Diabetes Basics
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Diabetes Basics



Diabetes Basics

Diabetes Basics



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Diabetes Basics Diabetes Basics Presentation Transcript

  • DIABETES BASICS Dr. K. Jeganathan Consultant Physician.
  • WHAT GOES WRONG IN DIABETES ?  Metabolic disorder characterized by chronic hyperglycaemia with disturbance of carbohydrate protein and fat metabolism.  Disease in which the body doesn’t produce or properly use insulin, leading to hyperglycemia.
  • DM- PREVALENCE IN SL  1990 study on rural community-2.5%  2005 study- men 14.2% women 13.5% Latest cross sectional study by Diabetic research unit of the University of Colombo Urban population- 16.4% Rural population- 8.7% T1DM- 4.4% Men-9.8% Women- 10.9% Previously undiagnosed- 36%
  • HOW DO YOU DIAGNOSE DM  Diagnosis of DM can be established in 4 ways,  Symptoms of DM plus casual plasma glucose level >200mg/dL (casual defined as any time of day)  FPG >126 mg/dL (fasting at least 8 hrs)  Oral Glucose Tolerance Test (OGTT)  HbA1C > 6.5
  • OGTT  75 grams of glucose dissolved in water, which patient drinks (consumed over a period of 5 min)  2 hours later, blood glucose level of 200 mg/dL or greater is a positive test  Done in the morning after 8 hrs of over night fasting following atleast 3 days of unrestricted diet
  • POINTS TO REMEMBER  If asymptomatic - Need more than one value  Capillary blood glucose - 18mg higher than plasma  FPG may be normal due to suppression of hepatic glucose output but PPBS may be high
  • CLASSIFICATION AND DIAGNOSIS 1. Type 1 diabetes (due to b-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive insulin secretory defect on the background of insulin resistance) 3. Other specific types of diabetes due to other causes, e.g., genetic defects in b-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced (such as in the treatment of HIV/AIDS or after organ transplantation) 4. Gestational diabetes mellitus (GDM) (diabetes diagnosed during pregnancy that is not clearly overt diabetes
  • PHYSIOLOGY OF INSULIN SECRETION  Insulin secretion in 24 hrs is 30-40 units  50% is secreted in basal condition and the remainder in response meal
  • 0 10 20 30 40 50 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Hours) Meal Meal Meal Basal Insulin Needs Bolus insulin needs Seruminsulin(mU/L)
  • PHYSIOLOGY OF INSULIN SECRETION  Ultrdian pulses occur every 90-120 min  Exaggerated after each meal  Besides this rapid oscillation of insulin level occurs every 8-16min  Oscillatory insulin inhibit hepatic glucose output
  • Insulin affects many organs: • It stimulates skeletal muscle fibers. • It stimulates liver cells. • It acts on fat cells • It inhibits production of certain enzyme. In each case, insulin triggers these effects by binding to the insulin receptor. protein synthesis amino acids uptake enzyme production glycogen breaking glucose uptake glycogen synthesis fat synthesis
  • •Insulin decrease blood glucose by facilitating glucose uptake in muscles and adipose tissue •Insulin increase glycogen synthesis (glycogenesis)in liver& decrease glycogen breakdown (glycogenolysis) •Insulin is an anabolic hormone & promotes the rate of protein synthesis by: - stimulating amino acid uptake in the liver and skeletal muscle - inhibiting protein breakdown - inhibiting conversion of amino acids to glucose (gluconeogenesis)
  • • Insulin inhibit the breakdown of stored lipid (by hormone-sensitive lipase) and decrease free fatty acid levels in circulation • stimulate fatty acid synthesis from glucose in the liver • promoting glycerol synthesis in lipid cells • Insulin promotes storage of fat and decreases its utilization by: • promoting carbohydrate utilization so that fat is spared
  • HOW THE FPG IS CONTROLLED Hepatic glucose production is the primary factor determining FPG
  • HOW PPBS IS REGULATED  Clearance of ingested glucose  Peripheral clearance of glucose  Inhibition of hepatic glucose production
  • PHASES OF INSULIN RELEASE • First phase – Release starts as soon as food comes to the stomach – Preformed stored insulin is released – 10-fold increase in levels within 3-5 minutes – Speeds up the use of glucose – Within 5-10 minutes, insulin secretion decreases by half
  • PHASES OF INSULIN RELEASE • Second phase – Rising glucose levels send signals to the beta cell nucleus  DNA produces mRNA  mRNA produces more insulin – Causes a less acute rise in insulin levels – Reaches a plateau in 2-3 hours
  • DID YOU KNOW HOW MUCH PANCREAS IS LEFT WHEN YOUR FPG IS 110MG  Almost 50% beta cell function is lost  FPG >140 mg- 75% is lost  FPG > 180 mg-acute insulin response is totally lost
  • BETA CELL MASS  May vary by 3-5 million in adults  Beta cell mass expands in the first decade of life and is mostly established by late adolescence  Adult beta cells live for many years and have little proliferative or regenerative capacity  Young beta cells have considerable proliferative capacity
  • WHAT WOULD BE THE PHYSIOLOGICAL THERAPEUTIC APPROACH  Drugs to stimulate insulin secretion Surviving 25% of beta cells has to compensate for the lost 75% • Cause beta cell apoptosis • Co secretion of amylin lead to amyloid deposits between islet cells  Restore the defective early phase insulin secretion by insulin  Drugs to stimulate regeneration of beta cells [GLP analogues]
  • Consider insulin when FPG is more than 140mg How early to use insulin
  • MANAGEMENT OF DM • The major components of the treatment of diabetes are: • Diet and ExerciseA • Oral hypoglycaemic therapyB • Insulin TherapyC
  • EXERCISE  Increase the supply of fuel and oxygen to working muscles while maintaining the supply to brain and other vital organs  In the resting phase muscles derive 90% of energy by oxidation of free fatty acids  Increased demand is met by breakdown of muscles and liver glycogen and from neoglucogenesis
  •  Exercise • Short burst • Muscle glycogen breaks down first  Moderate intensity exercise • Fall in insulin level • Rise in glucagon -  High intensity exercise • Exercise prolonged beyond 30 minutes • Free fatty acids generated by adipocyte lipolysis account for major portion muscle fuel • Exercise induced rise in glucagon stimulate hepatic fat oxidation Hepatic Glycogenolysis & Hepatic Neoglucogenesis
  • American College of Sports Medicine recommendation • 3-5 exercise session per week • Each session should be between 20-30 min • Maximal heart rate – 70% of age adjusted target heart rate(220 minus age) Continued exercise program • Improve insulin sensitivity • Reduce TG level • Reduce blood pressure
  • RECOMMEND EXERCISES  Brisk walking  Aerobic dancing  Slow running  Swimming  Cycling  Skipping  Physical activity and moderate weight loss have been shown lower T2DM risk by 58% in high risk population
  • ORAL ANTI-DIABETIC AGENTS  There are currently five classes of oral anti-diabetic agents: • Biguanides • Insulin Secretagogues – Sulphonylureas Non-sulphonylureas Glinides • α-glucosidase inhibitors • Thiazolidinediones (TZDs) • Incretin
  • BIGUANIDES (Insulin Sensitizers) Work by improving insulin target cell response  It increases glucose uptake and utilization by target tissues  Metformin reduces plasma glucose levels by inhibiting hepatic gluconeogenesis.  It also slows the intestinal absorption of sugars. It also reduces hyperlipidemia (↓LDL & VLDL cholesterol and ↑ HDL).  It is the only oral hypoglycemic shown to reduce cardiovascular mortality.
  • These agents promote the release of insulin from β-cells (secretogogues);  Mechanism:  These agents require functioning β-cells, they stimulate release by blocking ATP-sensitive K+ channels resulting in depolarization with Ca+2 influx which promotes insulin secretion.  They also reduce glucagon secretion and increase the binding of insulin to target tissues. SULFONYLUREAS
  • SULFONYLUREAS  First generation sulfonylureas • Tolbutamide • Chlorpropamide  Second generation • Glibenclamide • Glipizide • Gliclazide  Third generation • Glimeperide
  • MEGLITINIDE ANALOGUES  Mechanism:  These agents bind to ATP sensitive K+channels like sulfonylureas acting in a similar fashion to promote insulin secretion however their onset and duration of action are much shorter.  They are particularly effective at mimicking the prandial & post- prandial release of insulin.
  •  These agents are insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective Mechanism of Action:  These agents act through the activation of peroxisome proliferator- activated receptor-γ (PPAR-γ).  Agents binding to PPAR-γ result in increased insulin sensitivity is adipocytes, hepatocytes and skeletal muscle.  Accumulation of subcutaneous fat occurs with these agents. THIAZOLIDINEDIONES (GLITAZONES)
  • Α-GLUCOSIDASE INHIBITORS  Acarbose and miglitol are two agents of this class used for type 2 diabetes.  Mechanism of action: • These agents are oligosaccharide derivatives taken at the beginning of a meal. • They delay carbohydrate digestion by competitively inhibiting α- glucosidase, a membrane bound enzyme of the intestinal brush border.  Pharmacokinetics: Acarbose is poorly absorbed remaining in the intestinal lumen.  Exert their effect in the intestinal lumen.
  • INCRETIN THERAPY  Incretins are naturally occurring hormones that the gut releases throughout the day; the level of active incretins increases significantly when food is ingested.  Endogenous incretins GLP-1 (glucagon-like peptide 1) GIP (glucose-dependent insulinotropic peptide)
  •  These incretins are released from the gut in response to ingestion of food • Stimulate glucose-dependent insulin release from pancreatic beta cells (GLP-1 and GIP): • Decrease glucagon production from pancreatic alpha cells (GLP-1) when glucose levels are elevated.  The combination of increased insulin production and decreased glucagon secretion reduces hepatic glucose production when plasma glucose is elevated. INCRETIN THERAPY
  •  The Incretin Effect Is Diminished in Type 2 Diabetes • Levels of GLP-1 are decreased. • The insulinotropic response to GIP is diminished.  Defective GLP-1 release and diminished response to GIP may be important factors in glycemic dysregulation in type 2 diabetes. T2DM and INCRETIN
  • INCRETIN BASED THERAPY The physiologic activity of incretins is limited by the enzyme dipeptidyl peptidase-4 (DPP-4), which rapidly degrades active incretins after their release 1. GLP1 receptor agonist • Short acting (exenatid , liraglutide(victoza) • Long acting 2. Dipeptidyl peptidase 4(DPP-4)inhibitors • Sitagliptin • Saxagliptin • Vildalagliptin
  • INSULIN  Discovered by Banting and Best  Consist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A)~~~~  A = 21amino acids B = 30 amino acids
  • Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s) Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version. INSULIN DRUG EVOLUTION
  •  Stage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin®). Yeast is also used to produce insulin (trade name =Novolin®) (1987).  Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog® and NovoLog®) or slower (Lantus®) than regular human insulin.
  • INSULIN THERAPY Short-term use:  Acute illness, surgery, stress and emergencies  Pregnancy  Breast-feeding  Insulin may be used as initial therapy in type 2 diabetes in marked hyperglycaemia  Severe metabolic decompensation (diabetic ketoacidosis, hyperosmolar nonketotic coma, lactic acidosis, severe hypertriglyceridaemia) Long-term use:  If targets have not been reached with combination therapy
  • TYPES OF INSULIN  Bolus insulin 1. Rapid acting (Actrapid, Humalin R) 2. Short acting (Lispro-humalog , Aspart-novorapid) 3. Ultra rapid acting  Basal insulin 1. Intermediate acting ( isophane. Humalin N, Insultard) 2. Long acting (Glargine-lantus, Detemir-levimir)  Premixed insulin
  • BOLOUS INSULINS (MEALTIME OR PRANDIAL) Insulin Type Onset of action Peak of action Duration of action Human regular Short acting 30-60 minutes 2-4 hours 8-10 hours Insulin analogs (Lispro,Aspart ,Glulisin) Rapid acting 5-15 minutes 1-2 hours 4-5 hours The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only.
  • Blood Sugar Time hrs 0 1 2 30 min Soluble insulin Human insulin
  • PHYSIOLOGIC INSULIN SECRETION: BASAL/BOLUS CONCEPT Nutritional (Prandial) Insulin Insulin (µU/mL) Glucose (mg/dL) Breakfast Lunch Supper Basal Glucose 150 100 50 0 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 A.M. P.M. Time of Day Basal Insulin 50 25 0 Nutritional Glucose Suppresses Glucose Production Between Meals & Overnight
  • THE BASAL/BOLUS INSULIN CONCEPT  Basal Insulin 1. Suppress glucose production between meals and overnight 2. Nearly constant levels 3. 50% of daily needs  Bolus insulin(Mealtime and prandial) 1. Limits hyperglycaemia after meals 2. Immediate rise and sharp peak at 1 hour 3. 10% to 20% of daily insulin requirement at each meal
  • THE GOAL OF INSULIN THERAPY Administration of insulins are arranged to mimic the normal basal, prandial and post-prandial secretion of insulin. Short acting forms are usually combined with longer acting preparations to achieve this effect.
  • WHAT IS THE RATIONAL E FOR BE D TIME INSUL IN AND DAY TIME SUL FONY LURE A  Bed time insulin lower FBG by suppressing the hepatic glucose output  Day time sulfonylurea augment the insulin release and also promotes the glucose uptake in peripheral tissues and control PPBS
  • IS THE RE A PL ACE FOR IN TE N SIVE IN SUL IN THE RAPY IN N E W LY D IAG N OSE D T2D M ?  Transient intensive insulin treatment  Re-establish responsiveness for several years
  • PREDIABETES & DIABETES diabetesprediabetesnormoglycemic 100mg/dl 125 mg/dl 140 mg/dl 199 mg/dl Fasting glucose 2hr Plasma glucose Prediabetes is a condition in which the blood sugar level is higher than normal, but not high enough to be classified as diabetes. HbA1c 5.7- 6.4 Risk of developing DM in 5 years is 25%-50%
  • TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS  Testing to detect type 2 diabetes and pre diabetes in asymptomatic people should be considered in adults of any age who are • Overweight or obese (BMI -25 kg/m2) • DM in a first degree relative • Sedentary lifestyle • History of delivering a baby weighing>4.1kg
  • TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS  Hypertension  Dyslipidemia (HDL<35,TG>250)  Polycystic ovary syndrome  History of vascular disease  In those without these risk factors, testing should begin at age 45 years If tests are normal, repeat testing at least at 3-year intervals is reasonable
  • TAKE HOME MESSAGE  Normal FBS does not exclude diabetes  Diet and exercise are important as OHD  Metformin should be the first drug  Pancreas exhaustion rapidly occures at rate of 2-4 % year, and in 10 years majority of patient needs insulin  Insulin should be introduced early ,do not wait until all OHDs fail  Consider drugs which stimulate beta cell mass proliferation(GLP analog)
  • Thank You
  • GESTATIONAL DIABETES  Screen for undiagnosed type 2 diabetes at the first prenatal visit  In those with risk factors, using standard diagnostic criteria  Screen for GDM at 24–28 weeks of gestation in pregnant women not previously known to have diabetes.  Screen women with GDM for persistent diabetes at 6–12 weeks postpartum, using the OGTT and non pregnancy diagnostic criteria  Women with a history of GDM should have lifelong screening for the development of diabetes or pre diabetes at least every 3 years  Women with a history of GDM found to have pre diabetes should receive lifestyle interventions
  • GLYCEMIC GOALS IN PREGNANT WOMEN  Recommendations from the Fifth International Workshop- Conference on Gestational Diabetes Mellitus  Capillary glucose concentrations: • Preprandial: #95 mg/dL (5.3 mmol/L) • 1-h postmeal: #140 mg/dL (7.8 mmol/L) • 2-h postmeal: #120 mg/dL (6.7 mmol/L)