1. What is NEW in T2DM?
Anil Bhansali
Department of Endocrinology
PGIMER, Chandigarh

2. Recents in T2DM
 Prevalence
 Pathogenesis
 Diagnosis
 Treatment
-Targets
- Incretins
- Novel Insulin
- Newer Drugs
 Novel therapies
 Conclusions

3. Prevalence of DM
Rank 2000 2030
1 India 31.7 India 79.4
2 China 20.8 China 42.3
3 US 17.7 US 30.3
4 Indonesia 8.4 Indonesia 21.3
5 Japan 6.8 Pakistan 13.9
6 Pakistan 5.2 Brazil 11.3
7 Russian Fed. 4.6 Bangladesh 11.1
8 Brazil 4.6 Japan 8.9
9 Italy 4.3 Philippines 7.8
10 Bangladesh 3.2 Egypt 6.7
Wild et al Diabetes Care 2004
Wang et al NEJM 2010
China 2010- 92.4 million adults

4. State Pre-diabetes Diabetes
Maharashtra 12.8 8.4
Tamilnadu 8.3 10.4
Jharkhand 8.1 5.3
Chandigarh 14.6 13.6

6. PATHOPHYSIOLOGY

7. Two Defects of T2DM
 Insulin resistance
 Insulin deficiency
AJM 2000

8. Three Defects of T2DM
 Insulin resistance
 Insulin deficiency
 Incretin deficiency
-Impaired insulin secretion
-Impaired glucose-glucagon axis

9. Iso-glycaemic profiles
Glucose
concentration
0 10 20 30 40 50 60 70 80 90
minutes
Glucose given orally
Glucose given intravenously
to achieve the same profile

10. Iso-glycaemic profiles
Insulin
concentration
0 10 20 30 40 50 60 70 80 90
minutes
Glucose given orally
Glucose given intravenously
to achieve the same profile
Incretin effect

11. Incretins
 Enteroendocrine cells (K/L cells): GIP and
GLP-1
 Released in response to mixed meal/ glucose
 Potentiate the glucose induced insulin secretion
 Insulin secretion is glucose dependent
 Contributes 60% of prandial insulin release
 Inhibits glucagon

12. Glucose-Glucagon Axis
 Normally rising glucose levels inhibits glucagon
and vice versa
 In T2DM, glucose mediated inhibition of α- cells
is impaired
 GLP-1
-Stimulating insulin (Intra-islet insulin)
-Direct inhibition of α-cells
-Restores glucose sensitivity to α-cells

13. Insufficient Insulin and Elevated Glucagon in T2DM
( Insulin/Glucagon Ratio)
CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus
Adapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115.
CHO meal
0
NGT
T2DM
-60
Time (min)
0 60 120 180 240
Glucose
100
200
300
400
mg/dL
0
Insulin
50
100
150
μU/mL
NGT
T2DM
Glucagon
75
100
125
150
pg/mL
NGT
T2DM

14. Pancreatic Islet Dysfunction Leads
to Hyperglycemia in T2DM
↑ Glucose
Fewer
-cells
-cells
Hypertrophy
Insufficient
Insulin
Excessive
Glucagon
–
+
↓ Glucose
Uptake
↑ HGO
+

15. The Ominous Octet
Islet -cell
Impaired
Insulin Secretion
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake
Islet -cell
Increased
Glucagon Secretion
Increased
Lipolysis
Increased Glucose
Reabsorption
Increased
HGP
Decreased
Incretin Effect

16. Diagnosis of DM

17. Diagnosis
 FPG 126 mg/dl
 2h PG 200 mg/dl (75 gm anhydrous glucose)
 RPG 200 mg/dl with symptoms
Reconfirmation on subsequent days
Limitations
 Ensure fasting
 Influenced by exercise and activity
 Analytical variability
 Intra-individual variations

18. Glycated Hb (HbA1c)
 Diagnosis of DM
- HbA1c  6.5%
- FPG ≥126mg/dl, RPG > 200 mg/dl with
symptoms
- Confirm with a repeat HbA1c
 Prediabetes (IFG, IGT)
- HbA1c 5.7 - 6.4%

19. Glycated Hb (HbA1c)
 Single estimation
 Any time of the day
 Better index of overall glycemic exposure
 Substantially less biologic variability
 Better pre-analytic stability
 Denotes risk of long term complications
 Standardized and aligned to the
DCCT/UKPDS

20. Total no. people approached -2368
Included in the study - 2245
123 (non responders), Refused = 48
Out of station = 64, Sickness = 9
Pregnancy = 2
18 Excluded – 2hr PG-Not available
Refused to take glucose = 7, Taken
tea/food and later refused = 5
Under took physical activity = 3
Not available on 2 consecutive visits = 2
Finally evaluable in the study - 2227 - 2245
HbA1c not available = 255
HbA1c available - 1972
Flow summary of study subjects
JCEM, Bhansali et al 2010

21. HbA1c for diagnosis of diabetes
Cut-off level Sensitivity Specificity
5.7 92 63
5.8 92 68
6.0 83 77
6.1 81 81
6.2 76 84
6.3 73 86
6.4 70 87
6.5 65 88
6.6 62 89
6.9 47 91
7.0 42 92
JCEM, Bhansali et al 2010

23. SE

24. HbA1c and Pre-diabetes
Both the ADA and IEC
HbA1c cut-offs under-diagnosed the presence of
pre-diabetes in 38% and 64% of these subjects
Bhansali et al. Diab Med Dec 2012

25. Management Algorithms

26. At insulin initiation, the average patient had:
 5 years with A1C >8%
 10 years with A1C >7%
Standard Approaches to Therapy Result in
Prolonged Exposure to Elevated Glucose
Brown JB, et al. Diabetes Care. 2004;27:1535-1540.
Sulfonylurea or
Metformin
Monotherapy
ADA
Goal
<7%
Combination
Therapy
Diet/Exercise
Mean
A1C
at
Last
Visit
Years
Diagnosis 2 3 4 5 6 7 8 9 10
9.6%
9.0%
8.6%
6%
7%
8%
9%
10% Insulin

28. DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedione
AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007; 13 (Suppl 1): 16–34.
American Association of Clinical Endocrinologists:
algorithm for patients with T2DM
Drug-naïve patients
HbA1c 6%–7%
Initiate monotherapy
Metformin, TZD, secretagogues,
DPP-4 inhibitors, α-glucosidase inhibitors
HbA1c 7%–8% Initiate combination therapy
Secretagogue + metformin, TZD, or α-glucosidase inhibitor
TZD + metformin
DPP-4 + metformin or TZD
Secretagogue + metformin + TZD
Fixed-dose combinations
Insulin
As above
Exenatide may be combined with oral therapies in patients
not achieving goals
Patients currently
pharmacologically
treated
HbA1c 8%–10% Intensify combination therapy
To address fasting and postprandial glucose levels
HbA1c >10% Initiate / intensify insulin therapy
Lifestyle
Changes

29. WHAT SHOULD BE TARGETED ?
 Fasting plasma glucose
 Post prandial glucose

30. Post-prandial
hyperglycaemia
Post-prandial
hyperglycaemia
contributes HbA1c ~1%
B=breakfast; L=lunch; D=dinner.
Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.
Plasma
glucose
(mg/dL)
300
200
100
0
Time of day (h)
6 12 18 24 6
Uncontrolled Diabetes HbA1c 8%
Fasting
hyperglycaemia
Basal hyperglycaemia
contributes ~2%

B

L

D
Normal
HbA1c ~5%
Basal vs Post-Prandial
Hyperglycemia – A1c

35. INCRETINS

36. DPP-IV Inhibitors
Vildagliptin
IC50DPPIV 3nmol/L
DPPIV specificity 32-250
Glucagon ↓ ↓ ↓
Intact GLP-1 levels ↑ ↑
T½ 3 hrs
Metabolism 85%hydrolyzed
in liver
HbA1c reduction 0.4-0.9%
Infections ↑
With insulin Approved
Renal insufficiency Moderate to severe
Hepatic dysfunction Caution
Sitagliptin
18 nmol/L
>2600
↓ ↓
↑
12.4 hr
80% excreted
by kidneys
0.4-0.9%
↑
Not approved
Mild to moderate
Use with caution
Saxagliptin
26 nmol/L
NA
↓ ↓
↑
2 hr
33-60% by kidney
40 -67% hepatic
0.43 – 0.54 %
↑
Not approved
Mild to moderate
Use with caution

37. Linagliptin
 New class of DPP-IV inhibitor
 Exclusively metabolized through entero-
hepatic route
 Safe in renal and liver failure
 HbA1c reduction by 0.6-0.8%
 Reduces albuminuria independent of
glycemic control
 Can be given OD or BID

38. All GLP-1 Analogues are Same !

39. All GLP-1 receptor agonists are not the same
Meier Nat Rev Endocrinol 2012
Liraglutide
Native human GLP
Lixisenatide, exenatide

40. PDY10931: effects of lixisenatide and liraglutide on post-prandial glucose and insulin
Source: www.clinicaltrial.gov NCT01175473, IDF 2011 D-0740, Sanofi internal data
Lixisenatide (D-1)
Lixisenatide (D28)
Meal 451 kcal
Glucose (mg/dL)
Time (minutes)
p<0.0001
0
0
40
60
70
270
210
90
30
50
30
20
60 150
Meal 451 kcal
Insulin free (µIU/mL)
Time (minutes)
Liraglutide (D-1)
Liraglutide (D28)

41. Newer concepts of GLP-1 analogues
Nat.Rev.Endocrinol Sep 2012

43. Effect of Incretin on Islet cell Mass

46. Novel Insulin (Degludec)
 Ultra long acting basal insulin- insulin Degludec
 Extreme dosing intervals of 8–40 h
 Daily injection time of IDeg can be varied without
compromising glycemic control or safety
 Less hypoglycemia, particularly nocturnal hypoglycemia
Diabetes care Jan 2013
Feb 12, 2013
 FDA rejected approval of Degludec
Need of additional CVS safety data

47. SGLT2 Inhibitors
Abdul-Ghani ; Endo Rev 2011

48. SGLT2 Inhibitor (Dapagliflozin)
Abdul-Ghani ; Endo Rev 2011

49. Glucokinase Activator (Piragliatin)

50. Glucokinase Activator (Piragliatin)
 Pre-clinical studies
 Increases insulin secretion,
 Decreases HGO
 Concerns
 Hypoglycemia,
 Fatty liver,
 Hyperlipidemia
Matschinsky F et al Diabetes care 2012

51. GPR 40 Modulator
(TAK 875)
 TAK-875 50–200-mg OD
reduced A1C similar to 1
mg glimepiride OD
 HbA1c reduction was
0.65%-1.37% with
increasing doses
Kaku K Diabetes Care 2013

52. Stem Cells Dev. 2009 Dec;18(10):1407-16
Efficacy Of Autologous Bone Marrow Derived Stem
Cell Transplantation In Patients With Type 2 Diabetes
Mellitus.
Bhansali A, Upreti V, Khandelwal N, Marwaha N, Gupta V, Sachdeva N,
Sharma RR, Saluja K, Dutta P, Walia R, Minz R, Bhadada S, Das S,
Ramakrishnan S.
PGIMER , Chandigarh,

53. BASELINE PARAMETERS
 N=10 (8 men)
 Mean age: 57.5± 5.9 years
 Mean duration of DM: 14.6 ± 7.5 years
 Mean duration of insulin therapy: 5.6 ± 3 years
 Mean dose of insulin: 69.4 ± 6.6 units/day
 Mean weight : 74.5 ± 11.6 kg
 Mean BMI: 26.5 ± 3.4 kg/m2
 Mean waist circumference: 93.2 ± 7.8 cm

56. RESULTS
 Primary end points
 Reduction in insulin requirement by ≥ 50%
 Improvement in glucagon stimulated C– peptide
levels at the end of 6 months
 Secondary end points
 Change in weight, HbA1c and insulin- glucose
homeostasis
Responders :7, Nonresponders:3

57. RESULTS
Parameters Baseline 6 months p value
INSULIN REQUIREMENT/ DAY (U)*
Group 69.4±6.6 28.2±7.4 0.007
Responders 75.3± 8.2 18.9± 7.4 0.02
Non-responders 55.7± 6.2 50± 9.9 0.29
FPG (mg/dl)
Group 136.5± 25.1 119.1± 21.3 0.059
Responders 133.9± 28.8 112.3± 4.6 0.063
Non-responders 142.7± 16.1 134.7± 37.8 0.59
HbA1c*
Group 8.4 ± 0.6 7.3 ± 0.8 0.009
Responders 8.1 ± 0.2 7.3 ± 0.4 0.04
Non–responders 8.9 ± 0.2 7.5 ± 0.2 0.11

58. RESULTS
Parameters Baseline 6 months p value
STIMULATED C- PEPTIDE (ng/ml)*
Group 1.1± 0.2 2.1± 0.3 0.03
Responders 1.2± 0.1 2.6± 0.3 0.03
Non–responders 0.8± 0.7 0.9± 0.6 0.99
HOMA- B
Group 46.1± 14.0 174.5± 52.9 0.02
Responders 37.7± 18.4 154.5±74.3 0.04
Non–responders 67.3±9.8 224.5± 2.8 0.18
HOMA- IR
Group 4.74±1.4 3.37± 0.95 0.74
Responders 5.14± 1.94 3.86± 1.27 0.89
Non–responders 3.75±1.75 2.15± 0.75 0.66

59. Bariatric surgery- an option or ultimate
solution
HbA1c> 7.5% inspite of optimal therapy
Endocrine Pract 2013

60. Outcomes
Wt Loss
Diabetes
Remission
Co-morbidities

61.  At 2 years, diabetes remission in no patients in the
medical-therapy group
 75% in the gastric-bypass group and
 95% in the biliopancreatic-diversion group
NEJM 2012

62. Future
 Motto of ADA “Living with diabetes”
 With bariatric surgery: “LIVING WITHOUT
DIABETES”

63. Conclusions
 Enormous advances have been made in
understanding of the disease , diagnosis and
treatment.
 Treatment of diabetes should be tailor-made
and needs to be individualized
 Future is pregnant with many possibilities