Diabetic neuropathy Diabetes <ul><li>Smoking </li></ul><ul><li>Hypertension </li></ul><ul><li>Dyslipidaemia </li></ul>Abnormal foot posture Reduced pain and proprioception A-V shunting <ul><li>Orthopaedic problems </li></ul><ul><li>Charcot arthropathy </li></ul>Increased foot pressures Reduced tissue nutrition Callus formation Ischaemia Ulceration Infection Pathways to Diabetic Foot
  34. 37. Foot ulceration Charcot arthropathy Diabetic Foot
  35. 38. Laboratory Findings <ul><li>◇ Analysis of urine glucose : </li></ul><ul><ul><li>Factors affecting the result: </li></ul></ul><ul><ul><li>kidney threshold for glucose excretion </li></ul></ul><ul><ul><li>glomerulosclerosis </li></ul></ul><ul><li>◇ Other substances in the urine : </li></ul><ul><ul><li>ketonuria </li></ul></ul><ul><ul><li>proteinuria </li></ul></ul><ul><ul><li>microaluminuria </li></ul></ul><ul><ul><ul><li>urine albumin excretion rate (AER) </li></ul></ul></ul>- ± + ++ +++ ++++
  36. 39. <ul><li>◇ Blood glucose testing: </li></ul><ul><ul><li>venous blood sample for diagnosis </li></ul></ul><ul><ul><li>capillary blood sample for self monitoring </li></ul></ul><ul><li>◇ Glycosylated hemoglobin assay: </li></ul><ul><ul><li>GHbA 1C comprised major form of GHb. </li></ul></ul><ul><ul><li>reflects the state of glycemia over the past 2~3 months. </li></ul></ul><ul><li>◇ Glucose tolerance test : </li></ul><ul><ul><li>OGTT: </li></ul></ul><ul><ul><li>IVGTT </li></ul></ul>6 8 10 12 14 16 18 20 0 10 20 30 40 50 60 control PATIENT 0.693 K (glucose)= × 100 t 1/2
  37. 40. Insulin (mU/L) 30 60 90 120 150 180 210 min T2DM Normal T1DM <ul><li>◇ Serum insulin concentration: </li></ul><ul><ul><li>fasting. </li></ul></ul><ul><ul><li>challenged with glucose. </li></ul></ul><ul><ul><li>Reflection of insulin storage and sensitivity </li></ul></ul>
  38. 41. C peptide A chain B chain <ul><li>◇ Serum C peptide concentration: </li></ul><ul><ul><li>in equimolar amounts with insulin </li></ul></ul><ul><ul><li>during cleavage from proinsulin </li></ul></ul><ul><ul><li>reflection of insulin secretion </li></ul></ul><ul><ul><li>fasting and post-load indicating basal and storage of insulin </li></ul></ul><ul><li>◇ Lipid profile: </li></ul><ul><ul><li>dependent on normal level and action of insulin </li></ul></ul><ul><ul><li>dyslipidemia characteristic of a high level of serum triglyceride, </li></ul></ul><ul><ul><li>with low HDL-C but increased LDL-C concentration </li></ul></ul><ul><ul><li>sufficient insulin supplement in T1DM, or improvement in </li></ul></ul><ul><ul><li>insulin sensitivity in T2DM may rectify the disorder </li></ul></ul>
  39. 42. Diagnosis of Diabetes Mellitus <ul><li>Symptoms of diabetes plus a random plasma glucose concetration >11.1 mmol/L. </li></ul><ul><li>Fasting plasma glucose >7.0 mmol/L after an overnight (at least 8-hour) fast. </li></ul><ul><li>Two-hour plasma glucose > 11.1 mmol/L during a standard 75 g oral glucose tolerance test. </li></ul><ul><li>Impaired fasting glucose (IFG): plasma glucose after an overnight fast that is >6.1 mmol/L but less than 7.0 mmol/L. </li></ul>
  40. 43. Treatment of Diabetes Mellitus Management Goals <ul><li>Obtain optimal glycemic control </li></ul><ul><li>Prevent and retard microvascular complications </li></ul><ul><li>Reduce macrovascular complications </li></ul><ul><li>Avoid acute diabetic complications </li></ul><ul><li>Better quality and lengthen span of life </li></ul><ul><li>Strategies </li></ul><ul><li>Earlier diagnosis and treatment </li></ul><ul><li>Acting on results of SMBG and GHbA 1c </li></ul><ul><li>Combination therapy </li></ul><ul><li>Education for healthy life style and self management </li></ul>
  41. 44. LDL-c mmol/L <2.5 2.5-4.4 >4.5 ★ According to UKPDS data . Targets for Diabetic Control Good Moderate Poor FPG mmol/L 4.4-6.1 ≤ 7.0 >7.0 PBS mmol/L 4.4-8.0 ≤ 10.0 >10.0 HbA1c ★ % <6.2 6.2-8.0 >8.0 BMI Kg/m 2 M<25 F<24 M<27 F<26 M ≥ 27 F ≥ 26 T ch mmol/L <4.5 ≥ 4.5 6.0 HDL-c mmol/L >1.1 1.1-0.9 <0.9 TG mmol/L <1.5 <2.2 ≥ 2.2
  42. 45. Major Therapeutic Trials 1 <ul><li>DCCT (Diabetes Control & Complications Trial) 1983-1993 </li></ul><ul><li>1441 Type 1 patients (726 no retinopathy or microalbuminuria; 715 non-prolif. retinopathy and microalbuminuria) </li></ul><ul><li>Randomised to INTENSE or CONVENTIONAL Rx * </li></ul><ul><li>Average follow-up 6.5 years </li></ul><ul><li>INTENSE Rx reduced by approx. 60% the risk of retinopathy, nephropathy and neuropathy. </li></ul><ul><li>3-fold increase in risk of hypoglycemia in INTENSE group. </li></ul><ul><li>* INTENSE = tid INS or pump frequently adjusted by at least qds BG </li></ul><ul><li>CONVENTIONAL = qd/bid INS and single daily BG or urine check </li></ul>
  43. 46. Major Therapeutic Trials 2 <ul><li>UKPDS (UK Prospective Diabetes Study) 1977-1997 </li></ul><ul><li>5102 newly diagnosed Type 2 patients from 23 centres </li></ul><ul><li>Median follow up of 11 years </li></ul><ul><li>Randomised to diet or Rx (INS, SU or Meformin) </li></ul><ul><li>All Rx showed similar efficacy over diet </li></ul><ul><li>Good glycaemic reduced risk of microvasculopathy </li></ul><ul><li>Approx. 35% reduction for each 1% fall in HbA1c </li></ul><ul><li>Macrovascular disease risk not affected * </li></ul><ul><li> function deteriorated steadily during the study regardless of Rx </li></ul><ul><li>* Only reduced by anti-hypertensive Rx in a sub study where the impact of aggressive BP control mirrored HOT trial. </li></ul>
  44. 47. <ul><li>◆ Set total calorie Intake </li></ul><ul><ul><ul><ul><ul><li>according to ideal body weight (IBW) and working strength </li></ul></ul></ul></ul></ul><ul><ul><ul><li>◆ Sample calorie distribution </li></ul></ul></ul><ul><ul><li>50-60 % CHO </li></ul></ul><ul><ul><li>15-20 % Protein </li></ul></ul><ul><ul><li>20-30 % Fat </li></ul></ul><ul><li>◆ About sweeteners </li></ul><ul><ul><li>FDA approves 4 sugar substitutes which have no CHO: </li></ul></ul><ul><ul><ul><li>aspartame, saccharin, acesulfame-K, sucralose </li></ul></ul></ul><ul><li>◆ Limitative drinking </li></ul><ul><li>◆ Reduce Sodium Intake </li></ul>Diet
  45. 48. Food Pyramid <ul><li>Food Group/Servings </li></ul><ul><li>starch 6 - 11 </li></ul><ul><li>vegetable 3 - 5 </li></ul><ul><li>fruit 3 - 4 </li></ul><ul><li>milk 2 - 3 </li></ul><ul><li>meat/protein 2 - 3 </li></ul><ul><ul><li>use fats, sweets, and alcohol sparingly </li></ul></ul>
  46. 49. Physical Activities <ul><li>◇ Benefits: </li></ul><ul><ul><li>※ Lowers glucose levels in blood </li></ul></ul><ul><ul><li>※ Improves blood circulation in the entire body </li></ul></ul><ul><ul><li>※ Contributes to weight loss </li></ul></ul><ul><ul><li>※ Improves physical and mental wellbeing </li></ul></ul><ul><ul><li>※ Helps the body to utilize insulin more efficiently </li></ul></ul>
  47. 50. Exercise Guidelines ※ Monitor BG before and after exercise. ※ Avoid exercise if BG >250 mg/dl, ketones present. ※ Use caution with exercise if BG>300 mg/dl, without ketones. ※ Eat CHO if BG < 100 mg/dl ※ If exercise is planned for just after a meal, consider reducing the short acting insulin that covers that meal. ※ If exercise is planned for 3-4 hours after a meal, consider reducing the long-acting insulin. ※ For unplanned exercise, consider adding carbohydrate. ※ Consume CHO before, during, or after exercise to prevent hypoglycemia. ※ Always keep CHO foods readily available during exercise.
  48. 51. Oral Hypoglycemic Agents
  49. 52. Sulphonylureas <ul><li>Mode of action: </li></ul><ul><li>Increase pancreatic insulin secretion </li></ul><ul><li>May improve insulin sensitivity in peripheral tissue and decrease hepatic glucose output </li></ul>
  50. 53. Sulfonylurea Activates Insulin Secretion Small figure shows the site of action.
  51. 54. <ul><li>◇ Contra-indications : </li></ul><ul><ul><li>pregnancy, surgery, severe renal failure, </li></ul></ul><ul><ul><li>type 1diabetes, hypersensitivity </li></ul></ul><ul><li>◇ Side effects: </li></ul><ul><ul><li>hypoglycaemia </li></ul></ul><ul><ul><li>weight gain </li></ul></ul><ul><li>◇ Administer: before meal </li></ul>
  52. 55. Secondary Failure <ul><li>Secondary failure rate 5% to 10% a year (UKPDS 7% a year) </li></ul><ul><ul><li>Decreasing β-cell function </li></ul></ul><ul><ul><li>Obesity </li></ul></ul><ul><ul><li>Non-adherence to treatment </li></ul></ul><ul><ul><li>Lack of exercise </li></ul></ul><ul><ul><li>Intercurrent illness </li></ul></ul>
  53. 56. Biguanides (Metformin) Mode of action: ◇ reduces hepatic glucose production ◇ decreased intestinal absorption of glucose ◇ increases peripheral utalisation of glucose in muscle & fat tissue ◇ decreased insulin requirements for glucose disposal
  54. 57. Precautions: ● chronic renal or cardiac failure ● hepatic impairment ● elderly ● excessive alcohol intake Side effects: ◆ gastrointestinal disturbances ◆ metallic taste ◆ malabsorption of B12 Administer: with or after meals
  55. 58. Alpha Glucosidase Inhibitor (Acarbose) <ul><li>Mode of action: </li></ul><ul><ul><li>Delays breakdown of CHO such as starch & sucrose </li></ul></ul><ul><li>Contra-indications: </li></ul><ul><ul><li>Pregnancy, renal impairment, gastrointestinal disorders </li></ul></ul><ul><li>Side effects: </li></ul><ul><ul><li>Gastrointestinal, rash, erythema </li></ul></ul><ul><li>Administer: </li></ul><ul><ul><li>With the first few spoons of the meal </li></ul></ul>
  56. 59. Thiazolidinedione <ul><li>Mode of action: </li></ul><ul><li>Peroxisome proliferator-activated receptor gamma agonist (PPAR-  ) </li></ul><ul><li>Improves sensitivity to insulin in skeletal muscle and adipose tissue </li></ul><ul><li>Enhances peripheral glucose uptake, reduces hepatic glucose production </li></ul><ul><li>Preserves pancreatic function </li></ul><ul><li>Optimum effect seen in 12 weeks </li></ul><ul><li>Contra-indications: </li></ul><ul><li>Heart failure, moderate to severe hepatic impairment. </li></ul>
  57. 60. Insulin <ul><li>Indications: </li></ul><ul><ul><li>Type 1 diabetes </li></ul></ul><ul><ul><li>Type 2 diabetes whose hyperglycemia does not respond to diet therapy and oral hypoglycemic drugs </li></ul></ul><ul><ul><li>Pregnancy and delivery </li></ul></ul><ul><ul><li>Acute diabetic complications </li></ul></ul><ul><ul><li>Severe chronic complications </li></ul></ul><ul><ul><li>Severe infections, major surgery, stress etc </li></ul></ul><ul><ul><li>Secondary insulin insufficiency: pancreaectomy </li></ul></ul>
  58. 61. Insulin preparations and time of reaching peak and duration
  59. 62. Lipoatrophy due to long term injection of ‘impure’ insulin preparations.
  60. 63. Novopen Inhaled insulin Insulin pump
  61. 64. Oral Agents + Insulin in Type 2 Diabetes <ul><li>Simplifies insulin regimen </li></ul><ul><li>Improves glycemic control </li></ul><ul><li>Better patient acceptance </li></ul><ul><li>Compliance </li></ul><ul><li>Convenience </li></ul><ul><li>Lower doses of exogenous insulin </li></ul><ul><li>Less weight gain </li></ul>Rationale:
  62. 65. Diabetic Ketoacidosis Presentation Physical examination Laboratory results Polyuria, polydipsia Nausea, vomiting Diarrhea, abd. Pain Evolution for a few days Stupor or coma in Loss of skin turgor Kussmaul breathing Acetone odor Cerebral edema PH <7.3, HCO 3 <15 Eq/L Glucose > 250 mg/dl Elevated anion gap High serum ketones High uric acid Normal osmolality
  63. 66. Precipitating Factors of DKA <ul><li>Noncompliance with medication </li></ul><ul><li>Infection </li></ul><ul><li>myocardial infarction </li></ul><ul><li>Cerebrovascular accident </li></ul><ul><li>Trauma </li></ul><ul><li>Pancreatitis </li></ul><ul><li>Emotional stress </li></ul><ul><li>Insulin pump dysfunction </li></ul><ul><li>Pregnancy </li></ul>
  64. 67. Treatment of DKA – IV fluid Normal saline 1 liter/hr until not orthostatic hypotensive, then NS at 500 ml/hr Electrolytes every 2 hrs initially, then every 4 hours Glucose <250 mg/dl, change to Dextrose with 1:4 regular insulin at 250-500 ml/hr When anion gap normal, bicarbonate >15 mEq/L, taking PO fluid, give meal and SC insulin
  65. 68. Treatment of DKA – Insulin IV insulin at 5-10 u/hr in adult, 0.1 u/kg/hr in child Check glucose hourly, if no change in 2 hrs double the insulin infusion Glucose <250 mg/dl, slow insulin to 2-4 u/hr Discontinue IV insulin 2-3 hrs after SC insulin dose
  66. 69. Treatment of DKA – Potassium Potassium repletion if initial K is normal or low at 10-40 mEq/hr Check potassium every 2- 4 hrs Replete total body potassium stores over 2- 3 days
  67. 70. Treatment of DKA – Bicarbonate, Phosphorus Bicarbonate replacement if pH less than 6.90 Check phosphorus 12 hrs into treatment. Replace if < 1 mEq/L

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