The document summarizes the management of diabetes mellitus. It discusses the types and pathophysiology of diabetes, signs and symptoms, diagnosis, treatment goals, and management of type 1 and type 2 diabetes. Recent advances discussed include new insulin regimens, hypoglycemic drugs for type 1 diabetes, and combination drug therapies for type 2 diabetes.

1. Management of
Diabetes mellitus
Dr. Kartik Doshi
25.1.2012

2. Overview
• Learning Objectives • Management of type 1
DM
• Introduction
• Management of type 2
• Disease burden DM
• Physiology • Recent advances
• Pathogenesis • Summary
• References

3. Objective
• Types and pathogenesis of DM
• Signs, symptoms and laboratory investigations
• Management of type 1 and type 2 DM
• Recent advances in DM management

4. History
• In 1869 , German medical student – Pancreas has two
distinct group of cells. PAUL LANGERHANS
• Frederick Banting. J j r Macleod. Charles Best. J b Collip.
• Indian physician ( charak and sushruta ) – “mudhumeha”

5. 1921 – Banting and Best

7. Introduction
• Definition *
Diabetes mellitus is a group of metabolic disease
characterized by hyperglycemia resulting from defect
in insulin secretion, insulin action or both.
• 246 million worldwide
• Prediabetes – great concern
*American diabetic association (ADA) Diabetic Care 28:2005

8. Spectrum of glucose homeostasis and DM
Source :
Harrison
18E

10. Physiology of glucose metabolism

11. Regulation of insulin secretion

13. Insulin – tissue level

14. Pathophysiology of DM

15. Signs and symptoms
• Polyurea – osmotic diuresis
• Polydypsia
• Weight loss – catabolic state
• Fatigue
• Weakness
• Frequent superficial infections
• Blurred vision
• Look for complications

16. Physical examination
Weight / BMI Injection sites
Retinal examination Vibratory sensation
Foot examination Tooth examination
Orthostatic blood Peripheral pulses
pressure

17. Diagnosis*
Symptom of DM + RBS > 200mg/dl
(Random Blood Sugar)
FBG (Fasting Blood > 126mg/dl
Glucose)
HbA1C (glycosylated Hb) > 6.5%
PPG (OGTT – 75 gm > 200mg/dl
anhydrous glucose)
PPG – post prandial glucose *ADA- American Diabetic Association

18. Categorize into types
Type 1 Type 2
• Age < 30 years • Age >30 years
• Lean body habitus • 80% obese, can be lean
• Autoimmune attack on β • Insulin resistance, relative
cells or idiopathic insulin deficiency
• OHAs + insulin
• Require insulin as therapy
• HHS, type 2 DKA prone
• DKA
• Component of metabolic
• Other autoimmune disorder
disorders • LADA – latent autoimmune
diabetes of adult

19. Laboratory assessment
FBG
PPBG
Glycosylated Hb (HbA1c )
SMBG ( self monitoring of blood glucose)
 Lipid level
 TFT
 Urine for protein
 Stress testing (in high risk pt.)

20. Advantages of HbA1C Testing Compared With FPG or
2HPG
for the Diagnosis of Diabetes
Standardized and aligned to the DCCT/UKPDS
Better index of overall glycemic exposure and risk for long-term
complications
Substantially less biologic variability
Substantially less pre-analytic instability
No need for fasting or timed samples
Relatively unaffected by acute perturbations in glucose levels

21. Treatment goals for diabetic adults
Glucemic control
A1c < 7.0%
Pre-prandial capillary 70-130mg/dl
plasma glucose
Peak post prandial <180mg/dl
plasma glucose
BP <130/80
Lipids (LDL) <100mg/dl

22. Comprehensive diabetes care
nutritionist
Endocrinologist patient specialists
DM
educator

23. Interlocking ideas
Diabetes
education
Nutrition
Exercise

24. Monitoring level of glycemic control
• Short term – SMBG complimentary
• Long term – HbA1c to each other
• SMBG
 3-4 times/day (pt. taking multiple insulin)
 Site – fingertip
• CGMS (continuous glucose monitoring system)
• Ketone bodies – β hydroxybuterate in blood
• Fructosamine assay - hemoglobinopathies

25. Management Type 1 DM
• Partially or completely lack
insulin
• INSULIN replacement is
essential
• Basal, exogenous –prevent
glycogen breakdown,
gluconeogenesis
• Meal time – glucose uptake
and storage

26. What are the types
of insulin regimens?
• Premixed regimen
• Split mix regimen
• Basal bolus regime (multidose)
• Bedtime dosing alone (detemir/Glargine)
• Infusion

27. Premixed insulin
Advantages
• More accurate dosing
• Lesser injections
• Pen devices administer premixed forms
Disadvantages
• Fine tuning may not be possible
• Strict meal pattern
• Nocturnal hypoglycemia
• May need “diet changes for insulin” rather than “insulin
changes for diet”

28. Split-mixed insulin
Advantages
• Less hypoglycemia, with fine tuning
• More physiologic
• Adjustable meal pattern
Disadvantages
• More patient education required
• Cumbersome mixing
• Pen device not feasible if two injections are planned
for.

29. Insulin dosage
0.5-1unit/kg per day in divided doses
• 50% - basal insulin
• Insulin – sensitive to heat and O2

30. Insulin regimes

31. Cont…

32. cont…
B – breakfast
L – Lunch
S –Supper
HS – night
NPH – Neutral protein hagedon

33. CSII

35. Hypoglycemic drugs in Type 1 Dm
Pramlinitide
 Amylin analogue, given before meal
 15µg start – up to 30-60 µg
 Reduce gastric emptying, Glucagon ↓
Acarbose
 Alpha glucosidase inhibitor
 Reduce absorption of glucose
 Hypoglycemic reaction – Rx Glucose

36. Diabetic ketoacidosis
• Diabetic coma
• Its an emergency!!!
• s/s –
nausea, vomitting, thirst
, polyurea
• PPt. events
• Insulin ↓,glucagon↑↑
• Hyperglucemia, ketosis,
acidosis, hyperkelemia,
hyponatremia

37. Point to remember
DKA
Always treat in emergency/ICU
setting in initially 24-48 hours.

38. Confirm diagnosis (plasma glucose,
serum ketones, metabolic acidosis)
Assess : serum electrolytes, acid
base status, RFT
Replace fluids, 2-3 L of 0.9% saline
over 1-3 hrs(15-20ml/kg/hr), 0.45%
saline at 250-500ml/hr.
Short acting insulin IV(0.1units/kg)
f/b infusion 0.1units/kg/hr, ↑es
2-4hr- no response
Replace K+ . Replace with long
acting insulin

39. Monitor following measures
• Assess ppt factor – CXR, culture, USG
• Capillary glucose 1-2 hrly
• Acid-base status and e - 4 hrly for 24 hr
• BP, pulse, respiration, mental status, Urine
input-output 1-4 hrly
• Measure K+ every 1-2 hourly
• Measure PO4
• ECG

40. Hyperglycemic hyperosmolar state
(HHS)
• Elderly person type 2 DM
• Several week H/O polyurea, weight loss,
• Hypotension, tachycardia, altered mental
status
• Relative insulin deficiency and fluid intake ↓
• Glucose – 1000mg/dl, osmolarity >350mos/l
• Prenatal azotemia
• Mortality – 15%

41. Treatment of HHS
• Fluid balance
 Start with 0.9% NS 1-3L over 1-3 hr
 Fast Repletion of fluid – neurological dysfunction
 Na > 150meq/l - 0.45% NS use
 Hemodynamic stability – 0.5 % dextrose use
 Glucsoe – insulin infusion after glucose 250mg/dl
 Insulin – same as DKA

42. Type 2 DM

43. Food and exercise
• Medical nutrition
therapy
• Glycemic index ( GI)
• 150 min/wk (atleast for
3 days)
• Type 2 – resistance
training
• Exercise – can lead
hypo/hyper- glycemia
• Pre/inter/after exercise
glucose testing

44. The economic driving factors……
> Rs. 70/-
per kg
Rs. 90/-
per kg
…Consumer Price Index shifts favour unhealthy products
Adam Drewnowski and SE Specter. Poverty, obesity, and diet costs. Am J Clin Nutr 2004;79:6 –16

45. Drug options
• Sulfonylureas
• Meglitinides
• Metformin
• Thiazolidinediones
• α- glucosidase inhibitors
• Peptide analogues
• DPP4 inhibitors
• Insulin

46. Different site actions of OHAs
AGI,
Pramlinitide
Incretins ,
SU,
Meglitnides
TZD
Metformin

47. Pharmacotherapy of type 2 DM
LIFE STYLE MODIFICATION
A1c 6.5-7.5 A1c 7.5 - 9 A1c >9
Drug naïve Under treatment
Monotherapy
Met/ TZD/DPP4 inh./AGI Symptom free
Symptom +nt
Dual therapy
Triple therapy
Insulin /insulin agonist
Insulin / insulin agonist
No response – after at least 2-3 months therapy

48. • Mono therapy
• Dual therapy
Met DPP4/ GLP 1, TZD,
Glinide/SU
TZD DPP4/GLP 1
Met Colesevalam, AGI
• Triple therapy
Met + GLP 1 or DPP4 TZD
SU or glinide

49. Monotherapy for HbA1c 6-7.5%
• Metformin (insulin sensitizer) – 1st choice
• Except,
1. Renal disease
2. Hepatic disease
3. GI intolerance
4. Lactic acidosis
• Secretogogues –not preferred

50. Cont…
• TZD – take time to act, remains for long
time, associated with bone fractures
• Use : metabolic syndrome, NAFLD
• Proceed to next step – after max. dose for
adequate duration

51. Dual therapy
• Metformin – preferred for 1st line for dual
therapy
• TZD – after metformin preferred ( central drug
for combination)
• Met > TZD,
• Incretin mimetic > DPP4 inh. > Glinides > SU
• GLP-1 analogue – meal induced glucose
excursion , weight loss

52. • Glinides – more helpful in meal induced
glucose ↑ ( HbA1c 7.5%)
• Standard dual therapy – met + TZD
• Other regime
Metformin + colesevalam
(safe, LDL ↓es)
Metformin + AGI
(anti- atherosclerotic actions)

53. Triple therapy
• 6 options available
• Metformin 1st agent unless CI
• Exenetide – 2nd agent ( or DPP4 inh.)
• Exenetide – CI ( pancreatitis)
• 3rd agent – glinides/TZD/SU

54. Insulin
• Reason – no b cell reserve
• Can be combined with OHAs
• Most useful – metformin
• Can be with TZD ( CHF)
• 3 regime
1. Basal insulin ( glargine )
2. Pre mixed insulin ( 2 injections )
3. Basal + bolus (4 injections)

55. HbA1c 7.5-9%
• Start with dual therapy
• Metformin – 1st agent
• Combinations
1. Metformin + GLP1 analogue
2. Metformin + DPP4 inh.
3. Metformin + TZD ( wt. gain, edema)
4. Metformin + SU ( more glucose lowering
action require)
5. Metformin + glinides

56. Triple therapy
• Same as above category
• Differences
1. No use of glinides, AGI, colesevalam
2. Metformin +TZD +SU – weight gain, edema,
hypoglycemia
• Insulin – same as above
• Discontinue ≥1 OHAs
• Incretins + insulin – NOT APPROVED

57. HbA1c >9%
• Triple therapy
• Insulin – should give drug naïve patients
• SU – give importance
Faster action
Robust Glucose lowering effect
• Insulin – gradually discontinue after
HbA1c<6.5%
• Give dual/triple therapy

58. Insulin in type 2 DM
DM – not controlled with max. dose
(metformin – 2500mg/day)
Physiological stress, infection
Use of parentral nutrition/high caloric diet
DKA/HHS
Gestational DM
CRF
Progressive complication (D. retinopathy)

59. Selection of drugs
 Level of hyperglycemia – choice of initial therapy
 Mild – moderate DM (200-250 mg/dl) – often
respond to monotherapy
 More rapid glucose control – glucose toxicity ↓↓
 Fast control – AGI and Insulin secretogogues
 No single agent – distinct advantage
 TZD – target basic problem in type 2
 Cost effective – metformin, SU

60. Combination therapy
• Same dose as monotherapy
• Different M/A – So additive
• Eg. SU and Metformin
• Insulin + TZD – more chances of hypoglycemia,
weight gain

61. CIs of combination therapy
× Complicated DM
× DM with sepsis
× DM with tissue hypoxia and systemic BP less
then 90 mm of Hg
× Type 1 DM
× DKA
× DM with pregnancy
× Auto immune DM

62. Pharmacological agents
Bigunides - Metformin, phenformin
 Most commonly used drug
 M/A – AMP Protein kinase
 HGP ↓, peripheral utilization
 500mg -1000mg bd/day

63. Mechanism of action

64. Alpha glucosidase inhibitor
• Acarbose, voglibose
 Dose – 25 mg evening meal – 50-100mg/every
meal (acarbose)
 Hypoglycemia – glucose as a treatment
 Additional actions
 Anti atherosclerotic
 Anti platelet
 Decrease fibrinogen, inflammation
 Cardio protective in IGT patients

65. Insulin secretogogues
Meglitinide
Sulfonylurease Glucose , AA
analogues
GLP-1 receptor DPP4
agonist inhibitors

66. Modes of action: Glimepiride (SU)
Most Sulphonylureas K+
Glimepiride
140 - cell
Glimepiride kDa membrane
65
Sulphonylurea kDa
Receptor
KATP channel
K+
GLUT-4
So What ??
65kDa Component absent in Cardiovascular System
Safer to use in patients with a higher cardiovascular risk

67. Incretins
• Entero- insular axis / entero-hypothalamo-
insular axis
• GIP – glucose dependent insulinotropic
peptide
• GLP 1 – glucagon like peptide
• Preserve B cell mass
• Synthetic incretins – use as a drug
• “Incretomimetic” and “incretin enhancer”

68. Incretin hormones
GLP-1 receptor agonist GIP
• Secreted by L cells • Secreted K cells
• Stimulate – glucose induced • Stimulate – glucose induced
• Effect on glucagon • No effect on glucagon
• Delay gastric emptying • Does not delay gastric
emptying
• Circulating level of GLP-1 • Circulating level GIP are
reduced normal/high
• Enhance B cell proliferation • Same effect
• Eg. Exenetide, liraglutide • None

69. GLP – 1 secretion and metabolism
STIMULATES
INSULIN
RELEASE
INCRETIN LOWERING
GLP -1 OF BLOOD
GLUCOSE
•INHIBITS
GLUCAGON
RELEASE
DPP – 4 ENZYME
INACTIVATES GLP-1
DPP-4 INHIBITORS (DRUGS)
BLOCK DPP-4 AND DECREASE
GLUCOSE

71. Doses
Metformin 0.5-2.5gm 2-3 doses/day
Glimipiride 1-6mg 1
Pioglitazone 15-45 mg 1
Nateglinide 180-480mg 3-4 doses/day
Exenetide (SC) 10-20µg 2 doses/day
Sitagliptin 100mg 1

72. Recent advances

73. Cont…
Oral insulin – physiological insulin
Use – Ecuador ( india – biocon )
 Cortisone Cortisol (active)
 Enzyme – 11-B hydroxysteroid dehydrogense
 Activators of glucokinase
Statins – pravastatin (most useful)

74. Molecular size correlates with rate of
absorption
Multi-hexamers
Duration of Action
Di-Hexamer
Hexamer
Monomer
Molecular size

75. Insulin degludec:
Mechanism of protraction
Multi-hexamers Subcutaneous tissue
Monomers
Capillary membrane
Insulin degludec in blood Albumin binding
Capillary blood
Cell Membrane Insulin Receptors

76. Gestational and other DM
• Intensive treatment required
• Fetal macrosomia
• Insulin only is used
• 30-60% - chance of type 2 DM
Pediatric DM
• More chances – hypoglycemia, coma
• Metformin – only approved (10mg/ml)

77. Prediabetes : What’s in a Name?
 Use for IGT and IFG
 If 50% chance of DM – next 10 years
 Forerunners of DM, CV risk
 Life style modification and metformin*
1. <60 years of age
2. BMI >35kg/m2
3. Family history
4. TG, HDL
5. HT
6. A1c > 6.0%

78. References
• Harrison 18th edition
• Goodman and gillman. Pharmacological basis
of therapeutics. 12th edition
• KDT 6th edition
• Medicine update 2008. Vol.18
• An algorithm for glycemic control. AACE/ACE
consensus statement. Endocr Pract.
2009;15(No. 6)

79. 1st – Acetohexamide,
Tolbutamide,
Chlorpropamide,
SULFONYLUREAS Tolzamide.
2nd – Glibenclamide,
SECRETAGOGUES K+ATP Glipizide, Gliclazide
3rd – Glimepiride
INSULIN
MEGLITINIDES/ Nateglinide,
PHENYLALANINE Repaglinide
GLP -1 Exenatide, Liraglutide
ANALOG
DPP IV Sitagliptin, Vildagliptin, Saxagliptin
INHIBITORS
BIGUANIDES Metformin
SENSITIZERS
TZD (PPAR) Rosiglitazone, Pioglitazone
α - GLUCOSIDASE Acarbose, Miglitol, Voglibose
OTHERS INHIBITORS
AMYLIN ANALOG Pramlintide

80. Thank you